Prescribing Patterns of Psychotropic Drugs and Risk of Violent Behavior: A Prospective, Multicenter Study in Italy.

BACKGROUND: This prospective cohort study aimed at evaluating patterns of polypharmacy and aggressive and violent behavior during a 1-year follow-up in patients with severe mental disorders. METHODS: A total of 340 patients (125 inpatients from residential facilities and 215 outpatients) were evaluated at baseline with the Structured Clinical Interview for DSM-IV Axis I and II, Brief Psychiatric Rating Scale, Specific Levels of Functioning scale, Brown-Goodwin Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Barratt Impulsiveness Scale, and State-Trait Anger Expression Inventory-2. Aggressive behavior was rated every 15 days with the Modified Overt Aggression Scale and treatment compliance with the Medication Adherence Rating Scale. RESULTS: The whole sample was prescribed mainly antipsychotics with high levels of polypharmacy. Clozapine prescription and higher compliance were associated with lower levels of aggressive and violent behavior. Patients with a history of violence who took clozapine were prescribed the highest number of drugs. The patterns of cumulative Modified Overt Aggression Scale mean scores of patients taking clozapine (n = 46), other antipsychotics (n = 257), and no antipsychotics (n = 37) were significantly different (P = .001). Patients taking clozapine showed a time trend at 1-year follow-up (24 evaluations) indicating a significantly lower level of aggressive behavior. Patient higher compliance was also associated with lower Modified Overt Aggression Scale ratings during the 1-year follow-up. CONCLUSION: Both inpatients and outpatients showed high levels of polypharmacy. Clozapine prescription was associated with lower Modified Overt Aggression Scale ratings compared with any other antipsychotics or other psychotropic drugs. Higher compliance was associated with lower levels of aggressive and violent behavior.

Multivariate factor analysis of milk fatty acid composition in relation to the somatic cell count of single udder quarters.

The present study investigated whether the fatty acid composition of milk changes in relation to an increase in the milk somatic cell count (SCC) of separate udder quarters. We investigated the potential of multivariate factor analysis to extract metabolic evidence from data on the quantity and quality of milk of quarters characterized by different SCC levels. We collected data from individual milk samples taken from single quarters of 49 Italian Holstein cows from the same dairy farm. Factor analysis was carried out on 64 individual fatty acids. In line with a previous study on multivariate factor analysis, a variable was considered to be associated with a specific factor if the absolute value of its correlation with the factor was ≥0.60. Seven factors were extracted that explained the following groups of fatty acids or functions: de novo synthesis, energy balance, uptake of dietary fatty acids, biohydrogenation, short-chain fatty acids, very long chain fatty acids, and odd- and branched-chain fatty acids. An ANOVA of factor scores highlighted the significant effects of the SCC level on de novo fatty acids and biohydrogenation. The de novo fatty acid factor decreased significantly with a high level of SCC, from just 10,000 cells/mL, whereas the biohydrogenation factor showed a significantly higher level in quarters with SCC levels greater than 400,000 cells/mL. This statistical approach enabled us to reduce the number of variables to a few latent factors with biological significance and to represent groups of fatty acids with a common origin and function. Multivariate factor analysis could therefore be key to studying the influence of SCC on the lipid metabolism of single quarters. This approach also demonstrated the metabolic differences between quarters of the same animal showing a different level of SCC.

Comparison of T1 mapping and fixed T1 method for dynamic contrast-enhanced MRI perfusion in brain gliomas.

OBJECTIVES: To compare dynamic contrast-enhanced MRI (DCE-MRI) data obtained using different prebolus T1 values in glioma grading and molecular profiling. METHODS: We retrospectively reviewed 83 cases of gliomas: 46 lower-grade gliomas (LGG; grades II and III) and 37 high-grade gliomas (HGG; grade IV). DCE-MRI maps of plasma volume fraction (Vp), extravascular-extracellular volume fraction (Ve), and tracer transfer constant from plasma to tissue (Ktrans) were obtained using a fixed T1 value of 1400 ms and a measured T1 obtained with variable flip angle (VFA). Tumour segmentations were performed and first-order histogram parameters were extracted from volumes of interest (VOIs) after co-registration with the perfusion maps. The two methods were compared using Wilcoxon matched-pairs signed-rank test and Bland-Altman analysis. Diagnostic accuracy was obtained and compared using ROC curve analysis and DeLong's test. RESULTS: Perfusion parameters obtained with the fixed T1 value were significantly higher than those obtained with the VFA. As regards diagnostic accuracy, there were no significant differences between the two methods both for glioma grading and molecular classification, except for few parameters of both methods. CONCLUSIONS: DCE-MRI data obtained with different prebolus T1 are not comparable and the definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI. KEY POINTS: • DCE-MRI data obtained with different prebolus T1 are significantly different, thus not comparable. • The definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI for glioma grading. • The use of a fixed T1 value represents a valid alternative to T1 mapping for DCE-MRI analysis.

CO2 Adsorption Investigation on an Innovative Nanocomposite Material with Hierarchical Porosity.

A NaX nanozeolite-geopolymer monolith, with hierarchical porosity, has been produced by a one-pot hydrothermal synthesis using metakaolin as alluminosilicate source and a sodium silicate solution as activator. Its final composition, reported in terms of oxides, is 1.3-Na2O-3.0SiO2-1Al2O3-12H2O. Its microstructural and chemical features and CO2 adsorption performance have been investigated. The microstructure of the composite is characterized by NaX zeolite nanocrystals glued by the geopolymeric binder to form a complex three-dimensional network of pores. Overall porosity resulted ~23.5%, whereas compressive strength is 16±0.7 MPa. Monolith showed BET surface area of 350 m²/g, a micropore surface area of 280 m²/g and a mesopore volume, due to the geopolymeric binder, of 0.09 cm³/g. Its CO2 adsorption capacity has been measured at the temperatures of 7, 25 and 42 °C up to 15 bar using an optimized Sievert-type (volumetric) apparatus. All the adsorption data were evaluated by Toth/Langmuir isotherm model and commercial pure NaX zeolite was used as reference. CO2 adsorption isotherms show a maximum uptake value around 21 wt% at (~7 °C) that decrease to 18 wt% at high temperature (~42 °C) passing through 19 wt% at room temperature (~25 °C). The homogeneity grade of the surface, as obtained using Toth analysis performed on the adsorption isotherm, is close to t ≅ 0.40, lower than the 0.61 obtained for pure commercial NaX zeolite, as a consequence of the binder formation. Monolith exhibits a notably higher K values and quicker saturation with respect to reference that can be ascribed to the presence of mesoporosity that provides an easier and faster transport of CO2 in the NaX nanozeolite framework. The produced composite is a potential solid adsorbent candidate in industrial process.

Correction to: Inert gas narcosis in scuba diving, different gases different reactions.

The original version of this article unfortunately contained a mistake.

Inert gas narcosis in scuba diving, different gases different reactions.

PURPOSE: Underwater divers face several potential neurological hazards when breathing compressed gas mixtures including nitrogen narcosis which can impact diver's safety. Various human studies have clearly demonstrated brain impairment due to nitrogen narcosis in divers at 4 ATA using critical flicker fusion frequency (CFFF) as a cortical performance indicator. However, recently some authors have proposed a probable adaptive phenomenon during repetitive exposure to high nitrogen pressure in rats, where they found a reversal effect on dopamine release. METHODS: Sixty experienced divers breathing Air, Trimix or Heliox, were studied during an open water dive to a depth of 6 ATA with a square profile testing CFFF measurement before (T0), during the dive upon arriving at the bottom (6 ATA) (T1), 20 min of bottom time (T2), and at 5 m (1.5 ATA) (T3). RESULTS: CFFF results showed a slight increase in alertness and arousal during the deep dive regardless of the gas mixture breathed. The percent change in CFFF values at T1 and T2 differed among the three groups being lower in the air group than in the other groups. All CFFF values returned to basal values 5 min before the final ascent at 5 m (T3), but the Trimix measurements were still slightly better than those at T0. CONCLUSIONS: Our results highlight that nitrogen and oxygen alone and in combination can produce neuronal excitability or depression in a dose-related response.

Retreatability of two hydraulic calcium silicate-based root canal sealers using rotary instrumentation with supplementary irrigant agitation protocols: a laboratory-based micro-computed tomographic analysis.

AIM: To investigate the retreatability of two calcium silicate-based materials (BioRoot RCS, Septodont, Saint-Maur-des-Fossés, France and GuttaFlow Bioseal, Colténe/Whaledent AG, Langenau, Germany) using rotary instrumentation combined with supplementary irrigant agitation techniques using extracted teeth in a laboratory setting. METHODOLOGY: The root canals of extracted single-rooted mandibular premolars were prepared to size 40, .04 taper and randomly divided into two experimental groups (n = 36) depending on the root filling material. Root canals were filled with gutta-percha and GuttaFlow Bioseal (GB, group 1) or BioRoot RCS (BR, group 2), scanned using a micro-CT scanner and stored in phosphate-buffered saline for 4 months. Removal of root filling was performed with rotary instruments, and specimens were randomly allocated to one of the subgroups for supplementary irrigant agitation (n = 12): subgroup A, syringe irrigation (control); subgroup B, Tornado Brush (M.I.B, Suresnes, France) and subgroup C, ultrasonically activated irrigation. Specimens were re-scanned with micro-CT to calculate the volume of remnant root filling material. Data were analysed statistically by two-way ANOVA and post hoc Tukey's tests (P = 0.05). RESULTS: Specimens filled with GuttaFlow Bioseal were associated with a significantly smaller volume of root filling remnants compared with BioRoot RCS (P < 0.05). There was no significant difference between the supplementary irrigant agitation subgroups in the removal of GB (P > 0.05). In group 2 (BioRoot RCS), subgroups B (Tornado Brush) and C (ultrasonically activated irrigation) were associated with a significantly smaller volume of root filling remnants compared with subgroup A (syringe irrigation) (P < 0.05). There was no significant difference between subgroups B and C (P > 0.05). CONCLUSIONS: Significantly smaller volumes of root filling remnants of GuttaFlow Bioseal, than BioRoot RCS, were present after their removal with rotary instruments and irrigation. Supplementary irrigant agitation techniques were associated with smaller volumes of remnants during the removal of BioRoot RCS but not that of GuttaFlow Bioseal.

Cell-free fetal DNA analysis in maternal plasma as screening test for trisomies 21, 18 and 13 in twin pregnancy.

OBJECTIVES: To evaluate in twin pregnancy the utility of non-invasive prenatal testing using circulating cell-free fetal DNA (cfDNA) in screening for the three main autosomal fetal trisomies. METHODS: cfDNA testing was offered to 492 patients with a twin pregnancy without ultrasound anomaly as a first-line screening test or after routine serum screening. Data were collected prospectively and a retrospective analysis was performed. cfDNA analysis was performed by massively parallel sequencing. The fetal-fraction threshold used for test evaluation was 8%. Regression analysis was performed to investigate the effect on the test failure rate of maternal and pregnancy characteristics, and the performance of the test was also reported. RESULTS: cfDNA analysis was performed as a first-line test (after the first-trimester scan) in 377 patients and following serum screening in 115. Of the 420 pregnancies for which outcome was available and cfDNA screening was assessed, 78.7% were dichorionic-diamniotic. The test failed on the first attempt in 12 (2.9%) pregnancies, and regression analysis demonstrated that only maternal weight was a significant independent predictor of test failure. A result was subsequently achieved in the 10 cases for which a second sample was obtained. cfDNA analysis identified all three cases of trisomy 21 and the only case of trisomy 18. For trisomy 21, the specificity was 99.8% (95% CI, 98.7-100.0%). When considering pregnancies according to whether they were conceived spontaneously or after assisted reproductive technology, there were no significant differences in terms of maternal weight or no-result rate for cfDNA screening between these two groups. CONCLUSIONS: In twin pregnancy without fetal ultrasound abnormality, cfDNA screening for trisomies 21, 18 and 13 had a high success rate and good performance. Therefore, in routine practice, cfDNA analysis could be considered as a first- or second-line screening test. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

A canonical discriminant analysis to study the association between milk fatty acids of ruminal origin and milk fat depression in dairy cows.

Although milk fat depression (MFD) has been observed and described since the beginning of the last century, all the molecular and biochemical mechanisms involved are still not completely understood. Some fatty acids (FA) originating during rumen biohydrogenation have been proposed as causative elements of MFD. However, contradictory results were obtained when studying the effect of single FA on MFD. An alternative could be the simultaneous evaluation of the effect of many FA using a multivariate approach. The aim of this study was to evaluate the relationship between individual milk FA of ruminal origin and MFD using canonical discriminant analysis, a multivariate technique able to distinguish 2 or more groups on the basis of a pool of variables. In a commercial dairy herd, a diet containing 26% starch on a DM basis induced an unintentional MFD syndrome in 14 cows out of 40. Milk yielded by these 14 animals showed a fat content lower than 50% of the ordinary value, whereas milk production and protein content were normal. The remaining 26 cows secreted typical milk fat content and therefore were considered the control group, even though they ate the same diet. The stepwise discriminant analysis selected 14 milk FA of ruminal origin most able to distinguish the 2 groups. This restricted pool of FA was used, as variables, in a run of the canonical discriminant analysis that was able to significantly discriminate between the 2 groups. Out of the 14 FA, 5 conjugated linoleic acid isomers (C18:2 trans-10,trans-12, C18:2 trans-8,trans-10, C18:2 trans-11,cis-13, C18:2 cis-9,cis-11, C18:2 cis-10,cis-12) and C15:0 iso were more related to the control group, whereas C18:2 trans-10,cis-12, C16:1 trans-6-7, C16:1 trans-9, C18:1 trans-6-8, C18:1 trans-9, C18:1 trans-10, C18:1 cis-11, and C18:3n-3 were positively associated with the MFD group, allowing a complete discrimination. On the basis of these results, we can conclude that (1) the shift of ruminal biohydrogenation from C18:1 trans-11 to C18:1 trans-10 seemed to be strongly associated with MFD; (2) at the same time, other C18:1 trans isomers showed a similar association; (3) on the contrary, conjugated linoleic acid isomers other than C18:2 trans-10,cis-12 seemed to be associated with a normal fat secretion. Results confirmed that MFD is the consequence of a combined effect of the outflow of many ruminal FA, which collectively affect mammary fat synthesis. Because the animals of the 2 groups were fed the same diet, these results suggested that factors other than diet are involved in the MFD syndrome. Feeding behavior (i.e., ability to select dietary ingredients in a total mixed ration), rumen environment and the composition of ruminal bacteria are additional factors able to modify the products of rumen biohydrogenation. Results of the present work confirmed that the multivariate approach can be a useful tool to evaluate a metabolic pathway that involves several parameters, providing interesting suggestions about the role of some FA involved in MFD. However, results about the MFD syndrome obtained in the present research require a deep molecular investigation to be confirmed.

Dietary linseed supplementation affects the fatty acid composition of the sn-2 position of triglycerides in sheep milk.

In the human intestine, lipids are absorbed as sn-2 monoglycerides (sn-2, also named ß-position), produced mainly by pancreatic lipases, which hydrolysate the triglyceride molecule in positions 1 and 3 (sn-1,3, α-position). The fatty acids esterified in sn-2 are thus preferentially absorbed, which means that the bioavailability of a single fatty acid is affected by its position on the triglyceride. This experiment is carried out with the milk used to make cheese applied in a study with 42 human volunteers. In that study the authors detected an improvement in the blood lipid profile. The aim of the present study was to examine the effectiveness of this kind of cheese in improving human health by studying how linseed supplementation affects the milk fatty acid composition of the 3 different triglyceride positions and thus the fatty acid bioavailability. The sn-2 were obtained by reacting total milk lipids with swine pancreatic lipase. The milk came from 24 sheep fed a control diet and 24 sheep fed a diet containing 200 g of extruded linseed per day. The sn-2 were separated by thin-layer chromatography. The fatty acid composition of total lipids and sn-2 was obtained by a gas chromatography-flame ionization detector apparatus equipped with a high polar 100 m length capillary column. The bioavailability of the fatty acids was evaluated by a putative preferential intestinal absorption index (PPIAi), where PPIAi <0 indicated a disadvantageous nutritional condition and PPIAi >0 indicated a preferential intestinal absorption. With regard to the fatty acid composition of triglycerides, the linseed group showed a significantly higher content of both linolenic acid and rumenic acid compared with the control. As a consequence of linseed supplementation, the linolenic and rumenic acid content esterified in the ß-position increased greatly. This was highlighted by the PPIAi. The results of the present study suggest that the linolenic acid and conjugated linoleic acid affinity for lyso-phosphatidic acid acyl-transferase increased with its tissue availability.

A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.

Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

Effects of candidate gene polymorphisms on the detailed fatty acids profile determined by gas chromatography in bovine milk.

Association analyses between candidate genes and bovine milk fatty acids can improve our understanding of genetic variation in milk fatty acid profiles and reveal potential opportunities to tailor milk fat composition through selection strategies. In this work, we investigated the association of 51 single nucleotide polymorphisms (SNP) selected from 37 candidate genes using a functional and positional approach, with 47 fatty acids, 9 fatty acid groups, and 5 Δ(9)-desaturation indices in milk samples from Brown Swiss cows. Individual milk samples were collected from 1,158 Italian Brown Swiss cows, and gas chromatography was used to obtain detailed milk fatty acid compositions. A GoldenGate assay system (Illumina, San Diego, CA) was used to perform genotype 96 selected SNP located in 54 genes across 22 chromosomes. In total, 51 polymorphic SNP in 37 candidate genes were retained for the association analysis. A Bayesian linear animal model was used to estimate the contribution of each SNP. A total of 129 tests indicated relevant additive effects between a given SNP and a single fatty acid trait; 38 SNP belonging to 30 genes were relevant for a total of 57 fatty acid traits. Most of the studied fatty acid traits (~81%) were relevantly associated with multiple SNP. Relevantly associated SNP were mainly found in genes related to fat metabolism, linked to or contained in previously identified quantitative trait loci for fat yield or content, or associated with genes previously identified in association analyses with milk fatty acid profiles in other cow breeds. The most representative candidate genes were LEP, PRL, STAT5A, CCL3, ACACA, GHR, ADRB2, LPIN1, STAT1, FABP4, and CSN2. In particular, relevant associations with SNP located on bovine chromosome 19 (BTA19) were found. Two candidate genes on BTA19 (CCL3 and ACACA) were relevantly associated with de novo short- and medium-chain fatty acids, likely explaining the high heritability values found for these fatty acids (with the exception of C6:0). Two additional genes on BTA19 (CCL2 and GH1) showed associations with saturated and branched-chain fatty acids. Our findings provide basic information on genes and SNP affecting the milk fatty acid composition of dairy cows. These results may support the possibility of using genetic selection to modify milk fatty acid profiles to promote beneficial health-related effects.

Genetic and environmental relationships of detailed milk fatty acids profile determined by gas chromatography in Brown Swiss cows.

The aim of this study was to characterize the profile of 47 fatty acids, including conjugated linoleic acid (CLA), 13 fatty acid groups, and 5 Δ(9)-desaturation indices in milk samples from Brown Swiss cows. The genetic variation was assessed and the statistical relevance of the genetic background for each trait was evaluated using the Bayes factor test. The additive genetic, herd-date, and residual relationships were also estimated among all single fatty acids and groups of fatty acids. Individual milk samples were collected from 1,158 Italian Brown Swiss cows and a detailed analysis of fat percentages and milk fatty acid compositions was performed by gas chromatography. Bayesian animal models were used for (co)variance components estimation. Exploitable genetic variation was observed for most of the de novo synthesized fatty acids and saturated fatty acids, except for C4:0 and C6:0, whereas long-chain fatty acids and unsaturated fatty acids (including CLA) were mainly influenced by herd-date effects. Herd-date effect explained large portions of the total phenotypic variance for C18:2 cis-9,cis-12 (0.668), C18:3 cis-9,cis-12,cis-15 (0.631), and the biohydrogenation and elongation products of these fatty acids. The desaturation ratios showed higher heritability estimates than the individual fatty acids, except for CLA desaturation index (0.098). Among the medium-chain fatty acids, C12:0 had greater heritability than C14:0 (0.243 vs. 0.097, respectively). Both C14:0 and C16:0 showed negative additive genetic correlations with the main monounsaturated and polyunsaturated fatty acids of milk fat, suggesting that their synthesis in the mammary gland may be influenced by the presence of unsaturated fatty acids. No correlation was observed between C4:0 and the other short-chain fatty acids (except for C6:0), confirming the independence of C4:0 from de novo mammary fatty acid synthesis. Among the genetic correlations dealing with potentially beneficial fatty acids, C18:0 was positively correlated with vaccenic and rumenic acids and negatively with linoleic acid. Finally, fatty acids C6:0 through C14:0 showed relevant correlations due to unknown environmental effects, suggesting the potential existence of genetic variances in micro-environmental sensitivity. This study allowed us to acquire new knowledge about the genetic and the environmental relationships among fatty acids. Likewise, the existence of genetic variation for most of de novo synthetized fatty acids and saturated fatty acids was also observed. Overall, these results provide useful information to combine feeding with genetic selection strategies for obtaining a desirable milk fatty acids profile, depending on the origin of fatty acids in milk.

Multivariate factor analysis of detailed milk fatty acid profile: Effects of dairy system, feeding, herd, parity, and stage of lactation.

We investigated the potential of using multivariate factor analysis to extract metabolic information from data on the quantity and quality of milk produced under different management systems. We collected data from individual milk samples taken from 1,158 Brown Swiss cows farmed in 85 traditional or modern herds in Trento Province (Italy). Factor analysis was carried out on 47 individual fatty acids, milk yield, and 5 compositional milk traits (fat, protein, casein, and lactose contents, somatic cell score). According to a previous study on multivariate factor analysis, a variable was considered to be associated with a specific factor if the absolute value of its correlation with the factor was ≥0.60. The extracted factors were representative of the following 12 groups of fatty acids or functions: de novo fatty acids, branched fatty acid-milk yield, biohydrogenation, long-chain fatty acids, desaturation, short-chain fatty acids, milk protein and fat contents, odd fatty acids, conjugated linoleic acids, linoleic acid, udder health, and vaccelenic acid. Only 5 fatty acids showed small correlations with these groups. Factor analysis suggested the existence of differences in the metabolic pathways for de novo short- and medium-chain fatty acids and Δ9-desaturase products. An ANOVA of factor scores highlighted significant effects of the dairy farming system (traditional or modern), season, herd/date, parity, and days in milk. Factor behavior across levels of fixed factors was consistent with current knowledge. For example, compared with cows farmed in modern herds, those in traditional herds had higher scores for branched fatty acids, which were inversely associated with milk yield; primiparous cows had lower scores than older cows for de novo fatty acids, probably due to a larger contribution of lipids mobilized from body depots on milk fat yield. The statistical approach allowed us to reduce a large number of variables to a few latent factors with biological meaning and able to represent groups of fatty acids with a common origin and function. Multivariate factor analysis would therefore be a valuable tool for studying the influence of different production environments and individual animal factors on milk fatty acid composition, and for developing nutritional strategies able to manipulate the milk fatty acid profile according to consumer demand.

Milk fatty acid composition, rumen microbial population, and animal performances in response to diets rich in linoleic acid supplemented with chestnut or quebracho tannins in dairy ewes.

The aim of the study was to evaluate milk fatty acid (FA) profile, animal performance, and rumen microbial population in response to diets containing soybean oil supplemented or not with chestnut and quebracho tannins in dairy ewes. Eighteen Comisana ewes at 122±6 d in milking were allotted into 3 experimental groups. Diets were characterized by chopped grass hay administered ad libitum and by 800 g/head and day of 3 experimental concentrates containing 84.5 g of soybean oil/kg of dry matter (DM) and 52.8 g/kg of DM of bentonite (control diet), chestnut tannin extract (CHT diet), or quebracho tannin extract (QUE diet). The trial lasted 4 wk. Milk yield was recorded daily, and milk composition and blood parameters were analyzed weekly. At the end of the experiment, samples of rumen fluid were collected to analyze pH, volatile fatty acid profile, and the relative proportions of Butyrivibrio fibrisolvens and Butyrivibrio proteoclasticus in the rumen microbial population. Hepatic functionality, milk yield, and gross composition were not affected by tannin extracts, whereas milk FA composition was characterized by significant changes in the concentration of linoleic acid (CHT +2.77% and QUE +9.23%), vaccenic acid (CHT +7.07% and QUE +13.88%), rumenic acid (CHT -1.88% and QUE +24.24%), stearic acid (CHT + 8.71% and QUE -11.45%), and saturated fatty acids (CHT -0.47% and QUE -3.38%). These differences were probably due to the ability of condensed versus hydrolyzable tannins to interfere with rumen microbial metabolism, as indirectly confirmed by changes in the relative proportions of B. fibrisolvens and B. proteoclasticus populations and by changes in the molar proportions of volatile fatty acids. The effect of the CHT diet on the milk FA profile and microbial species considered in this trial was intermediate between that of QUE and the control diet, suggesting a differential effect of condensed and hydrolyzable tannins on rumen microbes. Compared with control animals, the presence of B. fibrisolvens increased about 3 times in ewes fed CHT and about 5 times in animals fed QUE. In contrast, the abundance of B. proteoclasticus decreased about 5- and 15-fold in rumen liquor of ewes fed CHT and QUE diets, respectively. The use of soybean oil and a practical dose of QUE or CHT extract in the diet of dairy ewes can be an efficient strategy to improve the nutritional quality of milk.

Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours.

BACKGROUND: Olaparib, an oral PARP inhibitor, has shown antitumour activity as monotherapy in patients with germline BRCA1/2 (gBRCA)-mutated breast and ovarian cancer. This study evaluated olaparib capsules in combination with liposomal doxorubicin (PLD) in patients with advanced solid tumours (NCT00819221). METHODS: Patients received 28-day cycles of olaparib, continuously (days 1-28) or intermittently (days 1-7), plus PLD (40 mg m(-2), day 1); seven olaparib dose cohorts (50-400 mg bid) were explored to determine the recommended dose. Assessments included safety, pharmacokinetics, pharmacodynamics and preliminary efficacy (objective response rate (ORR)). RESULTS: Of 44 patients treated (ovarian, n=28; breast, n=13; other/unknown, n=3), two experienced dose-limiting toxicities (grade 3 stomatitis and fatal pneumonia/pneumonitis (200 mg per 28-day cycle); grade 4 thrombocytopenia (400 mg per 7-day cycle)). The maximum tolerated dose was not reached using continuous olaparib 400 mg bid plus PLD. Grade ≥3 and serious AEs were reported for 27 (61%) and 12 (27%) patients, respectively. No major pharmacokinetic interference was observed between olaparib and PLD. The ORR was 33% (n=14 out of 42; complete response, n=3). A total of 13 responders had ovarian cancer: 10 were platinum-sensitive, 11 had a gBRCA mutation. CONCLUSIONS: Continuous/intermittent olaparib (up to 400 mg bid) combined with PLD (40 mg m(-2)) was generally tolerated and showed evidence of antitumour activity in ovarian cancer.

Generative Adversarial Networks for Brain MRI Synthesis: Impact of Training Set Size on Clinical Application.

We evaluated the impact of training set size on generative adversarial networks (GANs) to synthesize brain MRI sequences. We compared three sets of GANs trained to generate pre-contrast T1 (gT1) from post-contrast T1 and FLAIR (gFLAIR) from T2. The baseline models were trained on 135 cases; for this study, we used the same model architecture but a larger cohort of 1251 cases and two stopping rules, an early checkpoint (early models) and one after 50 epochs (late models). We tested all models on an independent dataset of 485 newly diagnosed gliomas. We compared the generated MRIs with the original ones using the structural similarity index (SSI) and mean squared error (MSE). We simulated scenarios where either the original T1, FLAIR, or both were missing and used their synthesized version as inputs for a segmentation model with the original post-contrast T1 and T2. We compared the segmentations using the dice similarity coefficient (DSC) for the contrast-enhancing area, non-enhancing area, and the whole lesion. For the baseline, early, and late models on the test set, for the gT1, median SSI was .957, .918, and .947; median MSE was .006, .014, and .008. For the gFLAIR, median SSI was .924, .908, and .915; median MSE was .016, .016, and .019. The range DSC was .625-.955, .420-.952, and .610-.954. Overall, GANs trained on a relatively small cohort performed similarly to those trained on a cohort ten times larger, making them a viable option for rare diseases or institutions with limited resources.

Growth performance, proximate composition and fatty acid profile of black soldier fly larvae reared on two grape pomace varieties.

The black soldier fly (Hermetia illucens) is attracting increasing interest for its ability to convert low-value substrates into highly nutritious feed. This study aimed at evaluating grape pomace from two varieties (Becuet - B; Moscato - M) as rearing substrates for black soldier fly larvae (BSFL), focusing on the related effects on larval growth performance, proximate composition, and fatty acid profile. A total of six replicates per treatment, and 1 000 BSFL per replica, were used. Larval development was assessed by larvae weight, which was recorded eight times during the trial: the day after the beginning of the trial, and then on days 5, 8, 13, 15, 20, 22, and 27 (day in which the 30% of BSFL reached the prepupal stage). Production and waste reduction efficiency parameters, namely the growth rate, substrate reduction and substrate reduction index, were calculated. The two grape pomace varieties were analysed for their proximate composition and fatty acid profile; the same analyses were conducted on BSFL (30 larvae per replica) that were collected at the end of the trial (day 27). The growth rate of BSFL showed a higher value when the larvae were reared on B substrate (4.4 and 3.2 mg/day for B and M, respectively; P < 0.01). The rearing substrate did not significantly affect the proximate composition of BSFL. The percentage of total lipids (TL) in M-fed BSFL was significantly higher than in B ones. Total saturated (P < 0.001) and monounsaturated fatty acids (P < 0.05) were significantly higher in M-fed BSFL, while an opposite trend was observed for total branched-chain (P < 0.001) and total polyunsaturated fatty acids (P < 0.001). Interestingly, some conjugated linoleic acid (CLA) isomers [i.e., C18:2 c9t11(+t7c9+t8c10) and t9t11] were detected in low amounts in both rearing substrates (total CLA equal to 0.085 and 0.16 g/100 g TL in B and M substrate, respectively). Some CLA isomers (i.e., C18:2 c9t11, t7c9, and t10c12) were also found in BSFL, reaching a total CLA concentration equal to 2.95 and 0.052 g/100 g of TL in B-fed and M-fed BSFL, respectively. This study demonstrates that winery by-products from different grape varieties can significantly affect the development and lipid composition of BSFL. The CLA biosynthesis potential of BSFL opens newsworthy perspectives for a new valorisation of winery by-products to produce full-fat black soldier fly meal and black soldier fly oil enriched in specific fatty acids of potential health-promoting interest.

Effect of different diet composition on the fat profile of two different black soldier fly larvae populations.

Black soldier fly larvae (Hermetia illucens; BSFL) can transform organic wastes into nutritional biomass useful in animal feeding. The aim of this work was to study the effect of five diets (meat, fruit, vegetable substrates, a mix of them and control) on the profile of fatty acids (FAs) and sterols of BSFL. For a more exhaustive characterization of the nutritional properties, the profile of esterified FAs in the sn-2 position of the triglycerides, the most absorbed lipid component during animal digestion was evaluated. The dietary effect was estimated on two different Hermetia illucens populations (Greek - UTH and Italian - UNIPI). The diet affected all the lipid fractions examined. Regardless of diet, the fat was characterized mainly of lauric acid and other saturated FAs, which were found to be synthesized by the larvae, as it was not present in any of the five substrates. In general, UTH larvae contained a higher level of lipids (7.38 vs 2.48 g/100 g of larvae; P < 0.001) and saturated FAs (49.71 vs 36.10 g/100 g of Total Lipids; P < 0.001) and a lower percentage of monounsaturated FAs (14.74 vs 26.70 g/100 g of Total Lipids), C18:3n-3 (0.67 vs 1.13 g/100 g of Total Lipids; P < 0.001), and C18:2c9t11 (2.02 vs 2.80 g/100 g of Total Lipids; P < 0.001). Irrespective of the populations, BSFL reared on control and fruit substrates showed higher level of lipids (8.06 and 5.61 g/100 g of larvae, respectively), and saturated FA (38.99 and 71.19 g/100 g of Total Lipids, respectively), while the presence of meat increased the level of C20:4n-6, C20:5n-3 and C22:5n-3 (0.70, 0.13 and 0.45 g/100 g of Total Lipids, respectively). The results confirmed that BSFL accumulate phytosterols in their lipid fraction. The sterol profile was strongly influenced by the substrate on which the larvae were reared, with higher levels of cholesterol in the larvae of the meat group (38.55 mg/100 g of Total Lipids) and of stigmasterol and campesterol (9.04 and 15.23 mg/100 g of Total Lipids, respectively) in those of the vegetable group. The sterol content between the two populations was significantly different, with a higher percentage in UTH larvae (113.28 vs 34.03 mg/100 g of Total Lipids; P < 0.001). Finally, BSFLs showed a high plasticity of the lipid profile depending on both the substrate and the metabolism linked to the different populations. This variability allows the nutritional characteristics of the BSFL to be shaped by modifying the substrate, to adapt it to the technological and feeding needs to which the larvae are destined.

AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn's disease is suppressed by rfaP and ybaT deletion.

Mucosal enrichment of the Adherent-Invasive E. coli (AIEC) pathotype and the expansion of pathogenic IFNγ-producing Th17 (pTh17) cells have been linked to Crohn's Disease (CD) pathogenesis. However, the molecular pathways underlying the AIEC-dependent pTh17 cell transdifferentiation in CD patients remain elusive. To this aim, we created and functionally screened a transposon AIEC mutant library of 10.058 mutants to identify the virulence determinants directly implicated in triggering IL-23 production and pTh17 cell generation. pTh17 cell transdifferentiation was assessed in functional assays by co-culturing AIEC-infected human dendritic cells (DCs) with autologous conventional Th17 (cTh17) cells isolated from blood of Healthy Donors (HD) or CD patients. AIEC triggered IL-23 hypersecretion and transdifferentiation of cTh17 into pTh17 cells selectively through the interaction with CD-derived DCs. Moreover, the chronic release of IL-23 by AIEC-colonized DCs required a continuous IL-23 neutralization to significantly reduce the AIEC-dependent pTh17 cell differentiation. The multi-step screenings of the AIEC mutant's library revealed that deletion of ybaT or rfaP efficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFNγ-producing pTh17 cells. Overall, our findings indicate that ybaT (inner membrane transport protein) and rfaP (LPS-core heptose kinase) represent novel and attractive candidate targets to prevent chronic intestinal inflammation in CD.