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Treatment adherence is crucial for optimal outcomes in advanced breast cancer, but can be challenging due to various factors, i.e. patients’ attitudes and behavior upon diagnosis, and complex therapies with high adverse effect rates. Our aim was to explore the adherence to oral anticancer medications (OAM) in women with advanced breast cancer, focusing on cyclin-dependent kinase 4 and 6 inhibitors (CDKI), and identify factors associated with the adherence. We conducted a cross-sectional study at the University Hospital Centre Zagreb, Croatia, involving women with stage IV advanced breast cancer receiving OAM. Data collection included a questionnaire assessing socio-demographic and clinical information, Beck Depression Inventory-II for depressive symptoms, Medication Adherence Report Scale (MARS-5) for adherence to OAM, and Beliefs about Medicines Questionnaire. Plasma concentrations of CDKI were confirmed by LC-MS/MS in three randomly selected participants. A total of 89 women were included. The most prescribed OAMs were anti-estrogen (71.3 %) and CDKI (60.9 %). MARS-5 scores (mean: 24.1 ± 1.6) correlated with CDKI plasma concentrations. Forgetfulness was the primary reason for non-adherence (25.9 %). Women receiving CDKI (p = 0.018), without depressive symptomatology (p = 0.043), and with more positive beliefs about medicines were more adherent (p < 0.05). This study enhances understanding of medication adherence in advanced breast cancer and identifies influential factors.

Abstract Background Epidemiological studies associate consumption of whole grain foods, including breads, with reduced cardiovascular disease (CVD) risk; however, few studies have compared wheat whole grains with wheat refined grains. Methods This study investigated effects of 6-week consumption of whole grain wheat sourdough bread in comparison to white bread on fasting serum lipids in normoglycemic/normoinsulinemic (NGI; n = 14) and hyperglycemic/hyperinsulinemic (HGI; n = 14) adults. The influence of single-nucleotide polymorphisms, 3 within the APOE gene (E2, E3, E4) and 2 within the hepatic lipase gene promoter (LIPC -514C>T, LIPC -250G>A) were considered. Results At baseline, HGI participants had significantly higher body weight, waist circumference, body fat, and fasted glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), glucagon, triacylglycerols (TAG) and TAG:HDL-cholesterol, compared to NGI participants; however, none of these in addition to none of the other serum lipids, differed between bread treatments, within either participant group. For participants with the APOE E3/E3 genotype, LDL-cholesterol (P = 0.02) increased in the NGI group (n = 7), and TAG (P = 0.03) and TAG:HDL-cholesterol (P = 0.04) increased in the HGI group (n = 10), following consumption of whole grain wheat sourdough compared to white bread. Conclusions In summary, 6-week consumption of whole grain wheat sourdough bread did not significantly modulate serum lipids in NGI or HGI adults; however, it significantly increased LDL-cholesterol, TAG and TAG:HDL-cholesterol in participants with the APOE E3/E3 genotype. These data add to limited literature comparing wheat whole grains to wheat refined grains on CVD risk and highlight the need to consider genetic variation in relation to lipoprotein lipid content and CVD risk.

Background: Breast conservation therapy is a widely accepted approach in treating breast cancer, yet the average re-excision rates are approximately 25% despite surgical advancements. The Food and Drug Administration (FDA)-approved MarginProbe ® device uses radiofrequency spectroscopy for intraoperative margin assessment, potentially reducing re-excision rates. This study evaluated the effectiveness of MarginProbe ® in reducing re-excisions compared with standard of care (SOC)., Methods: A prospective cohort with MarginProbe ® usage during partial mastectomies from June 2019 to July 2023 (153 patients) was compared with a retrospective control group without the device from January 2015 to May 2019 (300 patients). Both groups underwent partial mastectomies performed by two breast surgeons. Positive margins were defined as tumor on ink for invasive cancers and within 2 mm for ductal carcinoma in situ., Results: When control was used for patient demographics and tumor characteristics, the findings showed that MarginProbe ® significantly decreased the probability of re-excision by 58% (p < 0.001), although it led to a higher shave volume, with an average of 9.8 cc additional tissue removed compared with SOC (p < 0.001). Human epidermal growth factor 2 (HER2) positivity was significantly associated with increased odds of re-excision (p = 0.036). MarginProbe ® demonstrated a sensitivity of 70.1% and a specificity of 47.5%., Conclusions: MarginProbe ® is an effective adjunct for intraoperative margin assessment to decrease re-excision rates. However, patient selection is paramount. Given its significant increase in shave volume, women with small breasts may be at higher risk for poor cosmesis. Surgeons should exercise clinical judgement when determining the suitability of MarginProbe ® use for patients undergoing breast conservation. Further research is necessary to refine MarginProbe ® 's specificity and to optimize its clinical application., (© 2024. Society of Surgical Oncology.)

Prenatal multivitamins, including folic acid, are commonly consumed in excess, whereas choline, an essential nutrient and an important source of labile methyl groups, is underconsumed. Here, we characterized profiles of one-carbon metabolism and related pathways and patterns of DNA methylation in offspring exposed to excess or imbalanced micronutrients prenatally. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). Offspring were weaned to a high-fat diet for 12 weeks. Circulating metabolites were analyzed with a focus on the hypothalamus, an area known to be under epigenetic regulation. HV, HFolRC, and HFolNC males had higher body weight (BW) and lower plasma choline and methionine consistent with lower hypothalamic S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) and global DNA methylation compared with RV. HV and HFolNC females had higher BW and lower plasma 5-methyltetrahydrofolate and methionine consistent with lower hypothalamic global DNA methylation compared with RV. Plasma dimethylglycine (DMG) and methionine were higher as with hypothalamic SAM:SAH and global DNA methylation in HFolRC females without changes in BW compared with RV. Plasma trimethylamine and trimethylamine-N-oxide were higher in males but lower in females from HFolRC compared with RV. Network modeling revealed a link between the folate-dependent pathway and SAH, with most connections through DMG. Final BW was negatively correlated with choline, DMG, and global DNA methylation. In conclusion, prenatal intake of excess or imbalanced micronutrients induces distinct metabolic and epigenetic perturbations in offspring that reflect long-term nutritional programming of health., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Herein, we present the case of accidental intravenous injection of gasoline in a 62-year-old male who was admitted to a dialysis center for his regular hemodialysis. Due to previous contact with another SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) positive patient, the hemodialysis was conducted in an isolated room. At the end of the procedure, the nurse, wearing all necessary personal protective equipment (PPE), in the intent to clean the dialysis catheter, applied medical gasoline, instead of 0.9% sodium chloride, intravenously to the patient. Soon afterwards, the patient's clinical condition deteriorated, and cardiopulmonary resuscitation was started. Despite the immediate reaction of the medical staff, after two successful cardiopulmonary reanimation and necessary intensive care measures, the patient suffered respiratory, metabolic, and lactic acidosis, hypotension, and tachyarrhythmia and ultimately died 7 h after the incident. The autopsy was conducted under the order of the district attorney. Main autopsy findings were marked congestion; right pleural and pericardial effusion; brain and lung edema; enlarged heart with left ventricle thickening and mild perivascular fibrosis; nephrosclerosis; tubular thyroidization; and interstitial fibrosis with inflammation. Gasoline presence was indisputably proven by conducted toxicology analysis in lung, bile, and brain samples. Traces of gasoline could be noted in the patient's blood sample in comparison to the blood that did not contain gasoline, but it was not possible to confidently claim that gasoline was present in the blood. Based on relevant findings, we concluded that the death of the patient was violent and that the cause of death was acute intoxication by gasoline., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Disparities in insurance and socioeconomic status (SES) may impact surgical management and subsequent postoperative outcomes for patients with craniosynostosis. This systematic review summarizes the evidence on possible differences in surgical care, including procedure type, age at surgery, and differences in surgical outcomes such as complications, length of hospital stay, and child development based on SES., Design: The databases Scopus, PubMed, and CINAHL were searched between May and July 2022. Following PICO criteria, studies included focused on patients diagnosed with craniosynostosis; corrective surgery for craniosynostosis; comparison of insurance, income, or zip code; and surgical management of postoperative outcomes., Results: The initial search yielded 724 articles. After three stages of screening, 13 studies were included. Assessed outcomes included: type of procedure (6 articles), age at time of surgery (3 articles), post-operative complications (3 articles), referral delay (2 articles), length of stay (2 articles), hospital costs (2 articles), and child development (1 article). Of the studies with significant results, insurance type was the main SES variable of comparison. While some findings were mixed, these studies indicated that patients with public medical insurance were more likely to experience a delay in referral, undergo an open rather than minimally-invasive procedure, and have more complications, longer hospitalization, and higher medical charges., Conclusions: This study demonstrated that SES may be associated with several differences in the management of patients with craniosynostosis. Further investigation into the impact of SES on the management of patients with craniosynostosis is warranted to identify possible interventions that may improve overall care., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Simultaneous free flap breast reconstruction combined with contralateral mastopexy or breast reduction can increase patient satisfaction and minimize the need for a second procedure. Surgeon concerns of increases in operative time, postoperative complications, and final breast symmetry may decrease the likelihood of these procedures being done concurrently. This study analyzed postoperative outcomes of simultaneous contralateral mastopexy or breast reduction with free flap breast reconstruction., Methods: By using the American College of Surgeons National Surgical Quality Improvement Program database (2010-2020), we analyzed 2 patient cohorts undergoing (A) free flap breast reconstruction only and (B) free flap breast reconstruction combined with contralateral mastopexy or breast reduction. The preoperative variables assessed included demographic data, comorbidities, and perioperative data. Using a neighbor matching algorithm, we performed a 1:1 propensity score matching of 602 free flap breast reconstruction patients and 621 with concurrent contralateral operation patients. Bivariate analysis for postoperative surgical and medical complications was performed for outcomes in the propensity-matched cohort., Results: We identified 11,308 cases who underwent microsurgical free flap breast reconstruction from the American College of Surgeons National Surgical Quality Improvement Program database from the beginning of 2010 to the end of 2020. A total of 621 patients underwent a free flap breast reconstruction combined with contralateral mastopexy or breast reduction. After propensity score matching, there were no significant differences in patient characteristics, perioperative variables or postoperative medical complications between the 2 cohorts., Conclusions: Simultaneous free flap breast reconstruction combined with contralateral mastopexy or breast reduction can be performed safely and effectively without an increase in postoperative complication rates. This can improve surgeon competence in offering this combination of procedures as an option to breast cancer survivors, leading to better patient outcomes in terms of symmetrical and aesthetically pleasing results, reduced costs, and elimination of the need for a second operation., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to investigate the serum metabolomic profile of obese and lean cats as well as obese cats before and after energy restriction for weight loss. Thirty cats, 16 obese (body condition score 8 to 9/9) and 14 lean (body condition score 4 to 5/9), were fed a veterinary weight loss food during a 4-week period of weight maintenance (L-MAINT and O-MAINT). The 16 obese cats were then energy restricted by a 60% energy intake reduction with the same food for a 10-week period (O-RESTRICT). Fasted serum metabolites were measured using nuclear magnetic resonance and direct infusion mass spectrometry after the maintenance period for L-MAINT and O-MAINT cats and after the energy restriction period for O-RESTRICT and compared between groups using a two-sided t-test. Obese cats lost 672 g ± 303 g over the 10-week restriction period, representing a weight loss rate of 0.94 ± 0.28% per week. Glycine, l-alanine, l-histidine, l-glutamine, 2-hydroxybutyrate, isobutryric acid, citric acid, creatine, and methanol were greater in O-RESTRICT compared to O-MAINT. There was a greater concentration of long-chain acylcarnitines in O-RESTRICT compared to both O-MAINT and L-MAINT, and greater total amino acids compared to O-MAINT. Glycerol and 3-hydroxybutyric acid were greater in O-MAINT compared to L-MAINT, as were several lysophosphatidylcholines. Thus, energy restriction resulted in increased dispensable amino acids in feline serum which could indicate alterations in amino acid partitioning. An increase in lipolysis was not evident, though greater circulating acylcarnitines were observed, suggesting that fatty acid oxidation rates may have been greater under calorie restriction. More research is needed to elucidate energy metabolism and substrate utilization, specifically fatty acid oxidation and methyl status, during energy restriction in strict carnivorous cats to optimize weight loss., Competing Interests: The authors declare no conflicts of interest. CG held the Nestle Purina Professorship in Companion Animal Nutrition at the Ontario Veterinary College at the time of manuscript drafting, is the owner of Grant Veterinary Nutrition Services and consults with Simmons Pet Food. MT is currently employed by Royal Canin. The study was conducted before this employment during MT’s Doctor Veterinary Sciences Degree at the Ontario Veterinary College. HG declares that they have participated in paid internships and engagements with pet food companies within Canada. AKS is the Champion Petfoods Chair in Canine and Feline Nutrition, Physiology and Metabolism, consults for Champion Petfood, was previously employed by P&G and Mars Pet Care, serves on the Scientific Advisory Board for Trouw Nutrition, and has received honoraria and research funding from various commodity groups, pet food manufacturers, and ingredient suppliers. AV is the Royal Canin Veterinary Diets Endowed Chair in Canine and Feline Clinical Nutrition and declares that they serve on the Health and Nutrition Advisory Board for Vetdiet. AV has also received honoraria and research funding from various pet food manufacturers and ingredient suppliers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Grant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Choline is beneficial for energy metabolism and growth in various species. Choline may work similarly in kittens at risk of obesity. Direct infusion MS (Di-MS) and NMR spectroscopy were used to investigate the metabolomic signatures of kittens supplemented with or without additional dietary choline for 12 weeks. Fifteen intact male kittens consumed a base diet (3310 mg choline/kg DM) to their daily metabolisable energy requirement (DER) over an 11-week acclimation. Kittens were gonadectomised and assigned, based on body weight, to the base diet (CONTROL, n 7) or the base diet with 300 mg/kgBW 0·75 additional choline as choline chloride (CHOLINE, n 8) and offered three times their individual energy requirement divided into three meals. At weeks -1 and 12, fasted blood was sampled and serum analysed for 130 metabolites via Di-MS and fifty-one metabolites via NMR spectroscopy. Changes in fasted metabolites were assessed using a repeated-measures GLIMMIX procedure with time and group as fixed effects, and time as a repeated measure. Metabolites of one-carbon metabolism and lipids increased, and medium-chain acyl carnitines decreased from week -1 to 12 for CHOLINE ( P < 0·05), but not CONTROL ( P > 0·05). Increases in amino acid, biogenic amine and organic compound concentrations were observed in both groups ( P < 0·05). The results suggest impacts of dietary choline at greater intakes than currently recommended on one-carbon metabolism and fatty acid oxidation, and these may promote healthy growth in post-gonadectomy kittens.

Introduction: Due to the involvement in one-carbon metabolism and lipid mobilization, choline and L-carnitine supplementation have been recommended to minimize hepatic lipid accumulation and support fat oxidation, respectively. This study investigated the lipotropic benefits of choline or L-carnitine supplementation in lean and obese cats maintaining body weight (BW)., Methods: Lean [ n = 9; body condition score (BCS): 4-5/9] and obese ( n = 9; BCS: 8-9/9) adult male neutered colony cats were used in a replicated 3 x 3 complete Latin square design. Treatments included choline (378 mg/kg BW 0.67 ), L-carnitine (200 mg/kg BW) and control (no supplement). Treatments were supplemented to the food for 6 weeks each, with a 2-week washout between treatments. Cats were fed once daily to maintenance energy requirements, and BW and BCS were assessed weekly. Fasted blood collection, indirect calorimetry, and dual-energy X-ray absorptiometry occurred at the end of each treatment period. Serum was analyzed for cholesterol (CHOL), high-density lipoprotein CHOL (HDL-C), triglycerides (TAG), non-esterified fatty acids (NEFA), glucose, creatinine (CREAT), urea, alkaline phosphatase (ALP) and alanine aminotransferase (ALT). Very low-density lipoprotein CHOL (VLDL) and low-density lipoprotein CHOL (LDL-C) were calculated. Data were analyzed using proc GLIMMIX, with group and period as random effects, and treatment, body condition, and their interaction as fixed effects, followed by a Tukey's post-hoc test when significance occurred., Results: Cats supplemented choline had lower food intake ( P = 0.025). Treatment did not change BW, BCS and body composition ( P > 0.05). Obese cats had greater ALP, TAG, and VLDL, and lower HDL-C compared to lean cats ( P < 0.05). Choline resulted in greater CHOL, HDL-C, LDL-C and ALT ( P < 0.05). L-carnitine resulted in lower CREAT ( P = 0.010). Following the post-hoc test, differences between treatment means were not present for ALP ( P = 0.042). No differences were found for glucose, urea or NEFA ( P > 0.05). Obese cats had a lower fed respiratory quotient (RQ), regardless of treatment ( P = 0.045). Treatment did not affect fed or fasted RQ and energy expenditure ( P > 0.05)., Discussion: Choline appeared to increase circulating lipid and lipoprotein concentrations regardless of body condition, likely through enhanced lipid mobilization and hepatic elimination. Neither dietary choline or L-carnitine altered body composition or energy metabolism in the lean or obese cats, as compared to control., Competing Interests: AR declares that they have participated in paid engagements with and received scholarships from pet food companies within Canada. At the time of the study, SV-S held the position of Registered Veterinary Technician in Clinical Nutrition funded by Nestlé Purina Proplan Veterinary Diets, they were previously employed by Hill's Pet Nutrition, and received honoraria from pet food manufacturers. AS is the Champion Petfoods Chair in Canine and Feline Nutrition, Physiology and Metabolism, consults for Champion Petfood, was previously employed by P&G and Mars Pet Care, serves on the Scientific Advisory Board for Trouw Nutrition, and has received honoraria and research funding from various commodity groups, pet food manufacturers, and ingredient suppliers. AV is the Royal Canin Veterinary Diets Endowed Chair in Canine and Feline Clinical Nutrition, serves on the Health and Nutrition Advisory Board for Vetdiet and has received honoraria and research funding from various pet food manufacturers and ingredient suppliers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rankovic, Verton-Shaw, Shoveller, Bakovic, Kirby and Verbrugghe.)

The maintenance of phospholipid homeostasis is increasingly being implicated in metabolic health. Phosphatidylethanolamine (PE) is the most abundant phospholipid on the inner leaflet of cellular membranes, and we have previously shown that mice with a heterozygous ablation of the PE synthesizing enzyme, Pcyt2 ( Pcyt2 +/- ), develop obesity, insulin resistance, and NASH. Skeletal muscle is a major determinant of systemic energy metabolism, making it a key player in metabolic disease development. Both the total PE levels and the ratio of PE to other membrane lipids in skeletal muscle are implicated in insulin resistance; however, the underlying mechanisms and the role of Pcyt2 regulation in this association remain unclear. Here, we show how reduced phospholipid synthesis due to Pcyt2 deficiency causes Pcyt2 +/- skeletal muscle dysfunction and metabolic abnormalities. Pcyt2 +/- skeletal muscle exhibits damage and degeneration, with skeletal muscle cell vacuolization, disordered sarcomeres, mitochondria ultrastructure irregularities and paucity, inflammation, and fibrosis. There is intramuscular adipose tissue accumulation, and major disturbances in lipid metabolism with impaired FA mobilization and oxidation, elevated lipogenesis, and long-chain fatty acyl-CoA, diacylglycerol, and triacylglycerol accumulation. Pcyt2 +/- skeletal muscle exhibits perturbed glucose metabolism with elevated glycogen content, impaired insulin signaling, and reduced glucose uptake. Together, this study lends insight into the critical role of PE homeostasis in skeletal muscle metabolism and health with broad implications on metabolic disease development., Competing Interests: The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society.)

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In mammalian cells, mitochondrial respiration produces reactive oxygen species (ROS) such as superoxide (O 2 - ), which is then converted by the SOD1 enzyme into hydrogen peroxide (H 2 O 2 ), the predominant form of cytosolic ROS. ROS at high levels can be toxic, but below this threshold are important for physiological processes acting as a second messenger similar to Ca 2+ . Mitochondrial Ca 2+ influx from the ER increases ATP and ROS production, while ATP and ROS can regulate Ca 2+ homeostasis, leading to an intricate interplay between Ca 2+ , ROS, and ATP synthesis. The Unfolded Protein Response (UPR) proteins ATF6α and XBP1 contribute to protection from oxidative stress through upregulation of Sod1 and Catalase genes. Here, UPR-associated protein CREB3 is shown to play a role in balancing Ca 2+ , ROS, and ATP homeostasis. Creb3-deficient mouse embryonic fibroblast cells (MEF -/- ) were susceptible to H 2 O 2 -induced oxidative stress while having a functioning antioxidant gene expression response compared to MEF +/+ . MEF -/- cells also contained elevated basal cytosolic ROS levels, which was attributed to drastically increased basal mitochondrial respiration and spare respiratory capacity relative to MEF +/+ . MEF -/- cells also showed an increase in endoplasmic reticulum Ca 2+ release and mitochondrial Ca 2+ levels hinting at a potential cause for MEF -/- cell mitochondrial dysfunction. These results suggest that CREB3 is essential for maintaining proper Ca 2+ , ATP, and ROS homeostasis in mammalian cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

Choline participates in methyl group metabolism and has been recognized for its roles in lipid metabolism, hepatic health and muscle function in various species. Data regarding the impacts of choline on feline metabolic pathways are scarce. The present study investigated how choline intake affects the metabolomic profile of overweight cats fed at maintenance energy. Overweight (n = 14; body condition score:6-8/9) male adult cats were supplemented with five doses of choline in a 5x5 Latin Square design. Cats received a daily dose of choline on extruded food (3620 mg choline/kg diet) for three weeks at maintenance energy requirements (130 kcal/kgBW0.4). Doses were based on body weight (BW) and the daily recommended allowance (RA) for choline for adult cats (63 mg/kg BW0.67). Treatment groups included: Control (no additional choline, 1.2 x NRC RA, 77 mg/kg BW0.67), 2 x NRC RA (126 mg/kg BW0.67), 4 x NRC RA (252 mg/kg BW0.67), 6 x RA (378 mg/kg BW0.67), and 8 x NRC RA (504 mg/kg BW0.67). Serum was collected after an overnight fast at the end of each treatment period and analyzed for metabolomic parameters through nuclear magnetic resonance (NMR) spectroscopy and direct infusion mass spectrometry (DI-MS). Data were analyzed using GLIMMIX, with group and period as random effects, and dose as the fixed effect. Choline up to 8 x NRC RA was well-tolerated. Choline at 6 and 8 x NRC RA resulted in greater concentrations of amino acids and one-carbon metabolites (P < 0.05) betaine, dimethylglycine and methionine. Choline at 6 x NRC RA also resulted in greater phosphatidylcholine and sphingomyelin concentrations (P < 0.05). Supplemental dietary choline may be beneficial for maintaining hepatic health in overweight cats, as it may increase hepatic fat mobilization and methyl donor status. Choline may also improve lean muscle mass in cats. More research is needed to quantify how choline impacts body composition., Competing Interests: The authors declare no conflicts of interest. AR and HG declare that they have participated in paid internships and engagements with pet food companies within Canada. CG holds the Nestle Purina Professorship in Companion Animal Nutrition at the Ontario Veterinary College, is the owner of Grant Veterinary Nutrition Services and consults with Simmons Pet Food. AKS is the Champion Petfoods Chair in Canine and Feline Nutrition, Physiology and Metabolism, consults for Champion Petfood, was previously employed by P&G and Mars Pet Care, serves on the Scientific Advisory Board for Trouw Nutrition, and has received honoraria and research funding from various commodity groups, pet food manufacturers, and ingredient suppliers. AV is the Royal Canin Veterinary Diets Endowed Chair in Canine and Feline Clinical Nutrition and declares that they serve on the Health and Nutrition Advisory Board for Vetdiet. AV has also received honoraria and research funding from various pet food manufacturers and ingredient suppliers. At the time of the study, the Ontario Veterinary College received funding from Nestlé Purina Proplan Veterinary Diets to support a Registered Veterinary Technician in Clinical Nutrition, who helped perform the described animal trial. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Rankovic et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Phosphatidylethanolamine is the major inner-membrane lipid in the plasma and mitochondrial membranes. It is synthesized in the endoplasmic reticulum from ethanolamine and diacylglycerol (DAG) by the CDP-ethanolamine pathway and from phosphatidylserine by decarboxylation in the mitochondria. Recently, multiple genetic disorders that impact these pathways have been identified, including hereditary spastic paraplegia 81 and 82, Liberfarb syndrome, and a new type of childhood-onset neurodegeneration-CONATOC. Individuals with these diseases suffer from multisystem disorders mainly affecting neuronal function. This indicates the importance of maintaining proper phospholipid homeostasis when major biosynthetic pathways are impaired. This study summarizes the current knowledge of phosphatidylethanolamine metabolism in order to identify areas of future research that might lead to the development of treatment options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 St Germain, Iraji and Bakovic.)

Background: The endoplasmic reticulum senses alterations to cellular homeostasis that activates the unfolded protein response (UPR). UPR proteins are known to aid in regulating glucose and lipid metabolism. CREB3 is a UPR-associated transcription factor whose potential role in regulating energy metabolism remains unclear., Methods: Eight-week-old wild-type (WT) and Creb3 +/- mice were placed on control and high-fat diets (HFD) for 8 weeks, and metabolic phenotypes characterized by weekly weighing, indirect calorimetry, body composition scans, glucose tolerance tests, plasma analysis, tissue lipid quantifications and gene/protein expression analysis., Results: HFD weight gain in Creb3 +/- males was reduced by 34% (p < 0.0001) and females by 39.5% (p = 0.014) from their WT counterparts. No differences were found in HFD food intake or total fecal lipids between genotypes. Creb3 +/- mice had increased energy expenditure and respiratory exchange ratios (p = 0.002) relative to WT. Creb3 +/- mice had significant reductions in absolute fat and lean tissue, while Creb3 +/- females had significant reductions in body fat% and increased lean% composition (p < 0.0001) compared to WT females. Creb3 +/- mice were protected from HFD-induced basal hyperglycemia (males p < 0.0001; females p = 0.0181). Creb3 +/- males resisted HFD-induced hepatic lipid accumulation (p = 0.025) and glucose intolerance compared to WT (p < 0.0001) while Creb3 +/- females were protected from lipid accumulation in skeletal muscle (p = 0.001). Despite the metabolic differences of Creb3 +/- mice on HFD, lipid plasma profiles did not significantly differ from WT. Fasted Creb3 +/- mice additionally revealed upregulation of hepatic energy expenditure and gluconeogenic genes such as Pgc-1a and Gr (glucocorticoid receptor) (p < 0.05), respectively., Conclusions: Reduced expression of CREB3 increased energy expenditure and the respiratory exchange ratio, and protected mice from HFD-induced weight gain, basal hyperglycemia, and sex-specific tissue lipid accumulation. We postulate that CREB3 is a novel key regulator of diet-induced obesity and energy metabolism that warrants further investigation as a potential therapeutic target in metabolic disorders., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Choline is an essential nutrient linked to hepatic lipid metabolism in many animal species, including cats. The current study investigated the serum lipid profiles, serum liver enzymes, respiratory quotients, and energy expenditures of overweight cats fed maintenance diets, in response to graded doses of supplemental dietary choline. Overweight (body condition score [BCS]: ≥6/9) adult male neutered cats (n = 14) were supplemented with five choline chloride doses for 3-wk periods, in a 5 × 5 Latin square design. Doses were based on individual body weight (BW) and the daily recommended allowance (RA) for choline (63 mg/kg BW0.67) according to the National Research Council. Doses were control (no additional choline: 1.2 × RA, 77 mg/kg BW0.67), 2 × RA (126 mg/kg BW0.67), 4 × RA (252 mg/kg BW0.67), 6 × RA (378 mg/kg BW0.67), and 8 × RA (504 mg/kg BW0.67). Choline was top-dressed over the commercial extruded cat food (3,620 mg choline/kg diet), fed once a day at maintenance energy requirements (130 kcal/kgBW0.4). Body weight and BCS were assessed weekly. Fasted blood samples were taken and indirect calorimetry was performed at the end of each 3-wk period. Serum was analyzed for cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, non-esterified fatty acids, glucose, creatinine, blood urea nitrogen (BUN), alkaline phosphatase (ALP), and alanine aminotransferase. Very low-density lipoprotein cholesterol (VLDL) and low-density lipoprotein cholesterol were calculated. Data were analyzed via SAS using proc GLIMMIX, with group and period as the random effects, and treatment as the fixed effect. Statistical significance was considered at P < 0.05. Body weight and BCS did not change (P > 0.05). Serum cholesterol, HDL-C, triglycerides, and VLDL increased with 6 × RA (P < 0.05). Serum ALP decreased with 8 × RA (P = 0.004). Choline at 4 × and 6 × RA decreased serum BUN (P = 0.006). Fed or fasted respiratory quotient and energy expenditure did not differ among dietary choline doses (P > 0.05). These results suggest that dietary choline supplementation at 6 × RA may increase hepatic fat mobilization through increased lipoprotein transport and beneficially support hepatic health in overweight cats. Future studies that combine these results with existing knowledge of feline weight loss and hepatic lipidosis are warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this pathway are linked to a variety of human diseases, including cancer. Altered phosphatidylcholine and phosphatidylethanolamine membrane content, phospholipid metabolite levels, and fatty acid profiles are frequently identified as hallmarks of cancer development and progression. This review summarizes the research on how phospholipid metabolism changes over oncogenic transformation, and how phospholipid profiling can differentiate between human cancer and healthy tissues, with a focus on colorectal cancer, breast cancer, and non-small cell lung cancer. The potential for phospholipids to serve as biomarkers for diagnostics, or as anticancer therapy targets, is also discussed.

Gonadectomy is a major risk factor for feline obesity. The lipotropic effects of choline have demonstrated benefits for growth and carcass composition in livestock. The consumption of supplemental choline on body weight (BW), body composition, lipid metabolism, energy expenditure (EE), and serum satiety hormones were evaluated in 15 gonadectomized male kittens. Kittens were offered a base diet formulated for growth (3310mg choline/kg dry matter [DM]) to daily energy requirements (DER) over an 11-week acclimation. Post-gonadectomy, kittens were assigned to a base diet (CONTROL, n = 7) or choline group (base diet with additional choline at 300mg/kg BW0.75 as a top dress) (CHOLINE, n = 8). For 12-weeks post-neuter, kittens were offered three times their DER over three meals to mimic ad libitum feeding. At week -1 and 12, body composition was assessed using dual energy x-ray absorptiometry (DXA), 24-hour indirect calorimetry was performed for EE and respiratory quotients (RQ), and fasted serum samples were analyzed for lipid compounds and satiety hormones. Daily food intake (FI) and weekly BW were measured. Data was analyzed as a repeated measures of variance (ANCOVA) using the GLIMMIX procedure with time and group as fixed effects. CHOLINE had lower mean daily FI and lower rates of BW accretion (P<0.05) in contrast to CONTROL. All absolute body composition data increased over time for both groups, with lower increases in total tissue mass (P = 0.031) and fat mass (P = 0.005) in CHOLINE. Serum satiety hormones and lipid compounds did not differ (P>0.05) between groups, but both groups experienced a decrease in low-density lipoproteins and increase in high-density lipoproteins (P<0.05). Primary substrate utilization showed lipid use when fasted and use of protein or mixed macronutrients in the fed state. Fed state EE decreased post-gonadectomy (P = 0.004), however, CHOLINE did not affect total EE or RQ. These results suggest that supplemental dietary choline reduces FI, BW, and fat mass and may help to reduce the propensity of weight gain and subsequent obesity in gonadectomized feline populations., Competing Interests: The authors declare no conflicts of interest. AV is the Royal Canin Veterinary Diets Endowed Chair in Canine and Feline Clinical Nutrition and declares that they serve on the Health and Nutrition Advisory Board for Vetdiet. AV has received honoraria and research funding from various pet food manufacturers and ingredient suppliers. HG declares that they have paid engagements with pet food companies within Canada. AR declares that they have participated in paid internships and engagements with pet food companies within Canada. CG holds the Nestlé Purina Professorship in Companion Animal Nutrition at the Ontario Veterinary College, is the owner of Grant Veterinary Nutrition Services and consults with Simmons Pet Food. The Ontario Veterinary College received funding from Nestlé Purina Proplan Veterinary Diets to support a Registered Veterinary Technician in Clinical Nutrition, who assisted with this study. AKS was previously employed by P&G and Mars Pet Care, serves on the Scientific Advisory Board for Trouw Nutrition, and has received honoraria and research funding from various commodity groups, pet food manufacturers, and ingredient suppliers. SKA is the owner of Sit, Stay Speak Nutrition LLC and provides nutrition consultation to industry partners. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Uncontrolled hypertension disproportionately affects Black men. Patient engagement with health promotion and health behavior programs for hypertension control is low. We held evidence-based hypertension classes at a Federally Qualified Health Center., Aims: The aim of this project was to elicit patient preferences and expectations for community-based hypertension classes., Methods: Group hypertension classes were held at a Federally Qualified Health Center. The priority population was Black men with hypertension. Semi-structured interviews were conducted with the group class attendees. Two independent coders performed content analysis using field notes from the interviews., Results: Seven group class attendees were interviewed. Six interviewees were Black males, one was a Black female, and the mean age was 65.7 years. Content analysis of the interview field notes revealed five content areas: (1) Recommendation of Group Classes to a Friend, (2) Expectations for the Group Classes, (3) Reasons for Continued Attendance, (4) Lifestyle Changes and Adopting the Group Class Lessons, and (5) Feedback and Recommendations to Improve Group Classes. Findings suggest that creating a cultural context in which open, transparent discussion of blood pressure occur can be achieved. Thus, regarding acceptability, classes fulfilled and often exceeded the attendees' expectations and needs., Linking Evidence to Action: Our findings suggest that community-based group classes are a viable intervention to contribute toward addressing the disparity of hypertension control among Black men. When designing peer-group interventions, taking patient preferences and expectations into account increases the effectiveness of these interventions. The qualitative narrative provided in this paper contributes to the development of similar community-based group classes for the management of severe hypertension., (© 2022 Sigma Theta Tau International.)

Background: The high prevalence of uncontrolled hypertension (systolic blood pressure [SBP] ≥140 mmHg or diastolic blood pressure [DBP] ≥90 mmHg) in Black patients represents a significant racial health disparity in the United States., Aims: This study evaluated the efficacy of a telephone-based strategy for inviting high-risk patients with severe hypertension to weekly self-management education classes. Further, the study assessed how the outreach intervention correlated with relevant quality improvement outcomes, including improved blood pressure and primary care follow-up among our clinic population of Black men with severe hypertension., Methods: A cohort of 265 Black men aged ≥18 years with SBP ≥160 mmHg or DBP ≥100 mmHg at the most recent clinic visit were identified using Epic reports formatted for Federal Uniformed Data Set annual reporting. Telephone outreach was used to invite the cohort to attend weekly in-person classes facilitated by various healthcare professionals. Logistic regression was performed to determine the associations between being reached by phone with (1) class attendance and (2) follow-up appointment attendance., Results: Most of the Black men were single (57.4%, n = 152), 49.1% had history of alcohol or substance use (n = 130), and 35.8% (n = 95) was uninsured. The average age was 55.6 years (SD = 11.6). After controlling for sociodemographic factors, being reached by phone was significantly associated with an increased likelihood of patient attendance at follow-up appointments (OR = 1.91, p = .038) but not with class attendance (OR = 2.45, p = .155). Patients who attended a follow-up appointment experienced significant reductions in both SBP and DBP at 9 months., Linking Evidence to Action: Telephone outreach was labor-intensive but effective in keeping under-resourced patient populations engaged in primary care. Future work should aim to develop more efficient strategies for engaging high-risk patients in self-monitoring education to manage hypertension., (© 2022 Sigma Theta Tau International.)

The mechanisms of NASH development in the context of age and genetics are not fully elucidated. This study investigates the age-dependent liver defects during NASH development in mice with heterozygous deletion of Pcyt2 (Pcyt2 +/- ), the rate limiting enzyme in phosphatidylethanolamine (PE) synthesis. Further, the therapeutic potential of Pcyt2 substrate, phosphoethanolamine (PEtn), is examined. Pcyt2 +/- were investigated at 2 and 6-8 months (mo) of age and in addition, 6-mo old Pcyt2 +/- with developed NASH were supplemented with PEtn for 8 weeks and glucose and fatty acid metabolism, insulin signaling, and inflammation were examined. Heterozygous ablation of Pcyt2 causes changes in liver metabolic regulators from young age, prior to the development of liver disease which does not occur until adulthood. Only older Pcyt2 +/- experiences perturbed glucose and fatty acid metabolism. Older Pcyt2 +/- liver develops NASH characterized by increased glucose production, accumulation of TAG and glycogen, and increased inflammation. Supplementation with PEtn reverses Pcyt2 +/- steatosis, inflammation, and other aspects of NASH, showing that was directly caused by Pcyt2 deficiency. Pcyt2 deficiency is a novel mechanism of metabolic dysregulation due to reduced membrane ethanolamine phospholipid synthesis, and the metabolite PEtn offers therapeutic potential for NASH reversion., (© 2022. The Author(s).)

Grain-based ingredients are replaced in part by pulse ingredients in grain-free pet foods. Pulse ingredients are lower in methionine and cysteine, amino acid (AA) precursors to taurine synthesis in dogs. Although recent work has investigated plasma and whole blood taurine concentrations when feeding grain-free diets, supplementation of a grain-free diet with various nutrients involved in the biosynthesis of taurine has not been evaluated. This study aimed to investigate the effects of supplementing a complete grain-free dry dog food with either methionine (MET), taurine (TAU), or methyl donors (choline) and methyl receivers (creatine and carnitine; CCC) on postprandial AA concentrations. Eight healthy Beagle dogs were fed one of the three treatments or the control grain-free diet (CON) for 7 d in a 4 × 4 Latin square design. On day 7, cephalic catheters were placed and one fasted sample (0 min) and a series of nine post-meal blood samples were collected at 15, 30, 60, 90, 120, 180, 240, 300, and 360 min. Data were analyzed as repeated measures using the PROC GLIMMIX function in SAS (Version 9.4). Dogs fed MET had greater plasma and whole blood methionine concentrations from 30 to 360 min after a meal (P < 0.0001) and greater plasma homocysteine concentrations from 60 to 360 min after a meal (P < 0.0001) compared with dogs fed CON, TAU, and CCC. Dogs fed TAU had greater plasma taurine concentrations over time compared with dogs fed CON (P = 0.02) but were not different than dogs fed MET and CCC (P > 0.05). In addition, most AAs remained significantly elevated at 6 h post-meal compared with fasted samples across all treatments. Supplementation of creatine, carnitine, and choline in grain-free diets may play a role in sparing the methionine requirement without increasing homocysteine concentrations. Supplementing these nutrients could also aid in the treatment of disease that causes metabolic or oxidative stress, including cardiac disease in dogs, but future research is required., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)