Understanding the effect of formulation and processing parameters on microstructural and physical properties of ice cream, sensory perception and appetite

Ice cream is a fatty, low satiating food which may increase obesity levels. This thesis aims to understand if it is possible to develop a more satiating product by manipulating formulation and/or processing. First, the effect of two emulsifiers (mono and diglycerides, MDGs and Tween 80) on the thermal behaviour of a bulk fat matrix was investigated. MDGs were shown to possibly enhance ice cream fat destabilisation more than tween 80. This research continued on an ice cream matrix, investigating the effect of different HLB (hydrophilic-lipophilic balance) number emulsifiers (MDGs based). Low and high HLB number emulsifiers (compared with intermediate HLB numbers) led to the formation of a more structured fat network. Moreover, the investigation of different solid fat content (SFC) blends and the aging step showed that 1) the fat network became more structured as the SFC increased (unless this was too high); 2) aging step could be avoided; 3) it is feasible to considerably decrease the SFC without affecting consumers’ response; and 4) SFC had a predominant effect on palatability. Finally, an appetite study allowed answering the research question of this work, demonstrating that formulation manipulation could be a promising way to reduce food intake (i.e. obesity levels)

DREADD activation of pedunculopontine cholinergic neurons reverses motor deficits and restores striatal dopamine signaling in parkinsonian rats

The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson’s disease (PD), which correlates with axial motor deficits. PPN-Deep Brain Stimulation (DBS) can alleviate certain symptoms, but its mecha-nism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with Positron Emission Tomography (PET) imaging for in vivo in-terrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce pro-found motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor (DR) 1- and DR2-based medium spiny neuron (MSN) activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axi-al-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the Substantia Nigra pars compacta (SNpc) and the striatum, our data strongly favor the PPN cholinergic-midbrain dopaminergic connectome as mechanism for PPN-DBS’s therapeutic effects. These findings have implications for refining PPD-DBS as a promising treatment modality available to PD patients

Kinetic modelling of [(11)C]PBR28 for 18 kDa translocator protein PET data:A validation study of vascular modelling in the brain using XBD173 and tissue analysis

The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [11C]PBR28 and [11C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data. Here, we performed a validation of the kinetic model with the additional endothelial compartment through a displacement study. Seven subjects with schizophrenia, all high-affinity binders, underwent two [11C]PBR28 PET scans before and after oral administration of 90 mg of the TSPO ligand XBD173. The addition of the endothelial component provided a signal compartmentalization much more consistent with the underlying biology, as only in this model, the blocking study produced the expected reduction in the tracer concentration of the specific tissue compartment, whereas the non-displaceable compartment remained unchanged. In addition, we also studied TSPO expression in vessels using 3D reconstructions of histological data of frontal lobe and cerebellum, demonstrating that TSPO positive vessels account for 30% of the vascular volume in cortical and white matter

Quantitation of regional ejection fractions using gated tomographic imaging with Tc-99m-sestamibi

BACKGROUND: A new oro-dispersible film (ODF) formulation of sildenafil has been developed for the treatment of erectile dysfunction (ED) to overcome the drawbacks that some patients experience when taking the conventional film-coated tablet (FCT). AIM: To assess the effectiveness and safety of sildenafil ODF formulation in patients with ED who were using the conventional FCT. METHODS: From May 2017 through July 2017, 139 patients with ED were enrolled. Data from penile color-duplex ultrasound, medical history, hormonal evaluation, and patient self-administered questionnaires were collected. All patients were administered sildenafil 100-mg FCT for 4 weeks. Thereafter, they underwent a 2-week washout period and subsequently took sildenafil 75-mg ODF for 4 weeks. OUTCOMES: The International Index of Erectile Function (IIEF-15), Hospital Anxiety and Depression Scale (HADS), Patient Global Impressions of Improvement (PGI-I), and Clinician Global Impressions of Improvement (CGI-I) questionnaires were administered and severity of ED was classified as severe (IIEF-15 score ≤ 10), moderate (IIEF-15 score 11-16), or mild (IIEF-15 score = 17-25). RESULTS: All patients completed the final protocol. Differences in mean IIEF scores for erectile function, orgasmic function, sexual desire, and intercourse satisfaction were significantly in favor of sildenafil 100-mg FCT, whereas the mean score for overall satisfaction was in favor of sildenafil 75-mg ODF. A significant difference in changes in HADS score was found from washout to final follow-up (mean difference = -0.19; P < .01). For the ODF formulation, the median CGI-I score was 3.5 (interquartile range [IQR] = 2.5-4.5) and the median PGI-I score was 3.0 (IQR = 2.0-4.0). The median action time was 20.0 minutes (IQR = 15.0-30.0) and the median mouth time was 60.0 seconds (IQR = 30.0-120.0). CLINICAL IMPLICATIONS: The ODF formulation of a widely known drug, with the same safety and effectiveness of the FCT, was better appreciated by patients in overall satisfaction. STRENGTHS AND LIMITATIONS: This is the first clinical trial to assess the efficacy of a new formulation of sildenafil in patients with ED. The limitations of the study are related to the methodology used: it was not a case-control study and the patients were not drug-naïve for ED treatment. Therefore, only the "additional" side effects of the ODF formulation compared with FCT are reported. CONCLUSION: The new ODF formulation is as efficient and safe as the FCT formulation and offers a new choice of treatment to specialists for more precisely tailored therapy. Cocci A, Capece M, Cito G, et al. Effectiveness and Safety of Oro-Dispersible Sildenafil in a New Film Formulation for the Treatment of Erectile Dysfunction: Comparison Between Sildenafil 100-mg Film-Coated Tablet and 75-mg Oro-Dispersible Film. J Sex Med 2017;X:XXX-XXX

Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study

Background Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. Aims To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) Methods Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). Results 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p&lt;0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p&lt;0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0–4.1]; p&lt;0.001). Conclusions Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258)

Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge

The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.ISSN:0271-678XISSN:1559-701

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

© 2020 The Author(s). Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvβ6) integrin inhibitor, in participants with IPF. Methods: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: Baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvβ6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. Results: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI:-9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. Conclusions: This study demonstrated engagement of the αvβ6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. Trial registration: Clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years

PET-BIDS, an extension to the brain imaging data structure for positron emission tomography

The Brain Imaging Data Structure (BIDS) is a standard for organizing and describing neuroimaging datasets, serving not only to facilitate the process of data sharing and aggregation, but also to simplify the application and development of new methods and software for working with neuroimaging data. Here, we present an extension of BIDS to include positron emission tomography (PET) data, also known as PET-BIDS, and share several open-access datasets curated following PET-BIDS along with tools for conversion, validation and analysis of PET-BIDS datasets