Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs' potential for bone regeneration has been shown, issues associated with their ...therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (
≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (
≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (
≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (
≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration.
Context. RX J1713.7–3946 is the brightest shell-type supernova remnant (SNR) of the TeV γ-ray sky. Earlier Fermi-LAT results on low energy γ-ray emission suggested that, despite large uncertainties ...in the background determination, the spectrum is inconsistent with a hadronic origin. Aims. We update the GeV-band spectra using improved estimates for the diffuse Galactic γ-ray emission and more than double the volume of data. We further investigate the viability of hadronic emission models for RX J1713.7–3946. Methods. We produced a high-resolution map of the diffuse Galactic γ-ray background corrected for the HI self-absorption and used it in the analysis of more than five years worth of Fermi-LAT data. We used hydrodynamic scaling relations and a kinetic transport equation to calculate the acceleration and propagation of cosmic rays in SNR. We then determined spectra of hadronic γ-ray emission from RX J1713.7–3946, separately for the SNR interior and the cosmic-ray precursor region of the forward shock, and computed flux variations that would allow us to test the model with observations. Results. We find that RX J1713.7–3946 is now detected by Fermi-LAT with very high statistical significance, and the source morphology is best described by that seen in the TeV band. The measured spectrum of RX J1713.7–3946 is hard with index γ = 1.53 ± 0.07, and the integral flux above 500 MeV is F = (5.5 ± 1.1) × 10-9 photons cm-2 s-1. We demonstrate that scenarios based on hadronic emission from the cosmic-ray precursor region are acceptable for RX J1713.7–3946, and we predict a secular flux increase at a few hundred GeV at the level of around 15% over ten years, which may be detectable with the upcoming Cherenkov Telescope Array (CTA) observatory.
Purpose
To investigate predictors of testicular response and non-reproductive outcomes (height, body proportions) after gonadotropin-induced puberty in congenital hypogonadotropic hypogonadism (CHH).
...Design
A retrospective analysis of the puberty induction in CHH male patients, undergoing an off-label administration of combined gonadotropin (FSH and hCG).
Methods
Clinical and hormonal evaluations before and during gonadotropin stimulation in 19 CHH patients genotyped by Targeted Next Generation Sequencing for CHH genes; 16 patients underwent also semen analysis after gonadotropins.
Results
A lesser increase in testicular volume after 24 months of induction was significantly associated with: (I) cryptorchidism; (II) a positive genetic background; (III) a complete form of CHH. We found no significant correlation with the cumulative dose of hCG administered in 24 months. We found no association with the results of semen analyses, probably due to the low numerosity. Measures of body disproportion (eunuchoid habitus and difference between adult and target height: deltaSDSth), were significantly related to the: (I) age at the beginning of puberty induction; (II) duration of growth during the induction; (III) initial bone age. The duration of growth during induction was associated with previous testosterone priming and to partial forms of CHH.
Conclusions
This study shows that a strong genetic background and cryptorchidism, as indicators of a complete GnRH deficiency since intrauterine life, are negative predictors of testicular response to gonadotropin stimulation in CHH. Body disproportion is associated with a delay in treatment and duration of growth during the induction, which is apparently inversely related to previous androgenization.
The use of extracellular vesicles (EVs) is emerging as a promising acellular approach for bone regeneration, overcoming translational hurdles associated with cell-based therapies. Despite their ...potential, EVs short half-life following systemic administration hinders their therapeutic efficacy. EVs have been reported to bind to extracellular matrix (ECM) proteins and play an essential role in matrix mineralisation. Chitosan and collagen type I are naturally-derived pro-osteogenic biomaterials, which have been demonstrated to control EV release kinetics. Therefore, this study aimed to develop an injectable ECM-mimetic hydrogel capable of controlling the release of osteoblast-derived EVs to promote bone repair. Pure chitosan hydrogels significantly enhanced compressive modulus (2.48-fold) and osteogenic differentiation (3.07-fold), whilst reducing gelation times (2.09-fold) and proliferation (2.7-fold) compared to pure collagen gels (
≤ 0.001). EV release was strongly associated with collagen concentration (R
> 0.94), where a significantly increased EV release profile was observed from chitosan containing gels using the CD63 ELISA (
≤ 0.001). Hydrogel-released EVs enhanced human bone marrow stromal cells (hBMSCs) proliferation (1.12-fold), migration (2.55-fold), and mineralisation (3.25-fold) compared to untreated cells (
≤ 0.001). Importantly, EV-functionalised chitosan-collagen composites significantly promoted hBMSCs extracellular matrix mineralisation when compared to the EV-free gels in a dose-dependent manner (
≤ 0.001). Taken together, these findings demonstrate the development of a pro-osteogenic thermosensitive chitosan-collagen hydrogel capable of enhancing the therapeutic efficacy of osteoblast-derived EVs as a novel acellular tool for bone augmentation strategy.
Purpose
The aim of our study was to compare the incidence of idiopathic central precocious puberty (CPP) in our highly specialized Endocrinological Center before and after the onset of COVID-19 ...lockdown; we also aimed to identify any potential difference between girls with CPP from the two different time periods.
Methods
We retrospectively analyzed the auxological profile of 49 girls with idiopathic CPP: 30 with pre-lockdown onset and 19 with post-lockdown onset of the disease. We collected patients’ characteristics (medical history, physical examination, baseline and dynamic hormonal assessment, bone age, pelvic ultrasound) and compared them between the two groups.
Results
We registered an almost threefold increase in CPP incidence in the 2020–2021 period compared to the previous six years. In post-lockdown patients we found a trend for an earlier diagnosis in terms of both chronological age (
p
0.0866) and days between the onset of first pubertal signs and diagnosis (
p
0.0618). We also found that post-lockdown patients had a significantly lower hypothalamus-pituitary–gonadal axis activation (lower ∆LH% after GnRH test,
p
0.0497), a significantly lower increase in bone age calculated at RUS with TW3 method (
p
0.0438) and a significantly reduced ovarian activation in females (lower delta-4-androstenedione levels, p 0.0115). Interestingly, post-lockdown patients were born from mothers with an older age at menarche (
p
0.0039).
Conclusions
Besides confirming a significant increase in new diagnoses of CPP in the post-lockdown period, our findings among Post-lockdown girls also suggest a less progressive form of CPP and a stronger environmental influence compared to genetic background in determining the timing of pubertal onset.
To implement Area‐Wide Pest Management protocols at a regional scale (Liguria, northern Italy), egg deposition and adult flight of olive fruit fly, Bactrocera oleae, were monitored during 2009, 2010 ...and 2011. The consequence of complete generation in late winter – early spring was also examined. The reliability of a degree‐day model was tested to simulate the insect cycle, starting from October oviposition and considering a 379.01°C cumulative degree‐day (CDD) needed to complete development. The model was validated and then used to simulate olive fruit fly phenology in the region of Liguria, using a GIS approach and the agrometeorological network in the region. The output of the CDD model was mapped with two different spatialization modelling techniques, geostatistical autocorrelation and regression correlation, and altitude, aspect and distance from the sea were assessed as elements of variability. The regression correlation model provided a more accurate indication of B. oleae diversity at the local scale than the geostatistical autocorrelation model and identified the high spatial climatic variability of Liguria. The potential application of the distribution of days after oviposition and prediction error maps in support of pest management planning is discussed.
Decisions taken under the Paris Agreement of the UNFCCC do not clarify how the principle of equity is to be operationalized. Proper consideration of different national circumstances is of paramount ...importance when designing any multilateral agreements, such as the Paris Agreement . Here, a methodology is presented that implements the equity principle in sharing the global climate budget among countries on the basis of their national circumstances identified by socio-economic factors such as the population size, the per-capita gross domestic product and the current net GHG emission, and physical factors such as the population density and the average temperature. The historical responsibility for net GHG emission since 1990 is dealt with by the financial commitments made by developed countries. The impact of international trade on actual net GHG emission associated with consumption of goods is deemed compensated by the carbon rights underlying the production of such traded goods. Results obtained show that without a consideration of national circumstances, large emitters can claim a larger quota. Nevertheless, national circumstances change over time because of social and economic development as well as because technological improvements. Consequently, quotas have to be recalculated over time (e.g. at each global stocktake).
TeV J2032+4130 was the first unidentified source discovered at very high energies (VHEs; E > 100 GeV), with no obvious counterpart in any other wavelength. It is also the first extended source to be ...observed in VHE gamma rays. Following its discovery, intensive observational campaigns have been carried out in all wavelengths in order to understand the nature of the object, which have met with limited success. We report here on a deep observation of TeV J2032+4130 based on 48.2 hr of data taken from 2009 to 2012 by the Very Energetic Radiation Imaging Telescope Array System experiment. The source is detected at 8.7 standard deviations (sigma) and is found to be extended and asymmetric with a width of 9'.5 + or - 1'.2 along the major axis and 4'.0 + or - 0'.5 along the minor axis. The spectrum is well described by a differential power law with an index of 2.10 + or - 0.14 sub(stat) + or - 0.21 sub(sys) and a normalization of (9.5 + or - 1.6 sub(stat) + or - 2.2 sub(sys)) x 10 super(-13) TeV super(-1) cm super(-2) s super(-1) at 1 TeV. We interpret these results in the context of multiwavelength scenarios which particularly favor the pulsar wind nebula interpretation.
Information on the general health of transgender and gender diverse (TGD) individuals continues to be lacking. To bridge this gap, the National Institute of Health in Italy together with the National ...Office against Racial Discriminations, clinical centres, and TGD organizations carried out a cross-sectional study to define the sociodemographic profile, health-related behaviours, and experiences of healthcare access in Italian TGD adult population.
A national survey was conducted by Computer-Assisted Web Interviewing (CAWI) technique. Collected data were compared within the TGD subgroups and between TGD people and the Italian general population (IGP).
TGD respondents were 959: 65% assigned female at birth (AFAB) and 35% assigned male at birth (AMAB). 91.8% and 8.2% were binary and non-binary TGD respondents, respectively. More than 20% of the TGD population reported to be unemployed with the highest rate detectable in AMAB and non-binary people. Cigarette smoking and binge drinking were higher in the TGD population compared with IGP (p < 0.05), affecting TGD subgroups differently. A significant lower percentage of AFAB TGD people reported having had screening for cervical and breast cancer in comparison with AFAB IGP (p < 0.0001, in both cases). Over 40% was the percentage of AFAB and non-binary TGD people accessing healthcare who felt discriminated against because of their gender identity.
Our results are a first step towards a better understanding of the health needs of TGD people in Italy in order to plan the best policy choices for a more inclusive public health.
Purpose
There is a lack of uniformity in the definition of normal ovary ultrasound parameters. Our aim was to summarize and meta-analyze the evidence on the topic. Full-text English articles ...published through December 31, 2020 were retrieved via MEDLINE and Embase. Data available for meta-analysis included: ovarian follicular count, ovarian volume, and ovarian Pulsatility Index (PI) assessed by Doppler ultrasound.
Methods
Cohort, cross-sectional, prospective studies with a single or double arm were considered eligible. Interventional studies were included when providing baseline data. Both studies on pre- and post-menopausal women were screened; however, data on menopausal women were not sufficient to perform a meta-analysis. Studies on pre-pubertal girls were considered separately. Eighty-one papers were included in the meta-analysis.
Results
The mean ovarian volume was 6.11 5.81–6.42 ml in healthy women in reproductive age (5.81–6.42) and 1.67 ml 1.02–2.32 in pre-pubertal girls. In reproductive age, the mean follicular count was 8.04 7.26–8.82 when calculated in the whole ovary and 5.88 5.20–6.56 in an ovarian section, and the mean ovarian PI was 1.86 1.35–2.37. Age and the frequency of the transducers partly modulated these values. In particular, the 25–30-year group showed the higher mean follicular count (9.27 7.71–10.82), followed by a progressive age-related reduction (5.67 2.23–9.12 in fertile women > 35 years). A significant difference in follicular count was also found according to the transducer’s upper MHz limit.
Conclusion
Our findings provide a significant input to improve the interpretation and diagnostic accuracy of ovarian ultrasound parameters in different physiological and pathological settings.
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