Case report: long-acting oral cariprazine

Introduction: Cariprazine is a third-generation antipsychotic, approved for the treatment of schizophrenia and bipolar disorder and used off-label for schizoaffective disorder and treatment-resistant depression. Cariprazine is a partial agonist at dopamine receptors D2 and D3 and serotonin receptor 5HT1A and an antagonist at serotonin receptors 5HT2B and 5HT2A. It is metabolized by CYP3A4 in desmetyl-cariprazine and didesmethyl-cariprazine, both active metabolites with a half-life of 1-2 days and 2-3 weeks, respectively. Case Report: Here we show the cases of 3 outpatients diagnosed with bipolar I disorder (two patients) and schizoaffective disorder (one patients) and characterized by low adherence to treatment, satisfactory cognitive and personal functioning and average disease severity to whom we administered cariprazine as a monotherapy, on a two-times a week schedule (i.e., every 72-96 h). We evaluated response to treatment and disease remission according to conventional definitions, using rating scales BPRS, PANSS and BDI-II. Two-times a week treatment was set either after a disease relapse (one patient), after a sustained remission obtained with daily administration of cariprazine (one patient) or since our first evaluation (one patient). After 4 weeks of treatment all three patients satisfied criteria for response to treatment and remission, a result that was sustained for 8 (in one patients) and 12 months (in other two patients) and still ongoing. Discussion: Reported results support our hypothesis that long half-lives of cariprazine and its metabolites provide an adequate therapeutic response with a two-times a week administration. In selected patients, cariprazine administered as a "oral long-acting" seems effective in treating acute episodes of illness and in sustaining remission, combining advantages of oral and long-acting injectable antipsychotics concerning therapeutic alliance

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25 mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while beta-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment. The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and beta-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain. In conclusion, the present study demonstrates that 25 mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results

Cosmological and astrophysical parameters from the SDSS flux power spectrum and hydrodynamical simulations of the Lyman-alpha forest

(abridged) The flux power spectrum of the Lyman-alpha forest in quasar (QSO) absorption spectra is sensitive to a wide range of cosmological and astrophysical parameters and instrumental effects. Modelling the flux power spectrum in this large parameter space to an accuracy comparable to the statistical uncertainty of large samples of QSO spectra is very challenging. We use here a coarse grid of hydrodynamical simulations run with GADGET-2 to obtain a ``best guess'' model around which we calculate a finer grid of flux power spectra using a Taylor expansion of the flux power spectrum to first order. We find that the SDSS flux power spectrum alone is able to constrain a wide range of parameters including the amplitude of the matter power spectrum sigma_8, the matter density Omega_m, the spectral index of primordial density fluctuations n, the effective optical depth tau_eff and its evolution. The thermal history of the Intergalactic Medium (IGM) is, however, poorly constrained and the SDSS data favour either an unplausibly large temperature or an unplausibly steep temperature-density relation. By enforcing a thermal history of the IGM consistent with that inferred from high-resolution QSO spectra, we find the following values for the best fitting model (assuming a flat Universe with a cosmological constant and zero neutrino mass): Omega_ m=0.28 \pm 0.03, n=0.95\pm0.04, \sigma_8=0.91\pm0.07 (1\sigma error bars).We argue that the major uncertainties in this measurement are still systematic rather than statistical.Comment: 16 pages, 7 figures, 3 tables. Minor changes to match the accepted version. MNRAS, in pres

Comprehensive Brain Tumour Characterisation with VERDICT-MRI: Evaluation of Cellular and Vascular Measures Validated by Histology

The aim of this work was to extend the VERDICT-MRI framework for modelling brain tumours, enabling comprehensive characterisation of both intra- and peritumoural areas with a particular focus on cellular and vascular features. Diffusion MRI data were acquired with multiple b-values (ranging from 50 to 3500 s/mm2), diffusion times, and echo times in 21 patients with brain tumours of different types and with a wide range of cellular and vascular features. We fitted a selection of diffusion models that resulted from the combination of different types of intracellular, extracellular, and vascular compartments to the signal. We compared the models using criteria for parsimony while aiming at good characterisation of all of the key histological brain tumour components. Finally, we evaluated the parameters of the best-performing model in the differentiation of tumour histotypes, using ADC (Apparent Diffusion Coefficient) as a clinical standard reference, and compared them to histopathology and relevant perfusion MRI metrics. The best-performing model for VERDICT in brain tumours was a three-compartment model accounting for anisotropically hindered and isotropically restricted diffusion and isotropic pseudo-diffusion. VERDICT metrics were compatible with the histological appearance of low-grade gliomas and metastases and reflected differences found by histopathology between multiple biopsy samples within tumours. The comparison between histotypes showed that both the intracellular and vascular fractions tended to be higher in tumours with high cellularity (glioblastoma and metastasis), and quantitative analysis showed a trend toward higher values of the intracellular fraction (fic) within the tumour core with increasing glioma grade. We also observed a trend towards a higher free water fraction in vasogenic oedemas around metastases compared to infiltrative oedemas around glioblastomas and WHO 3 gliomas as well as the periphery of low-grade gliomas. In conclusion, we developed and evaluated a multi-compartment diffusion MRI model for brain tumours based on the VERDICT framework, which showed agreement between non-invasive microstructural estimates and histology and encouraging trends for the differentiation of tumour types and sub-regions

Tiny events: tales of urban domesticity from Lingotto, a former working-class neighborhood in Turin

Article published by 12 authors, coordinated by Filippo De Pieri and Gaia Caramellino, as "The Housing History Collective

Cosmic evolution of the CIV in high-resolution hydrodynamic simulations

We investigate the properties of triply ionized Carbon (CIV) in the Intergalactic Medium using a set of high-resolution and large box-size cosmological hydrodynamic simulations of a $\Lambda$CDM model. We rely on a modification of the GADGET-2 code that self-consistently follows the metal enrichment mechanism by means of a detailed chemical evolution model. We focus on several numerical implementations of galactic feedback: galactic winds in the energy driven and momentum driven prescriptions and Active Galactic Nuclei (AGN) powered by gas accretion onto massive black holes. We extract mock IGM transmission spectra in neutral hydrogen (HI) and CIV and perform Voigt profile fitting. The results are then compared with high-resolution quasar (QSO) spectra obtained with the UVES spectrograph at the VLT and the HIRES spectrograph at Keck. We find that feedback has little impact on statistics related to the neutral hydrogen, while CIV is more affected by galactic winds and/or AGN feedback. When the same analysis is performed over observed and simulated CIV lines, we find reasonables good agreement between data and simulations over the column density range $N_{\rm CIV}=10^{12.5-15}$ cm$^{-2}$. Also the CIV line-widths distribution appears to be in agreement with the observed values, while the HI Doppler parameters, $b_{\rm HI}$, are in general too large showing that the diffuse cosmic web is heated more than what is inferred by observations. The simulation without feedback fails in reproducing the CIV systems at high column densities at all redshift, while the AGN feedback case agrees with observations only at $z<3$, when this form of feedback is particularly effective. We also present scatter plots in the $b-N$ and in the $N_{\rm CIV}-N_{\rm HI}$ planes, showing that there is rough agreement between observations and simulations only when feedback is taken into account.Comment: 22 pages, 20 figures, minor revisions, accepted for publication in MNRA

Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE)

An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. All consecutive hospitalised patients from February 21st to March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included. In-hospital mortality and discharge were evaluated by competing risk analysis. The Fine and Gray model was fitted in order to estimate the effect of covariates on the cumulative incidence functions (CIFs) for in-hospital mortality and discharge. 426 adult patients [median age 68 (IQR 56 to 77&nbsp;years)] were admitted with confirmed COVID-19 over a 5-week period; 292 (69%) were male. By 21 April 2020, 141 (33%) of these patients had died, 239 (56%) patients had been discharged and 46 (11%) were still hospitalised. Among these 46 patients, updated as of 30 May, 2020, 5 (10.9%) had died, 8 (17.4%) were still in ICU, 12 (26.1%) were transferred to lower intensity care units and 21 (45.7%) were discharged. Regression on the CIFs for in-hospital mortality showed that older age, male sex, number of comorbidities and hospital admission after March 4th were independent risk factors associated with in-hospital mortality. Older age, male sex and number of comorbidities definitively predicted in-hospital mortality in hospitalised patients with COVID-19

A cross-correlation study of the Fermi-LAT γ\gamma-ray diffuse extragalactic signal

In this work, starting from 21 months of data from the Fermi-Large Area Telescope, we derive maps of the residual isotropic gamma-ray emission, a relevant fraction of which is expected to be contributed by the extragalactic diffuse gamma-ray background. We compute the angular two-point auto-correlation function of the residual Fermi-LAT maps at energies E>1GeV, E>3GeV and E>30GeV well above the Galactic plane and find no significant correlation signal. This is, indeed, what is expected if the EGB were contributed by BL Lacertae, Flat Spectrum Radio Quasars or star-forming galaxies, since, in this case, the predicted signal is very weak. Then, we search for the Integrated Sachs-Wolfe signature by cross-correlating the Fermi-LAT maps with the WMAP7-Cosmic Microwave Background map. We find a cross-correlation consistent with zero, even though the expected signal is larger than that of the EGB auto-correlation. Finally, in an attempt to constrain the nature of the gamma-ray background we cross-correlate the Fermi-LAT maps with the angular distributions of objects that may contribute to the EGB: QSOs in the SDSS-DR6 catalog, NVSS galaxies, 2MASS galaxies and LRG in the SDSS catalog. The cross-correlation is always consistent with zero, in agreement with theoretical expectations, but we find (with low statistical significance) some interesting features that may indicate that some specific classes of objects contribute to the EGB. A chi2 analysis confirms that the correlation properties of the 21-month data do not provide strong constraints of the EGB origin. However, the results suggest that the situation will significantly improve with the 5- and 10-year Fermi-LAT data. The future EGB analysis will then allow placing significant constraints on the nature of the EGB and might provide in addition a detection of the ISW signal. (Abridged)Comment: 18 pages, 23 figures, 2 tables, MNRAS in pres