Hexagonal Boron Nitride as Filler for Silica-Based Elastomer Nanocomposites

Two-dimensional hexagonal boron nitride (hBN) has attracted tremendous attention over the last few years, thanks to its stable structure and its outstanding properties, such as mechanical strength, thermal conductivity, electrical insulation, and lubricant behavior. This work demonstrates that hBN can also improve the rheological and mechanical properties of elastomer composites when used to partially replace silica. In this work, commercially available pristine hBN (hBN-p) was exfoliated and ball-mill treated in air for different durations (2.5, 5, and 10 h milling). Functionalization occurred with the -NH and -OH groups (hBN-OH). The functional groups were detected using Fourier-Transform Infrared pectroscopy (FT-IR) and were estimated to be up to about 7% through thermogravimetric analysis. The presence of an increased amount of oxygen in hBN-OH was confirmed using Scanning Electron Microscopy coupled with Energy-Dispersive X-ray Spectroscopy. (SEM-EDS). The number of stacked layers, estimated using WAXD analysis, decreased to 8–9 in hBN-OH (10 h milling) from about 130 in hBN-p. High-resolution transmission electron microscopy (HR-TEM) and SEM-EDS revealed the increase in disorder in hBN-OH. hBN-p and hBN-OH were used to partially replace silica by 15% and 30%, respectively, by volume, in elastomer composites based on poly(styrene-co-butadiene) from solution anionic polymerization (S-SBR) and poly(1,4-cisisoprene) from Hevea Brasiliensis (natural rubber, NR) as the elastomers (volume (mm3) of composites released by the instrument). The use of both hBNs in substitution of 30% of silica led to a lower Payne effect, a higher dynamic rigidity, and an increase in E0 of up to about 15% at 70 C, with similar/lower hysteresis. Indeed, the composites with hBN-OH revealed a better balance of tan delta (higher at low temperatures and lower at high temperatures) and better ultimate properties. The functional groups reasonably promote the interaction of hBN with silica and with the silica’s coupling agent, sulfur-based silane, and thus promoted the interaction with the elastomer chains. The volume of the composite, measured using a high-pressure capillary viscometer, increased by about 500% and 400% after one week of storage in the presence of hBN-p and hBN-OH. Hence, both hBNs improved the processability and the shelf life of the composites. Composites obtained using hBN-OH had even filler dispersion without the detachments of the filler from the elastomer matrix, as shown through TEM micrographs. These results pave the way for substantial improvements in the important properties of silica-based composites for tire compounds, used to reduce rolling resistance and thus the improve environmental impacts

Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression

Evaluation of Factors Associated With Appropriate Drug Prescription and Effectiveness of Informative and Educational Interventions-The EDU.RE.DRUG Project

Background: EDU.RE.DRUG study is a prospective, multicentre, open-label, parallel-arm, controlled, pragmatic trial directed to general practitioners (GPs) and their patients. Methods: The study data were retrieved from health-related administrative databases of four local health units (LHUs) of Lombardy and four LHUs in Campania. According to the LHUs, the GPs/patients were assigned to (A) intervention on both GPs (feedback reports about appropriate prescribing among their patients and online courses) and patients (flyers and posters on proper drug use), (B) intervention on GPs, (C) intervention on patients, and (D) no intervention (control arm). A set of appropriate prescribing indicators (potential drug-drug interactions [pDDIs], potential and unnecessary therapeutic duplicates [pTDs], and inappropriate prescriptions in the elderly [ERD-list]) were measured at baseline and after the intervention phase. The effectiveness of the intervention was evaluated estimating the absolute difference in percentages of selected indicators carrying out linear random-intercept mixed-effect models. Results: A cohort of 3,586 GPs (2,567 in intervention groups and 1,019 in the control group) was evaluated. In Campania, the mean pre-intervention percentage of patients with at least one pDDI was always greater than 20% and always lower than 15% in Lombardy. The pre-post difference was quite heterogeneous among the LHUs, ranging from 1.9 to -1.4 percentage points. The mean pre-intervention percentage of patients with pTDs ranged from 0.59 to 2.1%, with slightly higher values characterizing Campania LHUs. The magnitude of the pre-post difference was very low, ranging from -0.11 to 0.20. In Campania, the mean pre-intervention percentage of patients with at least one ERD criterium was considerably higher than in Lombardy (approximately 30% in Lombardy and 50% in Campania). The pre-post difference was again quite heterogeneous. The results from the models accounting for GP geographical belonging suggested that none of the interventions resulted in a statistically significant effect, for all the three indicators considered. Conclusion: The proposed strategy was shown to be not effective in influencing the voluntary changes in GP prescription performance. However, the use of a set of explicit indicators proved to be useful in quantifying the inappropriateness. Further efforts are needed to find more efficient strategies and design more tailored interventions

Telomere length shortening is associated with treatment-free remission in chronic myeloid leukemia patients

We studied telomere length in 32 CML patients who discontinued imatinib after achieving complete molecular remission and 32 age-sex-matched controls. The relative telomere length (RTL) was determined by q-PCR as the telomere to single copy gene (36B4) ratio normalized to a reference sample (K-562 DNA). Age-corrected RTL (acRTL) was also obtained. The 36-month probability of treatment-free remission (TFR) was 59.4 %. TFR patients showed shorter acRTL compared to relapsed (mean ± SD = 0.01 ± 0.14 vs 0.20 ± 0.21; p = 0.01). TFR was significantly higher in CML patients with acRTL ≤0.09 (78.9 vs 30.8 %, p = 0.002). CML stem cells harboring longer telomeres possibly maintain a proliferative potential after treatment discontinuation

Differences in sex distribution between genetic and sporadic FTD

AbstractBackgroundThe reported sex distribution differs between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that have resulted in variable findings. Our aim was to determine the sex distribution in a large international retrospective cohort of sporadic and genetic FTD.MethodWe included patients with probable and definite behavioural variant frontotemporal dementia (bvFTD), non‐fluent variant primary progressive aphasia (nfvPPA), semantic variant primary progressive aphasia (svPPA) and right temporal variant frontotemporal dementia (rtvFTD) from the Amsterdam Dementia Cohort, the Montreal Neurological Institute Cohort, the University of Ulm and Technical University of Munich Cohort (part of the German Consortium of Frontotemporal Lobal Degeneration), the Policlinico Milan Cohort and the Sydney FRONTIER Cohort. We compared sex distribution between genetic and sporadic FTD using χ2 tests.ResultA total of 910 subjects were included (56.3% male), of whom 654 had bvFTD, 99 nfvPPA, 117 svPPA and 40 rtvFTD. Of these, 215 had genetic FTD and the sex distribution was equal (51.2% male), which did not differ significantly from sporadic FTD (57.8% male, χ2 p=0.081). In the sporadic bvFTD subgroup, we found a male predominance (61.6% males compared to 52.9% males in the bvFTD genetic group, χ 2 p=0.04). No sex distribution differences between sporadic and genetic cases were found in the other clinical FTD subgroups (all p>0.05).ConclusionDifferences in sex distribution between genetic and sporadic behavioural variant of FTD may provide important clues for its differential pathogenesis and warrants further research

The coding and long noncoding single-cell atlas of the developing human fetal striatum.

Deciphering how the human striatum develops is necessary for understanding the diseases that affect this region. To decode the transcriptional modules that regulate this structure during development, we compiled a catalog of 1116 long intergenic noncoding RNAs (lincRNAs) identified de novo and then profiled 96,789 single cells from the early human fetal striatum. We found that D1 and D2 medium spiny neurons (D1- and D2-MSNs) arise from a common progenitor and that lineage commitment is established during the postmitotic transition, across a pre-MSN phase that exhibits a continuous spectrum of fate determinants. We then uncovered cell type-specific gene regulatory networks that we validated through in silico perturbation. Finally, we identified human-specific lincRNAs that contribute to the phylogenetic divergence of this structure in humans. This work delineates the cellular hierarchies governing MSN lineage commitment

Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB

Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated