Precision Nutrition and Cardiovascular Disease Risk Reduction: the Promise of High-Density Lipoproteins.

PURPOSE OF REVIEW: Emerging evidence supports the promise of precision nutritional approaches for cardiovascular disease (CVD) prevention. Here, we discuss current findings from precision nutrition trials and studies reporting substantial inter-individual variability in responses to diets and dietary components relevant to CVD outcomes. We highlight examples where early precision nutrition research already points to actionable intervention targets tailored to an individual's biology and lifestyle. Finally, we make the case for high-density lipoproteins (HDL) as a compelling next generation target for precision nutrition aimed at CVD prevention. HDL possesses complex structural features including diverse protein components, lipids, size distribution, extensive glycosylation, and interacts with the gut microbiome, all of which influence HDL's anti-inflammatory, antioxidant, and cholesterol efflux properties. Elucidating the nuances of HDL structure and function at an individual level may unlock personalized dietary and lifestyle strategies to optimize HDL-mediated atheroprotection and reduce CVD risk. RECENT FINDINGS: Recent human studies have demonstrated that HDL particles are key players in the reduction of CVD risk. Our review highlights the role of HDL and the importance of personalized therapeutic approaches to improve their potential for reducing CVD risk. Factors such as diet, genetics, glycosylation, and gut microbiome interactions can modulate HDL structure and function at the individual level. We emphasize that fractionating HDL into size-based subclasses and measuring particle concentration are necessary to understand HDL biology and for developing the next generation of diagnostics and biomarkers. These discoveries underscore the need to move beyond a one-size-fits-all approach to HDL management. Precision nutrition strategies that account for personalized metabolic, genetic, and lifestyle data hold promise for optimizing HDL therapies and function to mitigate CVD risk more potently. While human studies show HDL play a key role in reducing CVD risk, recent findings indicate that factors such as diet, genetics, glycosylation, and gut microbes modulate HDL function at the individual level, underscoring the need for precision nutrition strategies that account for personalized variability to optimize HDL's potential for mitigating CVD risk.

Predictors of fatal and nonfatal overdose after prescription of opioids for chronic pain: a systematic review and meta-analysis of observational studies.

BACKGROUND: Higher doses of opioids, mental health comorbidities, co-prescription of sedatives, lower socioeconomic status and a history of opioid overdose have been reported as risk factors for opioid overdose; however, the magnitude of these associations and their credibility are unclear. We sought to identify predictors of fatal and nonfatal overdose from prescription opioids. METHODS: We systematically searched MEDLINE, Embase, CINAHL, PsycINFO and Web of Science up to Oct. 30, 2022, for observational studies that explored predictors of opioid overdose after their prescription for chronic pain. We performed random-effects meta-analyses for all predictors reported by 2 or more studies using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Twenty-eight studies (23 963 716 patients) reported the association of 103 predictors with fatal or nonfatal opioid overdose. Moderate- to high-certainty evidence supported large relative associations with history of overdose (OR 5.85, 95% CI 3.78-9.04), higher opioid dose (OR 2.57, 95% CI 2.08-3.18 per 90-mg increment), 3 or more prescribers (OR 4.68, 95% CI 3.57-6.12), 4 or more dispensing pharmacies (OR 4.92, 95% CI 4.35-5.57), prescription of fentanyl (OR 2.80, 95% CI 2.30-3.41), current substance use disorder (OR 2.62, 95% CI 2.09-3.27), any mental health diagnosis (OR 2.12, 95% CI 1.73-2.61), depression (OR 2.22, 95% CI 1.57-3.14), bipolar disorder (OR 2.07, 95% CI 1.77-2.41) or pancreatitis (OR 2.00, 95% CI 1.52-2.64), with absolute risks among patients with the predictor ranging from 2-6 per 1000 for fatal overdose and 4-12 per 1000 for nonfatal overdose. INTERPRETATION: We identified 10 predictors that were strongly associated with opioid overdose. Awareness of these predictors may facilitate shared decision-making regarding prescribing opioids for chronic pain and inform harm-reduction strategies SYSTEMATIC REVIEW REGISTRATION: Open Science Framework (https://osf.io/vznxj/).

HDL Function across the Lifespan: From Childhood, to Pregnancy, to Old Age.

The function of high-density lipoprotein (HDL) particles has emerged as a promising therapeutic target and the measurement of HDL function is a promising diagnostic across several disease states. The vast majority of research on HDL functional biology has focused on adult participants with underlying chronic diseases, whereas limited research has investigated the role of HDL in childhood, pregnancy, and old age. Yet, it is apparent that functional HDL is essential at all life stages for maintaining health. In this review, we discuss current data regarding the role of HDL during childhood, pregnancy and in the elderly, how disturbances in HDL may lead to adverse health outcomes, and knowledge gaps in the role of HDL across these life stages.

Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line.

Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer's disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AßO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AßO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AßO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AßO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AßO + fructose + LPS having the strongest effect. Combination treatment with Chol + AßO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AßO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD.

A Ketogenic Diet in Combination with Gemcitabine Mitigates Pancreatic Cancer-Associated Cachexia in Male and Female KPC Mice.

Cancer-associated cachexia (CAC) is a critical contributor to pancreatic ductal adenocarcinoma (PDAC) mortality. Thus, there is an urgent need for new strategies to mitigate PDAC-associated cachexia; and the exploration of dietary interventions is a critical component. We previously observed that a ketogenic diet (KD) combined with gemcitabine enhances overall survival in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. In this study, we investigated the effect and cellular mechanisms of a KD in combination with gemcitabine on the maintenance of skeletal muscle mass in KPC mice. For this purpose, male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD), a KD, a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. We observed that a KD or a KG-mitigated muscle strength declined over time and presented higher gastrocnemius weights compared CD-fed mice. Mechanistically, we observed sex-dependent effects of KG treatment, including the inhibition of autophagy, and increased phosphorylation levels of eIF2α in KG-treated KPC mice when compared to CG-treated mice. Our data suggest that a KG results in preservation of skeletal muscle mass. Additional research is warranted to explore whether this diet-treatment combination can be clinically effective in combating CAC in PDAC patients.

Prevalence and intensity of persistent post-surgical pain following breast cancer surgery: a systematic review and meta-analysis of observational studies.

BACKGROUND: The prevalence and intensity of persistent post-surgical pain (PPSP) after breast cancer surgery are uncertain. We conducted a systematic review and meta-analysis to further elucidate this issue. METHODS: We searched MEDLINE, Embase, CINAHL, and PsycINFO, from inception to November 2018, for observational studies reporting persistent pain (≥3 months) after breast cancer surgery. We used random-effects meta-analysis and the Grading of Recommendations, Assessment, Development and Evaluations approach to rate quality of evidence. RESULTS: We included 187 observational studies with 297 612 breast cancer patients. The prevalence of PPSP ranged from 2% to 78%, median 37% (inter-quartile range: 22-48%); the pooled prevalence was 35% (95% confidence interval [CI]: 32-39%). The pooled pain intensity was 3.9 cm on a 10 cm visual analogue scale (95% CI: 3.6-4.2 cm). Moderate-quality evidence supported the subgroup effects of PPSP prevalence for localized pain vs any pain (29% vs 44%), moderate or greater vs any pain (26% vs 44%), clinician-assessed vs patient-reported pain (23% vs 36%), and whether patients underwent sentinel lymph node biopsy vs axillary lymph node dissection (26% vs 43%). The adjusted analysis found that the prevalence of patient-reported PPSP (any severity/location) was 46% (95% CI: 36-56%), and the prevalence of patient-reported moderate-to-severe PPSP at any location was 27% (95% CI: 10-43%). CONCLUSIONS: Moderate-quality evidence suggests that almost half of all women undergoing breast cancer surgery develop persistent post-surgical pain, and about one in four develop moderate-to-severe persistent post-surgical pain; the higher prevalence was associated with axillary lymph node dissection. Future studies should explore whether nerve sparing for axillary procedures reduces persistent post-surgical pain after breast cancer surgery.

Comparing Cephalic Index and Midsagittal Vector Analysis in Assessing Morphology in Sagittal Synostosis: A CT-Based Morphometric Analysis.

INTRODUCTION: Assessment of cranial dysmorphism in sagittal synostosis is often subjective but objective measures can be applied. These include cephalic index (CI) and midsagittal vector analysis (MSVA). OBJECTIVE: To assess discriminant validity, construct validity, and responsiveness of CI and MSVA measured from computed tomography (CT) in patients with sagittal synostosis. METHODS: Patients with nonsyndromic isolated sagittal synostosis with complete preoperative (n = 30) and postoperative (n = 13) CT data were included. Age-matched control group (n = 24) comprised of normocephalic patients who underwent CT for reasons related to trauma. OUTCOME MEASURES: Retrospective CT evaluation of CI and MSVA was conducted and correlated with a dysmorphism numeric rating scale (D-NRS) that measured surgeon-rated severity of sagittal synostosis. Responsiveness of CI and MSVA was evaluated using dysmorphism global rating of change (D-GRC). RESULTS: Thirty patients with sagittal synostosis were demographically similar to 24 normocephalic patients. The difference in CI and MSVA was statistically significant between normocephalic and scaphocephalic patients. Cephalic index had a good correlation with D-NRS (r = -0.665, ρ = -0.667), but not with MSVA (r = 0.250, ρ = 0.203). Change in CI (r = 0.738, ρ = 0.657) was well correlated with D-GRC, but not with MSVA (r = -0.409, ρ = -0.301). CONCLUSION: Cephalic index appears to quantify the severity of sagittal synostosis better than MSVA. Cephalic index also has better responsiveness than MSVA to measure a reduction in severity of disease; however, MSVA is a better descriptive craniometric measurement. Midsagittal vector analysis was able to quantify the shift in morphology in sagittal synostosis following surgical treatment.

Sex-Specific Differences in an ApoE(-/-):Ins2(+/Akita) Mouse Model of Accelerated Atherosclerosis.

Diabetic patients have a twofold to fourfold increased risk of cardiovascular disease. Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of cardiovascular disease are unclear. To further our understanding of how diabetes promotes atherosclerosis, we have established, characterized, and manipulated a new model of hyperglycemia-induced atherosclerosis: the apolipoprotein E-deficient (ApoE(-/-)):Ins2(+/Akita) mouse. All mice were fed a standard chow diet. Male ApoE(-/-):Ins2(+/Akita) mice developed chronic hyperglycemia, which significantly accelerated atherosclerosis. Female ApoE(-/-):Ins2(+/Akita) mice presented hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, advanced atherosclerosis was observed at 15 weeks of age compared with ApoE(-/-) females. To better understand these differences, subsets of mice were castrated or ovariectomized at 5 weeks of age. Castrated ApoE(-/-):Ins2(+/Akita) mice showed a reduction in blood glucose levels that correlated with the amelioration of atherosclerosis. Interestingly, castrated normoglycemic ApoE(-/-) mice developed larger atherosclerotic lesions than sham-operated on controls. Ovariectomized ApoE(-/-):Ins2(+/Akita) mice presented chronic hyperglycemia, and atherosclerosis appeared to be advanced. We have characterized the distinctive sex-specific phenotypes exhibited by the ApoE(-/-):Ins2(+/Akita) mouse model and present evidence for the action of sex hormones on pancreatic ß-cell function and the vasculature that affect the regulation of blood glucose levels and the development of atherosclerosis. This model will provide a test bed to further delineate these effects.

Peritenolysis and Debridement for Main Body (Mid-Portion) Achilles Tendinopathy in Athletic Patients: Results of 107 Procedures.

Achilles tendinopathy in the main body (mid-portion) of the tendon is a common pathologic finding among active and athletic populations and can be debilitating without proper and adequate treatment. Numerous surgical approaches for this common pathologic finding have been reported, with variable outcomes. We evaluated the surgical outcomes of peritenolysis and debridement of main body Achilles tendinopathy among athletic populations using the return to activity (RTA) and decreased desired activity (DDA) as our primary outcome measures. A total of 100 patients underwent 107 procedures by the senior author (A.S.) from January 2001 through December 2015 met the inclusion criteria, 65 (65%) of whom were runners. The mean follow-up duration was 106.6 ± 55.5 months from the index procedure, and the mean interval necessary to RTA for the entire group was 10.9 ± 5.3 weeks. The average RTA after debridement was 14.1 ± 5.2 weeks and after peritenolysis was 7.3 ± 2.0 weeks (p = .00001). Of the 100 patients, 3 (3%) had experienced a DDA at the last follow-up visit. With >97% of the patients able to return to their desired activities, we have concluded that peritenolysis and debridement are favorable surgical techniques for main body Achilles tendinopathy.

Treatment of Plantar Fasciitis With Radial Soundwave "Early" Is Better Than After 6 Months: A Pilot Study.

Extracorporeal shock wave therapy/radial soundwave therapy has been predominantly used for chronic or recalcitrant plantar fasciitis with strong scientific evidence of reliable outcomes. Most of the studies included patients with plantar fasciitis with symptoms >6 months in duration. Only 2 known studies have investigated acute plantar fasciitis, which is <6 weeks in duration. They both found suboptimal results for the use of extracorporeal shock wave therapy. To the best of our knowledge, no studies have investigated radial soundwave therapy for the subacute stage or early stage of plantar fasciitis. Data were prospectively collected from 28 eligible patients who underwent radial soundwave therapy (RSWT) during a 9-month period in 2014. Of the 28 subjects, 14 were enrolled in the "early group" with a symptom duration of <3 months and 14 in the "standard/control" group with a symptom duration of >6 months. The pretreatment and posttreatment visual analog scale scores, Roles-Maudlsey scores, and activity level were recorded and compared. The early implementation of RSWT yielded comparable outcomes when compared with the standard group. RSWT is a valid treatment modality that can be implemented soon after the initial treatment options or first-phase treatment options have failed. Early treatment is more likely to allow for maintenance of patients' activity level. Also, waiting 6 months to treat plantar fasciitis with RSWT results in delays and inferior results. Early treatment is better for active and athletic patients.

Latitudinal variation in the response of tidepool copepods to mean and daily range in temperature.

Understanding the evolutionary potential of organisms to adapt to a changing climate, and the fitness consequences of temperature fluctuations, are critical to forecasting the future of biodiversity. Geographic variation among populations in life history response to temperature mean and variability offers one view of the potential for local adaptation to broaden the thermal niche. We used laboratory growth experiments to examine the effects of temperatures between 13 degrees C and 30 degrees C on five life history traits and the intrinsic rate of increase for 15 Tigriopus californicus populations distributed over 17 degrees of latitude. Different life history stages showed distinct latitudinal shifts in thermal response, while the temperature of peak population growth consistently declined with increasing latitude. In addition, high-latitude populations grew faster at optimal temperatures but showed steeper fitness declines at high temperature. To test geographic population variation in response to the amplitude of daily thermal fluctuations, we grew three northern and three southern populations and manipulated nightly low and daily high temperatures. We found the lowest fitness overall in the treatment with the highest mean temperature, and the treatment with the greatest variability showed high fitness despite an 80C greater daily range. Population responses to daily thermal variability were unrelated to latitude of origin. Our results indicate that trade-offs between adaptation to high vs. low temperature, and between growth and maturation vs. survival and fecundity, govern local adaptation along the latitudinal gradient. They also indicate that, T. californicus populations can maintain fitness over a wide range of daily variability but are more sensitive to small changes in the mean temperature.

Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype.

Introduction: The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. Methods: In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. Results: LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). Discussion: These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.

Lutein and Zeaxanthin Enhance, Whereas Oxidation, Fructosylation, and Low pH Damage High-Density Lipoprotein Biological Functionality.

High-density lipoproteins (HDLs) are key regulators of cellular cholesterol homeostasis but are functionally altered in many chronic diseases. The factors that cause HDL functional loss in chronic disease are not fully understood. It is also unknown what roles antioxidant carotenoids play in protecting HDL against functional loss. The aim of this study was to measure how various disease-associated chemical factors including exposure to (1) Cu2+ ions, (2) hypochlorous acid (HOCL), (3) hydrogen peroxide (H2O2), (4) sialidase, (5) glycosidase, (6) high glucose, (7) high fructose, and (8) acidic pH, and the carotenoid antioxidants (9) lutein and (10) zeaxanthin affect HDL functionality. We hypothesized that some of the modifications would have stronger impacts on HDL particle structure and function than others and that lutein and zeaxanthin would improve HDL function. HDL samples were isolated from generally healthy human plasma and incubated with the corresponding treatments listed above. Cholesterol efflux capacity (CEC), lecithin-cholesterol acyl transferase (LCAT) activity, and paraoxonase-1 (PON1) activity were measured in order to determine changes in HDL functionality. Median HDL particle diameter was increased by acidic pH treatment and reduced by HOCl, high glucose, high fructose, N-glycosidase, and lutein treatments. Acidic pH, oxidation, and fructosylation all reduced HDL CEC, whereas lutein, zeaxanthin, and sialidase treatment improved HDL CEC. LCAT activity was reduced by acidic pH, oxidation, high fructose treatments, and lutein. PON1 activity was reduced by sialidase, glycosidase, H2O2, and fructose and improved by zeaxanthin and lutein treatment. These results show that exposure to oxidizing agents, high fructose, and low pH directly impairs HDL functionality related to cholesterol efflux and particle maturation, whereas deglycosylation impairs HDL antioxidant capacity. On the other hand, the antioxidants lutein and zeaxanthin improve or preserve both HDL cholesterol efflux and antioxidant activity but have no effect on particle maturation.

Academic Achievement in School-Aged Children with Single Suture Craniosynostosis Over Time.

Introduction: Children with single suture craniosynostosis (SSC) are at risk for neurocognitive problems. The reported magnitude of differences between children with SSC and their normative peers on standardized tests of academic and intellectual ability are small. Evaluation of real-world academic outcomes of these children and its impact on educational resources have not been conducted. Methods: A retrospective cohort study of academic outcomes of children with SSC was conducted using the data from Ontario's Education Quality and Accountability Office (EQAO) standardized provincial reading, writing and mathematics tests. The need for special education was identified by documentation of the child's need for an Identification, Placement, and Review Committee (IPRC). Results: Of 296 eligible children, 42 participated in the study. Half of the children had sagittal synostosis, while the remaining were 10 (24%) unicoronal, 9 (21%) metopic, and 2 (5%) lambdoid synostosis. Thirty-six (86%) underwent operative management. The EQAO scores of operated children with SSC met the provincial academic standards on the Grade 3 and 6 EQAO scores across the 3 academic subjects. Converted grade-matched EQAO scores decreased in reading and writing over time, while math improved. Of the 21 patients with special education data, one child required an IPRC in Grade 3, while an additional four (24%) required an IPRC in Grade 6. Conclusions: Operated children with SSC had average academic performance, however, their needs appeared to change over time. Future studies are needed to evaluate academic difficulties and special education needs as these children progress through grade school.

Introduction: Les enfants ayant une craniosynostose simple (CSS) sont à risque de troubles neurocognitifs. Selon les tests standardisés des capacités scolaires et intellectuelles, les enfants ayant une CSS présentent des différences légères par rapport à leurs homologues en bonne santé. Les résultats scolaires concrets de ces enfants n'ont pas été évalués, ni leurs répercussions sur les ressources pédagogiques. Méthodologie: Les chercheurs ont effectué une étude de cohorte rétrospective des résultats des enfants ayant une CSS aux examens de lecture, d'écriture et de mathématique au moyen des données provinciales standardisées de l'Office de la qualité et de la responsabilité en éducation de l'Ontario (OQRÉO). Les besoins en éducation spécialisée étaient indiqués par un avis du comité d'identification, de placement et de révision (CIPR) au dossier de l'enfant. Résultats: Des 296 enfants admissibles, 42 ont participé à l'étude. La moitié des enfants présentaient une synostose sagittale (scaphocéphalie), tandis que dix (24 %) avaient une synostose unicoronale, neuf (21 %), une synostose métopique (trigonocéphalie), et deux (5 %), une synostose lambdoïde. Au total, 36 (86 %) ont été opérés. Les scores de l'OQRÉO des enfants opérés à cause d'une CSS respectaient les normes scolaires provinciales pour la 3e et la 6e années dans les trois matières scolaires. Les scores de l'OQRÉO convertis en fonction du degré ont diminué en lecture et en écriture au fil du temps, mais se sont améliorés en mathématiques. Des 21 patients sur qui les chercheurs possédaient des données en éducation spécialisée, un enfant a eu besoin d'un avis du CIPR en 3e année, et quatre (24 %), en 6e année. Conclusions: Les enfants opérés à cause d'une CSS avaient une performance scolaire moyenne, mais leurs besoins semblaient évoluer au fil du temps. D'autres études devront être réalisées pour évaluer les problèmes scolaires et les besoins d'éducation spécialisée des enfants au primaire.

A single 36-h water-only fast vastly remodels the plasma lipidome.

Background: Prolonged fasting, characterized by restricting caloric intake for 24 h or more, has garnered attention as a nutritional approach to improve lifespan and support healthy aging. Previous research from our group showed that a single bout of 36-h water-only fasting in humans resulted in a distinct metabolomic signature in plasma and increased levels of bioactive metabolites, which improved macrophage function and lifespan in C. elegans. Objective: This secondary outcome analysis aimed to investigate changes in the plasma lipidome associated with prolonged fasting and explore any potential links with markers of cardiometabolic health and aging. Method: We conducted a controlled pilot study with 20 male and female participants (mean age, 27.5 ± 4.4 years; mean BMI, 24.3 ± 3.1 kg/m2) in four metabolic states: (1) overnight fasted (baseline), (2) 2-h postprandial fed state (fed), (3) 36-h fasted state (fasted), and (4) 2-h postprandial refed state 12 h after the 36-h fast (refed). Plasma lipidomic profiles were analyzed using liquid chromatography and electrospray ionization mass spectrometry. Results: Several lipid classes, including lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylethanolamine, and triacylglycerol were significantly reduced in the 36-h fasted state, while free fatty acids, ceramides, and sphingomyelin were significantly increased compared to overnight fast and fed states (P < 0.05). After correction for multiple testing, 245 out of 832 lipid species were significantly altered in the fasted state compared to baseline (P < 0.05). Random forest models revealed that several lipid species, such as LPE(18:1), LPC(18:2), and FFA(20:1) were important features in discriminating the fasted state from both the overnight fasted and postprandial state. Conclusion: Our findings indicate that prolonged fasting vastly remodels the plasma lipidome and markedly alters the concentrations of several lipid species, which may be sensitive biomarkers of prolonged fasting. These changes in lipid metabolism during prolonged fasting have important implications for the management of cardiometabolic health and healthy aging, and warrant further exploration and validation in larger cohorts and different population groups.

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana.

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. Objective: The goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. Methods: HDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. Results: There were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. Conclusions: Mothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry number: The study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866.

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. This study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

Routine chest X-ray prior to thyroid surgery: is it always necessary?

BACKGROUND: Despite lack of evidence-based support, chest X-ray (CXR) prior to thyroid surgery is often used to identify tracheal deviation that may predict difficulty with intubation. The aim of this study is to establish the utility of preoperative CXR to assess tracheal deviation in this group of patients. METHODS: We analyzed a prospective database of 1,000 consecutive patients who underwent thyroid surgery. Patients' charts were reviewed for demographic data, CXR readings, other imaging findings, anesthesia records, and pathology findings. Patients with tracheal deviation (TD) on CXR were compared to patients without (no TD). RESULTS: Six hundred eighty-nine (69 %) patients had a CXR performed prior to surgery. TD was identified in 252 (37 %) patients while 437 (63 %) did not have TD. The two groups did not significantly differ in mean age, BMI, or gender. Patients with TD on CXR had larger thyroid glands (51 ± 4 vs. 28 ± 2 g, p < 0.001) and reported a higher rate of tracheal compressive symptoms (19 vs. 12 %, p = 0.005). However, this did not translate into more difficult intubations as reported by the anesthesiologist (5 vs. 7 %, p = 0.31) or more intubation attempts (1.2 ± 0 vs. 1.1 ± 0, p = 0.1). Lung findings on CXR that resulted in further workup were identified in 32 (5 %) patients, with additional pathology found in only 6 (1 %) patients. CONCLUSION: There is no correlation between a finding of tracheal deviation on preoperative CXR and difficult intubation in thyroid patients. Therefore, CXR for the sole purpose of identifying tracheal deviation in thyroid surgery candidates is not warranted.

A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.

Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood ß-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.

Correction: A Ketogenic Diet in Combination with Gemcitabine Increases Survival in Pancreatic Cancer KPC Mice.

[This corrects the article DOI: 10.1158/2767-9764.CRC-22-0256.][This corrects the article DOI: 10.1158/2767-9764.CRC-22-0256.].