Somatic structural variant formation is guided by and influences genome architecture.

The occurrence and formation of genomic structural variants (SVs) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the occurrence of massive complex rearrangements, which allows us to study the sources of SV formation and their consequences on gene regulation. We observe an action-reaction interplay whereby the 3D chromatin architecture directly impacts the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing, and gene regulation in cis We show that SVs have a strong tendency to occur between similar chromatin compartments and replication timing regions. Moreover, we find that SVs frequently occur at 3D loop anchors, that SVs can cause a switch in chromatin compartments and replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes. Finally, we provide evidence for a general mechanistic bias of the 3D chromatin on SV occurrence using data from more than 2700 patient-derived cancer genomes.

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.

Is it possible to predict neurosensory alterations in impacted lower third molar removal based on preoperative imaging procedures? A prospective cohort study.

BACKGROUND: Surgical extraction of the lower third molar (LTM) may trigger neurosensory injury of the inferior alveolar nerve, making extraction a real challenge. This study set out to assess whether is it possible to predict neurosensory alterations from preoperative imaging. MATERIAL AND METHODS: A total of 99 patients underwent 124 impacted lower third molar (ILTM) surgeries. Prior to surgery, panoramic and CBCT images were evaluated in an attempt to predict a neurosensory disturbance. Preoperative data (ILTM position, panoramic radiograph signs, inferior alveolar nerve (IAN) location and its contact with the ILTM roots) and intra/postoperative findings (extraction difficulty and sensitivity alterations) were recorded. Descriptive and bivariate data analysis was performed. Statistical comparison applied the chi-square test, Fisher test, and one-way ANOVA test. Statistical significance was established with a confidence interval (CI) of 95%. RESULTS: In 4.03% of cases, patients experienced neurosensory alterations. Of 124 ILTM positions in panoramic radiographs, 76 cases were considered to exhibit a potential neurosensory risk as they presented two or more types of superimposed relationships between ILTM and mandibular canal. Of these, alterations were reported in only three cases (3.95%). Of the 48 remaining ILTM images presenting only one sign, neurosensory alterations were observed in two cases (4.17%). No permanent alterations were recorded in any of the five cases observed. CONCLUSIONS: Within the limitations of the present study, prediction of neurosensory alterations prior to ILTM extraction by means of preoperative imaging did not show a significant statistical correlation with post-surgical incidence. Nevertheless, interruption of the canal´s white line (ICWL) or a diversion of the canal (DC) may predict an increased risk of IAN injury.

Cyanoacrylate versus suture as flap closure methods in mandibular third molar surgery: a split-mouth randomized controlled clinical study.

BACKGROUND: Sutures have been the standard flap closure method of choice following mandibular third molar surgery but can lead to some complications. Tissue adhesives, including cyanoacrylate, have emerged as alternative flap closure method in this surgery to overcome such drawbacks. However, limited clinical trials can be found. Therefore, the aim of this clinical study was to compare two methods of flap closure in mandibular third molar surgery, cyanoacrylate and 4/0 silk sutures, by assessing post-operative outcome measures (pain, swelling, trismus, and healing) and patient-reported outcome measures (PROMs). MATERIAL AND METHODS: A randomized split-mouth clinical trial was designed, in which mandibular third molar (M3M) extractions were performed, where the control side flap was closed with 4/0 silk sutures and the test side flap with cyanoacrylate. Swelling, pain, trismus, healing, and PROMs were recorded post-operatively. These variables were analyzed by means of the nonparametric Mann-Whitney U test, using SPSS statistical software version 28.0.0 (IBM® SPSS®, Chicago, IL, USA). For all results, a 95% confidence interval was recorded (significance level p < 0.05, two-tailed). RESULTS: A total of 17 patients were recruited and 34 mandibular third molar extractions were performed. No statistically significant differences were found in terms of swelling, pain, trismus, healing, and PROMs between both groups (p<0.05). CONCLUSIONS: No statistically significant differences were found between flap closure with 4/0 silk sutures and cyanoacrylate, in terms of surgical post-operative outcomes and PROMs. However, further studies with larger sample sizes are required to be able to affirm it with greater certainty.

Updated guidelines for gene nomenclature in wheat.

KEY MESSAGE: Here, we provide an updated set of guidelines for naming genes in wheat that has been endorsed by the wheat research community. The last decade has seen a proliferation in genomic resources for wheat, including reference- and pan-genome assemblies with gene annotations, which provide new opportunities to detect, characterise, and describe genes that influence traits of interest. The expansion of genetic information has supported growth of the wheat research community and catalysed strong interest in the genes that control agronomically important traits, such as yield, pathogen resistance, grain quality, and abiotic stress tolerance. To accommodate these developments, we present an updated set of guidelines for gene nomenclature in wheat. These guidelines can be used to describe loci identified based on morphological or phenotypic features or to name genes based on sequence information, such as similarity to genes characterised in other species or the biochemical properties of the encoded protein. The updated guidelines provide a flexible system that is not overly prescriptive but provides structure and a common framework for naming genes in wheat, which may be extended to related cereal species. We propose these guidelines be used henceforth by the wheat research community to facilitate integration of data from independent studies and allow broader and more efficient use of text and data mining approaches, which will ultimately help further accelerate wheat research and breeding.

Economic evaluations of radioembolization with yttrium-90 microspheres in liver metastases of colorectal cancer: a systematic review.

BACKGROUND: Transarterial radioembolization with yttrium-90 (Y-90 TARE) microspheres therapy has demonstrated positive clinical benefits for the treatment of liver metastases from colorectal cancer (lmCRC). This study aims to conduct a systematic review of the available economic evaluations of Y-90 TARE for lmCRC. METHODS: English and Spanish publications were identified from PubMed, Embase, Cochrane, MEDES health technology assessment agencies, and scientific congress databases published up to May 2021. The inclusion criteria considered only economic evaluations; thus, other types of studies were excluded. Purchasing-power-parity exchange rates for the year 2020 ($US PPP) were applied for cost harmonisation. RESULTS: From 423 records screened, seven economic evaluations (2 cost-analyses [CA] and 5 cost-utility-analyses [CUA]) were included (6 European and 1 USA). All included studies (n = 7) were evaluated from a payer and the social perspective (n = 1). Included studies evaluated patients with unresectable liver-predominant metastases of CRC, refractory to chemotherapy (n = 6), or chemotherapy-naïve (n = 1). Y-90 TARE was compared to best supportive care (BSC) (n = 4), an association of folinic acid, fluorouracil and oxaliplatin (FOLFOX) (n = 1), and hepatic artery infusion (HAI) (n = 2). Y-90 TARE increased life-years gained (LYG) versus BSC (1.12 and 1.35 LYG) and versus HAI (0.37 LYG). Y-90 TARE increased the quality-adjusted-life-year (QALY) versus BSC (0.81 and 0.83 QALY) and versus HAI (0.35 QALY). When considering a lifetime horizon, Y-90 TARE reported incremental cost compared to BSC (range 19,225 to 25,320 $US PPP) and versus HAI (14,307 $US PPP). Y-90 TARE reported incremental cost-utility ratios (ICURs) between 23,875 $US PPP/QALY to 31,185 $US PPP/QALY. The probability of Y-90 TARE being cost-effective at £ 30,000/QALY threshold was between 56% and 57%. CONCLUSIONS: Our review highlights that Y-90 TARE could be a cost-effective therapy either as a monotherapy or when combined with systemic therapy for treating ImCRC. However, despite the current clinical evidence on Y-90 TARE in the treatment of ImCRC, the global economic evaluation reported for Y-90 TARE in ImCRC is limited (n = 7), therefore, we recommend future economic evaluations on Y-90 TARE versus alternative options in treating ImCRC from the societal perspective.

Fitting parameters and therapies of ODE tumor models with senescence and immune system.

This work is devoted to introduce and study two quasispecies nonlinear ODE systems that model the behavior of tumor cell populations organized in different states. In the first model, replicative, senescent, extended lifespan, immortal and tumor cells are considered, while the second also includes immune cells. We fit the parameters regulating the transmission between states in order to approximate the outcomes of the models to a real progressive tumor invasion. After that, we study the identifiability of the fitted parameters, by using two sensitivity analysis methods. Then, we show that an adequate reduced fitting process (only accounting to the most identifiable parameters) gives similar results but saving computational cost. Three different therapies are introduced in the models to shrink (progressively in time) the tumor, while the replicative and senescent cells invade. Each therapy is identified to a dimensionless parameter. Then, we make a fitting process of the therapies' parameters, in various scenarios depending on the initial tumor according to the time when the therapies started. We conclude that, although the optimal combination of therapies depends on the size of initial tumor, the most efficient therapy is the reinforcement of the immune system. Finally, an identifiability analysis allows us to detect a limitation in the therapy outcomes. In fact, perturbing the optimal combination of therapies under an appropriate therapeutic vector produces virtually the same results.

The circular RNome of primary breast cancer.

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Of the circRNAs that match exon boundaries of the same gene, 668 showed a poor or even negative (R < 0.2) correlation with the expression level of the linear gene. In silico analysis showed only a minority (8.5%) of circRNAs could be explained by known splicing events. Both these observations suggest that specific regulatory processes for circRNAs exist. We confirmed the presence of circRNAs of CNOT2, CREBBP, and RERE in an independent pool of primary breast cancers. We identified circRNA profiles associated with subgroups of breast cancers and with biological and clinical features, such as amount of tumor lymphocytic infiltrate and proliferation index. siRNA-mediated knockdown of circCNOT2 was shown to significantly reduce viability of the breast cancer cell lines MCF-7 and BT-474, further underlining the biological relevance of circRNAs. Furthermore, we found that circular, and not linear, CNOT2 levels are predictive for progression-free survival time to aromatase inhibitor (AI) therapy in advanced breast cancer patients, and found that circCNOT2 is detectable in cell-free RNA from plasma. We showed that circRNAs are abundantly present, show characteristics of being specifically regulated, are associated with clinical and biological properties, and thus are relevant in breast cancer.

Experimental Search for Neutron to Mirror Neutron Oscillations as an Explanation of the Neutron Lifetime Anomaly.

An unexplained >4σ discrepancy persists between "beam" and "bottle" measurements of the neutron lifetime. A new model proposed that conversions of neutrons n into mirror neutrons n^{'}, part of a dark mirror sector, can increase the apparent neutron lifetime by 1% via a small mass splitting Δm between n and n^{'} inside the 4.6 T magnetic field of the National Institute of Standards and Technology Beam Lifetime experiment. A search for neutron conversions in a 6.6 T magnetic field was performed at the Spallation Neutron Source which excludes this explanation for the neutron lifetime discrepancy.

Economic evaluations of radioembolization with Itrium-90 microspheres in hepatocellular carcinoma: a systematic review.

BACKGROUND: Transarterial radioembolization (TARE) with yttrium-90 microspheres is a clinically effective therapy for hepatocellular carcinoma (HCC) treatment. This study aimed to perform a systematic review of the available economic evaluations of TARE for the treatment of HCC. METHODS: The Preferred Reported Items for Systematic reviews and Meta-Analyses guidelines was followed by applying a search strategy across six databases. All studies identified as economic evaluations with TARE for HCC treatment in English or Spanish language were considered. Costs were adjusted using the 2020 US dollars based on purchasing-power-parity ($US PPP). RESULTS: Among 423 records screened, 20 studies (6 cost-analyses, 3 budget-impact-analyses, 2 cost-effectiveness-analyses, 8 cost-utility-analyses, and 1 cost-minimization analysis) met the pre-defined criteria for inclusion. Thirteen studies were published from the European perspective, six from the United States, and one from the Canadian perspectives. The assessed populations included early- (n = 4), and intermediate-advanced-stages patients (n = 15). Included studies were evaluated from a payer perspective (n = 20) and included both payer and social perspective (n = 2). TARE was compared with transarterial chemoembolization (TACE) in nine studies or sorafenib (n = 11). The life-years gained (LYG) differed by comparator: TARE versus TACE (range: 1.3 to 3.1), and TARE versus sorafenib (range: 1.1 to 2.53). Of the 20 studies, TARE was associated with lower treatment costs in ten studies. The cost of TARE treatment varied widely according to Barcelona Clinic Liver Cancer (BCLC) staging system and ranged from 1311 $US PPP/month (BCLC-A) to 71,890 $US PPP/5-years time horizon (BCLC-C). The incremental cost-utility ratio for TARE versus TACE resulted in a 17,397 $US PPP/Quality-adjusted-Life-Years (QALY), and for TARE versus sorafenib ranged from dominant (more effectiveness and lower cost) to 3363 $US PPP/QALY. CONCLUSIONS: Economic evaluations of TARE for HCC treatment are heterogeneous. Overall, TARE is a cost-effective short- and long-term therapy for the treatment of intermediate-advanced HCC.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Interrelationship between diseases and calving season and their impact on reproductive parameters and milk production of tropical dairy cows.

The interactions between calving season, the occurrence of retained placenta, intrauterine infections (IUI), and early mastitis, and their effects on the reproductive performance and milk yield of Holstein-Friesian cows in a tropical environment were studied using data from 3320 calvings (1948 cows) from two farms in El Salvador. Based on environmental conditions, season of calving was categorized into: quadrimester 1 (November-February), quadrimester 2 (March-June), and quadrimester 3 (July-October) where quadrimester 2 and 3 had the highest ambient temperature and relative humidity, respectively. Cows were classified into 1, 2, and 3 + parities. The effects of quadrimester and of diseases on days to first service, services per conception, days open, interval between services and 305-day milk yield were studied in separated multivariate regressions. The likelihood of experiencing a disease contingent on the calving season and the likelihood of a cow being culled due to poor fertility associated with experiencing a disease were evaluated using logistic regression. Cows calving in quadrimester 2 and 3 were more likely to suffer from IUI and showed poorer reproduction than cows calving in quadrimester 1. Reproduction was more strongly affected by IUI. Mastitis increased the days to first service, days open, and interval between services. Mastitis and IUI also caused a lower 305-day milk yield. Overall, hotter and more humid conditions lead to higher incidence of disease and poorer reproductive performance. The physiological responses that lead to these phenomena should be further studied to understand the interactions between diseases, environmental conditions and reproduction.

The electronic nose as a rule-out test for tuberculosis in an indigenous population.

INTRODUCTION: To end the tuberculosis (TB) epidemic, efficient diagnostic tools are needed. In a previous calibration study, a portable 'point of care' electronic nose device (AeonoseTM ) proved to be a promising tool in a hospital setting. We evaluated this technology to detect TB in an indigenous population in Paraguay. METHODS: A total of 131 participants were enrolled. eNose results were compared with anamnesis, physical examinations, chest radiography and mycobacterial cultures in individuals with signs and symptoms compatible with TB. The eNose analysis was performed in two stages: first, the training with a combination of a previous study population plus 47 participants from the new cohort (total n = 153), and second, the 'blind prediction' of 84 participants. RESULTS: 21% of all participants (n = 131) showed symptoms and/or chest radiography abnormalities suspicious of TB. No sputum samples resulted culture positive for Mycobacterium tuberculosis complex. Only one patient had a positive smell print analysis. In the training model, the specificity was 92% (95% confidence interval (CI): 85%-96%) and the negative predictive value (NPV) was 95%. In the blind prediction model, the specificity and the NPV were 99% (95% CI: 93%-99%) and 100%, respectively. Although the sensitivity and positive predictive value of the eNose could not be assessed in this cohort due to the small sample size, no active TB cases were found during a one year of follow-up period. CONCLUSION: The eNose showed promising specificity and negative predictive value and might therefore be developed as a rule-out test for TB in vulnerable populations.

CDDA: extension and analysis of the discrete dipole approximation for chiral systems.

Discrete dipole approximation (DDA) is a computational method broadly used to solve light scattering problems. In this work, we propose an extension of DDA that we call Chiral-DDA (CDDA), to study light-chiral matter interactions with the capability of describing the underlying physics behind. Here, CDDA is used to solve and analyze the interaction of a nanoantenna (either metallic or dielectric) with a chiral molecule located in its near field at different positions. Our method allowed to relate near field interactions with far field spectral response of the system, elucidating the role that the nanoantenna electric and magnetic polarizabilities play in the coupling with a chiral molecule. In general, this is not straightforward with other methods. We believe that CDDA has the potential to help researchers revealing some of the still unclear mechanisms responsible for the chiral signal enhancements induced by nanoantennas.

Dynamic reflective color pixels based on molybdenum oxide.

Active materials which show phase transitions, usually known as Phase Change Materials (PCM), have paved the way to a new generation of reconfigurable plasmonic platforms. Tunable color devices have experienced a great development in the recent years. In particular, reflective color filters can take advantage from sunlight to select and reflect a specific resonant wavelength in the visible spectrum range. Reflective displays are usually structural color filters based on asymmetric Fabry-Perot cavities (AFPCs). For a fixed geometry, most of AFPCs filters generate static color, limiting their potential as tunable color devices. Dynamic color is achieved by introducing an active layer whose optical properties can be modulated by an external stimuli. In this paper, we propose AFPCs based on molybdenum oxide (MoOx, 2

Improved Neutron Lifetime Measurement with UCNτ.

We report an improved measurement of the free neutron lifetime τ_{n} using the UCNτ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10^{6} surviving ultracold neutrons (UCNs) after storing in UCNτ's magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract τ_{n} from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate τ_{n} measurements and by performing a global likelihood fit to all data while self-consistently incorporating the ß-decay lifetime. Both techniques achieve consistent results and find a value τ_{n}=877.75±0.28_{stat}+0.22/-0.16_{syst} s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

Ruling out Color Transparency in Quasielastic

Quasielastic ^{12}C(e,e^{'}p) scattering was measured at spacelike 4-momentum transfer squared Q^{2}=8, 9.4, 11.4, and 14.2 (GeV/c)^{2}, the highest ever achieved to date. Nuclear transparency for this reaction was extracted by comparing the measured yield to that expected from a plane-wave impulse approximation calculation without any final state interactions. The measured transparency was consistent with no Q^{2} dependence, up to proton momenta of 8.5 GeV/c, ruling out the quantum chromodynamics effect of color transparency at the measured Q^{2} scales in exclusive (e,e^{'}p) reactions. These results impose strict constraints on models of color transparency for protons.

Sequence subtyping of Trichomonas gallinae from Bonelli's eagle (Aquila fasciata) during four years (2014-2017) reveals that MLS type is associated with lesions.

Avian trichomonosis is a parasitic disease that affects wild birds. The objective of this work was to determine the importance of avian trichomonosis in Bonelli's eagles to improve conservation measures in this population. One hundred and eighty-eight birds were studied: 181 chicks, two juveniles, one subadult and four adults. The birds were externally examined and gross lesions at the oropharynx registered. Samples from the oropharyngeal cavity were obtained for Trichomonas spp. detection by culture and PCR, and positive samples were subjected to a multilocus sequence typing approach, including the ITS1/5.8S/ITS2 region (ITS), ribosomal RNA small subunit (18S) and Fe-hydrogenase gene (FeHyd). Global prevalence of T. gallinae infection was 37.8% in total, 45.5% in nestlings. Thirty-three percent of the birds developed lesions that ranged from mild (n = 41) to moderate (n = 14) or severe (n = 7). Multilocus sequence typing analysis showed five different MLS types, ITS-A/18S-VI/FeHyd-A1 and ITS-D/18S-II/Fe-C4 being the most frequent. An association between ITS-A/18S-VI/FeHyd-A1 and moderate or severe lesions was observed, but birds with type ITS-A/18S-VI/FeHyd-A2 also developed lesions. On the contrary, birds with MLS type ITS-D/18S-II/FeHyd-C4 displayed only a low proportion of mild lesions. Chicks raised in nests were at higher risk for T. gallinae infection and development of lesions than chicks raised in captivity. Discordances between samples cultured in TYM and samples subjected to PCR from oropharyngeal swabs were observed, swab-ITS-PCR being more sensitive.RESEARCH HIGHLIGHTS 45.5% of Bonelli's eagles in the nest carried T. gallinae and 39.4% showed lesions.PCR from oral swabs showed higher sensitivity than culture in TYM for detection of T. gallinae.MLS types ITS-A/18S-VI/Fe-A1 (and A2) are a risk factor for the development of lesions.

A mild case of hemolytic disease of the fetus and newborn due to anti-Sc2.

We report the case of a newborn girl with jaundice due to increased indirect bilirubin with a positive direct antiglobulin test (DAT) and compensated hemolysis. The result of the newborn's DAT was discrepant with the negative result of the mother's indirect antiglobulin test. The multiparous mother had a previous history of fetal hydrops miscarriage, with no known cause, and no record of the cause was found at the hospital where she was treated. After referring samples from the mother and newborn to a reference laboratory, the rare alloanti-Sc2 was identified in the mother's plasma and in the newborn's eluate. HEA BeadChip genotyping of the newborn's DNA sample predicted the SC:1,2 phenotype.We report the case of a newborn girl with jaundice due to increased indirect bilirubin with a positive direct antiglobulin test (DAT) and compensated hemolysis. The result of the newborn's DAT was discrepant with the negative result of the mother's indirect antiglobulin test. The multiparous mother had a previous history of fetal hydrops miscarriage, with no known cause, and no record of the cause was found at the hospital where she was treated. After referring samples from the mother and newborn to a reference laboratory, the rare alloanti-Sc2 was identified in the mother's plasma and in the newborn's eluate. HEA BeadChip genotyping of the newborn's DNA sample predicted the SC:1,2 phenotype.

Lipid-induced mononuclear cell cytokine secretion in the development of metabolic aberration and androgen excess in polycystic ovary syndrome.

STUDY QUESTION: What is the effect of saturated fat ingestion on mononuclear cell (MNC) TNFα, IL-6 and IL-1ß secretion and circulating IL-6 levels in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with PCOS exhibit increases in MNC-derived TNFα, IL-6 and IL-1ß secretion and circulating IL-6 following saturated fat ingestion even in the absence of obesity, and these increases are linked to metabolic aberration and androgen excess. WHAT IS KNOWN ALREADY: Cytokine excess and metabolic aberration is often present in PCOS. STUDY DESIGN, SIZE, DURATION: A cross-sectional design was used in this study of 38 reproductive-age women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Groups of 19 reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory controls (10 lean, 9 obese) participated in this study that was performed at a tertiary academic medical centre. TNFα, IL-6 and IL-1ß secretion was measured from cultured MNC, and IL-6 was measured in plasma from blood sampling while fasting and 2, 3 and 5 h after saturated fat ingestion. Insulin sensitivity was determined using the Matsuda index following an oral glucose tolerance test. Androgen secretion was evaluated with blood sampling while fasting and 24, 48 and 72 h after an HCG injection. MAIN RESULTS AND THE ROLE OF CHANCE: Lean and obese women with PCOS exhibited lipid-induced incremental AUC increases in MNC-derived TNFα (489-611%), IL-6 (333-398%) and IL-1ß (560-695%) secretion and in plasma IL-6 levels (426-474%), in contrast with lean control subjects. In both PCOS groups, insulin sensitivity was lower (42-49%) and androgen secretion after HCG injection was greater (63-110%) compared with control subjects. The MNC-derived TNFα, IL-6 and IL-1ß and circulating IL-6 responses were inversely associated with insulin sensitivity and directly associated with fasting lipids and androgen secretion after HCG injection. LIMITATIONS, REASONS FOR CAUTION: The sample size of each of the four study groups was modest following group assignment of subjects by body mass. WIDER IMPLICATIONS OF THE FINDINGS: This study showcases the unique pro-inflammatory contribution of circulating MNC in the development of metabolic aberration and androgen excess in PCOS. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by grant R01 DK107605 to F.G. from the National Institutes of Health, the Indiana Clinical and Translational Sciences Institute Clinical Research Center which is funded in part by grant UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award, and the Indiana University Center for Diabetes and Metabolic Diseases funded by grant P30 DK097512 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. No conflicts of interest, financial or otherwise, are declared by the authors. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01489319.