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Background and Objective: Heated tobacco products (HTPs) are a class of non-combustible, inhaled tobacco products with the potential to reduce the harm associated with cigarette smoking due to reduced cigarette smoke toxicant exposure. Subjective and nicotine pharmacokinetics measures taken over the course of product use provide a framework for abuse liability (AL) assessment of tobacco and nicotine products as well as information on adoption potential for a new tobacco product, which are important aspects for premarket tobacco product authorization by the US Food and Drug Administration. This study aimed to assess the AL of glo HTPs, operated in either Standard or Boost Modes, compared with high- and low-AL comparators (subjects' usual brand cigarettes and nicotine gum, respectively)., Methods: Nicotine uptake and pharmacodynamics measures (including subjective and physiological measures) were assessed in a clinical study of 75 healthy adult non-menthol or menthol smokers using an open-label, randomized crossover study design. Comparisons were made between glo HTPs (Standard or Boost Modes) and each of usual brand (UB) cigarettes and nicotine gum to evaluate nicotine exposure and subjective effects measures., Results: Nicotine uptake, as reflected in the area under the curve (AUC) at 15 and 240 min after product use (AUC 0-15 and AUC 0-240 , respectively) and maximum nicotine concentration (C max ) were significantly lower for all glo HTPs compared to UB cigarettes, regardless of the glo device mode. AUC 0-15 values for glo HTPs ranged from 41.26 to 75.71 ng × min/mL, versus 158.04 to 165.53 ng × min/mL for UB cigarettes. Similarly, AUC 0-240 values for glo HTPs ranged from 379 to 596 ng × min/mL, compared to 1123.73 and 1283.37 ng × min/mL for UB cigarettes. The C max for glo HTPs ranged from 5.46 to 9.00 ng/mL, whereas UB cigarettes had C max values of 16.29 to 16.76 ng/mL. The time to reach maximum nicotine concentration (T max ) was significantly shorter for glo HTPs (4-5 min) compared to UB cigarettes (6-7 min), except for one variant of glo HTP in Standard Mode. Nicotine gum exhibited a slower nicotine absorption profile, with a T max of 45 min and C max of 4.60 ng/mL. AUC 0-15 and AUC 0-240 values for nicotine gum were 6.18 and 5.22 ng × min/mL, and 647.80 and 687.68 ng × min/mL for non-menthol and menthol groups, respectively. Subjective measures indicated that glo HTPs were rated significantly lower than UB cigarettes in terms of product liking, smoking urge reduction, product effects, and intent to use again, but were comparable to nicotine gum., Conclusion: glo HTPs demonstrated lower AL than combustible cigarettes while delivering sufficient nicotine to support product adoption among current smokers. This positions glo HTPs as a potential tool in tobacco harm reduction, offering a less harmful alternative to traditional cigarettes., Trial Registry: Clinical trial ID NCT05114863., (© 2024. The Author(s).)

Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis.

Background: Introduction of new tobacco products in the United States, including those that may be lower on the risk continuum than traditional combustible cigarettes, requires premarket authorization by the US Food and Drug Administration and information on the potential impact of the products on consumer behaviors. Efficient recruitment and data capture processes are needed to collect relevant information in a near-to-real-world environment., Objective: The aim of this pilot study was to develop and test a protocol for an actual use study of a new tobacco product. The product included in this study was a commercially available oral nicotine pouch. Through the process of study design and execution, learnings were garnered to inform the design, execution, analysis, and report writing of future full-scale actual use studies with tobacco products., Methods: A small sample (n=100) of healthy adult daily smokers of 7 or more cigarettes per day were recruited to participate in an 8-week prospective observational study conducted at 4 geographically dispersed sites in the United States. A smartphone-based customized electronic diary (eDiary) was employed to capture daily tobacco product use, including 1 week of baseline smoking and 6 weeks during which participants were provided with oral nicotine pouches for use as desired., Results: Online screening procedures with follow-up telephone interviews and on-site enrollment were successfully implemented. Of 100 participants, 97 completed the study, with more than half (59/99, 60%) identifying as dual- or poly-users of cigarettes and other types of tobacco products at baseline. There was more than 90% (91-93/99, 92%-94%) compliance with daily eDiary reporting, and the majority (92/99, 93%) of participants expressed satisfaction with the study processes. Product use data from the eDiary indicated that after an initial period of trial use, pouches per day increased among those continuing to use the products, while per day average cigarette consumption decreased for 82% (79/97) of all study participants. At the end of the week 6, 16% (15/97) of participants had reduced their cigarette consumption by more than half., Conclusions: The design of this study, including recruiting, enrollment, eDiary use, and oversight, was successfully implemented through the application of a detailed protocol, a user-friendly eDiary, electronically administered questionnaires, and remote monitoring procedures. High-resolution information was obtained on prospective changes in tobacco product use patterns in the context of availability of a new tobacco product. Future, larger actual use studies will provide important evidence supporting the role that alternatives to combustible cigarettes may play in smoking reduction and/or cessation and lowering the population health burden of tobacco and nicotine-containing products., (©Chris Campbell, Michael Feehan, Claudia Kanitscheider, Patrudu S Makena, Jenny Cai, Sarah A Baxter. Originally published in JMIR Formative Research (https://formative.jmir.org), 19.08.2022.)

Leucine-rich α2 glycoprotein (LRG1), a serum protein produced by hepatocytes, has been implicated in angiogenesis and tumor promotion. Our laboratory previously reported the expression of LRG1 in murine myeloid cell lines undergoing neutrophilic granulocyte differentiation. However, the presence of LRG1 in primary human neutrophils and a role for LRG1 in regulation of hematopoiesis have not been previously described. Here we show that LRG1 is packaged into the granule compartment of human neutrophils and secreted upon neutrophil activation to modulate the microenvironment. Using immunofluorescence microscopy and direct biochemical measurements, we demonstrate that LRG1 is present in the peroxidase-negative granules of human neutrophils. Exocytosis assays indicate that LRG1 is differentially glycosylated in neutrophils, and co-released with the secondary granule protein lactoferrin. Like LRG1 purified from human serum, LRG1 secreted from activated neutrophils also binds cytochrome c. We also show that LRG1 antagonizes the inhibitory effects of TGFβ1 on colony growth of human CD34+ cells and myeloid progenitors. Collectively, these data invoke an additional role for neutrophils in innate immunity that has not previously been reported, and suggest a novel mechanism whereby neutrophils may modulate the microenvironment via extracellular release of LRG1., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To determine differences in bone geometry, estimates of bone strength, muscle size and bone strength relative to load, in women runners with and without a history of stress fracture., Methods: We recruited 32 competitive distance runners aged 18-35, with (SFX, n=16) or without (NSFX, n=16) a history of stress fracture for this case-control study. Peripheral quantitative computed tomography (pQCT) was used to assess volumetric bone mineral density (vBMD, mg/mm 3 ), total (ToA) and cortical (CtA) bone areas (mm 2 ), and estimated compressive bone strength (bone strength index; BSI, mg/mm 4 ) at the distal tibia. ToA, CtA, cortical vBMD, and estimated strength (section modulus; Zp, mm 3 and strength strain index; SSIp, mm 3 ) were measured at six cortical sites along the tibia. Mean active peak vertical (pkZ) ground reaction forces (GRFs), assessed from a fatigue run on an instrumented treadmill, were used in conjunction with pQCT measurements to estimate bone strength relative to load (mm 2 /N∗kg -1 ) at all cortical sites., Results: SSIp and Zp were 9-11% lower in the SFX group at mid-shaft of the tibia, while ToA and vBMD did not differ between groups at any measurement site. The SFX group had 11-17% lower bone strength relative to mean pkZ GRFs (p<0.05)., Conclusion: These findings indicate that estimated bone strength at the mid-tibia and mean pkZ GRFs are lower in runners with a history of stress fracture. Bone strength relative to load is also lower in this same region suggesting that strength deficits in the middle 1/3 of the tibia and altered gait biomechanics may predispose an individual to stress fracture., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: To compare retention rates of Super Flex (Eagle Vision, Memphis, Tennessee, USA; Softplug-Oasis Medical Inc, Glendora, California, USA) vs Parasol (Odyssey Medical, Memphis, Tennessee, USA; Beaver Visitec International, Waltham, Massachusetts, USA) punctal plugs., Design: Randomized, double-masked, interventional controlled clinical trial., Methods: Institutional study at Hotel Dieu Hospital (Queen's University) of 50 eyes, from patients with moderate to severe dry eye. Each eye from eligible patients was separately randomized to receive Super Flex or Parasol punctal plugs. The main outcome measure was plug retention at 6 months. Secondary outcome measures included objective tests of Schirmer I (mm), tear meniscus height (mm), tear break-up time (s), inferior fluorescein corneal staining (National Eye Institute [NEI] scale), and average lissamine green conjunctival staining (NEI scale)., Results: Punctal plug retention was significantly different at 6 months (P = .011). Sixty-eight percent of Parasol plugs were retained compared to 32% of Super Flex plugs. Parasol plugs required less frequent artificial tear use at 6 months (P = .024). There was a statistically significant improvement in all secondary outcome measures (Schirmer, tear meniscus height, tear break-up time, fluorescein corneal staining) at 6 months within plug groups except conjunctival staining. There were no additional significant differences between groups and no plug complications reported., Conclusions: Punctal plugs improve symptoms of moderate to severe dry eye; however, retention rates differ significantly. These data will allow us to guide patient decision making for the safe and effective treatment of punctal plugs for moderate to severe dry eye., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Peanut skin is a rich source of polyphenols including procyanidins and is shown to have hypolipidemic properties. This study investigated the bioavailability of peanut skin polyphenols using a rat model. First, the bioavailability of peanut skin polyphenols in rat plasma was evaluated. Our results showed procyanidin A2 levels in plasma peaked within 30 min of ingestion. The results of a second study show that peanut skin extract supplemented in addition to oil gavage resulted in significant decrease in plasma triglyceride and VLDL within 5h. In the third study, rats were given a Western type diet for 5 weeks with peanut skin extract at a dose of 150 and 300 mg/kg body weight. The main effects observed were lowering of total blood lipid and reduction of the plasma fatty acids profile. Our results suggest that procyanidin A may impart a key role of hypolipidemic effect seen in peanut skin polyphenols., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chemokines encompass a large family of proteins that act as chemoattractants and are involved in many biological processes. In particular, chemokines guide the migration of leukocytes during normal and inflammatory conditions. Recent studies reveal that the heterophilic interactions between chemokines significantly affect their biological activity, possibly representing a novel regulatory mechanism of the chemokine activities. The co-localization of platelet-derived chemokines in vivo allows them to interact. Here, we used nano-spray ionization mass spectrometry to screen eleven different CXC and CC platelet-derived chemokines for possible interactions with the two most abundant chemokines present in platelets, CXCL4 and CXCL7. Results indicate that many screened chemokines, although not all of them, form heterodimers with CXCL4 and/or CXCL7. In particular, a strong heterodimerization was observed between CXCL12 and CXCL4 or CXCL7. Compared to other chemokines, the main structural difference of CXCL12 is in the orientation and packing of the C-terminal alpha-helix in relation to the beta-sheet. The analysis of one possible structure of the CXCL4/CXCL12 heterodimer, CXC-type structure, using molecular dynamics (MD) trajectory reveals that CXCL4 may undergo a conformational transition to alter the alpha helix orientation. In this new orientation, the alpha-helix of CXCL4 aligns in parallel with the CXCL12 alpha-helix, an energetically more favorable conformation. Further, we determined that CXCL4 and CXCL12 physically interact to form heterodimers by co-immunoprecipitations from human platelets. Overall, our results highlight that many platelet-derived chemokines are capable of heterophilic interactions and strongly support future studies of the biological impact of these interactions., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Numerous rehabilitation protocols exist for postoperative rotator cuff repairs. Because the goal of early rehabilitation is to prevent postoperative adhesions while protecting the repaired tendons, it would be advantageous to know which range-of-motion exercises allow the rotator cuff to remain the most passive in a painful, guarded, postsurgical shoulder., Methods: Twenty-six subjects who had undergone subacromial decompression, distal clavicle resection, or a combination of both procedures volunteered to participate within the first 4 days after surgery. Fine-wire electrodes were inserted into the subject's supraspinatus (SS) and infraspinatus (IS). Muscle activity was recorded at resting baseline (BL) and during 14 exercises that have been found in the passive phase of rotator cuff protocols and tested in healthy subjects. Each exercise was compared with BL activity as well as with other exercises in the same movement group., Results: The SS remained as passive as BL during therapist- and self-assisted external rotation, therapist-assisted elevation, pendulums, and isometric internal rotation and adduction. The IS was activated greater than BL for all 14 exercises studied., Conclusion: Of the 14 exercises studied, 6 allowed the SS and 0 allowed the IS to remain as passive as quiet-stance BL in postsurgical subacromial decompression/distal clavicle resection patients., (Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.)

The homeobox transcription factor PROX1 is essential for the development and maintenance of lymphatic vasculature. How PROX1 regulates lymphatic endothelial cell fate remains undefined. PROX1 has been shown to upregulate the expression of Cyclin E, which mediates the G(1) to S transition of the cell cycle. Here we demonstrate that PROX1 activates the mouse Cyclin E1 (Ccne1) promoter via two proximal E2F-binding sites. We have determined that the N-terminal region of PROX1 is sufficient to activate a 1-kb Ccne1 promoter, whereas the homeodomain is dispensable for activation. We have identified that the Prospero domain 1 (PD1) is required for the nuclear localization of PROX1. Our comparison of two DNA-binding-deficient constructs of PROX1 showed a cell-type-specific difference between these two proteins in both their localization and function. We demonstrated that siRNA-mediated knockdown of PROX1 in lymphatic endothelial cells decreases progression from G(1) to S phase of the cell cycle. We conclude that PROX1 activates the Ccne1 promoter independent of DNA binding, and our results illustrate a novel role for PROX1 in the regulation of lymphatic endothelial cell proliferation., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Purpose: There are 2 methods of corneal tissue procurement currently in widespread use: in situ extraction of the corneal button directly to preservation media and whole-globe enucleation of eyes with removal of the button to preservation media at a later time. This study evaluates the effects of these 2 procurement procedures on the initial quality of donor corneal tissue., Methods: Slit-lamp examination results and endothelial cell counts were compared for a total of 468 donor corneas harvested at 2 remote locations: one where in situ procurement was practiced and the other that used whole-globe enucleation procedures., Results: In both univariate and multivariate analysis, in situ corneas were found to have a lower incidence of moderate or severe haze and folds in Descemet membrane. No differences in mean endothelial cell counts were noted between the 2 populations of donated tissue., Conclusions: In situ procurement of corneal tissue results in higher initial corneal tissue quality than whole-globe procedures.

Punctal plugs appear to be a relatively safe, effective, and reversible method of preserving aqueous and artificial tears on the ocular surface to reduce the signs and symptoms of dry eye. An absorbable plug may be used temporarily to assess the effectiveness of this therapy prior to insertion of a longterm nonabsorbable plug (Freeman-type, Herrick Lacrimal Plug, or SmartPlug) or cautery. Indications and contraindications for use of punctal plugs are discussed, as are features of various plugs, techniques of insertion and removal, complications, and outcomes.