Tobacco Quitline Retreatment Interventions Among Adults With Socioeconomic Disadvantage: A Factorial Randomized Clinical Trial.

Importance: A single round of standard tobacco quitline treatment may not be sufficient to sustain abstinence, particularly among people experiencing socioeconomic disadvantage. Adaptive retreatment may help more individuals with socioeconomic disadvantage achieve abstinence and reduce disparities in smoking cessation outcomes. Objective: To evaluate 4 evidence-based strategies for adults with limited education, no insurance, or Medicaid eligibility who continued smoking after quitline treatment. Design, Setting, and Participants: A factorial randomized clinical trial with 4 factors adapting quitline strategies was conducted for participants enrolled from June 7, 2018, to January 25, 2023, with 6-month follow-up. Adults using the Wisconsin Tobacco Quit Line who were smoking cigarettes 3 to 6 months after prior quitline treatment who were uninsured, Medicaid insured, or had no more than a high school education were included. Interventions: Quitline retreatment strategies were (1) increased counseling intensity (4 calls vs 1 call), (2) increased nicotine replacement therapy intensity (4 weeks of combination nicotine patch plus nicotine lozenge vs 2 weeks of nicotine patch), (3) text-message support (National Cancer Institute SmokefreeTXT program vs none), and (4) financial incentives for engagement in counseling and SmokefreeTXT ($30/call and/or 6-week SmokefreeTXT retention vs no incentives). Main Outcomes and Measures: Primary outcome was 7-day point-prevalence biochemically confirmed abstinence 26 weeks after the target quit day. Intention-to-treat analysis was performed. Results: Of 6019 people assessed for eligibility, 1316 (21.9%) participants were randomized (mean [SD] age, 53.1 [11.9] years; 760 [57.8%] women), and 919 (69.8%) provided final follow-up. Intention-to-treat analyses showed 162 participants (12.3%) had biochemically confirmed abstinence at 26 weeks (368 [28.0% self-reported abstinence]). There were no significant main effects for the primary outcome: 1 call (11.6% [77 of 662]) vs 4 calls (13.0% [85 of 654]) (odds ratio [OR], 1.04; 95% CI, 0.88-1.24), 2-week patch (11.2% [73 of 654]) vs 4-week combination nicotine replacement therapy (13.4% [89 of 662]) (OR, 1.12; 95% CI, 0.94-1.34), no SmokefreeTXT (13.4% [88 of 657]) vs SmokefreeTXT (11.2% [74 of 659]) (OR, 0.88; 95% CI, 0.74-1.05), and no financial incentives (12.8% [85 of 662]) vs financial incentives (11.8% [77 of 654]) (OR, 0.94; 95% CI, 0.78-1.11). Conclusions and Relevance: In this randomized clinical trial evaluating enhancements to tobacco quitlines for adults with socioeconomic disadvantage who were smoking after quitline treatment, none of the adaptive treatment strategies robustly improved long-term abstinence. Strategies are needed to enhance quitline retreatment effectiveness for adults with socioeconomic disadvantage. Trial Registration: ClinicalTrials.gov Identifier: NCT03538938.

Spontaneous Bilateral Patellar Tendon Rupture in Patient with Ehlers-Danlos Syndrome: A Case Report.

Introduction: Bilateral spontaneous patellar tendon ruptures are rare, though it is hypothesized to be more common in patients with risk factors such as connective tissue disorders such as Ehlers-Danlos syndrome (EDS), systemic disorders weakening collagen structures, chronic stress around the patellar tendon, medications, and obesity or sedentary lifestyles. Clinicians should maintain a high degree of clinical suspicion for concerning features on clinical examination and radiological investigations to facilitate prompt diagnosis and operative management. This case report describes the first documented case of an adult patient with EDS who sustained bilateral spontaneous patellar tendon ruptures. There is one previously reported acute bilateral patellar tendon rupture occurring in a pediatric patient with EDS. Within the adult literature, two case reports have reported patients with EDS: One acute unilateral patellar tendon rupture who underwent operative management and one chronic patellar tendon tear requiring reconstruction 2.5 years following initial end-to-end repair. Case Report: A 45-year-old male sustained bilateral patellar tendon ruptures after falling onto his knees while pushing a heavy cart. The patient reported a giving-way sensation and was unable to mobilize independently. On presentation to the emergency department, the patient was noted to have an absent straight-leg raise and a palpable gap between the distal pole of the patella and patellar tendon. Plain radiograph and ultrasound investigations confirmed bilateral complete patellar tendon ruptures. The patient underwent operative management 5 days following injury through bilateral direct patellar tendon repair utilizing the Krackow technique with transosseous fixation. Twelve months post-operatively, the patient had returned to pre-injuries activities of daily living, a full active range of motion without extensor lag, and recorded "fair knee function" on the Lysholm Knee Scoring Scale. Conclusion: This case report described the first reported bilateral spontaneous patellar tendon rupture in an adult patient with EDS, who underwent operative management and achieved a return to pre-injury function. Furthermore, this case report summarizes the pre-existing literature on spontaneous bilateral patellar tendon ruptures and patellar tendon ruptures in patients with EDS.

Bone and joint infections due to melioidosis; diagnostic and management strategies to optimise outcomes.

BACKGROUND: Melioidosis, a life-threatening infection caused by the gram negative bacterium Burkholderia pseudomallei, can involve almost any organ. Bone and joint infections (BJI) are a recognised, but incompletely defined, manifestation of melioidosis that are associated with significant morbidity and mortality in resource-limited settings. METHODOLOGY/PRINCIPAL FINDINGS: We identified all individuals with BJI due to B. pseudomallei managed at Cairns Hospital in tropical Australia between January 1998 and June 2023. The patients' demographics, their clinical findings and their treatment were correlated with their subsequent course. Of 477 culture-confirmed cases of melioidosis managed at the hospital during the study period, 39 (8%) had confirmed BJI; predisposing risk factors for melioidosis were present in 37/39 (95%). However, in multivariable analysis only diabetes mellitus was independently associated with the presence of BJI (odds ratio (95% confidence interval): 4.04 (1.81-9.00), p = 0.001). BJI was frequently only one component of multi-organ involvement: 29/39 (74%) had infection involving other organs and bacteraemia was present in 31/39 (79%). Of the 39 individuals with BJI, 14 (36%) had osteomyelitis, 8 (20%) had septic arthritis and 17 (44%) had both osteomyelitis and septic arthritis; in 32/39 (83%) the lower limb was involved. Surgery was performed in 30/39 (77%). Readmission after the initial hospitalisation was necessary in 11/39 (28%), 5/39 (13%) had disease recrudescence and 3/39 (8%) had relapse; 4/39 (10%) developed pathological fractures. ICU admission was necessary in 11/39 (28%) but all 11 of these patients survived. Only 1/39 (3%) died, 138 days after admission, due to his significant underlying comorbidity. CONCLUSIONS: The case-fatality rate from melioidosis BJI in Australia's well-resourced health system is very low. However, recrudescence, relapse and orthopaedic complications are relatively common and emphasise the importance of collaborative multidisciplinary care that includes early surgical review, aggressive source control, prolonged antibiotic therapy, and thorough, extended follow-up.

Global arthropod beta-diversity is spatially and temporally structured by latitude.

Global biodiversity gradients are generally expected to reflect greater species replacement closer to the equator. However, empirical validation of global biodiversity gradients largely relies on vertebrates, plants, and other less diverse taxa. Here we assess the temporal and spatial dynamics of global arthropod biodiversity dynamics using a beta-diversity framework. Sampling includes 129 sampling sites whereby malaise traps are deployed to monitor temporal changes in arthropod communities. Overall, we encountered more than 150,000 unique barcode index numbers (BINs) (i.e. species proxies). We assess between site differences in community diversity using beta-diversity and the partitioned components of species replacement and richness difference. Global total beta-diversity (dissimilarity) increases with decreasing latitude, greater spatial distance and greater temporal distance. Species replacement and richness difference patterns vary across biogeographic regions. Our findings support long-standing, general expectations of global biodiversity patterns. However, we also show that the underlying processes driving patterns may be regionally linked.

Short communication: Metabolic synthesis of vitamin D2 by the gut microbiome.

The origin of vitamin D2 in herbivorous animals was investigated in vivo in sheep and in bovine as well as mouse gastrointestinal tracts. A high concentration of 25-hydroxyvitamin D2 in blood plasma of sheep both in summer and winter appeared to be incompatible with the undetectable level of vitamin D2 in the pasture on which the sheep were grazing. Studies with bovine rumen contents from a cow grazing the same pasture as the sheep, demonstrated an increased concentration of vitamin D2 on anaerobic incubation in a 'Rusitec' artificial rumen, which was further enhanced when cellulose powder was added as a fermentation substrate. The colon contents of mice that were fed from weaning on a vitamin D-free diet were found to contain vitamin D2. The results of these comparative studies in 3 animal species indicated that vitamin D2 was being generated by microbial anaerobic metabolism in the gastrointestinal tract.

Periodontal disease in patients with WHIM syndrome.

AIM: WHIM (warts, hypogammaglobulinaemia, infections and myelokathexis) syndrome is a rare combined primary immunodeficiency disease caused by gain-of-function (GOF) mutations in the chemokine receptor CXCR4 and includes severe neutropenia as a common feature. Neutropenia is a known risk factor for periodontitis; however, a detailed periodontal evaluation of a WHIM syndrome cohort is lacking. This study aimed to establish the evidence base for the periodontal status of patients with WHIM syndrome. MATERIALS AND METHODS: Twenty-two adult WHIM syndrome patients and 22 age- and gender-matched healthy volunteers (HVs) were evaluated through a comprehensive medical and periodontal examination. A mouse model of WHIM syndrome was assessed for susceptibility to naturally progressing or inducible periodontitis. RESULTS: Fourteen patients with WHIM syndrome (63.6%) and one HV (4.5%) were diagnosed with Stage III/IV periodontitis. No WHIM patient presented with the early onset, dramatic clinical phenotypes typically associated with genetic forms of neutropenia. Age, but not the specific CXCR4 mutation or absolute neutrophil count, was associated with periodontitis severity in the WHIM cohort. Mice with a Cxcr4 GOF mutation did not exhibit increased alveolar bone loss in spontaneous or ligature-induced periodontitis. CONCLUSIONS: Overall, WHIM syndrome patients presented with an increased severity of periodontitis despite past and ongoing neutrophil mobilization treatments. GOF mutations in CXCR4 may be a risk factor for periodontitis in humans.

Dissociation of murine oral mucosal tissues for single cell applications.

Single-cell RNA sequencing and flow cytometry approaches have been instrumental in understanding cellular states within various tissues and organs. However, tissue dissociation methods can potentially alter results and create bias due to preferential recovery of particular cell types. Here we present efforts to optimize methods for dissociation of murine oral mucosal tissues and provide three different protocols that can be utilized to isolate major cell populations in the oral mucosa. These methods can be used both in health and in states of inflammation, such as periodontitis. The optimized protocols use different enzymatic approaches (collagenase II, collagenase IV and the Miltenyi whole skin dissociation kit) and yield preferential recovery of immune, stromal and epithelial cells, respectively. We suggest choosing the dissociation method based on the cell population of interest to study, while understanding the limitations of each approach.

A medium-chain fatty acid analogue prevents hepatosteatosis and decreases inflammatory lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis.

BACKGROUND: Parenteral (intravenous) nutrition is lifesaving for patients with intestinal failure, but long-term use of parenteral nutrition often leads to liver disease. SEFA-6179 is a synthetic medium-chain fatty acid analogue designed to target multiple fatty acid receptors regulating metabolic and inflammatory pathways. We hypothesized that SEFA-6179 would prevent hepatosteatosis and lipotoxicity in a murine model of parenteral nutrition-induced hepatosteatosis. METHODS: Two in vivo experiments were conducted. In the first experiment, six-week-old male mice were provided an ad lib fat-free high carbohydrate diet (HCD) for 19 days with orogastric gavage of either fish oil, medium-chain triglycerides, or SEFA-6179 at a low (0.3mmol/kg) or high dose (0.6mmol/kg). In the second experiment, six-week-old mice were provided an ad lib fat-free high carbohydrate diet for 19 days with every other day tail vein injection of saline, soybean oil lipid emulsion, or fish oil lipid emulsion. Mice then received every other day orogastric gavage of medium-chain triglyceride vehicle or SEFA-6179 (0.6mmol/kg). Hepatosteatosis was assessed by a blinded pathologist using an established rodent steatosis score. Hepatic lipid metabolites were assessed using ultra-high-performance liquid chromatography-mass spectrometry. Effects of SEFA-6179 on fatty acid oxidation, lipogenesis, and fatty acid uptake in human liver cells were assessed in vitro. RESULTS: In the first experiment, mice receiving the HCD with either saline or medium-chain triglyceride treatment developed macrovesicular steatosis, while mice receiving fish oil or SEFA-6179 retained normal liver histology. In the second experiment, mice receiving a high carbohydrate diet with intravenous saline or soybean oil lipid emulsion, along with medium chain triglyceride vehicle treatment, developed macrovescular steatosis. Treatment with SEFA-6179 prevented steatosis. In each experiment, SEFA-6179 treatment decreased arachidonic acid metabolites as well as key molecules (diacylglycerol, ceramides) involved in lipotoxicity. SEFA-6179 increased both ß- and complete fatty oxidation in human liver cells, while having no impact on lipogenesis or fatty acid uptake. CONCLUSIONS: SEFA-6179 treatment prevented hepatosteatosis and decreased toxic lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. An increase in both ß- and complete hepatic fatty acid oxidation may underlie the reduction in steatosis.

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.

BACKGROUND & AIMS: At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. METHODS: Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179. RESULTS: Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). CONCLUSIONS: In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

Serum 1,25-dihydroxyvitamin D levels in the diagnosis and pathogenesis of nutritional rickets - a multivariable re-analysis of a case-control study.

BACKGROUND: A multivariable logistic regression model resulting from a case-control study of nutritional rickets in Nigerian children suggested that higher levels of serum 25(OH)D may be required to prevent nutritional rickets in populations with low-calcium intakes. OBJECTIVES: This current study evaluates if adding serum 1,25-dihydroxyvitamin D [1,25(OH)2D] to that model shows that increased levels of serum 1,25(OH)2D are independently associated with risk of children on low-calcium diets having nutritional rickets. METHODS: Multivariable logistic regression analysis was used to model the association between serum 1,25(OH)2D and risk of having nutritional rickets in cases (n = 108) and controls (n = 115) after adjusting for age, sex, weight-for age z-score, religion, phosphorus intake and age began walking and the interaction between serum 25(OH)D and dietary calcium intake (Full Model). RESULTS: Serum 1,25(OH)2D levels were significantly higher (320 pmol/L vs. 280 pmol/L) (P = 0.002), and 25(OH)D levels were lower (33 nmol/L vs. 52 nmol/L) (P < 0.0001) in children with rickets than in control children. Serum calcium levels were lower in children with rickets (1.9 mmol/L) than in control children (2.2 mmol/L) (P < 0.001). Dietary calcium intakes were similarly low in both groups (212 mg/d) (P = 0.973). In the multivariable logistic model, 1,25(OH)2D was independently associated with risk of having rickets [coefficient = 0.007 (95% confidence limits: 0.002-0.011)] after adjusting for all variables in the Full Model. CONCLUSIONS: Results confirmed theoretical models that in children with low dietary calcium intake, 1,25(OH)2D serum concentrations are higher in children with rickets than in children without rickets. The difference in 1,25(OH)2D levels is consistent with the hypothesis that children with rickets have lower serum calcium concentrations which prompt the elevation of PTH levels resulting in an elevation of 1,25(OH)2D levels. These results support the need for additional studies to identify dietary and environmental risks for nutritional rickets.

Differences in career paths of alumni of the Cornell Leadership Program from North American universities compared with those alumni from universities in other countries.

OBJECTIVE: To characterize and compare the careers of alumni of the Cornell Leadership Program for Veterinary Students according to the countries where they studied and obtained their veterinary qualification. The Cornell Leadership Program is a 10-week residential research experience program for veterinary students from around the world who have ambitions for research-related careers. SAMPLE: Data on the career development of all 672 alumni were collected each year over the period of 1990 to 2019. PROCEDURES: The annual career profile of each alumnus was recorded and coded in 1 of 28 different categories. The careers and postveterinary qualifications of alumni from universities in the US and Canada (referred to as North American universities) were compared with those alumni who graduated from universities in other countries. RESULTS: Analysis of this 30-year database revealed that a considerable proportion (45.7% [307/672]) of the total 672 alumni are following the traditional career path of veterinary clinical practice rather than the research-related careers they aspired to as students during the Leadership Program. Furthermore, a higher proportion of the 325 North American alumni (56% [182/325]) were in clinical practice compared with 33.6% (112/333) of the 333 alumni from other countries. CLINICAL RELEVANCE: Many veterinary schools now provide research experience programs to encourage highly talented students who have ambitions for careers in which they can advance knowledge about animal disease and contribute to solving the health problems of animals through hypothesis-based research. Comparison of the careers of the Leadership Program alumni indicates that research experience alone is not sufficient to maintain the career goals of alumni. Follow-up mentoring of alumni of such programs is recommended while they complete their veterinary studies to reinforce their career aspirations and provide advice on how to achieve research-related careers.

The effect of electronic cigarette use on peri-implant conditions in men: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the effect of electronic cigarette (e-cigarette) use on clinical, radiographic, and immunologic peri-implant parameters in males. STUDY DESIGN: A comprehensive search of indexed databases was conducted to identify studies reporting data on both e-cigarette users and nonsmokers with implant-supported prosthesis with ≥1-year in function, up to May 2022. Marginal bone loss (MBL), probing depth (PD), plaque index (PI), and bleeding on probing (BOP) were recorded. Peri-implant sulcular fluid volume (PISF), tumor necrosis factor alpha (TNF-α) and interleukin 1ß (IL-ß) levels were also assessed. A meta-analysis was performed using random-effect models to determine the effect of e-cigarette use in primary and secondary outcomes. RESULTS: Four cross-sectional studies were included with a total of 327 participants (165 e-cigarette users and 162 nonsmokers). All studies showed greater MBL, PI, PD, and lower BOP in e-cigarette users compared with never smokers. The meta-analysis indicated significant heterogeneity for all outcomes except MBL for distal implant surfaces, with the mean difference between e-cigarette users and nonsmokers of 0.89 mm (95% CI: 0.67-1.11, P < .01). The PISF volume, TNF-α, and IL-1ß levels were increased in e-cigarette users (P < .01) with no heterogeneity present between studies. CONCLUSIONS: E-cigarette use shows a negative effect on clinical, radiographic, and immunologic parameters of dental implants.

Using institutional ethnography to analyse animal sheltering and protection II: Animal shelter work.

Efficient adoption is an important aim of animal shelters, but it is not possible for all animals including those with serious behavioural problems. We used institutional ethnography to explore the everyday work of frontline shelter staff in a large animal sheltering and protection organisation and to examine how their work is organised by standardised institutional procedures. Shelter staff routinely conduct behavioural evaluations of dogs and review intake documents, in part to plan care for animals and inform potential adopters about animal characteristics as well as protect volunteers and community members from human-directed aggression. Staff were challenged and felt pressure, however, to find time to work with animals identified as having behavioural problems because much of their work is directed toward other goals such as facilitating efficient adoption for the majority and anticipating future demands for kennel space. This work is organised by management approaches that broadly aim to maintain a manageable shelter animal population based on available resources, decrease the length of time animals spend in shelters and house animals based on individual needs. However, this organisation limits the ability of staff to work closely with long-stay animals whose behavioural problems require modification and management. This also creates stress for staff who care for these animals and are emotionally invested in them. Further inquiry and improvements might involve supporting the work of behavioural modification and management where it is needed and expanding fostering programmes for animals with special needs.

Animal sheltering: A scoping literature review grounded in institutional ethnography.

A diverse research literature now exists on the animals, staff and organisations involved in animal sheltering. We reviewed this research through the lens of institutional ethnography, a method of inquiry that focuses on the actual work that people do within institutions. The main topics, identified through a larger ethnographic study of animal sheltering, were: (i) research about shelter staff and officers; (ii) the relinquishment of animals to shelters; and (iii) animals' length of stay in shelters. After reviewing the literature, we held focus groups with shelter personnel to explore how their work experiences are or are not represented in the research. The review showed that stress caused by performing euthanasia has attracted much research, but the decision-making that leads to euthanasia, which may involve multiple staff and potential conflict, has received little attention. Research on 'compassion fatigue' has also tended to focus on euthanasia but a granular description about the practical and emotional work that personnel undertake that generates such fatigue is missing. Published research on both relinquishment and length of stay is dominated by metrics (questionnaires) and often relies upon shelter records, despite their limitations. Less research has examined the actual work processes involved in managing relinquishment as well as monitoring and reducing animals' length of stay. Institutional ethnography's focus on people's work activities can provide a different and more nuanced understanding of what is happening in animal sheltering and how it might better serve the needs of the animals and staff.

Using institutional ethnography to analyse animal sheltering and protection I: Animal protection work.

Animal protection laws exist at federal, provincial and municipal levels in Canada, with enforcement agencies relying largely upon citizens to report concerns. Existing research about animal protection law focuses on general approaches to enforcement and how legal terms function in the courts, but the actual work processes of animal law enforcement have received little study. We used institutional ethnography to explore the everyday work of Call Centre operators and Animal Protection Officers, and we map how this work is organised by laws and institutional polices. When receiving and responding to calls staff try to identify evidence of animal 'distress' as legally defined, because various interventions (writing orders, seizing animals) then become possible. However, many cases, such as animals living in deprived or isolated situations, fall short of constituting 'distress' and the legally mandated interventions cannot be used. Officers are also constrained by privacy and property law and by the need to record attempts to secure compliance in order to justify further action including obtaining search warrants. As a result, beneficial intervention can be delayed or prevented. Officers sometimes work strategically to advocate for animals when the available legal tools cannot resolve problems. Recommendations arising from this research include expanding the legal definition of 'distress' to better fit animals' needs, developing ways for officers to intervene in a broader range of situations, and more ethnographic research on enforcement work in jurisdictions with different legal systems to better understand how animal protection work is organised and constrained by laws and policies.

Icosabutate: targeting metabolic and inflammatory pathways for the treatment of NASH.

INTRODUCTION: Via pleiotropic targeting of membrane and nuclear fatty acid receptors regulating key metabolic and inflammatory pathways in the liver, long-chain omega-3 fatty acids could offer a unique therapeutic approach for the treatment of metabolic-inflammatory diseases such as NASH. However, they lack efficacy for the treatment of NASH, likely due to unfavorable distribution, metabolism, and susceptibility to peroxidation. AREAS COVERED: Structurally engineered fatty acids (SEFAs), as exemplified by icosabutate, circumvent the inherent limitations of unmodified long-chain fatty acids, and demonstrate markedly enhanced pharmacodynamic effects without sacrificing safety and tolerability. We cover icosabutate's structural modifications, their rationale and the fatty acid receptor and pathway targeting profile. We also provide an overview of the clinical data to date, including interim data from a Phase 2b trial in NASH subjects. EXPERT OPINION: Ideally, candidate drugs for NASH and associated liver fibrosis should be pleiotropic in mechanism and work upstream on multiple drivers of NASH, including lipotoxic lipid species, oxidative stress, and key modulators of inflammation, liver cell injury, and fibrosis. Icosabutate has demonstrated the ability to target these pathways in preclinical NASH models with interim data from the ICONA trial supporting, at least noninvasively, the clinical translation of highly promising pre-clinical data.

Dual peptide-functionalized hydrogels differentially control periodontal cell function and promote tissue regeneration.

Restoring the tooth-supporting tissues lost during periodontitis is a significant clinical challenge, despite advances in both biomaterial and cell-based approaches. This study investigated poly(ethylene glycol) (PEG) hydrogels functionalized with integrin-binding peptides RGD and GFOGER for controlling periodontal ligament cell (PDLC) activity and promoting periodontal tissue regeneration. Dual presentation of RGD and GFOGER within PEG hydrogels potentiated two key PDLC functions, alkaline phosphatase (ALP) activity and matrix mineralization, over either peptide alone and could be tuned to differentially promote each function. Hydrogel matrix mineralization, fostered by high concentrations of GFOGER together with RGD, identified a PDLC phenotype with accelerated matrix adhesion formation and expression of cementoblast and osteoblast genes. In contrast, maximizing ALP activity through high RGD and low GFOGER levels resulted in minimal hydrogel mineralization, in part, through altered PDLC pyrophosphate regulation. Transplantation of PDLCs in hydrogels optimized for either outcome promoted cementum formation in rat periodontal defects; however, only hydrogels optimized for in vitro mineralization improved new bone formation. Overall, these results highlight the utility of engineered hydrogel systems for controlling PDLC functions and their promise for promoting periodontal tissue regeneration.

Hydrogel Swelling-Mediated Strain Induces Cell Alignment at Dentin Interfaces.

Cell and tissue alignment is a defining feature of periodontal tissues. Therefore, the development of scaffolds that can guide alignment of periodontal ligament cells (PDLCs) relative to tooth root (dentin) surfaces is highly relevant for periodontal tissue engineering. To control PDLC alignment adjacent to the dentin surface, poly(ethylene glycol) (PEG)-based hydrogels were explored as a highly tunable matrix for encapsulating cells and directing their activity. Specifically, a composite system consisting of dentin blocks, PEG hydrogels, and PDLCs was created to control PDLC alignment through hydrogel swelling. PDLCs in composites with minimal hydrogel swelling showed random alignment adjacent to dentin blocks. In direct contrast, the presence of hydrogel swelling resulted in PDLC alignment perpendicular to the dentin surface, with the degree and extension of alignment increasing as a function of swelling. Replicating this phenomenon with different molds, block materials, and cells, together with predictive modeling, indicated that PDLC alignment was primarily a biomechanical response to swelling-mediated strain. Altogether, this study describes a novel method for inducing cell alignment adjacent to stiff surfaces through applied strain and provides a model for the study and engineering of periodontal and other aligned tissues.

Structurally-engineered fatty acid 1024 (SEFA-1024) improves diet-induced obesity, insulin resistance, and fatty liver disease.

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

Physiological significance of vitamin D produced in skin compared with oral vitamin D.

Since the discovery of vitamin D, it has been accepted that its physiological supply is either from food or by endogenous synthesis in skin exposed to solar UV light. Yet vitamin D is a component of very few foods and its supply as a natural nutrient is unable to maintain good vitamin D status for human populations. One aspect of vitamin D physiology that has been ignored is that the mechanisms for its transport and processing from these two sources are quite different. Excess intake of vitamin D causes hypercalcaemic toxicity. However, experiments with different animal species have shown that long-term supply of oral vitamin D in apparently non-toxic amounts causes atherosclerosis in large arteries. A mechanism for this toxicity is proposed. Alternative strategies for addressing widespread vitamin D deficiency by food fortification should be considered in light of the angiotoxicity caused by oral vitamin D in animal experiments.