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[beta]-Carotene biochemistry is a fundamental process in mammalian biology. Aberrations either through malnutrition or potentially through genetic variation may lead to vitamin A deficiency, which is a substantial public health burden. In addition, understanding the genetic regulation of this process may enable bovine improvement. While many bovine QTL have been reported, few of the causative genes and mutations have been identified. We discovered a QTL for milk [beta]-carotene and subsequently identified a premature stop codon in bovine [beta]-carotene oxygenase 2 (BCO2), which also affects serum [beta]-carotene content. The BCO2 enzyme is thereby identified as a key regulator of [beta]-carotene metabolism. DOI: 10.1534/genetics.109.101741

Pain and psychopathology are observed in 18% and 55% of patients, respectively, 1 year after intensive care unit (ICU) admission. It is well known that chronic pain and psychopathology have a bidirectional relation in the general population, but it is not known whether this holds true for ICU survivors. The aim of this study was to investigate whether pain before, during and after ICU admission is related to psychopathology in ICU survivors 1 year after discharge. We performed a cohort study in a mixed ICU in the Netherlands between 2013 and 2016. At 1-year follow-up, patients completed the Hospital Anxiety and Depression Scale, the Impact of Event Scale/Impact of Event Scale-Revised, and answered standardised questions regarding pain. Psychopathology was defined as having anxiety, depressive and/or post-traumatic stress disorder symptoms. We used multivariable logistic regression analysis to evaluate the association of pain before, during and after ICU admission with psychopathology at 1 year follow-up. We included 1105 patients of whom 558 (50%) (95% confidence interval (CI) 0.48 to 0.54) had psychopathology at 1 year follow-up. Pain before ICU admission (odds ratio (OR) 1.18; 95% CI 1.10 to 1.26) and pain after ICU admission (OR 2.38; 95% CI 1.68 to 3.35) were associated with psychopathology. Pain during ICU stay was not associated with psychopathology, but the memory of insufficient pain management during ICU stay was (OR 2.19; 95% CI 1.39 to 3.45). Paying attention to pain and pain treatment experiences related to ICU admission may therefore contribute to early identification of ICU survivors at risk of psychopathology development.

FebriDx is a rapid point-of-care test combining qualitative measurements of C-reactive protein (CRP) and Myxovirus Resistance Protein A (MxA) using a disposable test device to detect and differentiate acute bacterial from viral respiratory tract infections. The goal of this study was to investigate the diagnostic accuracy of FebriDx in patients with suspected respiratory tract infections in the emergency department (ED). This was an observational cohort study, performed in the ED of an academic hospital. Patients were included if they had a suspected infection. The primary outcome was the presence of a bacterial or viral infection, determined by clinical adjudication by an expert panel. The sensitivity, specificity, and positive and negative predictive value of FebriDx for the presence of bacterial versus non-bacterial infections, and viral versus non-viral infections were calculated. Between March 2019 and November 2020, 244 patients were included. A bacterial infection was present in 41%, viral infection was present in 24%, and 4% of the patients had both viral and bacterial pathogens. FebriDx demonstrated high sensitivity in the detection of bacterial infection (87%), high NPV (91%) to rule out bacterial infection, and high specificity (94%) for viral infection in patients with a suspected infection in the ED.

Background and Importance: Early identification of patients at risk of clinical deterioration may improve prognosis of infected patients in the emergency department (ED). Combining clinical scoring systems with biomarkers may result in a more accurate prediction of mortality than a clinical scoring system or biomarker alone., Objective: The objective of this study is to investigate the performance of the combination of National Early Warning Score-2 (NEWS2) and quick Sequential Organ Failure Assessment (qSOFA) score with soluble urokinase plasminogen activator receptor (suPAR) and procalcitonin to predict 30-day mortality in patients with a suspected infection in the ED., Design, Settings and Participants: This was a single-center prospective observational study, conducted in the Netherlands. Patients with suspected infection in the ED were included in this study and followed-up for 30 days. The primary outcome of this study was all cause 30-day mortality. The association between suPAR and procalcitonin with mortality was assessed in subgroups of patients with low and high qSOFA (<1 and ≥1) and low and high NEWS2 (<7 and ≥7)., Main Results: Between March 2019 and December 2020, 958 patients were included. A total of 43 (4.5%) patients died within 30 days after ED visit. A suPAR ≥ 6 ng/ml was associated with an increased mortality risk: 5.5 vs. 0.9% ( P  < 0.01) in patients with qSOFA = 0 and 10.7 vs. 2.1% ( P  = 0.02) in patients with qSOFA ≥ 1. There was also an association between procalcitonin ≥0.25 ng/ml and mortality: 5.5 vs. 1.9% ( P  = 0.02) for qSOFA = 0 and 11.9 vs. 4.1% ( P  = 0.03) for qSOFA ≥ 1. Similar associations were found within patients with a NEWS < 7 (5.9 vs. 1.2% for suPAR and 7.0 vs. 1.7% for procalcitonin, P  < 0.001)., Conclusion: In this prospective cohort study, suPAR and procalcitonin were associated with increased mortality in patients with either a low or high qSOFA and patients with low NEWS2., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: We developed and tested a Bayesian network(BN) model to predict ECT remission for depression, with non-response as a secondary outcome., Methods: We performed a systematic literature search on clinically available predictors. We combined these predictors with variables from a dataset of clinical ECT trajectories (performed in the University Medical Center Utrecht) to create priors and train the BN. Temporal validation was performed in an independent sample., Results: The systematic literature search yielded three meta-analyses, which provided prior knowledge on outcome predictors. The clinical dataset consisted of 248 treatment trajectories in the training set and 44 trajectories in the test set at the same medical center. The AUC for the primary outcome remission estimated on an independent validation set was 0.686 (95%CI 0.513-0.859) (AUC values of 0.505 - 0.763 observed in 5-fold cross validation of the model within the train set). Accuracy 0.73 (balanced accuracy 0.67), sensitivity 0.55, specificity 0.79, after temporal validation in the independent sample. Prior literature information marginally reduced CI width., Discussion: A BN model comprised of prior knowledge and clinical data can predict remission of depression after ECT with reasonable performance. This approach can be used to make outcome predictions in psychiatry, and offers a methodological framework to weigh additional information, such as patient characteristics, symptoms and biomarkers. In time, it may be used to improve shared decision-making in clinical practice., Competing Interests: Declaration of Competing Interest Yuri van der Does, Rosanne J. Turner, Miel J.H. Bartels, Karin Hagoort, Aäron Metselaar, Floortje Scheepers, Peter D. Grünwald, Metten Somers, Edwin van Dellen None of the authors declare any conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Predicting disease severity is important for treatment decisions in patients with COVID-19 in the intensive care unit (ICU). Different biomarkers have been investigated in COVID-19 as predictor of mortality, including C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), and soluble urokinase-type plasminogen activator receptor (suPAR). Using repeated measurements in a prediction model may result in a more accurate risk prediction than the use of single point measurements. The goal of this study is to investigate the predictive value of trends in repeated measurements of CRP, PCT, IL-6, and suPAR on mortality in patients admitted to the ICU with COVID-19., Methods: This was a retrospective single center cohort study. Patients were included if they tested positive for SARS-CoV-2 by PCR test and if IL-6, PCT, suPAR was measured during any of the ICU admission days. There were no exclusion criteria for this study. We used joint models to predict ICU-mortality. This analysis was done using the framework of joint models for longitudinal and survival data. The reported hazard ratios express the relative change in the risk of death resulting from a doubling or 20% increase of the biomarker's value in a day compared to no change in the same period., Results: A total of 107 patients were included, of which 26 died during ICU admission. Adjusted for sex and age, a doubling in the next day in either levels of PCT, IL-6, and suPAR were significantly predictive of in-hospital mortality with HRs of 1.523 (1.012-6.540), 75.25 (1.116-6247), and 24.45 (1.696-1057) respectively. With a 20% increase in biomarker value in a subsequent day, the HR of PCT, IL-6, and suPAR were 1.117 (1.03-1.639), 3.116 (1.029-9.963), and 2.319 (1.149-6.243) respectively., Conclusion: Joint models for the analysis of repeated measurements of PCT, suPAR, and IL-6 are a useful method for predicting mortality in COVID-19 patients in the ICU. Patients with an increasing trend of biomarker levels in consecutive days are at increased risk for mortality., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Introduction: Myxovirus resistance protein 1 (MxA) is a biomarker that is elevated in patients with viral infections. The goal of this study was to evaluate the diagnostic value of MxA in diagnosing COVID-19 infections in the emergency department (ED) patients., Methods: This was a single-center prospective observational cohort study including patients with a suspected COVID-19 infection. The primary outcome of this study was a confirmed COVID-19 infection by RT-PCR test. MxA was assessed using an enzyme immunoassay on whole blood and receiver operating chart and area under the curve (AUC) analysis was conducted. Sensitivity, specificity, negative predictive value, and positive predictive value of MxA on diagnosing COVID-19 at the optimal cut-off of MxA was determined., Results: In 2021, 100 patients were included. Of these patients, 77 patients had COVID-19 infection and 23 were non-COVID-19. Median MxA level was significantly higher (p < .001) in COVID-19 patients compared to non-COVID-19 patients, respectively 1933 and 0.1 ng/ml. The AUC of MxA on a confirmed COVID-19 infection was 0.941 (95% CI: 0.867-1.000). The optimal cut-off point of MxA was 252 ng/ml. At this cut-off point, the sensitivity of MxA on a confirmed COVID-19 infection was 94% (95% CI: 85%-98%) and the specificity was 91% (95% CI: 72%-99%)., Conclusion: MxA accurately distinguishes COVID-19 infections from bacterial infections and noninfectious diagnoses in the ED in patients with a suspected COVID-19 infection. If the results can be validated, MxA could improve the diagnostic workup and patient flow in the ED., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Patients with a severe COVID-19 infection often require admission at an intensive care unit (ICU) when they develop acute respiratory distress syndrome (ARDS). Hyperinflammation plays an important role in the development of ARDS in COVID-19. Procalcitonin (PCT) is a biomarker which may be a predictor of hyperinflammation. When patients with COVID-19 are in the emergency department (ED), elevated PCT levels could be associated with severe COVID-19 infections. The goal of this study is to investigate the association between PCT levels and severe COVID-19 infections in the ED., Methods: This was a retrospective cohort study including patients with a confirmed COVID-19 infection who visited the ED of Erasmus Medical Center in Rotterdam, the Netherlands, between March and December 2020. The primary outcome was a severe COVID-19 infection, which was defined as patients who required ICU admission, all cause in-hospital mortality and mortality within 30 days after hospital discharge. PCT levels were measured during the ED visit. We used logistic regression to calculate the odds ratio (OR) with 95% confidence interval (95% CI) and corresponding area under the curve (AUC) of PCT on a severe COVID-19 infection, adjusting for bacterial coinfections, age, sex, comorbidities, C-reactive protein (CRP) and D-dimer., Results: A total of 332 patients were included in the final analysis of this study, of which 105 patients reached the composite outcome of a severe COVID-19 infection. PCT showed an unadjusted OR of 4.19 (95%CI: 2.52-7.69) on a severe COVID-19 infection with an AUC of 0.82 (95% CI: 0.76-0.87). Corrected for bacterial coinfection, the OR of PCT was 4.05 (95% CI: 2.45-7.41). Adjusted for sex, bacterial coinfection, age any comorbidity, CRP and D-dimer, elevated PCT levels were still significantly associated with a severe COVID-19 infection with an adjusted OR of 2.11 (95% CI: 1.36-3.61). The AUC of this multivariable model was 0.85 (95%CI: 0.81-0.90)., Conclusion: High PCT levels are associated with high rates of severe COVID-19 infections in patients with a COVID-19 infection in the ED. The routine measurement of PCT in patients with a COVID-19 infection in the ED may assist physicians in the clinical decision making process regarding ICU disposition., (© 2022. The Author(s).)

Background: Sepsis can be detected in an early stage in the emergency department (ED) by biomarkers and clinical scoring systems. A combination of multiple biomarkers or biomarker with clinical scoring system might result in a higher predictive value on mortality. The goal of this systematic review is to evaluate the available literature on combinations of biomarkers and clinical scoring systems on 1-month mortality in patients with sepsis in the ED., Methods: We performed a systematic search using MEDLINE, EMBASE and Google Scholar. Articles were included if they evaluated at least one biomarker combined with another biomarker or clinical scoring system and reported the prognostic accuracy on 28 or 30 day mortality by area under the curve (AUC) in patients with sepsis. We did not define biomarker cut-off values in advance., Results: We included 18 articles in which a total of 35 combinations of biomarkers and clinical scoring systems were studied, of which 33 unique combinations. In total, seven different clinical scoring systems and 21 different biomarkers were investigated. The combination of procalcitonin (PCT), lactate, interleukin-6 (IL-6) and Simplified Acute Physiology Score-2 (SAPS-2) resulted in the highest AUC on 1-month mortality., Conclusion: The studies we found in this systematic review were too heterogeneous to conclude that a certain combination it should be used in the ED to predict 1-month mortality in patients with sepsis. Future studies should focus on clinical scoring systems which require a limited amount of clinical parameters, such as the qSOFA score in combination with a biomarker that is already routinely available in the ED.

In the publication of this article [1], there are two errors in contributing author affiliations. This has now been included in this correction article.

Background: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need., Methods: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days., Results: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities., Conclusions: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Gangliosides (GA) are found in animal tissues and fluids, such as blood and milk. These sialo-glycosphingolipids have bioactivities in neural development, the gastrointestinal tract, and the immune system. In this study, a high-performance liquid chromatography-mass spectrometry (HPLC-MS) method was validated to characterize and quantitate the GA in beef, chicken, pork, and fish species (turbot, snapper, king salmon, and island mackerel). For the first time, we report the concentration of GM3, the dominant GA in these foods, as ranging from 0.35 to 1.1 mg/100 g and 0.70 to 5.86 mg/100 g of meat and fish, respectively. The minor GAs measured were GD3, GD1a, GD1b, and GT1b. Molecular species distribution revealed that the GA contained long- to very-long-chain acyl fatty acids attached to the ceramide moiety. Fish GA contained only N-acetylneuraminic acid (NeuAc) sialic acid, while beef, chicken, and pork contained GD1a/b species that incorporated both NeuAc and N-glycolylneuraminic acid (NeuGc) and hydroxylated fatty acids.

Background: Procalcitonin (PCT) is a new biomarker with a higher accuracy in the diagnosis of bacterial infections. Utilization of PCT may reduce the number of unnecessary antibiotics prescribed to patients and consequently may decrease the rise in antibiotic resistance. The aim of this systematic review is to determine if a PCT-guided algorithm can safely reduce the number of antibiotics prescribed to all patients with a suspected of infection in the emergency department (ED)., Methods: MEDLINE, EMBASE, Web of Science, COCHRANE central, PubMed publisher, and Google scholar were searched. Two reviewers performed the screening independently. The QUADAS 2 tool was used to assess quality., Results: In total, 1621 articles were screened. Nine articles were included in the analysis. In the 6 studies on adult patients, only patients with respiratory tract infections were investigated. In these studies, a cutoff value of 0.25 μg/L was used, and PCT-guided therapy reduced the number of prescribed antibiotics significantly. Three studies were on pediatric patients, 2 on fever without source and 1 on respiratory complaints. Procalcitonin-guided therapy did not reduce antibiotic prescription in children. Procalcitonin-guided therapy did not result in an increase in adverse events in any of the studies., Discussion: Procalcitonin-guided therapy in the ED is only studied in subpopulations, where it was effective and safe in adult patients with respiratory tract infections and not effective but safe nonetheless in specific pediatric populations. Nonadherence is a significant problem in prospective PCT-guided therapy studies. There is not enough evidence to use PCT-guided therapy in a general ED population., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Fever is a common symptom in the emergency department(ED). Fever can be caused by bacterial infections, which are treated with antibiotics. Often, bacterial infections cannot be ruled out in the ED using standard diagnostics, and empiric antibiotic treatment is started. Procalcitonin(PCT) is a biomarker for bacterial infections, but its role in an undifferentiated ED population remains unclear. We hypothesize that PCT-guided therapy may reduce antibiotics prescription in undifferentiated febrile ED patients. The primary objectives of this study are to determine a) the efficacy, b) the safety of PCT-guided therapy, and c) the accuracy of the biomarker PCT for bacterial infections. The secondary objective is to study the cost-effectiveness of PCT-guided therapy., Methods/design: This is a multicenter noninferiority randomized controlled trial. All adult ED patients with fever(≥38.2 °C) are randomized between standard care with and without the addition of a PCT level, after written informed consent. a) For efficacy, the reduction of patients receiving antibiotics is calculated, using a superiority analysis: differences between the PCT-guided group and control group are assessed using a Fisher's exact test, and a multivariable logistic regression analysis to account for the effects of demographic and medical variables on the percentage of febrile patients receiving antibiotics. b) Safety consists of a composite endpoint, defined as mortality, intensive care admission and ED return visit within 14 days. Noninferiority of PCT will be tested using a one-sided 95 % confidence interval for the difference in the composite safety endpoint between the PCT-guided and control groups using a noninferiority margin of 7.5 %. c) Accuracy of PCT and CRP for the diagnosis of bacterial infections will be reported, using the sensitivity, specificity, and the area under the receiver-operating-characteristic curve in the definitive diagnosis of bacterial infections. The sample size is 550 patients, which was calculated using a power analysis for all primary objectives. Enrollment of patients started in August 2014 and will last 2 years., Discussion: PCT may offer a more tailor-made treatment to the individual ED patient with fever. Prospective costs analyses will reveal the economic consequences of implementing PCT-guided therapy in the ED., This Trial Is Registered in the Dutch Trial Register: NTR4949.

Selective breeding has strongly reduced the genetic diversity in livestock species, and contemporary breeding practices exclude potentially beneficial rare genetic variation from the future gene pool. Here we test whether important traits arising by new mutations can be identified and rescued in highly selected populations. We screened milks from 2.5 million cows to identify an exceptional individual which produced milk with reduced saturated fat content, and improved unsaturated and omega-3 fatty acid concentrations. The milk traits were transmitted dominantly to her offspring, and genetic mapping and genome sequencing revealed a new mutation in a previously unknown splice enhancer of the DGAT1 gene. Homozygous carriers show features of human diarrheal disorders, and may be useful for the development of therapeutic strategies. Our study demonstrates that high-throughput phenotypic screening can uncover rich genetic diversity even in inbred populations, and introduces a novel strategy to develop novel milks with improved nutritional properties.

Objectives: Ethical guidelines for human subject research require that the burdens and benefits of participation be equally distributed. This study aimed to provide empirical data on exclusion of trial participants and reasons for this exclusion. As a secondary objective, we assessed to what extent exclusion affects generalizability of study results., Study Design and Setting: Review of trials on secondary prevention of cardiovascular events., Results: One hundred thirteen trials were identified, of which 112 reported exclusion criteria. One study justified the exclusion criteria applied. Ambiguous exclusion criteria due to the opinion of the physician (28 of 112 = 25%) or physical disability (12 of 112 = 11%) were reported. Within groups of trials that studied similar treatments (ie, beta-blocker, clopidogrel, or statin therapy), baseline characteristics differed among trials. For example, the proportion of women ranged between 23.1-47.4%, 2.1-38.9%, and 10.6-50.6% for the clopidogrel, beta-blocker, and statin trials, respectively. Nevertheless, no evidence was found for heterogeneity of treatment effects., Conclusion: Almost none of the articles justified the applied exclusion criteria. No evidence was found that inclusion of dissimilar participants affected generalizability. To allow for a normative discussion on equitable selection of study populations, researchers should not only report exclusion criteria but also the reasons for using these criteria., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Emergency department (ED) patients are triaged to determine the urgency of care. The Finapres Portapres (FP) measures blood pressure (BP) and cardiac output (CO) non-invasively, and may be of added value in early detection of patients at risk for hemodynamic compromise., Objectives: Compare non-invasive BP measurements using FP and standard automated sphygmomanometry. Compare FP cardiac index (CI), CO corrected for body surface area, of normotensive patients, to chart-based physician estimate of shock, to discover if there is additional value in CI measurements in triage., Methods: ED Patients requiring BP measurement in triage were included. Systolic (SBP) and diastolic (DBP) BP were measured using both devices during a two minutes measurement. Two physicians independently judged probability of shock, defined as estimated CI ≤2.5 L min(-1) m(-2), based on chart review, three weeks after ED visit., Results: Of a total of 112 patients 97 patients were included. Pearson's correlation coefficient was 0.50 for SBP, 0.53 for DBP, with a Blant-Altman mean bias of 11.3 (upper limit 65.3, lower limit -42.8) and 7.7 (39.2, -23.7) for SBP and DBP respectively. In normotensive patients, the group with low FP CI measurements had significantly more cases with physician-estimated shock, compared to the normal to high measurements (P = .036)., Conclusions: When used as a triage device in the emergency department setting, non-invasive BP measurements using FP do not correlate well with automated sphygmomanometry. However, this study does indicate that use of the FP device in triage may aid physicians to recognize patients in early phases of shock., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the association between treatment adherence with antipsychotics and schizophrenia relapse on a continuous scale., Method: A cohort study with a total of 477 patients with schizophrenia who were recently discharged from an inpatient clinic was performed., Results: In the 160 people who relapsed within the six months after discharge the average medication possession ratio was 0.50. This was 0.59 in the 317 persons who were not readmitted. The resulting hazard ratio for the medication possession ratio on relapse risk was 0.60 (95% confidence interval: 0.42-0.88)., Conclusion: The found hazard ratio indicates that the risk of relapse is substantially decreased when a patient is properly adherent to the antipsychotic therapy that was prescribed at the inpatient clinic., (Copyright Georg Thieme Verlag KG Stuttgart · New York.)

Clinical studies have shown that total body fat mass is related to both bone density and fracture risk and that fat ingestion reduces bone turnover. These effects are at least partially mediated by endocrine mechanisms, but it is possible that lipids might act directly on bone. We assessed the effects of broad fractions of milk lipids in osteoblasts, bone marrow, and neonatal mouse calvariae. Several milk fractions and their hydrolysates inhibited osteoclastogenesis in bone marrow cultures, so we assessed the effects of free fatty acids in this model. Saturated fatty acids (0.1-10 microg/ml) inhibited osteoclastogenesis in bone marrow cultures and RAW264.7 cells. This effect was maximal for C14:0 to C18:0 fatty acids. The introduction of greater than 1 double bond abrogated this effect; omega3 and omega6 fatty acids had comparable low activity. Osteoblast proliferation was modestly increased by the antiosteoclastogenic compounds, ruling out a nonspecific toxic effect. Active fatty acids did not consistently change expression of receptor activator of nuclear factor-kappaB ligand or osteoprotegerin in osteoblastic cells nor did they affect the activity of key enzymes in the mevalonate pathway. However, receptors known to bind fatty acids were found to be expressed in osteoblastic (GPR120) and osteoclastic (GPR40, 41, 43, 120) cells. A synthetic GPR 40/120 agonist mimicked the inhibitory effects of fatty acids on osteoclastogenesis. These findings provide a novel link between lipid and bone metabolism, which might contribute to the positive relationship between adiposity and bone density as well as provide novel targets for pharmaceutical and nutriceutical development.