Synergistic production of TNF\u3b1 and IFN\u3b1 by human pDCs incubated with IFN\u3bb3 and IL-3

In this study, we investigated whether IFN\u3bb3 and IL-3 reciprocally influence their capacity to activate various functions of human plasmacytoid dendritic cells (pDCs). In fact, we preliminarily observed that IFN\u3bb3 upregulates the expression of the IL-3R\u3b1 (CD123), while IL-3 augments the expression of IFN\u3bbR1 in pDCs. As a result, we found that combination of IFN\u3bb3 and IL-3 induces a strong potentiation in the production of TNF\u3b1, IFN\u3b1, as well as in the expression of Interferon-Stimulated Gene (ISG) mRNAs by pDCs, as compared to either IFN\u3bb3 or IL-3 alone. In such regard, we found that endogenous IFN\u3b1 autocrinally promotes the expression of ISG mRNAs in IL-3-, but not in IFN\u3bb3 plus IL-3-, treated pDCs. Moreover, we uncovered that the production of IFN\u3b1 by IFN\u3bb3 plus IL-3-treated pDCs is mostly dependent on endogenously produced TNF\u3b1. Altogether, our data demonstrate that IFN\u3bb3 and IL-3 collaborate to promote, at maximal levels, discrete functional responses of human pDCs

A Rational Approach to Drug Repositioning in β-thalassemia: Induction of Fetal Hemoglobin by Established Drugs

Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', 'drug rescue', 'drug re-tasking' and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the 'off-label' use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial

Assessing the Origin of Phosphonic Acid Residues in Organic Vegetable and Fruit Crops: The Biofosf Project Multi-Actor Approach

Recently, on the EU market, phosphonic acid residues were detected in many organic goods, although fosetyl-derivates and phosphite salts are not allowed by Reg. EC n. 889/2009. The BIOFOSF project "Solving phosphite issue in organic fruit and horticultural crops" aimed at verifying whether the phosphonic acid contamination could be due to unproper use of fertilizers/plant protection products by organic farmers, or to the plant's ability to self-produce it spontaneously. Applying a participative approach, field case-studies on potato, rocket lettuce, and pears were carried out (organic vs. integrated systems). The ethyl-phosphonic acid and phosphonic acid were determined in soil, tubers, leaves, fruits, tree woody organs, used fertilizers, and plant protection products to correlate them to the applied farming management. Tested crops were not able to self-synthetize phosphonic acid, being its detection due to: (i) external inputs not allowed in organic farming; (ii) fertilizers/plant protection products allowed in organic farming, contaminated by fosetyl or phosphite. In addition, it was found that tree crops can stock the phosphite in their woody organs, then translocate it from branches to leaves and fruits over time. Regression models applied to field data showed that fruit trees decontamination could take more than 5 years, depending on the starting value of phosphonic acid contamination, useful to define the phosphite maximum residue limit in organic fruit crops

Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)

Introduction: β-thalassemia is caused by autosomal mutations in the β-globin gene, which induce the absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that a high production of fetal hemoglobin (HbF) is beneficial for patients with β-thalassemia. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus that serves as a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular, and clinical results of a sirolimus-based NCT03877809 clinical trial (a personalized medicine approach for β-thalassemia transfusion-dependent patients: testing sirolimus in a first pilot clinical trial, Sirthalaclin). Methods: Accumulation of γ-globin mRNA was analyzed using reverse-transcription quantitative polymerase chain reaction (PCR), while the hemoglobin pattern was analyzed using high-performance liquid chromatography (HPLC). The immunophenotype was analyzed using a fluorescence-activated cell sorter (FACS), with antibodies against CD3, CD4, CD8, CD14, CD19, CD25 (for analysis of peripheral blood mononuclear cells), or CD71 and CD235a (for analysis of in vitro cultured erythroid precursors). Results: The results were obtained in eight patients with the β+/β+ and β+/β0 genotypes, who were treated with a starting dosage of 1 mg/day sirolimus for 24–48 weeks. The first finding of this study was that the expression of γ-globin mRNA increased in the blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. This trial also led to the important finding that sirolimus influences erythropoiesis and reduces biochemical markers associated with ineffective erythropoiesis (excess free α-globin chains, bilirubin, soluble transferrin receptor, and ferritin). A decrease in the transfusion demand index was observed in most (7/8) of the patients. The drug was well tolerated, with minor effects on the immunophenotype, and an only side effect of frequently occurring stomatitis. Conclusion: The data obtained indicate that low doses of sirolimus modify hematopoiesis and induce increased expression of γ-globin genes in a subset of patients with β-thalassemia. Further clinical trials are warranted, possibly including testing of the drug in patients with less severe forms of the disease and exploring combination therapies. © The Author(s), 2022

Charged Particle Tracking in Real-Time Using a Full-Mesh Data Delivery Architecture and Associative Memory Techniques

We present a flexible and scalable approach to address the challenges of charged particle track reconstruction in real-time event filters (Level-1 triggers) in collider physics experiments. The method described here is based on a full-mesh architecture for data distribution and relies on the Associative Memory approach to implement a pattern recognition algorithm that quickly identifies and organizes hits associated to trajectories of particles originating from particle collisions. We describe a successful implementation of a demonstration system composed of several innovative hardware and algorithmic elements. The implementation of a full-size system relies on the assumption that an Associative Memory device with the sufficient pattern density becomes available in the future, either through a dedicated ASIC or a modern FPGA. We demonstrate excellent performance in terms of track reconstruction efficiency, purity, momentum resolution, and processing time measured with data from a simulated LHC-like tracking detector

Overview of prognostic systems for hepatocellular carcinoma and ITA.LI.CA external validation of MESH and CNLC classifications

Prognostic assessment in patients with HCC remains an extremely difficult clinical task due to the complexity of this cancer where tumour characteristics interact with degree of liver dysfunction, patient general health status, and a large span of available treatment options. Several prognostic systems have been proposed in the last three decades, both from the Asian and European/North American countries. Prognostic scores, such as the CLIP score and the recent MESH score, have been generated on a solid statistical basis from real life population data, while staging systems, such as the BCLC scheme and the recent CNLC classification, have been created by experts according to recent HCC prognostic evidences from the literature. A third category includes combined prognostic systems that can be used both as prognostic scores and staging systems. A recent example is the ITA.LI.CA prognostic system including either a prognostic score and a simplified staging system. This review focuses first on an overview of the main prognostic systems for HCC classified according to the above three categories, and, second, on a comprehensive description of the methodology required for a correct comparison between different systems in terms of prognostic performance. In this second section the main studies in the literature comparing different prognostic systems are described in detail. Lastly, a formal comparison between the last prognostic systems proposed for each of the above three categories is performed using a large Italian database including 6882 HCC patients in order to concretely apply the comparison rules previously described

Gastro-intestinal emergency surgery: Evaluation of morbidity and mortality. Protocol of a prospective, multicenter study in Italy for evaluating the burden of abdominal emergency surgery in different age groups. (The GESEMM study)

Gastrointestinal emergencies (GE) are frequently encountered in emergency department (ED), and patients can present with wide-ranging symptoms. more than 3 million patients admitted to US hospitals each year for EGS diagnoses, more than the sum of all new cancer diagnoses. In addition to the complexity of the urgent surgical patient (often suffering from multiple co-morbidities), there is the unpredictability and the severity of the event. In the light of this, these patients need a rapid decision-making process that allows a correct diagnosis and an adequate and timely treatment. The primary endpoint of this Italian nationwide study is to analyze the clinicopathological findings, management strategies and short-term outcomes of gastrointestinal emergency procedures performed in patients over 18. Secondary endpoints will be to evaluate to analyze the prognostic role of existing risk-scores to define the most suitable scoring system for gastro-intestinal surgical emergency. The primary outcomes are 30-day overall postoperative morbidity and mortality rates. Secondary outcomes are 30-day postoperative morbidity and mortality rates, stratified for each procedure or cause of intervention, length of hospital stay, admission and length of stay in ICU, and place of discharge (home or rehabilitation or care facility). In conclusion, to improve the level of care that should be reserved for these patients, we aim to analyze the clinicopathological findings, management strategies and short-term outcomes of gastrointestinal emergency procedures performed in patients over 18, to analyze the prognostic role of existing risk-scores and to define new tools suitable for EGS. This process could ameliorate outcomes and avoid futile treatments. These results may potentially influence the survival of many high-risk EGS procedure

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

Maxillary segmental micro osteotomy: a human cadaver study on the efficacy of the technique

Purpose: Ultrasonic bone cutting was recently introduced as a feasible alternative to the conventional tools of cranio-maxillofacial surgery because it offers improved precision and safety. This study examined the feasibility of minimally invasive orthodontic or preprosthetic surgery using a piezosurgery device for lateroposterior maxillary segmental osteotomy. Materials and Methods: Four fresh cadaveric heads were obtained for this study. Maxillary posterior osteotomy was performed using piezoelectric surgery. To preserve the vascular supply, only 1 vestibular incision was made during surgery. The Mectron Piezosurgery1 unit is a multipurpose device that uses micrometric ultrasonic piezoelectric vibrations with a variable frequency and cutting energy. The strategy for maxillary osteotomy included 1 horizontal osteotomy, 2 vertical osteotomies, and 1 palatal osteotomy performed transantrally without incision of the mucoperiosteum. The osteotomies were performed using a piezodevice (OT7-type inserts: 0.55 and 0.35mm). In total, 1 horizontal cut (3mmabove the roots of the teeth), 2 vertical bone cuts, and 1 palatal osteotomy were made without incision of the palatal mucoperiosteum. Gentle dissection of the buccal fat pad was used to promote the healing of hard and soft tissues in the osteotomized zone. Results: No damage to soft tissues, including the palatal mucosa, occurred. The buccal fat pad was mobilized easily without requiring an additional incision. The osteotomic sites were linear and clean in the palatal aspect. The integrity of the vascular network was maintained because of the lack of damage to the palatal mucosa. No chisels were used during the osteotomies. Discussion: This cadaveric study shows the feasibility of using piezosurgery for segmental maxillary osteotomy. This report outlines a new and simple application of segmental maxillary micro-osteotom

La distalisation des molaires mandibulaires peut-elle être facilitée ? Une nouvelle méthode thérapeutique

Une jeune patiente consulte avec une agénésie des deux secondes prémolaires mandibulaires. Les paramètres cliniques et céphalométriques suggèrent l'indication d'une ouverture d'espace prothétique entre les premières prémolaires et les premières molaires avec l'objectif de rétablir une normoclusion molaire. L'alternative thérapeutique (fermeture des espaces d'agénésie) est écartée. Après l'alignement de l'arcade, une ostéotomie conservatrice en forme de coin a été effectuée en arrière des secondes molaires en piezo-chirurgie. Pour cette technique de découpe aux ultrasons, on utilise des inserts de petite taille (0,5–0,7 mm). Elle est bien acceptée par nos patients, la cicatrisation est rapide, et il n'y a pas d'effets secondaires indésirables. Les secondes et les premières molaires peuvent être distalées sans version, en un mouvement de translation. Une fois l'espace créé, le patient peut être implanté, et la réhabilitation occlusale finalisée. La validation de cette technique nécessitera d'en approfondir l'étude, mais elle paraît déjà présenter un réel progrès, par rapport aux méthodes conventionnelles, pour faciliter la distalisation dans des cas sélectionnés et probablement réduire le temps de traitement