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Abstract PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Background: Acute mediastinitis is rarely caused by haematogenous spread of a remote infection. In this respect, since the only medical therapy is usually unsuccessful, treating acute mediastinitis with no source of infection detected is very challenging and management not standardized. In this case report, we describe non-surgical management experience of acute mediastinitis caused by methicillin-sensitive Staphylococcus aureus. Case presentation: In a 79-year-old man judged not eligible for cardiac surgery, we attempted the infection source control through vacuum-assisted closure therapy, together with antimicrobial therapy. We observed gradual clinical, laboratory and radiologic improvements: reduced swelling and normalization of the white blood cell count and C-reactive protein level were associated with reduction in size of a periaortic abscess. Conclusion: We managed a clinical condition with high mortality risk with chronic antimicrobial therapy alone, a strategy that is rarely considered. With this medical strategy we achieved an optimal response to a clinical picture that does not allow any other approach.

Abstract To compare two different wavelengths of the surgical contact diode laser (CDL) for producing a posterior laryngofissure in in-vivo pigs. Anesthetized pigs underwent a tracheostomy and an anterior laryngofissure through a cervicotomy. They were randomly selected for the CDL wavelength and Power, according to the peak of Power set at device (980nm wavelength: Ppeak power of 10 W, 15 W, and 20 W, or 1470 nm wavelength: Ppeak 3 W, 5 W, 7 W, 10 W). At the end of the experiment, the laryngotracheal specimen was extracted and sent for histology and morphometry measurements (incision size, depth, area, and lateral thermal damage). Hemodynamic data and arterial blood gases were recorded during the incisions. Statistical analysis of the comparisons between the parameters and groups had a level of significance of p < 0.05. Twenty-six pigs were divided into CDL 980 nm (n = 11) and 1470 nm (n = 15). There was a greater incision area at the thyroid level in the 980 nm CDL and a wider incision at the trachea level, with a larger distance between mucosa borders. There were no significant differences in the area of lateral thermal damage between the two groups and neither difference among the power levels tested. Both wavelengths tested showed similar results in the various combinations of power levels without significant differences in the lateral thermal damage. The posterior laryngofissure incision can be performed by either of the wavelengths at low and medium power levels without great difference on lateral thermal damage.

Abstract Background Research study participants can stop taking part early, in various circumstances. Sometimes this experience can be stressful. Providing participants with the information they want or need when they stop could improve participants’ experiences, and may benefit individual studies’ objectives and research in general. A group of public contributors and researchers at the Clinical Trials Research Unit, University of Leeds, aimed to develop a communication template and researcher guidance. This would address how to provide information sensitively around the time when participants stop or significantly reduce their level of participation. Methods The project lead used scoping review methods to identify relevant prior evidence and derive a list of potential information topics to communicate to participants who stop taking part. The topic list was reviewed by research professionals and public contributors before finalisation. Further public contributors were identified from a range of networks. The contributors formed a ‘development group’, to work on the detail of the planned resources, and a larger ‘review group’ to review the draft output before finalisation. The involvement was planned so that the development group could shape the direction and pace of the work. Results The literature review identified 413 relevant reports, resulting in 94 information topics. The review suggested that this issue has not been well explored previously. Some evidence suggested early-stopping participants are sometimes excluded from important communications (such as study results) without clear justification. The development group agreed early to focus on guidance with reusable examples rather than a template. We took time to explore different perspectives and made decisions by informal consensus. Review group feedback was broadly positive but highlighted the need to improve resource navigability, leading to its final online form. Conclusions We co-developed a resource to provide support to research participants who stop taking part. A strength of this work is that several of the public contributors have direct lived experience of stopping research participation. We encourage others to review the resource and consider how they support these participants in their studies. Our work highlights the value of researchers and participants working together, including on complex and ethically challenging topics.

Abstract Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative l-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR–mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.

Abstract The peopling of Europe during the Middle Pleistocene is a debated topic among paleoanthropologists. Some authors suggest the coexistence of multiple human lineages in this period, while others propose a single evolving lineage from Homo heidelbergensis to Homo neanderthalensis. The recent reassessment of the stratigraphy at the Sedia del Diavolo (SdD) site (Latium, Italy), now dated to the beginning of marine isotope stage (MIS) 8, calls for a revision of the human fossils from the site. In this paper, we present the morphometric, biomechanical and palaeopathological study of the second right metatarsal SdD2, to both re-evaluate its taxonomical affinities and possibly determine the levels of physical activity experienced by the individual during lifetime. Results demonstrate the persistence of archaic features in SdD2 suggesting new insights into the technology and hunting strategies adopted by Homo between MIS 9 and MIS 8.

ABSTRACT Obesity is a prevalent chronic disease. The management of extreme obesity – i.e., body mass index (BMI) ≥ 50 kg/m2 or obesity class IV and V – is still far from ideal. Individuals with extreme obesity have a high risk of surgical complications, mortality, comorbidities, and reduced weight loss following bariatric surgery. Although lifestyle changes and anti-obesity medications are recommended for all patients with extreme obesity as adjuvants to weight loss, these measures are less effective than bariatric surgery. As a first step, sleeve gastrectomy or an inpatient very-low-calorie diet should be incentivized to enhance weight loss before definitive surgery. Although malabsorptive procedures lead to greater weight loss, they are associated with an increased risk of early complications and malnutrition. Nonstandard techniques employed in clinical trial protocols, such as transit bipartition, may be performed as they maintain a weight loss potency comparable to that of the classic duodenal switch but with fewer nutritional problems. Anatomical causes should be investigated in patients with postoperative suboptimal clinical response or recurrent weight gain. In these cases, the initiation of anti-obesity drugs, endoscopic therapies, or a conversion procedure might be recommended. More studies are needed to address the specific population of patients with extreme obesity, as their outcomes are expected to be distinct from those of patients with lower BMI.

The placebo and nocebo effects highlight the importance of expectations in modulating pain perception, but in everyday life we don’t need an external source of information to form expectations about pain. The brain can learn to predict pain in a more fundamental way, simply by experiencing fluctuating, non-random streams of noxious inputs, and extracting their temporal regularities. This process is called statistical learning. Here, we address a key open question: does statistical learning modulate pain perception? We asked 27 participants to both rate and predict pain intensity levels in sequences of fluctuating heat pain. Using a computational approach, we show that probabilistic expectations and confidence were used to weigh pain perception and prediction. As such, this study goes beyond well-established conditioning paradigms associating non-pain cues with pain outcomes, and shows that statistical learning itself shapes pain experience. This finding opens a new path of research into the brain mechanisms of pain regulation, with relevance to chronic pain where it may be dysfunctional.

Abstract Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but is still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development (referred to as the RAPID-E protocol). Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II, but additionally expressed Collagen X, indicative of hypertrophy. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.

BackgroundChildren diagnosed with cerebral palsy (CP) often experience various limitations, particularly in gross motor function and activities of daily living. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been used to improve movement, gross motor function, and activities of daily living. ObjectiveThis study aims to evaluate the potential additional effects of physiotherapy combined with tDCS in children with CP in comparison with physiotherapy only. MethodsThis is a 2-arm randomized controlled trial that will compare the effects of tDCS as an adjunctive treatment during rehabilitation sessions to rehabilitation without tDCS. Children with CP classified by the Gross Motor Function Classification System as levels I and II will be randomly assigned to either the sham + rehabilitation group or the tDCS + rehabilitation group. The primary outcome will be the motor skills assessed using the Gross Motor Function Measure domain E scores, and the secondary outcome will be the measurement scores of the children’s quality of life. The intervention will consist of a 10-day stimulation protocol with tDCS spread over 2 weeks, with stimulation or sham tDCS administered for 20 minutes at a frequency of 1 Hz, in combination with physiotherapy. Physical therapy exercises will be conducted in a circuit based on each child’s baseline Gross Motor Function Measure results. The participants’ changes will be evaluated and compared in both groups. Intervenient features will be tested. ResultsData collection is ongoing and is expected to be completed by January 2025. A homogeneous sample and clear outcomes may be a highlight of this protocol, which may allow us to understand the potential use of tDCS and for whom it should or should not be used. ConclusionsA study with good evidence and clear outcomes in children with CP might open an avenue for the potential best use of neurostimulation. Trial RegistrationBrazilian Registry of Clinical Trials RBR-104h4s4y; https://tinyurl.com/47r3x2e4 International Registered Report Identifier (IRRID)PRR1-10.2196/52922

Background: Anticoagulant drugs are a valuable tool for minimizing thrombotic risks in at-risk patients. The purpose of this study is to conduct a literature review highlighting the management of these drugs during daily clinical dental practice. Materials and Methods: We limited our search to English-language papers published between 1 January 1989, and 7 March 2024, in PubMed, Scopus and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords “anticoagulant AND dentistry” were used. Results: Twenty-five clinical trials were included for final review from 623 articles obtained from the databases Web of Science (83), PubMed (382), and Scopus (158), eliminating duplicates and 79 off-topic items, resulting in 419 articles after removing 315 entries and confirming eligibility. Overall, these studies support the use of local hemostatic measures to manage the risk of bleeding in patients on anticoagulant therapy undergoing dental procedures and highlight the importance of greater education and collaboration among healthcare professionals. Conclusions: Research and clinical investigation have improved understanding and management of dental procedures in patients undergoing anticoagulant or antiplatelet therapy. Hemostatic agents, clinical protocols, risk factors, and continuous education are essential for navigating the complexities of anticoagulant therapy, ensuring optimal outcomes and enhancing patient well-being.

Abstract 3D imaging is a powerful tool of high resolution and non-destructive imaging technology for the study of ancient weapons and military technology, which reveals the original microstructures and corrosion patterns that threaten these artefacts. Here we report quantitative analysis of the 3D distribution and the orientation of fractures, and uncorroded metal particles within a wrought iron javelin unearthed at the Phoenician-Punic site of Motya, Italy. The study aimed to gain a better understanding of the relationship between corrosion and local stresses within the artifact and to evaluate its manufacturing technology, as well as the effects of post-treatment with Paraloid B72 on concretion and mineralized layers. The cracks were quantified in terms of content, size, and orientation. The condition of artefact storage was evaluated by a multi-analytical approach, including X-ray microscopy, field emission electron microscopy and micro-Raman spectroscopy. The results indicated that a specific technique was used to create a sturdy, lightweight javelin with a central shaft for piercing or thrusting. The fractures appear elongated in the direction of the longitudinal axis of the blade, showing the forging direction of the original metallic block. The study concluded that the artifact had not yet been stabilized due to the presence of lepidocrocite.

Abstract The Lindblad master equation describes the evolution of a large variety of open quantum systems. An important property of some open quantum systems is the existence of decoherence-free subspaces. A quantum state from a decoherence-free subspace will evolve unitarily. However, there is no procedural and optimal method for constructing a decoherence-free subspace. In this paper, we develop tools for constructing decoherence-free stabilizer codes for open quantum systems governed by the Lindblad master equation. This is done by pursuing an extension of the stabilizer formalism beyond the celebrated group structure of Pauli error operators. We then show how to utilize decoherence-free stabilizer codes in quantum metrology in order to attain the Heisenberg limit scaling with low computational complexity.

Abstract Kidney cancer is a common urologic malignancy with either laparoscopic (LPN) or robotic partial nephrectomy as therapeutic options of choice for localized tumors. However, renal resection and suturing are challenging steps of the procedure that can lead to complications such as prolonged warm ischemia, bleeding, and urinary fistulas. LPN with a diode laser is an efficient technique due to its cutting and/or coagulation attributes. Surprisingly, key laser features such as wavelength and power remain undefined. Using a large porcine model, we evaluated the laser range of wavelength and power in a clamp-free LPN and compared it to the established gold-standard LPN technique (i.e., cold-cutting and suturing). By analyzing surgery duration, bleeding, presence of urine leak, tissue damage related to the resected renal fragment and the remaining organ, hemoglobin levels, and renal function, we show that an optimized experimental diode laser clamp-free LPN (wavelength, 980 nm; power, 15 W) had shorter surgery time with less bleeding, and better postoperative renal function recovery when compared to the well-established technique. Together, our data indicate that partial nephrectomy with a diode laser clamp-free LPN technique is an improved alternative to the gold-standard technique. Therefore, translational clinical trials towards human patient applications are readily feasible.

With a view to developing a much-needed non-invasive method for monitoring the healthy pluripotent state of human stem cells in culture, we undertook proteomic analysis of the waste medium from cultured embryonic (Man-13) and induced (Rebl.PAT) human pluripotent stem cells (hPSCs). Cells were grown in E8 medium to maintain pluripotency, and then transferred to FGF2 and TGFβ deficient E6 media for 48 hours to replicate an early, undirected dissolution of pluripotency. We identified a distinct proteomic footprint associated with early loss of pluripotency in both hPSC lines, and a strong correlation with changes in the transcriptome. We demonstrate that multiplexing of four E8- against four E6- enriched secretome biomarkers provides a robust, diagnostic metric for the pluripotent state. These biomarkers were further confirmed by Western blotting which demonstrated consistent correlation with the pluripotent state across cell lines, and in response to a recovery assay.

Introduzione l’alopecia da chemioterapia (CIA) ha un impatto emotivo negativo sugli assistiti in quanto vissuta come compromissione della propria immagine corporea e segno evidente della malattia in atto. Obiettivo comprendere il vissuto e le emozioni provate da persone in follow-up oncologico che hanno sofferto di alopecia indotta da chemioterapia. Materiali e metodi studio qualitativo fenomenologico condotto attraverso interviste semi-strutturate su un campione di convenienza di pazienti adulti oncologici tra giugno e dicembre 2022. Analisi effettuata attraverso il metodo Colaizzi da due esperti. Risultati sono state effettuate 12 interviste da cui sono emerse 4 tematiche principali: (I) emozioni vissute dagli assistiti dopo la perdita dei capelli, cioè come gli assistiti hanno vissuto l’esperienza relativa alla perdita dei capelli. (II) Alterazione della percezione del proprio aspetto fisico; la percezione di sé e le annesse reazioni emotive. (III) Relazione con gli altri ossia i cambiamenti del rapporto con gli altri. (IV) Infine, le persone più vicine durante i cambiamenti dell’identità personale e dell’immagine corporea dove si evidenzia il supporto educativo ed emotivo multidisciplinare. Discussione e Conclusioni i risultati sono in linea con la letteratura scientifica ed evidenziano un disagio dovuto alla CIA associato negativamente all’immagine corporea ed al benessere psico-sociale. Gli operatori sanitari devono acquisire consapevolezza dell’entità del disagio per interventi educativi mirati a sviluppare strategie di coping efficaci.

The occurrence of antibiotic-resistant bacteria in foodstuff involves a human health risk. Edible insects are a precious resource; however, their consumption raises food safety issues. In this study, the occurrence of antibiotic resistant bacteria in laboratory-reared fresh mealworm larvae (Tenebrio molitor L.) and frass was assessed. Antibiotics were not used during the rearing. Enterobacteriaceae and enterococci were isolated from 17 larvae and eight frass samples. In total, 62 and 69 isolates presumed to belong to Enterobacteriaceae and Enterococcus spp., respectively, were obtained and tested for antibiotic susceptibility via disk diffusion. Based on the results, isolates were grouped, and representative resistant isolates were identified at species level through 16S rRNA gene sequencing. For enterococci resistance, percentages higher than 15% were observed for vancomycin and quinupristin–dalfopristin, whereas Enterobacteriaceae resistance higher than 25% was found against cefoxitin, ampicillin, and amoxicillin–clavulanic acid. Based on the species identification, the observed resistances seemed to be intrinsic both for enterococci and Enterobacteriaceae, except for some β-lactams resistance in Shigella boydii (cefoxitin and aztreonam). These could be due to transferable genetic elements. This study suggests the need for further investigations to clarify the role of edible insects in the spreading of antibiotic resistance determinants through the food chain.

Cystinosis is a rare lysosomal storage disorder caused by autosomal recessive mutations in the CTNS gene that encodes for the cystine transporter cystinosin, which is expressed on the lysosomal membrane mediating the efflux of cystine. Cysteamine bitartrate is a cystine-depleting aminothiol agent approved for the treatment of cystinosis in children and adults. In this study, we developed and validated a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the determination of cysteamine levels in plasma samples. This LC-MS/MS method was validated according to the European Medicines Agency (EMA)’s guidelines for bioanalytical method validation. An ultra-performance liquid chromatograph (UPLC) coupled with a 6470 mass spectrometry system was used for cysteamine determination. Our validated method was applied to plasma samples from n = 8 cystinosis patients (median, interquartile range (IQR) = 20.5, 8.5–26.0 years). The samples were collected before cysteamine oral administration (pre-dose) and 1 h after (post-dose). Our bioanalytical method fulfilled the regulatory guidelines for method validation. The cysteamine plasma levels in pre-dose samples were 2.57 and 1.50–3.31 μM (median and IQR, respectively), whereas the post-dose samples reported a cysteamine median concentration of 28.00 μM (IQR: 17.60–36.61). Our method allows the rapid determination of cysteamine plasma levels. This method was successfully used in cystinosis patients and, therefore, could be a useful tool for the evaluation of therapy adherence and for future pharmacokinetic (PK) studies involving a higher number of subjects.

The COVID-19 pandemic has globally disrupted immunisation practices, impacting vulnerable populations such as pregnant women (PW), who harbour concerns about future children’s immunisations. This study aimed to assess the pandemic’s impact on PW’s attitudes towards childhood vaccinations. During three consecutive flu seasons from October 2019 to January 2022, a cross-sectional study was conducted in a large Italian teaching hospital using a questionnaire. The chi-square test was performed to compare each season. Across the 2019–2020 to 2021–2022 seasons, course attendance by PW surged from 105 to 340. Significant shifts in vaccination intentions were noted, including a 7.5% decrease in measles vaccination intent (p = 0.02) and a 10% decrease in that of pertussis (p = 0.004) from 2019–2020 to 2020–2021. While perceived contagion risk decreased, disease severity perceptions increased, with few significant differences. A statistically significant reduction was noted in the proportion of participants suspecting economic motives behind NHS workers’ promotion of childhood vaccinations. Furthermore, the pandemic period saw an increase in the perceived utility of non-institutional websites and the advice of physicians outside the NHS. These findings will help develop evidence-based, tailored interventions and communication strategies to address vaccine hesitancy and ensure optimal vaccination coverage among children born during and after the pandemic.

The goal of this review is to shed light on the management of orofacial discomfort after a cancer diagnosis in the head and neck region. A search was conducted on PubMed, Scopus, and Web of Science to identify studies on postoperative pain control in oral cancer. The review included open-access research, investigations into pain management, randomized clinical trials, retrospective studies, case-control studies, prospective studies, English-written studies, and full-text publications. Exclusion criteria included animal studies; in vitro studies; off-topic studies; reviews, case reports, letters, or comments; and non-English language. Three reviewers independently accessed databases and assigned a quality rating to the chosen articles. The review explores postoperative pain management in oral cancer patients; highlighting persistent opioid use; the efficacy of adjuvant drugs, such as gabapentin; and a multimodal approach. It emphasizes the need for personalized pain management, recognizing individual pain perception and tailoring interventions. Integrating pharmacological and non-pharmacological strategies is crucial for comprehensive pain management. The review also serves as a guide for future research, emphasizing the need for standardized methodologies and diverse participant populations.

During evolution, animals have returned from land to water, adapting with morphological modifications to life in an aquatic environment. We compared the osteochondral units of the humeral head of marine and terrestrial mammals across species spanning a wide range of body weights, focusing on microstructural organization and biomechanical performance. Aquatic mammals feature cartilage with essentially random collagen fiber configuration, lacking the depth-dependent, arcade-like organization characteristic of terrestrial mammalian species. They have a less stiff articular cartilage at equilibrium with a significantly lower peak modulus, and at the osteochondral interface do not have a calcified cartilage layer, displaying only a thin, highly porous subchondral bone plate. This totally different constitution of the osteochondral unit in aquatic mammals reflects that accommodation of loading is the primordial function of the osteochondral unit. Recognizing the crucial importance of the microarchitecture-function relationship is pivotal for understanding articular biology and, hence, for the development of durable functional regenerative approaches for treatment of joint damage, which are thus far lacking.

Makorin ring finger protein 3 (MKRN3) was identified as an inhibitor of puberty initiation with the report of loss-of-function mutations in association with central precocious puberty. Consistent with this inhibitory role, a prepubertal decrease in Mkrn3 expression was observed in the mouse hypothalamus. Here, we investigated the mechanisms of action of MKRN3 in the central regulation of puberty onset. We showed that MKRN3 deletion in hypothalamic neurons derived from human induced pluripotent stem cells was associated with significant changes in expression of genes controlling hypothalamic development and plasticity. Mkrn3 deletion in a mouse model led to early puberty onset in female mice. We found that Mkrn3 deletion increased the number of dendritic spines in the arcuate nucleus but did not alter the morphology of GnRH neurons during postnatal development. In addition, we identified neurokinin B (NKB) as an Mkrn3 target. Using proteomics, we identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) as another target of MKRN3. Interactome analysis revealed that IGF2BP1 interacted with MKRN3, along with several members of the polyadenylate-binding protein family. Our data show that one of the mechanisms by which MKRN3 inhibits pubertal initiation is through regulation of prepubertal hypothalamic development and plasticity, as well as through effects on NKB and IGF2BP1.

ABSTRACT Obesity is largely undertreated, in part because of the stigma surrounding the disease and its treatment. The use of the term “weight loss drugs” to refer to medications for the treatment of obesity may contribute to this stigma, leading to the idea that anyone who wants to lose weight could use them and that short-term use, only in the active weight loss phase would be enough. On the contrary, the use of terms such as “medications to treat obesity” or “anti-obesity medications” conveys the idea that the treatment is directed at the disease rather than the symptom. This joint statement by the Brazilian Association for the Study of Obesity and Metabolic Syndrome (ABESO) and the Brazilian Society of Endocrinology and Metabolism (SBEM) intends to alert the press, healthcare professionals and scientific community about the importance of the appropriate use of language, with the aim of improving obesity care.

PurposeTo assess the effectiveness of topical allogeneic platelet-rich plasma (PRP) eye drops for the treatment of symptoms and clinical signs in patients with severe dry eye disease as a secondary condition caused by Sjögren’s syndrome (SS).DesignCase series and literature review.MethodsSix eyes from three consecutive patients with severe dry eye from SS were evaluated. The eyes were treated with allogeneic topical PRP eye drops, with one drop applied six times daily for 3 months. A post-treatment follow-up evaluation was conducted 3 months after treatment suspension. We evaluated subjective symptoms, visual acuity, tear breakup time, the results of Schirmer’s I test, fluorescein corneal and conjunctival staining, and corneal sensitivity.ResultsThe symptoms and visual acuity improved significantly in all patients. There was a significant improvement in corneal sensitivity and a decrease or disappearance of fluorescein corneal staining.ConclusionThe treatment with allogenic PRP eye drops of patients with SS-related severe dry eye disease has proven to be very effective, with an improvement in symptoms and main clinical signs.

Abstract The fabrication of a Fe-based coated conductor (CC) becomes possible when Fe(Se,Te) is grown as an epitaxial film on a metallic oriented substrate. Thanks to the material’s low structural anisotropy, less strict requirements on the template microstructure allow for the design of a simplified CC architecture with respect to the REBCO multi-layered layout. This design, though, still requires a buffer layer to promote the oriented growth of the superconducting film and avoid diffusion from the metallic template. In this work, Fe(Se,Te) films are grown on chemically-deposited, CeO2-based buffer layers via pulsed laser deposition, and excellent properties are obtained when a Fe(Se,Te) seed layer is used. Among all the employed characterization techniques, transmission electron microscopy proved essential to determine the actual effect of the seed layer on the final film properties. Also, systematic investigation of the full current transport properties J(θ, H, T) is carried out: Fe(Se,Te) samples are obtained with sharp superconducting transitions around 16 K and critical current densities exceeding 1 MA cm−2 at 4.2 K in self-field. The in-field and angular behavior of the sample are in line with data from the literature. These results are the demonstration of the feasibility of a Fe-based CC, with all the relative advantages concerning process simplification and cost reduction.

Abstract Being able to observe the formation of multi-material nanostructures in situ, simultaneously from a morphological and crystallographic perspective, is a challenging task. Yet, this is essential for the fabrication of nanomaterials with well-controlled composition exposing the most active crystallographic surfaces, as required for highly active catalysts in energy applications. To demonstrate how X-ray ptychography can be combined with scanning nanoprobe diffraction to realize multimodal imaging, we study growing Cu2O nanocubes and their transformation into Au nanocages. During the growth of nanocubes at a temperature of 138 °C, we measure the crystal structure of an individual nanoparticle and determine the presence of (100) crystallographic facets at its surface. We subsequently visualize the transformation of Cu2O into Au nanocages by galvanic replacement. The nanocubes interior homogeneously dissolves while smaller Au particles grow on their surface and later coalesce to form porous nanocages. We finally determine the amount of radiation damage making use of the quantitative phase images. We find that both the total surface dose as well as the dose rate imparted by the X-ray beam trigger additional deposition of Au onto the nanocages. Our multimodal approach can benefit in-solution imaging of multi-material nanostructures in many related fields.

Environmental surveillance can be a complementary tool for detecting pathogens circulating in communities. We detected monkeypox virus DNA in wastewater from Italy’s largest airport by using real-time PCR assays targeting the G2R region and F3L and N3R genes and sequencing. Wastewater surveillance can be quickly adapted to investigate emerging threats.

Abstract Recent outbreaks of Zika virus (ZIKV) infection have highlighted the need for a better understanding of ZIKV-specific immune responses. The ZIKV envelope glycoprotein (EZIKV) is the most abundant protein on the virus surface and it is the main target of the protective immune response. EZIKV protein contains the central domain (EDI), a dimerization domain containing the fusion peptide (EDII), and a domain that binds to the cell surface receptor (EDIII). In this study, we performed a systematic comparison of the specific immune response induced by different EZIKV recombinant proteins (EZIKV, EDI/IIZIKV or EDIIIZIKV) in two mice strains. Immunization induced high titers of E-specific antibodies which recognized ZIKV-infected cells and neutralized the virus. Furthermore, immunization with EZIKV, EDI/IIZIKV and EDIIIZIKV proteins induced specific IFNγ-producing cells and polyfunctional CD4+ and CD8+ T cells. Finally, we identified 4 peptides present in the envelope protein (E1–20, E51–70, E351–370 and E361–380), capable of inducing a cellular immune response to the H-2Kd and H-2Kb haplotypes. In summary, our work provides a detailed assessment of the immune responses induced after immunization with different regions of the ZIKV envelope protein.

Abstract The short squeeze of GameStop (GME) shares in mid-January 2021 has been primarily orchestrated by retail investors of the Reddit r/wallstreetbets community. As such, it represents a paramount example of collective coordination action on social media, resulting in large-scale consensus formation and significant market impact. In this work we characterise the structure and time evolution of Reddit conversation data, showing that the occurrence and sentiment of GME-related comments (representing how much users are engaged with GME) increased significantly much before the short squeeze actually took place. Taking inspiration from these early warnings as well as evidence from previous literature, we introduce a model of opinion dynamics where user engagement can trigger a self-reinforcing mechanism leading to the emergence of consensus, which in this particular case is associated to the success of the short squeeze operation. Analytical solutions and model simulations on interaction networks of Reddit users feature a phase transition from heterogeneous to homogeneous opinions as engagement grows, which we qualitatively compare to the sudden hike of GME stock price. Although the model cannot be validated with available data, it offers a possible and minimal interpretation for the increasingly important phenomenon of self-organized collective actions taking place on social networks.

Abstract The ongoing evolution of SARS-CoV-2 and the emergence of new viral variants bearing specific escape mutations responsible for immune evasion from antibody neutralisation has required a more accurate characterisation of the immune response as one of the evolutive forces behind viral adaptation to a largely immunised human population. In this work, culturing in the presence of neutralising sera vigorously promoted mutagenesis leading to the acquisition of known escape mutations on the spike as well as new presumptive escape mutations on structural proteins whose role as target of the neutralizing antibody response might have been thus far widely neglected. From this perspective, this study, in addition to tracing the past evolution of the species back to interactions with neutralising antibody immune response, also offers a glimpse into future evolutive scenarios.

Abstract Active surveillance (AS) is a standard treatment option for low risk localized prostate cancer. However, the risk of anxiety and depression compared to other curative strategies, namely radical prostatectomy (RP) and radiotherapy (RT), is controversial. This study consisted in a French representative sample of 4174 5-years cancer survivors. Self-reported data, including quality-of-life assessment, were prospectively collected through telephone interviews. Among the 447 survivors with PC, we selected 292 patients with localized prostate cancer, T1–T2 stage, Gleason score ≤ 7 and we compared anxiety and depressive symptoms according to treatment strategy. Among patients on AS, 14.9% received curative treatment during the 5 years of follow-up. Anxiety was reported in 34.3% of cases in the AS group versus 28.6% in the RP group and 31.6% in the RT group (p = 0.400), while depressive symptoms were reported in 14.9% of cases in the AS group versus 10.7% in the RP group and 22.8% in the RT group (p = 0.770). Consumption of anxiolytics reported did not vary significantly between the 3 groups (p = 0.330). In conclusion, patients managed with AS for localized prostate cancer do not report more anxiety or depressive symptoms than patients managed with curative treatment, encouraging the extended use of active surveillance.

Abstract Background Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA) requiring urgent treatment. Standardization of its diagnosis and optimal management is challenging. This study aimed to evaluate the role of centralized, rapid testing of ADAMTS13 in patients experiencing acute TMAs requiring plasma-exchange (PEX) and to estimate the incidence of TTP in a large Italian Region. Methods We perfomed a cohort study in the frame of the project “Set-up of a Lombardy network for the study and treatment of patients undergoing apheresis”, including 11 transfusion centers in the Region. Consecutive patients referred from 2014 to 2016 with acute TMAs requiring PEX were enrolled. Centralized ADAMTS13 activity testing was performed at the Milan Hemophilia and Thrombosis Center within 24 h. Results Forty-three TMA patients (44 events) were enrolled, of whom 35 (81%) had severe ADAMTS13 deficiency. Patients with severe ADAMTS13 deficiency were younger, mainly women, with a higher prevalence of autoimmune disorders and a lower prevalence of cancer. Clinical and laboratory characteristics of patients with and without severe ADAMTS13 deficiency largely overlapped, with a lower platelet count being the only baseline marker that significantly differed between the two patient groups (ADAMTS13 activity

Summary: Background: In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed. Methods: We evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM). Findings: Our data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-α+ T cells. Interpretation: Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. Funding: Research Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Abstract Intestinal homeostasis is highly dependent on optimal epithelial barrier function and permeability. Intestinal epithelial cells (IEC) regulate these properties acting as cellular gatekeepers by selectively absorbing nutrients and controlling the passage of luminal bacteria. These functions are energy demanding processes that are presumably met through mitochondrial-based processes. Routine methods for examining IEC mitochondrial function remain sparse, hence, our objective is to present standardized methods for quantifying mitochondrial energetics in an immortalized IEC line. Employing the murine IEC4.1 cell line, we present adapted methods and protocols to examine mitochondrial function using two well-known platforms: the Seahorse Extracellular Flux Analyzer and Oxygraph-2 k. To demonstrate the applicability of these protocols and instruments, IEC were treated with and without the murine colitogenic agent, dextran sulfate sodium (DSS, 2% w/v). Profound impairments with DSS treatment were found with both platforms, however, the Oxygraph-2 k allowed greater resolution of affected pathways including short-chain fatty acid metabolism. Mitochondrial functional analysis is a novel tool to explore the relationship between IEC energetics and functional consequences within the contexts of health and disease. The outlined methods offer an introductory starting point for such assessment and provide the investigator with insights into platform-specific capabilities.

Abstract We present the results of a multi-disciplinary investigation on a deciduous human tooth (Pradis 1), recently recovered from the Epigravettian layers of the Grotte di Pradis archaeological site (Northeastern Italian Prealps). Pradis 1 is an exfoliated deciduous molar (Rdm2), lost during life by an 11–12-year-old child. A direct radiocarbon date provided an age of 13,088–12,897 cal BP (95% probability, IntCal20). Amelogenin peptides extracted from tooth enamel and analysed through LC–MS/MS indicate that Pradis 1 likely belonged to a male. Time-resolved 87Sr/86Sr analyses by laser ablation mass spectrometry (LA-MC-ICPMS), combined with dental histology, were able to resolve his movements during the first year of life (i.e. the enamel mineralization interval). Specifically, the Sr isotope ratio of the tooth enamel differs from the local baseline value, suggesting that the child likely spent his first year of life far from Grotte di Pradis. Sr isotopes are also suggestive of a cyclical/seasonal mobility pattern exploited by the Epigravettian human group. The exploitation of Grotte di Pradis on a seasonal, i.e. summer, basis is also indicated by the faunal spectra. Indeed, the nearly 100% occurrence of marmot remains in the entire archaeozoological collection indicates the use of Pradis as a specialized marmot hunting or butchering site. This work represents the first direct assessment of sub-annual movements observed in an Epigravettian hunter-gatherer group from Northern Italy.

ABSTRACT Obesity is a chronic disease associated with impaired physical and mental health. A widespread view in the treatment of obesity is that the goal is to normalize the individual's body mass index (BMI). However, a modest weight loss (usually above 5%) is already associated with clinical improvement, while weight losses of 10%-15% bring even further benefits, independent from the final BMI. The percentage of weight reduction is accepted as a treatment goal since a greater decrease in weight is frequently difficult to achieve due to metabolic adaptation along with environmental and lifestyle factors. In this document, the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society for the Study of Obesity and Metabolic Syndrome (ABESO) propose a new obesity classification based on the maximum weight attained in life (MWAL). In this classification, individuals losing a specific proportion of weight are classified as having “reduced” or “controlled” obesity. This simple classification – which is not intended to replace others but to serve as an adjuvant tool – could help disseminate the concept of clinical benefits derived from modest weight loss, allowing individuals with obesity and their health care professionals to focus on strategies for weight maintenance instead of further weight reduction. In future studies, this proposed classification can also be an important tool to evaluate possible differences in therapeutic outcomes between individuals with similar BMIs but different weight trajectories.

Abstract The new outbreak of coronavirus disease 2019 (COVID-19) has infected and caused the death of millions of people worldwide. Intensive efforts are underway around the world to establish effective treatments. Immunoglobulin from immunized animals or plasma from convalescent patients might constitute a specific treatment to guarantee the neutralization of the virus in the early stages of infection, especially in patients with risk factors and a high probability of progressing to severe disease. Worldwide, a few clinical trials using anti-SARS-CoV-2 immunoglobulins from horses immunized with the entire spike protein or fragments of it in the treatment of patients with COVID-19 are underway. Here, we describe the development of an anti-SARS-CoV-2 equine F(ab′)2 immunoglobulin using a newly developed SARS-CoV-2 viral antigen that was purified and inactivated by radiation. Cell-based and preclinical assays showed that the F(ab′)2 immunoglobulin successfully neutralizes the virus, is safe in animal models, and reduces the severity of the disease in a hamster model of SARS-CoV-2 infection and disease.

Abstract Phaseolus vulgaris (common bean), having a proposed Mexican origin within the Americas, comprises three centers of diversification: Mesoamerica, the southern Andes, and the Amotape-Huancabamba Depression in Peru-Ecuador. Rhizobium etli is the predominant rhizobium found symbiotically associated with beans in the Americasalthough closely related Rhizobium phylotypes have also been detected. To investigate if symbiosis between bean varieties and rhizobia evolved affinity, firstly nodulation competitiveness was studied after inoculation with a mixture of sympatric and allopatric rhizobial strains isolated from the respective geographical regions. Rhizobia strains harboring nodC types α and $$\upgamma$$ γ , which were found predominant in Mexico and Ecuador, were comparable in nodule occupancy at 50% of each in beans from the Mesoamerican and Andean gene pools, but it is one of those two nodC types which clearly predominated in Ecuadorian-Peruvian beans as well as in Andean beans nodC type $$\upgamma$$ γ predominated the sympatric nodC type δ. The results indicated that those beans from Ecuador-Peru and Andean region, respectively exhibited no affinity for nodulation by the sympatric rhizobial lineages that were found to be predominant in bean nodules formed in those respective areas. Unlike the strains isolated from Ecuador, Rhizobium etli isolated from Mexico as well from the southern Andes was highly competitive for nodulation in beans from Ecuador-Peru, and quite similarly competitive in Mesoamerican and Andean beans. Finally, five gene products associated with symbiosis were examined to analyze variations that could be correlated with nodulation competitiveness. A small GTPase RabA2, transcriptional factors NIN and ASTRAY, and nodulation factor receptors NFR1 and NFR5- indicated high conservation but NIN, NFR1 and NFR5 of beans representative of the Ecuador-Peru genetic pool clustered separated from the Mesoamerican and Andean showing diversification and possible different interaction. These results indicated that both host and bacterial genetics are important for mutual affinity, and that symbiosis is another trait of legumes that could be sensitive to evolutionary influences and local adaptation.

Early phase diagnosis of human diseases has still been a challenge in the medicinal field, and one of the efficient non-invasive techniques that is vastly used for this purpose is magnetic resonance imaging (MRI). MRI is able to detect a wide range of diseases and conditions, including nervous system disorders and cancer, and uses the principles of NMR relaxation to generate detailed internal images of the body. For such investigation, different metal complexes have been studied as potential MRI contrast agents. With this in mind, this work aims to investigate two systems containing the vanadium complexes [VO(metf)2]·H2O (VC1) and [VO(bpy)2Cl]+ (VC2), being metformin and bipyridine ligands of the respective complexes, with the biological targets AMPK and ULK1. These biomolecules are involved in the progression of Alzheimer’s disease and triple-negative breast cancer, respectively, and may act as promising spectroscopic probes for detection of these diseases. To initially evaluate the behavior of the studied ligands within the aforementioned protein active sites and aqueous environment, four classical molecular dynamics (MD) simulations including VC1 + H2O (1), VC2 + H2O (2), VC1 + AMPK + H2O (3), and VC2 + ULK1 + H2O (4) were performed. From this, it was obtained that for both systems containing VCs and water only, the theoretical calculations implied a higher efficiency when compared with DOTAREM, a famous commercially available contrast agent for MRI. This result is maintained when evaluating the system containing VC1 + AMPK + H2O. Nevertheless, for the system VC2 + ULK1 + H2O, there was observed a decrease in the vanadium complex efficiency due to the presence of a relevant steric hindrance. Despite that, due to the nature of the interaction between VC2 and ULK1, and the nature of its ligands, the study gives an insight that some modifications on VC2 structure might improve its efficiency as an MRI probe.

This real-world analysis investigated the characteristics and treatment patterns of patients with hereditary angioedema (HAE) in Italy using the administrative data of health units across Italy. Patients were identified via exemption code or HAE-specific treatments (thus, all known forms, type I, II and, III, were included). The index date was that of first prescription of HAE treatments within the inclusion period (01/2010–06/2021) or of the date of exemption. The number of HAE patients included was 148 (43.2% male, mean age 43.3 years). Gastrointestinal disorders affected 36.5% patients, hypertension affected 28.4%, hypercholesterolemia affected 11.5%, and depression affected 9.5%. The frequent gastrointestinal involvement was further confirmed by the use of antiemetics and systemic antihistamines that doubled after the index date. Among patients enrolled by treatment (n = 125), n = 105 (84%) were receiving a treatment for acute attacks. This analysis provided insights into the characterization of patients with HAE and their management in Italian clinical practice, suggesting that an unmet therapeutic need could be present for such patients in terms of the clinical burden.

Antibiotic resistance is a public health problem with increasingly alarming data being reported. Gram-positive bacteria are among the protagonists of severe nosocomial and community infections. The objective of this review is to conduct an extensive examination of emerging treatments for Gram-positive infections including ceftobiprole, ceftaroline, dalbavancin, oritavancin, omadacycline, tedizolid, and delafloxacin. From a methodological standpoint, a comprehensive analysis on clinical trials, molecular structure, mechanism of action, microbiological targeting, clinical use, pharmacokinetic/pharmacodynamic features, and potential for therapeutic drug monitoring will be addressed. Each antibiotic paragraph is divided into specialized microbiological, clinical, and pharmacological sections, including detailed and appropriate tables. A better understanding of the latest promising advances in the field of therapeutic options could lead to the development of a better approach in managing antimicrobial therapy for multidrug-resistant Gram-positive pathogens, which increasingly needs to be better stratified and targeted.

A skull of Hippopotamus recovered from the area of Tor di Quinto, within the urban area of Rome (central Italy) is here redescribed. Despite being one of the most complete specimens of hippopotamuses of the European Pleistocene, the Tor di Quinto skull did not attract much research interest, due to long-standing uncertainties on its provenance. This work begun in 2021, when the skull was restored, within a large renovation project on the vertebrate exposed at the Earth Science University Museum of Sapienza University of Rome. Original sediments were found inside the cranial and mandible cavities during the restoration work, which were sampled for petrographic analyses. By combining a review of the old paleontological, archeological and geological literature published during the 19th and 20th century on the Rome basin and the correlation of these new sedimentological and petrographic information with the lithostratigraphic and synthemic units of the national geological cartography, we clarify that the Hippopotamus skull was most likely to have been collected from a quarry called Cava Montanari, from a formation dated between 560 and 460 ka. Morphological and biometric analyses clearly support an attribution of the Cava Montanari specimen to the extant species Hippopotamus amphibius. The reassessment of the stratigraphic and geological data on Cava Montanari implies that the studied specimen is the earliest confirmed occurrence of Hippopotamus amphibius in the European fossil record.

The spreading of opium use poses new health related concerns. In some areas of Asia its use is believed to protect from cardiovascular disorders, such as coronary artery disease (CAD). However, whether opium use has an association with CAD is unclear. We aimed to investigate the association between non-medical opium use and CAD. We set up a case-control analysis, i.e., the Milano-Iran (MIran) study by enrolling consecutive young patients who underwent a coronary angiography at the Tehran Heart Center, between 2004 and 2011. Incident cases with CAD were contrasted with controls for opium use. Relative risks were calculated in terms of odds ratios (ORs) by logistic regression models adjusted for age, sex, cigarette smoking, body mass index, hypertension, hyperlipidaemia, and diabetes. Interaction analyses were performed between opium and major cardiovascular risk factors. 1011 patients with CAD (mean age 43.6 years) and 2002 controls (mean age 54.3 years) were included in the study. Habitual opium users had a 3.8-fold increased risk of CAD (95%CI 2.4-6.2) compared with non-users. The association was strongest for men, with a fully adjusted OR of 5.5 (95%CI 3.0-9.9). No interaction was observed for the combination of opium addiction and hypertension, or diabetes, but an excess in risk was found in opium users with hyperlipidaemia (OR 16.8, 95%CI 8.9-31.7, expected OR 12.2), suggesting supra-additive interaction. In conclusion, despite common beliefs, we showed that non-medical opium use is associated with an increased risk of CAD, even when other cardiovascular risk factors are taken into account.

Thermogenesis in brown adipose tissue (BAT) uses intracellular triglycerides, circulating free fatty acids and glucose as the main substrates. The objective of the current study was to analyse the role of CD36 fatty acid translocase in regulation of glucose and fatty acid utilisation in BAT. BAT isolated from spontaneously hypertensive rat (SHR) with mutant Cd36 gene and SHR-Cd36 transgenic rats with wild type variant was incubated in media containing labeled glucose and palmitate to measure substrate incorporation and oxidation. SHR-Cd36 versus SHR rats showed significantly increased glucose incorporation into intracellular lipids associated with reduced glycogen synthase kinase 3β (GSK-3β) protein expression and phosphorylation and increased oxidation of exogenous palmitate. It can be concluded that CD36 enhances glucose transport for lipogenesis in BAT by suppressing GSK-3β and promotes direct palmitate oxidation.

ObjectiveThe aim of this study was to evaluate the incidence of deep vein thrombosis (DVT) of the lower limbs in patients hospitalized with COVID-19 pneumonia in a non-ICU setting according to the different waves of the SARS-CoV-2 pandemic.MethodsMulticenter, prospective study of patients with COVID-19 pneumonia admitted to Internal Medicine units in Italy during the first (March-May 2020) and subsequent waves (November 2020 -April 2021) of the pandemic using a serial compression ultrasound (CUS) surveillance to detect DVT of the lower limbs.ResultsThree-hundred-sixty-three consecutive patients were enrolled. The pooled incidence of DVT was 8%: 13.5% in the first wave, and 4.2% in the subsequent waves (p = 0.002). The proportion of patients with early (< 4 days) detection of DVT was higher in patients during the first wave with respect to those of subsequent waves (8.1% vs 1.9%; p = 0.004). Patients enrolled in different waves had similar clinical characteristics, and thrombotic risk profile. Less patients during the first wave received intermediate/high dose anticoagulation with respect to those of the subsequent waves (40.5% vs 54.5%; p = 0.005); there was a significant difference in anticoagulant regimen and initiation of thromboprophylaxis at home (8.1% vs 25.1%; pConclusionsIn acutely ill patients with COVID-19 pneumonia, the incidence of DVT of the lower limbs showed a 3-fold decrease during the first with respect to the subsequent waves of the pandemic. A significant increase in thromboprophylaxis initiation prior to hospitalization, and the increase of the intensity of anticoagulation during hospitalization, likely, played a relevant role to explain this observation.

The interest in edible insects as food is growing, both in traditional and non-traditional insect-eating countries given their advantages in terms of sustainability and nutritional content. However, only a few studies have conducted cross-country investigations on the acceptance of including processed or whole insects in the diet. Thus, this study aimed to examine to which extent consumers were accepting (i) whole and visible mealworms, (ii) processed mealworms in their diet and (iii) to explore the factors affecting the acceptance level of consuming mealworms in countries with and without entomophagy tradition. An online survey was applied to collect responses (3,006) from five countries-i.e., Belgium, China, Italy, Mexico, and the US-using a quota sampling method. Moreover, an information treatment was included with about half of the participants receiving information about the advantages of edible insects as food (ingredient) and the presence of food safety regulations. Across countries, gender was the main factor affecting acceptance level as men accepted mealworms more than women. Entomophagy tradition mainly explained the differences among countries. Countries with entomophagy traditions (Mexico and China) showed higher acceptance of including whole or processed mealworms in the diet compared to countries with no entomophagy traditions (i.e., Belgium, Italy, and the US). While information and age did affect differently the acceptance of including processed mealworms in countries with entomophagy traditions showing that consumer acceptance was affected by information in Mexico and by age in China. Whereas it was found that younger people (below 42 years old) in countries without entomophagy tradition were more open to accepting processed mealworms in their diet. Moreover, across countries, the acceptance of including processed mealworms was higher compared to whole mealworms. These findings provide insights into which consumer segments to target and the potential impact of information when introducing new insect-based foods in countries with and without entomophagy traditions.

Fibromyalgia (FM) is a major chronic pain disease with prominent affective disturbances, and pain-associated changes in neurotransmitters activity and in brain connectivity. However, correlates of affective pain dimension lack. The primary goal of this correlational cross-sectional case-control pilot study was to find electrophysiological correlates of the affective pain component in FM. We examined the resting-state EEG spectral power and imaginary coherence in the beta (β) band (supposedly indexing the GABAergic neurotransmission) in 16 female patients with FM and 11 age-adjusted female controls. FM patients displayed lower functional connectivity in the High β (Hβ, 20-30 Hz) sub-band than controls (p = 0.039) in the left basolateral complex of the amygdala (p = 0.039) within the left mesiotemporal area, in particular, in correlation with a higher affective pain component level (r = 0.50, p = 0.049). Patients showed higher Low β (Lβ, 13-20 Hz) relative power than controls in the left prefrontal cortex (p = 0.001), correlated with ongoing pain intensity (r = 0.54, p = 0.032). For the first time, GABA-related connectivity changes correlated with the affective pain component are shown in the amygdala, a region highly involved in the affective regulation of pain. The β power increase in the prefrontal cortex could be compensatory to pain-related GABAergic dysfunction.