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Giuliano Lo Bianco,1 Michael E Schatman2,3 1Anesthesiology and Pain Department, Fondazione Istituto “G. Giglio”, Cefalù, Palermo, Italy; 2Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 3Department of Population Health - Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Michael E Schatman, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, 550 1st Ave, New York, NY, 10016, USA, Tel +1 425-647-4880, Email Michael.Schatman@NYULangone.org

Bioethics and the Ethics of Extinction This article explores the idea of rethinking bioethics in terms of an Ethics of extinction. After showing the centrality to contemporary ethical debates of extinction, the article shows how bioethics was the first broad disciplinary reflection on the ethical consequences of human actions potentially bringing about extinction. In particular, it will focus on a widely debated issue in bioethics related to our inability as individuals and as a collectivity to deal with current existential risks.

Applied ethics as singular or plural? Disciplinary Pluralism and the Centrality of Science in the new Horizons of Bioethics The accelerated scientific and technological advancements of the 20th and 21st centuries have, on the one hand, created a gap between Sapiens’ technical abilities and its moral psychology. On the other, it has offered our species unprecedented possibilities for hybridisation with the world outside. The need for a well-structured reflection on the ethical-philosophical aspects of the new scenarios was the driving force behind the transformation of Ethics. Toulmin, in a 1982 paper How medicine saved the life of Ethics, emphasised the key role that medicine played in giving new life to ethics and stimulating the birth of Bioethics, a kind of Applied Ethics at the center of a vast debate. In fact, to take up Toulmin’s expression and, in some ways, revive it, not only medicine, but the sciences of the biosciences as a whole, engineering in its various forms, information technology right up to the leading sectors of artificial intelligence and synthetic biology have fostered the emergence of new areas of reflection and the multiplication of applied ethics. Each area of applied ethics somehow claims its own autonomy, in terms of the elaboration of specific analytical tools, distinctive problems and specific skills that a scholar within that area should exhibit. Nonetheless, it is also clear that the common denominator between the various fields and the connecting elements that emerge in the differences and beyond them should not be overlooked. Faced with these scenarios, there are two main themes that the present Issue intends to focus on.1) To try to answer the question of whether disciplinary autonomy and pluralism in relation to Applied Ethics are the regulatory ideal to which we should adhere or rather (at least in some cases) an obstacle that prevents us from finding a more general framework for sectors of ethical reflection that often present points of contact and interconnected problems that it would be more effective to address by overcoming the hyper-specialisation that today seems to be the ultimate destiny (even) of the philosophical disciplines; 2) starting from the observation that in applied ethics the object of enquiry cannot be a mere Gegenstand (something that is in front of) but an active part of the process of reflection, a further question to be examined will be: what space in an ethics of science must scientific knowledge of reference occupy, in order to avoid making it the mere object of an external reflection?

The Future of Bioethics between current Scenarios and new Horizons Bioethics is a complex discipline whose contributions have marked a fundamental part of the philosophical and moral debate of the second half of the 20th century and early 2000s. Adriano Pessina, one of the protagonists of this debate, offers his analysis to shed light on some of these aspects and to reflect on the transformations taking place. The contribution examines issues such as the role of ethics committees, the relationship between bioethics understood as biomedical ethics and global bioethics, and whether it is possible to develop a universalist ethical model.

Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, Scopus and Google Scholar, including original articles, review articles, and metanalyses. We excluded non-English language articles and case reports/case series. Generally speaking, nutritional and inflammatory status largely affect medium and long-term prognosis in lung cancer patients. A correct stratification of patients could improve their preoperative general functional nutritional and inflammatory status, minimizing, therefore, possible treatment complications and improving long-term prognosis.

ObjectivesTo assess the reversibility of retinal microvascular changes in the long term and to investigate the potential links with other vascular diseases of COVID-19.MethodsWe designed a prospective multicenter observational study. Patients were enrolled from the Methuselah study cohort. Retinal vascular function was studied in these patients using optical coherence tomography angiography (OCTA); aortic stiffness was measured using aortic pulse wave velocity. These examinations were performed 1 (Visit 1) and 12 (Visit 2) months after the hospital discharge for severe COVID-19. A control subject group matched for age and sex was included to define normal values.ResultsA total of 28 control subjects (56 eyes) and 25 patients (50 eyes) completed the scheduled OCTA assessment; 18 patients (36 eyes) also completed the macrovascular examination. Compared to controls, the vessel density of the superficial capillary plexus (SCP) was reduced, whereas the foveal avascular zone area was enlarged at Visit 1 (p = 0.016 and

Breast cancer is the most common cancer in women and the second leading cause of cancer-related death. Breast cancer manifestations in the head and neck are relatively rare, and they are mostly bony metastasis to the mandible and maxilla. In this paper, we present a case report of a metastatic tumor in the mandibular angle originating from breast carcinoma. A 32-year-old female patient with a paresthesia/anesthesia in the left mandibular area was referred to us to aid in the differential diagnosis between osteonecrosis and metastasis. Her medical history revealed a radical bimastectomy 3 years ago for invasive lobular carcinoma of the breasts. Additionally, she received chemotherapy and radiotherapy 3 years ago, and intravenous zoledronic acid was administered every 3 weeks. Intraoral examination did not reveal any mucosal ulcer or fistula, and there was no radiological evidence of cyst. The patient demonstrated good oral hygiene. Palpable regional left submandibular lymph nodes and a few swellings on the lateral angular mandibular surface were observed. Cone-beam computed tomography (CBCT) and positron emission tomography (PET) were performed. CBCT showed small poorly diffused radiopacity in proximity to the mandibular angle on both medial and lateral surfaces. PET showed fluoro-2-deoxy-D-glucose uptake in the mandible in the left angle surface area. Based on the patient’s clinical history, signs, symptoms, and tomographic evidence, we were able to diagnose mandibular metastasis. This case also highlights the importance of proficiency in reading tomographic examinations, which can be carried out in dental clinics for various purposes. In the absence of symptoms, misdiagnosis can occur, underscoring the significance of accurate interpretation and diagnosis.

Background: Artificial intelligence (AI) has proved to be of great value in diagnosing and managing Sars-Cov-2 infection. ALFABETO (ALL-FAster-BEtter-TOgether) is a tool created to support healthcare professionals in the triage, mainly in optimizing hospital admissions. Methods: The AI was trained during the pandemic's “first wave” (February-April 2020). Our aim was to assess the performance during the “third wave” of the pandemics (February-April 2021) and evaluate its evolution. The neural network proposed behavior (hospitalization vs home care) was compared with what was actually done. If there were discrepancies between ALFABETO's predictions and clinicians' decisions, the disease's progression was monitored. Clinical course was defined as “favorable/mild” if patients could be managed at home or in spoke centers and “unfavorable/severe” if patients need to be managed in a hub center. Results: ALFABETO showed accuracy of 76%, AUROC of 83%; specificity was 78% and recall 74%. ALFABETO also showed high precision (88%). 81 hospitalized patients were incorrectly predicted to be in “home care” class. Among those “home-cared” by the AI and “hospitalized” by the clinicians, 3 out of 4 misclassified patients (76.5%) showed a favorable/mild clinical course. ALFABETO’s performance matched the reports in literature. Conclusions: The discrepancies mostly occurred when the AI predicted patients could stay at home but clinicians hospitalized them; these cases could be handled in spoke centers rather than hubs, and the discrepancies may aid clinicians in patient selection. The interaction between AI and human experience has the potential to improve both AI performance and our comprehension of pandemic management.

Recent advancements in the discovery of natural products have made significant progress in rapidly identifying known compounds from complex extracts using advanced spectroscopic technologies. Among these methods, one powerful approach called MS/MS molecular networking (MN) organizes chemical similarity based on MS/MS fragmentation data, serving as a valuable complement to traditional dereplication strategies. In our ongoing research focused on lead discovery from a sustainable medicinal source, an aquaculture soft coral Sarcophyton trocheliophorum, the MN profiling approach revealed the chemical diversity of biscembranoid analogs. By analyzing the MN pattern, biscembranoid derivatives with unique MS/MS fragments were prioritized for further investigation. Two novel biscembranoids, sarcotroxide A (1) and B (2), were successfully obtained through targeted isolation. These novel biscembranes contained an unprecedented 3-hydroperoxy-3-methylcyclohex-1-ene moiety compared with all biscembranoid analogs. The chemical structures of the two new biscembranoids were confirmed through spectroscopic analyses and in silico calculations. Their anti-inflammatory properties were assessed against the generation of superoxide anion (O2•−) and elastase release in activated human neutrophils. Sarcotroxides A (1) and B (2) exhibited anti-inflammatory activity by inhibiting O2•− accumulation (with 43.67% and 61.62% inhibition) and elastase release (with 38.21% and 61.62% inhibition) at 10 µM. These findings validated the potential of these biscembranoids from the cultured S. trocheliophorum as promising candidates for the future development of anti-inflammatory agents specifically designed to target neutrophils.

Giuliano Lo Bianco,1,2 Andrea Tinnirello,3 Alfonso Papa,4 Vito Torrano,5 Gianluca Russo,6 Agnes Stogicza,7 Sebastiano Mercadante,8 Andrea Cortegiani,9 Silvia Mazzoleni,3 Michael E Schatman10,11 1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 2Department of Anesthesiology and Pain, Fondazione Istituto G. Giglio, Cefalù, Italy; 3Department of Anesthesiology and Pain Medicine, ASST Franciacorta, Ospedale di Iseo, Iseo, Italy; 4Department of Pain Management– AO “Ospedali dei Colli” – Monaldi Hospital, Naples, Italy; 5Department of Anesthesia, Critical Care and Pain Medicine, Asst Grande Ospedale Metropolitano Niguarda, Milan, Italy; 6Department of Anesthesia, Postoperative Intensive Care and Pain Therapy, Lodi Hospital, Lodi, Italy; 7Department of Anesthesiology Saint Magdolna Hospital, Budapest, Hungary; 8Department of Pain Relief and Supportive Care, Private Hospital La Maddalena, Palermo, Sicilia, Italy; 9Department of Anesthesiology and Intensive Care, Università degli Studi di Palermo, Palermo, Italy; 10Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU School of Medicine, New York, NY, USA; 11Department of Population Health – Division of Medical Ethics, NYU School of Medicine, New York, NY, USACorrespondence: Andrea Tinnirello, Department of Anesthesiology and Pain Medicine, ASST Franciacorta, Ospedale di Iseo, Via Giardini Garibaldi 4, Iseo, 25049, Italy, Tel +393392599568, Email andreatinny@libero.itAbstract: In recent years, there has been a considerable increase in the number of image-guided interventional procedures performed for the management of acute and chronic pain. Concomitantly, there has also been an increase in the complication rate related to these procedures. The aim of this narrative review is to summarize the primary complications associated with commonly performed image-guided (fluoroscopic- or ultrasound-guided) interventional procedures. We conclude that although complications from interventional pain procedures can be mitigated to a certain degree, they cannot be eliminated altogether. In order to avoid adverse events, patient safety should be given considerable attention and physicians should be constantly aware of the possibility of developing complications.Keywords: chronic pain, pain management, analgesics, opioid, epidural injection, facet joints

Abstract Several types of (mostly) blue-green glass beads from Iron-Age archaeological sites in Central Italy were studied using a range of spectroscopic techniques: portable X-Ray Fluorescence spectrometry, Fibre Optics Reflectance Spectroscopy, Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectrometry, micro-Raman spectroscopy and Laser Ablation Inductively Coupled Plasma Mass Spectrometry. Complementary information was gathered from each technique and discussed in the frame of the archaeological typology of the objects. The systematic evaluation of the results allowed us to draw some conclusions on the raw materials employed for primary production and to highlight some provenance indicators in the glass. Some of the beads found in the Iron Age (IA) contexts were preliminarily attributed to the Final Bronze Age (FBA) production based on their typology, and the compositional data obtained in this work confirmed that they were low magnesium high potassium (LMHK) glass, typical of FBA in the Italian peninsula. Other beads were assigned to low magnesium glass (LMG) or high magnesium glass (HMG), thus giving further information on the fluxing agents employed in the Early Iron Age (EIA) and beyond. Colour variations among the beads reflected their chemical composition, with different bead typologies coloured in a specific way. In some instances, it was possible to establish different origins for the colouring raw materials. The provenance of the samples was difficult to place, but the chemical evidence suggested a subdivision within the raw glass used to produce the beads: for one set of samples, a local origin of the glass could be hypothesised, whereas several production sites in the Near East were suggested for most of the beads considered in this study. Some preliminary clues for the local working of imported glass were also highlighted for one typological group.

Background/purpose: Emerging evidence has shown that various failures in cancer therapy, such as drug resistance, metastasis, and cancer relapse are attributed to cancer stem cells (CSCs). Also, growing attention has been paid to the regulation of non-coding RNAs in cancer stemness. Here, we aimed to investigate the contribution of LINC01296 in the modulation of oral CSCs. Materials and methods: The phenotypic assays including migration, invasion, and colony-forming abilities were carried out in CSCs of two types of oral cancer cells (SAS and GNM) following the knockdown of LINC01296. In addition, the percentage of cells expressing stemness marker, ALDH1, and drug resistance marker, ABCG2, was examined as well as the self-renewal capacity after silencing of LINC01296. Moreover, a luciferase reporter was used to validate the direct interaction between LINC01296 and miR-143. Results: Our results showed that LINC01296 was significantly overexpressed in oral cancer tissues and positively correlated with stemness markers. The phenotypic and flow cytometry assays demonstrated that suppression of LINC01296 reduced the aggressiveness, cancer stemness features, and colony-forming and self-renewal abilities in oral CSCs. Furthermore, we demonstrated that LINC01296 may enhance cancer stemness features through suppression of the effect of miR-143. Conclusion: Silencing of LINC01296 may be a promising direction for oral cancer therapy by reducing cancer stemness via regulation of miR-143.

Giuliano Lo Bianco,1,2 Giovanni Misseri,2 Agnes R Stogicza,3 Gregoretti Cesare,2,4 Sean Li,5 Miles Day,6 David J Kennedy,7 Michael E Schatman8,9 1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 2Anesthesiology and Pain Department, Fondazione Istituto “G. Giglio”, Cefalù, Palermo, Italy; 3Anesthesia and Pain, Saint Magdolna Private Hospital, Budapest, Hungary; 4Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo, Palermo, Italy; 5National Spine and Pain Centers, Shrewsbury, NJ, USA; 6Pain Research, The Pain Center at Grace Clinic, Texas Tech University HSC, Lubbock, TX, USA; 7Department of PM&R, Vanderbilt University Medical Center, Nashville, TN, USA; 8Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 9Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Giuliano Lo Bianco, Anesthesia and Pain Medicine Department, Fondazione Giglio Cefalù, Contrada Pietrapollastra, Via Pisciotto, Cefalù, Palermo, 90015, Italy, Tel +393289682219, Email giulianolobianco@gmail.comBackground: Lumbar zygapophyseal joint dysfunction represents one of the major sources of chronic low back pain. Radiofrequency ablation (RFA) using a V-shaped active tip needle may offer a larger lesion of the medial branch nerves, improving clinical outcome. The aim of our study is to evaluate the efficacy and the feasibility of RFA using V-shaped active tip needles.Methods: This is a single-center observational retrospective study. Clinical records were screened and analyzed if they met the following inclusion criteria: adult patients (> 18 years), diagnosis of chronic lumbar zygapophyseal joint pain, failure of conservative treatments, ability to provide informed consent for data analysis and publication. Exclusion criteria: lumbar pain not related to zygapophyseal joints, previous spinal/lumbar surgery, incomplete data, absence or withdrawal of informed consent. The primary outcome of the study was a change in pain intensity at follow-up. The secondary outcomes were the evaluation of quality-of-life improvement, the occurrence of adverse events and the impact on post-procedural analgesic consumption. For these purposes, pre- and post-treatment numeric rating scale (NRS), neuropathic pain 4 questions (DN4), EuroQoL - EQ-5D-3L, EQ-VAS, EQ-index and North American Spine Society (NASS) index were retrieved and analysed.Results: Sixty-four patients were included. 7.8% of patients at 1-month (CI95% 0.026, 0.173), 37.5% at 3-month (CI95% 0.257, 0.505), 40.6% at 6-month (CI95% 0.285, 0.536) and 35.9% at 9-month (CI95% 0.243, 0.489) follow-up reported a reduction of more than 80% in NRS Statistical analysis indicated a significant change in NRS, DN4, EQ-index and EQ-5D-VAS (p-value < 0.001) at the different time-points.Conclusion: RFA using a V-shaped active tip needle might be a feasible and effective treatment for chronic lumbar zygapophyseal joint pain.Keywords: arthralgia, chronic pain, zygapophyseal joint, pain management, radiofrequency ablation, neuromodulation, lumbar facet joint

Giuliano Lo Bianco,1,2 Andrea Tinnirello,3 Alfonso Papa,4 Maurizio Marchesini,5 Miles Day,6 Gaetano Joseph Palumbo,7 Gaetano Terranova,8 Maria Teresa Di Dato,4 Simon J Thomson,9 Michael E Schatman10,11 1Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 2Anesthesiology and Pain Department, Fondazione Istituto G. Giglio, Cefalù, Italy; 3Anesthesiology and Pain Medicine Department, ASST Franciacorta, Ospedale di Iseo, Iseo, 25049, Italy; 4Pain Department, AO “Ospedali dei Colli”, Monaldi Hospital, Naples, Italy; 5Mininvasive Surgery Department, Unit of Pain Medicine IRCCS Maugeri Pavia, Pavia, 27100, Italy; 6Pain Research, The Pain Center at Grace Clinic, Texas Tech University HSC, Lubbock, TX, USA; 7Azienda Ospedale - Università Padova, Department of Anesthesia and Intensive Care, Padova, Italy; 8Anaesthesia and Intensive Care Department, Asst Gaetano Pini, Milano, Italy; 9Pain Management, Mid and South Essex University Hospitals NHSFT, Basildon, SS16 5NL, UK; 10Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU School of Medicine, New York, NY, USA; 11Department of Population Health – Division of Medical Ethics, NYU School of Medicine, New York, NY, USACorrespondence: Giuliano Lo Bianco, Email giulianolobianco@gmail.comAbstract: In patients where conservative approaches have failed to relieve from chronic pain, interventional procedures may be an option in well selected patients. In recent years there has been an increase in the use and development of invasive procedures. Concomitantly, there has also been an increase in the complications associated with these procedures. Taken this into consideration, it is important for healthcare providers to take a cautious and vigilant approach, with a focus on patient safety, in order to minimize the risk of adverse events and ensure the best possible outcome for the patient. This may include careful selection of patients for procedures, use of proper techniques and equipment, and close monitoring and follow-up after the procedure. The aim of this narrative review is to summarize the primary complications associated with commonly performed image-guided (fluoroscopy or ultrasound-guided) interventional procedures and provide strategies to reduce the risk of these complications. We conclude that although complications from interventional pain procedures can be mitigated to a certain degree, they cannot be eliminated altogether. In order to avoid adverse events, patient safety should be given considerable attention and physicians should be constantly aware of the possibility of developing complications.Keywords: chronic pain, pain management procedures, complications, spinal cord stimulation, intrathecal drug delivery, low back pain

Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.

Abstract Poor adherence to asthma preventer medication is associated with life-threatening asthma attacks. The quality and outcomes framework mandated primary care annual asthma review does not include adherence monitoring and the effect of poor adherence on lung function in paediatric primary care patients is unknown. The aim was to investigate the link between inhaled corticosteroid (ICS) adherence and spirometry, fraction of exhaled nitric oxide (FeNO) and asthma control in asthmatic school-age children in this cross-sectional observational study involving three Leicestershire general practices. Children 5–16 years on the practice’s asthma registers, were invited for a routine annual asthma review between August 2018 and August 2019. Prescription and clinical data were extracted from practice databases. Spirometry, bronchodilator reversibility (BDR) and FeNO testing were performed as part of the review. 130 of 205 eligible children (63.4%) attended their review. Mean adherence to ICS was 36.2% (SEM 2.1%) and only 14.6% of children had good adherence (≥75% prescriptions issued). We found no differences in asthma exacerbations in the preceding 12 months between the adherence quartiles. 28.6% of children in the lowest and 5.6% in the highest adherence quartile had BDR ≥ 12% but this was not statistically significant (p = 0.55). A single high FeNO value did not predict adherence to ICS. Adherence to ICS in children with asthma in primary care is poor. The link between adherence to ICS and asthma exacerbations, spirometry and FeNO is complex but knowledge of adherence to ICS is critical in the management of children with asthma.

Coronavirus pandemic infection is the most important health issue worldwide. Coronavirus disease 2019 is a contagious disease characterized by severe acute respiratory syndrome coronavirus 2. To date, excluding the possibility of vaccination, against SARS-CoV-2 infection it is possible to act only with supportive care and non-virus-specific treatments in order to improve the patient's symptoms. Pharmaceutical industry is investigating effects of medicinal plants, phytochemical extracts and aromatic herbs to find out natural substances which may act as antiviral drugs. Several studies have revealed how these substances may interfere with the viral life cycle, viral entry, replication, assembly or discharge, as well as virus-specific host targets or stimulating the host immune system, reducing oxidative stress and inflammatory response. A natural compound can be used as a prophylaxis by people professionally exposed to the risk of contagion and/or positive patients not in intensive care. The aim of this paper is to perform a narrative review of current literature in order to summarize the most studied natural compounds and their modes of action.

Abstract The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional co‑activator with PDZ‑binding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Summary: Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38).

Background: Meeting the challenge of antiretroviral therapy (ART) whose efficacy can last a lifetime requires continuous updating of the virological, pharmacological, and quality of life outcomes to be pursued and a continuous review of literature data on the efficacy and tolerability of new drugs and therapeutic strategies. Methods: With the aim of identifying open questions and answers about the current controversies in modern ART, we adapted the Design Thinking methodology to the needs of the design phase of a scientific article, involving a team of experts in HIV care. Results: Five main pillars of treatment success were discussed: sustained virologic suppression over time; immunological recovery; pharmacological attributes; long-term tolerability and safety of ART; and people’s satisfaction and quality of life. The definition of the outcomes to be achieved in each thematic area and the tools to achieve them were reviewed and discussed. Conclusions: Long-term treatment success should be intended as a combination of HIV-RNA suppression, immune recovery, and high quality of life. To achieve this, the regimen should be well-tolerated, with high potency, genetic barrier, and forgiveness, and should be tailored by a person-centered perspective, based on individual needs, preferences, and therapeutic history.

Na Leucemia Mieloide Crônica (LMC), pacientes que alcançam resposta molecular profunda sustentada (RMP) com inibidor de tirosinoquinase (ITQ) podem ter o tratamento descontinuado. A remissão livre de tratamento (RLT) ocorre na minoria dos pacientes e não há biomarcadores preditores de manutenção ou perda de resposta. A imunidade antitumoral mediada por Linfócitos T (LT) e Natural Killer (NK) pode contribuir para manutenção e resultar em respostas distintas durante e após a descontinuação. Correlacionamos o fenótipo T e NK com a cinética de doença residual mensurável (uso de ITQ) e com a perda da RLT (descontinuação-DES). Foram incluídos 10 controles saudáveis (CT) e 23 pacientes com LMC: 8 ao diagnóstico (DX), 4 tratados por mais de 3 anos com RM menor que log 3 (RM4,5) em DES, divididos e acompanhados em meses (m), no qual, 3m (n = 13), 6m (n = 8) e 9m (n = 7), e 8 que recaíram (R) no DES. Até o ponto 6m, os pacientes estavam com 50% da dose do ITQ e, após este ponto, tiveram o ITQ suspenso. Foram avaliados frequência, subtipos e maturação de NK e LT por citometria de fluxo do sangue periférico. Os subtipos NK (CD45hiCD19−CD3−) foram definidos como secretório (CD56brightCD16−) ou citotóxico (CD56dimCD16+), e a maturação funcional das células CD19−CD3−CD56+ foi classificada: CD11b−CD27− (tolerante); CD27+CD11b− (secretória imatura); CD27+CD11b+(secretória madura) e CD11b+CD27− (citotóxica), além dos marcadores de ativação CD57 e NKp80. A frequência destas subpopulações foi avaliada em subgrupos de pacientes de acordo com o nível de RM por RT-qPCR para o gene BCR::ABL1. Em comparação aos CT, amostras de LMC em atividade (DX, RM0,05). Em relação aos subtipos de NK, DX, RM 0,05). Na maturação funcional de NK, DX, RM 0,05). Na ativação de NK, DX, RM4,5 e DES, possuem perfil mais maduro de NK, no qual a atividade citotóxica é semelhante aos CT. Entretanto, pacientes maus respondedores (RM

O monitoramento da Leucemia Mieloide Aguda (LMA) é uma estratégia de avaliação prognóstica para identificar Doença Residual Mensurável (DRM). Indica-se o estudo de DRM por métodos moleculares em casos com mutações NPM1 /translocações tipo core-binding fator; mas a citometria de fluxo multiparamétrica (CFMP) é aplicável a mais de 90% das LMAs e preditora do sucesso terapêutico. Diante da escassez no acesso a métodos moleculares em países em desenvolvimento, um protocolo de determinação de DRM na rotina laboratorial é uma necessidade não atendida. Objetivamos implantar um protocolo de DRM por CFMP para LMA e avaliá-lo quanto à sua eficiência e como fator prognóstico adicional à estratificação de risco clássica. Foram incluídos 191 pacientes com LMA de novo ou secundária à síndrome mielodisplásica, entre 18 e 65 anos (09/2015 a 02/2023), com remissão morfológica completa após tratamento com 1 ou 2 ciclos de indução (ciclo 1:3 dias de daunorrubicina 60 mg/m2 e 7 dias de citarabina 200 mg/m2; ciclo 2:3 dias de daunorrubicina 60 mg/m2 e 6 dias de citarabina 1 g/m2 2x/dia). Na Consolidação foi administrada no ciclo1:citarabina 1 g/m2 2x/dia, 6 dias e no ciclo2: idem 1 ou transplante de Medula Óssea (MO) autólogo com condicionamento BuCy. Os pacientes foram estratificados (ELN2017*-exceto mutações TP53 ou ASXL1) de acordo com cariótipo, testes moleculares e coleta de dados clínicos. As DRMs 1, 2 (Pós-indução) e 4 (Pós consolidação), foram avaliadas com: CD45, CD34, CD117, CD33, CD38, CD19, CD123, CD7, CD56, CD13, CD11b, CD14, CD64, CD300e, CD15, CD133 e HLA-DR. Utilizamos a abordagem de LAIPs e DfN, comparando dados de MO saudável e diagnóstico e sendo DRM+ a frequência de células em CD45+ ≥ 0,1% (mínimo 1 fenótipo anormal). Analisamos Sobrevida Global e Livre de Recaída (SG e SLR) e Incidência Cumulativa de Recaída (ICR) - software R (α = 5%). Não foram encontradas associações entre DRM+ e idade, leucócitos, % de blastos, subtipo morfológico e alterações citogenéticas. Observou-se 21% de DRM+ na DRM1,13% na DRM2 e 12,5 % na DRM4. Na DRM1, a frequência de DRM+ para pacientes de risco baixo, intermediário e alto foi: 46,5%, 33,4%, 20,1% e nas DRMs 2 e 4, 33,4%/ 38,9%/ 27,7% e 48,8%/ 48,8%/ 14,4%, respectivamente. Globalmente as DRMs foram definidas como LAIPs ou DfN em 72,3% e 27,7% das amostras. A expressão de CD56 foi a mais frequente (22%), seguida por alterações em CD34/CD13 (21%) e CD33 (17%). DRMsnegativas foram mais frequentes em pacientes com NPM1mut (DRM1, 69,7%) do que em FLT3-ITD (15,2%). A DRM+ após o 2ºciclo de Indução implicou em maior risco de óbito (HR = 1329 (IC;75,16-235022), p = 0,002), maior ICR (44,5% em 30 meses, p = 0,033) e menor SG (4,4 meses, p = 0,018) no risco intermediário. A detecção de DRM+ não se associou aos riscos favorável e alto. Nossos achados demonstram a padronização da DRM por CFMP em uma população brasileira com tratamento único reprodutível usando painel racional com número limitado de marcadores. A detecção de fenótipos ao diagnóstico (LAIP) é mais útil do que os fenótipos semelhantes a DfN, embora sua combinação tenha validado o tubo proposto como “consenso”, aplicável a todos os casos a despeito do fenótipo inicial. Em pacientes de risco intermediário, o resultado da DRM por CFMP se mostrou fator de risco independente para SG. Sendo este grupo correspondente à cerca 1/3 dos casos, comumente com cariótipo normal e desfechos variáveis, a identificação de fatores prognósticos adicionais e dinâmicos tem grande utilidade e pode guiar as decisões terapêuticas. Por fim, a identificação dos fenótipos de DRM definidos neste protocolo pode contribuir na busca por alvos terapêuticos para erradicação das células leucêmicas resistentes.

A Leucemia Mieloide Aguda (LMA) se origina de anormalidades genéticas ao nível das células-tronco hematopoéticas (CTH), que adquirem propriedades de células-tronco leucêmicas (CTL) com capacidade aumentada de sobrevivência e bloqueio de maturação. Hipotetizamos que a parada de maturação leucêmica por meio de definição fenotípica das células de origem possa acrescentar informações importantes sobre a biologia da LMA e contribuir para a predição de desfechos. Assim, analisamos retrospectivamente em coorte brasileira de pacientes com LMA o perfil fenotípico de maturação de blastos leucêmicos e sua associação com achados clássicos de morfologia, risco genético e informações clínicas. Foram incluídos dados de imunofenotipagem de 359 indivíduos com LMA encaminhados para o estudo ICAML2015, entre 18 e 70 anos, acompanhados durante oito anos, exceto os casos de Leucemia Promielocítica Aguda (LPA) que só foram incluídos após 2020. A expressão de CD34, CD117, CD13, CD33, CD38, (c)MPO e HLA-DR foi avaliada para a categorização nos subtipos HSC: Hematopoietic stem cell; MPP: Multipotent progenitors; CMP: Common myeloid progenitors; GMP: Granulocyte-monocyte progenitors; MP: Monocyte progenitors; GP: Granulocyte progenitors. LMAs tipo HSC foram definidas por CD34+, CD117−/+, HLA-DR+, CD13/33−, MPO−. A expressão de CD13 e 33 definiu o subtipo MPP. A expressão de cMPO entre 10-70% definiu o subtipo CMP e > 70% GMP. Os subtipos MP/GP foram diferenciados pela expressão de HLA-DR no subtipo GP. A reclassificação dos casos demonstrou a seguinte distribuição: HSC (n = 31, 8.64%); MPP (n = 77, 21.45%); CMP (n = 37, 10.31%); GMP (n = 75, 20.89%); MP (n = 50, 13.93%); GP (n = 89, 24.79%). De acordo com a estratificação de risco da European-Leukemia Net 2017, dentre os subtipos HSC, MPP, CMP e GMP predominaram o risco favorável, seguidos de intermediário e adverso. Nos subtipos MP e GP, o risco intermediário foi mais prevalente em relação ao favorável e adverso. A correlação com a classificação morfológica demonstrou que LMA sem maturação, com maturação, mielomonocítica e monocítica se distribuíram de forma equivalente nos subtipos MPP, CMP, GMP, MP e GP; no subtipo HSC não se encontrou leucemia monocítica ou promielocítica, sendo esta caracteristicamente do tipo GP e raramente GMP. Para 325 pacientes, os dados dos genes NPM1, FLT3 -ITD, BAALC, EVI1 e CEBPA estavam disponíveis, sendo encontrada com maior frequência a mutação FLT3 -ITD no subtipo MPP (26/325) e NPM1 em GP (44/325). Em algum ponto de seu seguimento 57/359 pacientes recaíram, representando nos subtipos: HSC (5/31, 16%), MPP (15/77, 19%), CMP (6/37, 16%), GMP (16/75, 21%), MP (6/50, 12%) e GP (9/89, 10%). A sobrevida global foi avaliada em 309/359 pacientes, tendo-se observado maior taxa para o subtipo GP (66%) e menor para CMP (11%) aos 24 meses de seguimento (p = 0.03). Os achados apontam que as correlações entre o estado de parada de maturação da LMA e dados clínicos de estratificação de risco e sobrevida merecem atenção e melhor exploração. É possível que a combinação dos dados genéticos com a classificação imunofenotípica de origem leucêmica seja útil para aferir prognóstico na LMA, pois é plausível que as leucemias mais maduras tenham um microambiente inflamatorio exuberante, capaz de modificar a imunidade antitumoral e contribuir para os desfechos diversos.

A Leucemia Linfoblástica Aguda (LLA) é uma neoplasia de células linfoides imaturas T ou B, sendo a segunda leucemia aguda mais comum no adulto. Acomete cerca de 1 a 5 /100.000 indivíduos por ano nos Estados Unidos e cerca de 66% dos casos são LLA-B. O tratamento da LLA-B consiste em quimio/imunoterapia de alta intensidade, com objetivo primário de restaurar a hematopoese normal. A monitorização de remissão de doença (Doença Residual Mensurável - DRM) é realizada em diferentes etapas do tratamento por citometria de fluxo multiparamétrica (CFMP), sendo a técnica eficaz na detecção de clones leucêmicos pós-tratamento com quimioterapia de alta intensidade. Para pacientes recaídos/refratários a terapia de resgate mais indicada consiste em imunoterapia com agentes específicos, chamados de terapias-alvo (ex: anti-CD3 + anti-CD19 -Blinatumomabe, anti-CD22 -Inotuzumabe + Ozogamicin), e a terapia com células T geneticamente modificadas - CAR-T (do inglês, Chimeric antigen receptor T Cell). Com o surgimento de tais tratamentos surge também a demanda por padronização da monitorização de DRM nos pacientes, visto que terapia pode resultar em perda de expressão de marcadores, o que inviabiliza a análise pelos métodos anteriormente padronizados, enfatizando a possibilidade de recaídas com clones emergentes negativos para a expressão de CD19, por exemplo. Assim, foi objetivo do presente estudo determinar a viabilidade de implantação de novo protocolo para detecção de DRM com base em seleção alternativa de antígenos de células B para pacientes submetidos à terapia convencional ou anti-CD19 por CFMP. Foram analisadas as medulas ósseas de 2 doadores saudáveis, e 2 pacientes LLA-B tratados no Hospital das Clínicas de Ribeirão Preto - FMRP-USP, sendo um submetido à terapia HyperCVAD e 1 paciente refratário, tratado com CAR-T anti-CD19. As amostras foram preparadas de acordo com protocolo Euroflow e avaliadas quanto à expressão dos marcadores (CD45, CD34, CD38, CD81, CD10, CD20, CD19, CD22, CD24, CD66b, CD66c + CD123, CD73) por CFMP em citômetro BD Canto II e analisadas em software Infinicyt por dois observadores diferentes. Os resultados da análise DRM foram expressos como a porcentagem de células nucleadas viáveis que abrigam o fenótipo anormal, sendo a positividade definida quando igual ou maior do que 0,01%. No presente estudo de viabilidade a detecção de células B foi concordante entre os diferentes tubos, independente de marcação de CD19, não havendo diferença nas frequências observadas tanto para amostras de referência como no paciente analisado (p = 0,4478, Kruskal-Wallis). Não foi observada diferença entre as frequências de células anormais detectadas pelos observadores (p = 0,4, Kruskal Wallis) e nossos resultados demonstram reprodutibilidade entre as análises realizadas, com Correlação de Pearson calculada de 0,9995 (IC: 0,9949-0,999, r2 = 0,9989). A análise de Bland-Altman demonstrou não haver divergência entre as metodologias utilizadas. Não houve diferença nas frequências obtidas dos fenótipos caracterizados como DRM+, independente da combinação de marcadores para a gate de células B (CD19xCD22, CD22xCD24, e CD24xCD66b) p = 0,667, Friedman, α=0,05). Em conclusão, nossos dados indicam que o monitoramento da DRM para pacientes com LLA-B tratados com imunoterapia anti-CD19 é possível por CFMP resultando em dados altamente concordantes. O desempenho do resultado preliminar exposto deve garantir resultados comparáveis ao serem avaliados em múltiplos centros, etapa em fase de planejamento, para garantir o avanço da padronização da resposta de DRM por CFMP.

Objetivos: A Refratariedade Plaquetária (RP) é definida quando não há incremento plaquetário adequado, em pelo menos duas transfusões de plaquetas consecutivas, ABO compatíveis, coletadas a menos de 48 horas, podendo ser de causa imune ou não imune. Quando a causa da RP é imune, está indicada a transfusão de plaquetas compatíveis. Porém, quando não há disponibilidade de plaquetas compatíveis e o paciente apresenta sangramento ativo, uma alternativa de tratamento é a infusão lenta e contínua de plaquetas (em inglês, 24-continuous infusion of platelet ou platelet drip), que tem como objetivo principal o controle do sangramento através da manutenção da integridade do endotélio. O objetivo deste estudo foi avaliar os casos de refratariedade plaquetária imune em que este protocolo foi aplicado. Material e métodos: Estudo retrospectivo que avaliou no período de março/2021 a maio/2023 os pacientes com refratariedade plaquetária imune, sem doador compatível, no cenário de sangramento ativo (WHO grau ≥2), que receberam plaquetas incompatíveis no protocolo de infusão lenta e contínua (drip). Para identificação dos anticorpos anti-HLA realizamos o Painel de Reatividade contra Antígenos HLA (PRA) Classe I (LABScreen®,Single Antigen, One Lambda Inc.) e a prova cruzada de plaquetas por citometria de fluxo. Neste teste, o soro do paciente é incubado com as plaquetas de um ou mais doadores, os resultados obtidos em valores de Fluorescência de Canal Mediano (MCF) são transformados em valores de Deslocamento de Canal Mediano (MCS), na qual a intensidade de fluorescência do soro do paciente é comparada ao valor de intensidade de fluorescência do controle negativo. A prova cruzada é considerada positiva quando MCS for ≥90 canais. As plaquetaféreses que apresentaram o menor MCS foram selecionadas para transfusão e fracionadas em alíquotas com volumes menores, de aproximadamente 50 a 120 mL, dependendo do peso do paciente. Posteriormente, foram infundidas em 2 a 4 horas, continuamente, até parar o sangramento. Resultados: Foram avaliados seis pacientes com idade 02‒65 anos e mediana 47 anos, que apresentaram sangramento ativo e uma contagem média de plaquetas de 2500 mil. O PRA classe I variou entre 73%‒98%. O MCS das plaquetas infundidas variou de 228‒445. Os diagnósticos eram leucemia mielóide aguda, leucemia linfoblástica aguda B Ph+, leucemia promielocítica aguda, anemia aplásica, leucemia mielocítica crônica, mieloma múltiplo; dois desses pacientes (33%) realizaram transplante. O protocolo drip ficou ativo em uma média de 3 dias. Discussão: Em todos os casos analisados, as hemorragias cessaram e não foram reportadas reações durante as infusões de plaquetas incompatíveis. A média em dias para a recuperação plaquetária (alvo de 10 mil), após desativação do protocolo, foi de 7 dias. Conclusão: A transfusão lenta e contínua de plaquetas se mostrou uma abordagem eficaz e segura para pacientes com refratariedade plaquetária imune, incluindo os hipersensibilizados (PRA >80%), que não apresentam plaquetas compatíveis e necessitam de uma alternativa terapêutica para controle de sangramento crítico, que em alguns casos pode ser fatal.

Objetivos: A aloimunização a antígenos eritrocitários na gestação ocorre quando os fetos expressam na superfície das suas hemácias antígenos exclusivamente de origem paterna, os quais podem chegar à circulação materna, gerar uma resposta imune e sensibilizar a gestante. Dependendo da especificidade, quantidade e afinidade do anticorpo ao antígeno correspondente, a aloimunização pode causar a Doença Hemolítica Perinatal (DHPN) ou complicações mais graves para o feto, como hidropsia fetal e óbito. O objetivo deste trabalho foi analisar os anticorpos presentes no teste de Pesquisa de Anticorpos Irregulares (PAI) em gestantes no serviço de Hemoterapia do Hospital de Clínicas de Porto Alegre (HCPA). Material e métodos: Estudo retrospectivo que avaliou 68 gestantes atendidas no HCPA, no período de junho de 2020 a junho de 2023, que apresentaram PAI positivo. Foram realizados os levantamentos através das fichas materno-fetais e sistema informatizado Real Blood. A PAI foi realizada com a metodologia de cartão-gel automatizado. Resultados: Embora o anti-D (46,9%) tenha sido o anticorpo mais frequente, como o esperado, observou-se ainda um número de gestantes aloimunizadas por outros anticorpos de significado clínico como anti-E (8,6%). Das 68 gestantes avaliadas, 54 (79,4%) apresentaram um anticorpo, 12 (17,6) dois anticorpos, 2 (2,9%) três anticorpos. Ao verificarmos os principais anticorpos presentes nas 44 gestantes RhD Negativas, além da predominância de Anti-D (67,9%), observamos anti-E e anti-G (7,1%), anti-C (5,4%), Lea e Leb (3,6%). Observamos que algumas gestantes tiveram mais de um anticorpo (27,9%), sendo Anti-D,E e Anti-D,G (7,0%) e Anti-D,C (4,7%). Das 24 gestantes RhD positivas (35,2%), a maioria dos anticorpos foi indeterminada (19,2%), seguido de Anti-Lea (15,4%) e Anti-E (11,5%). Também foram observados múltiplos anticorpos em 8,3% dessas gestantes, sendo anticorpos anti-Jka,S (4,2%) e Anti-M,S (4,2%). Foi encontrado com menos frequência, em ambos grupos de gestantes, outros anticorpos como: anti-Lea (7,4%), anti-C (4,9%), anti-Leb (4,9%), anti-e (3,7%), anti-M (2,5%), anti-S (2,5%), anti-G (2,5%), anti-c (1,2%), anti-Cw (1,2%), anti-Dia (1,2%), anti-Fya (1,2%), anti-I (1,2%), anti-Jka (1,2%) e anti-K (1,2%), evidenciando a necessidade de pesquisa destes anticorpos não somente em gestantes RhD negativas, mas também como um exame obrigatório no pré-natal. Discussão: A maior parte dos casos graves de DHPN é causada pelo anticorpo Anti-D. Porém, devido às medidas preventivas direcionadas às mães RhD negativas (administração de imunoglobulina humana anti-D) tem sido observada uma diminuição dos casos de aloimunização por anti-D. No entanto, tem se observado a aloimunização por outros anticorpos, e nestes casos, a sensibilização materna (aloimunização) poderá ocorrer nas gestantes independente do fator RhD. Com isso, enfatizamos a necessidade de orientação dos profissionais da saúde sobre a importância da solicitação da PAI para todas as gestantes. Conclusão: Considerando que outros anticorpos, além do anti-D podem desenvolver DHPN, seria importante considerar a possibilidade de realizar a PAI no pré-natal de todas as gestantes, independente da tipagem RhD das mesmas, e seguir reforçando a importância da imunoprofilaxia para anti-D a fim de prevenir eventuais intercorrências nos neonatos.

Introdução/objetivos: O Teste da Antiglobulina Humana Direto (TAD) auxilia no diagnóstico de doença hemolítica perinatal, no entanto, a eluição tem se mostrado um teste com maior sensibilidade para detecção dos anticorpos envolvidos na incompatibilidade ABO e para auxiliar a decisão médica. O objetivo deste estudo foi avaliar e comparar a sensibilidade entre os testes TAD e eluato por congelamento na detecção de icterícia por incompatibilidade materno-fetal. Materiais e métodos: Realizamos os testes de TAD e eluição por congelamento (LUI) em amostras de recém-nascidos do grupo A, B ou AB com tipagem materna do grupo O, independente do resultado do TAD. As amostras foram oriundas das solicitações de exame dos neonatos nascidos no centro obstétrico do Hospital de Clínicas de Porto Alegre (HCPA) entre maio de 2019 e janeiro de 2020. Os dados clínicos e laboratoriais foram verificados no prontuário eletrônico, após a aprovação do projeto pelo Comitê de Ética e Pesquisa do HCPA. Resultados: Das 137 amostras analisadas, observamos que 80,3% apresentavam incompatibilidade O/A e 19,7% O/B. Do total de amostras avaliadas, 27% apresentavam TAD positivo e 83,2% LUI positivo (p = 0,005), sendo 48,9% de anti-A, 22,6% de anti-AB e 11,7% de anti-B. Em relação à análise da clínica dos neonatos, 65 (47,4%) apresentaram icterícia, 21 (15,3%) realizaram fototerapia e 9 (6,6%) realizaram transfusão de concentrado de hemácias (CH), nenhum necessitou de exsanguíneo transfusão. Ao correlacionar a clínica dos neonatos com os testes imuno-hematológicos, do total de 65 pacientes que apresentaram icterícia, apenas 19 tinham TAD positivo (p = 0,697). Apenas 1 neonato com TAD positivo realizou transfusão de CH (p = 0,444) e 8 realizaram fototerapia (p = 0,284). Dos 114 neonatos que obtiveram o teste de LUI positivo, 59 (50,8%) apresentaram icterícia (p = 0,021) e 21 realizaram fototerapia, ou seja, todos os pacientes que foram submetidos a fototerapia tiveram teste de LUI positivo (p = 0,004), ambos os achados foram considerados estatisticamente significativos. Dos 9 neonatos que receberam transfusão de CH, 7 (77,8%) obtiveram LUI positivo, porém este dado não foi estatisticamente significativo (p = 0,663). Observamos que 40 (54,1%) neonatos que apresentaram LUI positivo e TAD negativo apresentaram icterícia e 19 (52,8%) dos pacientes que apresentaram ambos os testes positivos exibiram o histórico de icterícia. Ao analisarmos a realização da fototerapia com os resultados dos testes imuno-hematológicos, verificamos que 13 (16,9%) neonatos apresentaram LUI positivo e TAD negativo; 8 (21,6%) LUI positivo e TAD positivo. Discussão: Neste estudo, a frequência de icterícia e a necessidade de fototerapia na população neonatal foi equivalente nos grupos com LUI positivo/TAD negativo e LUI positivo/TAD positivo. Desta forma, o risco de hemólise imunomediada por incompatibilidade ABO parece ter o mesmo comportamento biológico, nos pacientes com TAD positivo ou naqueles que apresentam apenas eluato positivo. Com essa avaliação será possível identificar precocemente uma possível incompatibilidade ABO como causa de hemólise ou icterícia, permitindo um manejo mais rápido e seguro para os pacientes. Conclusão: Conclui-se que o eluato seja um exame com potencial de melhor acurácia, sobretudo na sensibilidade do teste em relação ao TAD isoladamente, uma vez que apenas um terço dos pacientes com icterícia por incompatibilidade ABO foi identificada por esse exame.

Introdução/objetivos: Em transfusões de hemocomponentes plasmáticos não-isogrupo, como o concentrado de plaquetas, há risco de desenvolvimento de uma reação hemolítica transfusional. Um dos fatores associados é a presença de altos títulos de anti-A e/ou anti-B. Uma vez que nem sempre é possível respeitar a compatibilidade ABO devido a oferta limitada, para orientar na seleção dos hemocomponentes é necessário realizar a titulação das plaquetaféreses. O objetivo do trabalho foi identificar a distribuição de altos títulos de anticorpos anti-A e anti-B em doadores de plaquetaféreses. Materiais e métodos: Foram analisadas amostras de doadores de plaquetaféreses no período de maio a julho de 2023 no Serviço de Hemoterapia do Hospital de Clínicas de Porto Alegre. As amostras foram processadas no equipamento automatizado NEO Iris®Immucor ‒ Fresenius Kabi, utilizando técnica de titulação seriada em microplaca para o título de IgM e IgG. As amostras de doadores O foram testadas tanto para IgM quanto IgG, enquanto as amostras de doadores A e B, apenas para IgM. O título de IgM foi testado em 4 pontos (≤16, 32, 64 e ≥128) e IgG em 8 pontos (≤16, 64, 128, 256, 512, 1024, 2048, ≥4096). O ponto de corte utilizado para IgM foi ≤32 e para IgG≤64. Resultados: A média de idade foi de 43,7 anos (18‒69 anos). A maioria era do sexo masculino (166%‒89,2%) e doadores de repetição (105%‒56,5%), que possuiam 3 ou mais doações no ano até o período avaliado. Das 186 doações, 93 (50,0%) eram do grupo O, 69 (37,1%) do grupo A, 16 (8,6%) do grupo B e 8 (4,3%) do grupo AB. Das aféreses do grupo O testadas para IgM, 64 (68,8%) apresentaram baixos títulos de anti-A e anti-B e 69 (74,1%) baixo título para anti-A, 84 (90,3%) baixo título para anti-B e 4 (4,3%) alto título para ambos. Para IgG, 44 (47,3%) apresentaram baixos títulos de anti-A e anti-B, 47 (50,5%) baixo título para anti-A, 79 (84,9%) baixo título para anti-B e 11 (11,8%) alto título para ambos. Das plaquetaféreses do grupo A, a maioria teve baixo título de anti-B (61%‒88,4%) e das plaquetaféreses do grupo B, 15 (93,7%) apresentaram baixo título de anti-A. Em 11 plaquetaféreses do grupo O, os títulos de IgM e IgG de anti-A foram considerados altos, enquanto apenas 2 apresentaram ambos os títulos altos para anti-B. Discussão: Os pontos de corte da titulação ABO são definidos de acordo com cada instituição, considerando principalmente a metodologia empregada. Além disso, deve-se avaliar a disponibilidade de hemocomponentes do Serviço e o perfil dos pacientes atendidos. Mesmo que o perfil de doadores apresente em sua maioria títulos baixos de anti-A e anti-B é importante salientar que a identificação de plaquetaféreses com altos títulos de anticorpos ABO pode contribuir para redução do risco de reação hemolítica transfusional. Com a implementação da avaliação dos títulos anti-A e anti-B da classe IgG, identificou-se uma redução do número de plaquetáfereses de 68,8% para 47,3% com títulos considerados seguros de acordo com o nosso Serviço. Desse modo, garantimos um aumento na segurança transfusional das plaquetáfereses do grupo O. Conclusão: A triagem de plaquetaféreses com altos títulos de anti-A e anti-B (IgM e IgG) é uma estratégia acessível de ser implementada na rotina da imunohematologia do doador, além de ser uma abordagem segura e de baixo custo para a transfusão de plaquetas ABO incompatíveis.

Background Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still’s disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients.Methods Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters.Results K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients.Conclusions Four patient clusters in Still’s disease may be recognised by a multidimensional characterisation (‘Juvenile/Transitional’, ‘Uncomplicated’, ‘Hyperferritinemic’ and ‘Catastrophic’). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.

Objective Still’s disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still’s disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still’s disease.Methods Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still’s disease.Results A total of 411 patients suffering from Still’s disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still’s disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p

Artificial Intelligence (AI) and Machine Learning (ML) approaches that could learn from large data sources have been identified as useful tools to support clinicians in their decisional process; AI and ML implementations have had a rapid acceleration during the recent COVID-19 pandemic. However, many ML classifiers are “black box” to the final user, since their underlying reasoning process is often obscure. Additionally, the performance of such models suffers from poor generalization ability in the presence of dataset shifts. Here, we present a comparison between an explainable-by-design (“white box”) model (Bayesian Network (BN)) versus a black box model (Random Forest), both studied with the aim of supporting clinicians of Policlinico San Matteo University Hospital in Pavia (Italy) during the triage of COVID-19 patients. Our aim is to evaluate whether the BN predictive performances are comparable with those of a widely used but less explainable ML model such as Random Forest and to test the generalization ability of the ML models across different waves of the pandemic.

Risk stratification for malignant ventricular arrhythmias and sudden cardiac death is a daunting task for physicians in daily practice. Multiparametric mapping sequences obtained via cardiovascular magnetic resonance imaging can improve the risk stratification for malignant ventricular arrhythmias by unveiling the presence of pathophysiological pro-arrhythmogenic processes. However, their employment in clinical practice is still restricted. The present review explores the current evidence supporting the association between mapping abnormalities and the risk of ventricular arrhythmias in several cardiovascular diseases. The key message is that further clinical studies are needed to test the additional value of mapping techniques beyond conventional cardiovascular magnetic resonance imaging for selecting patients eligible for an implantable cardioverter defibrillator.

In tissue formation and regeneration processes, cells often move collectively, maintaining connections through intercellular adhesions. However, the specific roles of cell–substrate and cell-to-cell mechanical interactions in the regulation of collective cell migration are not yet fully understood. Finite element modeling (FEM) may be a way to assess more deeply the biological, mechanical, and chemical phenomena behind cell adhesion. FEM is a powerful tool widely used to simulate phenomena described by systems of partial differential equations. For example, FEM provides information on the stress/strain state of a cell adhering to a substrate, as well as on its mechanobiological behavior. This review paper, after briefly describing basic principles of cell adhesion, surveys the most important studies that have utilized FEM to investigate the structural response of a cell adhering to a substrate and how the forces acting on the cell–substrate adhesive structures affect the global cell mechanical behavior.

Abstract Background Antibiotic prophylaxis during implant placement may improve implant short term survival. Nevertheless, use of antibiotics carries risks of adverse effects and antibiotic resistance. The aim of the present study is to compare the use of antibiotics in dental implant procedures in terms of costs and effectiveness. Methods A decision-tree model was developed using TreeAge Pro Healthcare software. Two strategies were compared: Antibiotics and No antibiotics in implant placement procedures. The costs were calculated considering direct costs for implant placement, antibiotic costs, and costs for implant replacement in case of failure. Effectiveness was defined in terms of General Oral Health Assessment Index. Outcomes were evaluated as Incremental Cost Effectiveness Ratio (ICER). One-way sensitivity analysis and Probabilistic Sensitivity Analysis were performed for the most influential variables to test parameter uncertainty. Patient and healthcare perspectives were considered. Results Antibiotic prophylaxis resulted to be cost-effective compared to no use of antibiotics (ICER = 14,692,64 and ICER = 3841,18, respectively for patient’s and healthcare perspective). The cost of antibiotics, cost of implant replacement in case of failure and probability of adverse effects significantly influenced the results. Conclusions From an individual patient perspective, antibiotic strategy can be considered cost-effective, even when the cost of antibiotic therapy increases. We can conclude that the administration of antibiotics in association with implant placement is recommended in clinical practice, as it increases the success rate and makes the treatment more effective. However, attention should be placed when healthcare perspective is considered, particularly in terms of antibiotic resistance that may impact public health and associated costs.

(1) Background: The aim of this study was to compare the histopathological features of syndromic and non-syndromic odontogenic keratocysts (OKs) using conventional and Confocal Laser Scanning Microscopy (CLSM) with their biological behaviour. (2) Methods: Data from the medical records of 113 patients with histological diagnosis of (single and/or multiple) OKs were collected. Globally, 213 OKs (120 syndromic and 93 sporadic) were retrieved, and their histological slides were re-evaluated with conventional H&E staining and with autofluorescence on the same slides using CLSM (Nikon Eclipse E600 microscope). (3) Results: Syndromic OKs showed more satellite cysts than sporadic cases, as well as a basophilic layer in the basement membrane, which was absent in sporadic OKs; both were highlighted with CLSM. The basement membrane in syndromic OKs appeared amorphous and fragile, thus possibly being responsible for the epithelial detachment and collapse, with scalloped features. Furthermore, the basal epithelial layers in such cases also showed increased cellularity and proliferative activity. All these histological features may possibly justify their higher tendency to recur. (4) Conclusions: CLSM is useful advanced technology that could help to quickly and easily discriminate between syndromic and non-syndromic OKs and to more accurately predict their biological behaviour in order to set fitter clinico-radiological follow-ups for individual patients.

Abstract Background Ductal carcinoma in situ (DCIS) is the most common type of in situ premalignant breast cancers. What drives DCIS to invasive breast cancer is unclear. Basal-like invasive breast cancers are aggressive. We have previously shown that NRAS is highly expressed selectively in basal-like subtypes of invasive breast cancers and can promote their growth and progression. In this study, we investigated whether NRAS expression at the DCIS stage can control transition from luminal DCIS to basal-like invasive breast cancers. Methods Wilcoxon rank-sum test was performed to assess expression of NRAS in DCIS compared to invasive breast tumors in patients. NRAS mRNA levels were also determined by fluorescence in situ hybridization in patient tumor microarrays (TMAs) with concurrent normal, DCIS, and invasive breast cancer, and association of NRAS mRNA levels with DCIS and invasive breast cancer was assessed by paired Wilcoxon signed-rank test. Pearson’s correlation was calculated between NRAS mRNA levels and basal biomarkers in the TMAs, as well as in patient datasets. RNA-seq data were generated in cell lines, and unsupervised hierarchical clustering was performed after combining with RNA-seq data from a previously published patient cohort. Results Invasive breast cancers showed higher NRAS mRNA levels compared to DCIS samples. These NRAS high lesions were also enriched with basal-like features, such as basal gene expression signatures, lower ER, and higher p53 protein and Ki67 levels. We have shown previously that NRAS drives aggressive features in DCIS-like and basal-like SUM102PT cells. Here, we found that NRAS-silencing induced a shift to a luminal gene expression pattern. Conversely, NRAS overexpression in the luminal DCIS SUM225 cells induced a basal-like gene expression pattern, as well as an epithelial-to-mesenchymal transition signature. Furthermore, these cells formed disorganized mammospheres containing cell masses with an apparent reduction in adhesion. Conclusions These data suggest that elevated NRAS levels in DCIS are not only a marker but can also control the emergence of basal-like features leading to more aggressive tumor activity, thus supporting the therapeutic hypothesis that targeting NRAS and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.

Congenital adrenal hyperplasia (CAH) is a genetic disorder characterized by an impairment of steroid synthesis due to an altered production of 21-hydroxylase enzyme. Corticoid hormones are involved in the development and functioning of many organs. The aim of the present study was to review the international literature to collect data regarding oral manifestations of CAH. A review of the literature describing oral features of patients affected by CAH was performed using electronic databases (PubMed and Scopus). The data about number of patients, form of CAH, and oral findings were extracted and analyzed. Seven studies were included in the final analysis. The principal findings reported regarded an advanced dental development observed in patients with CAH. One paper reported amelogenesis imperfecta and periodontal issues. The dentist could be the first specialist involved in the CAH syndrome diagnosis, identifying the characteristic features described above, especially for the classical simple virilizing and non-classical form.

Giuliana Lo Cascio,1– 3 Alda Bazaj,1 Laura Trovato,2,4 Silvana Sanna,2,5 Stefano Andreoni,2,6 Elisabetta Blasi,2,7 Marco Conte,2,8 Paolo Fazii,2,9 Ester Oliva,10 Valentina Lepera,11 Gianluigi Lombardi,2,11 Claudio Farina2,10 1Clinical Microbiology and Virology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; 2Medical Mycology Committee, Italian Society of Clinical Microbiologist, Milan, Italy; 3Clinical Microbiology and Virology Unit, Azienda USL, Piacenza, Italy; 4Clinical Microbiology, Azienda Ospedaliera Universitaria- Policlinico Vittorio Emanuele, Catania, Italy; 5Microbiology and Virology Unit, Azienda Ospedaliera Universitaria, Sassari, Italy; 6Microbiology and Virology Unit, Azienda Ospedaliero Universitaria Maggiore della Carità, Novara, Italy; 7Clinical Microbiology, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy; 8Microbiology and Virology Unit, Grande Ospedale Metropolitano Bianchi- Melacrino- Morelli, Reggio, Calabria, Italy; 9Clinical Microbiology and Virology P.O. Spirito Santo, Pescara, Italy; 10Clinical Microbiology and Virology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy; 11Clinical Microbiology, ASST Grande Ospedale Metropolitano Niguarda, Milan, ItalyCorrespondence: Giuliana Lo Cascio, Email g.locascio@ausl.pc.itAbstract: In this study the activity of Isavuconazole, Voriconazole, Amphotericin B, and Caspofungin against 224 clinical isolates of Aspergillus spp. originating from seven Italian hospitals, was comparatively evaluated with two commercial antifungal susceptibility tests (AST): SensititreTM YeastOneTM (SYO) and MIC Test Strip. More attention was focused on Isavuconazole activity, given the new introduction of the drug in widely distributed antifungal susceptibilities methods in the clinical microbiology lab. The minimum inhibitory concentrations of antifungal drug that can inhibit the growth of pathogen by 90% (MIC90) for Isavuconazole detected by SYO were 0.5, 1, 0.25, and 2 μg/mL for Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger, respectively, whilst they were 0.25, 0.25, 0.5, and 0.75 μg/mL by MIC Test Strip. Essential agreement between the two tested methods for Isavuconazole is 70% for all the species tested, 75.7% for A. fumigatus, 45.2% for A. flavus, 90.6% for A. terreus, and 40% for A. niger. Although the tested strains do not express any phenotypic resistance, MIC results were quite different if tested with microdilution broth or gradient agar method. This is the first Italian multicenter report on Isavuconazole MIC obtained employing the widely used SensititreTM Yeast OneTM (SYO) and MIC Test Strip on clinical isolates of Aspergillus.Keywords: antifungal susceptibilities, Aspergillus Isavuconazole susceptibilities, Sensititre and MIC Test Strip

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a complex trait with an estimated prevalence of 25% globally. We aimed to identify the genetic variant underlying a four-generation family with progressive NAFLD leading to cirrhosis, decompensation, and development of hepatocellular carcinoma in the absence of common risk factors such as obesity and type 2 diabetes. Methods: Exome sequencing and genome comparisons were used to identify the likely causal variant. We extensively characterised the clinical phenotype and post-prandial metabolic responses of family members with the identified novel variant in comparison with healthy non-carriers and wild-type patients with NAFLD. Variant-expressing hepatocyte-like cells (HLCs) were derived from human-induced pluripotent stem cells generated from homozygous donor skin fibroblasts and restored to wild-type using CRISPR-Cas9. The phenotype was assessed using imaging, targeted RNA analysis, and molecular expression arrays. Results: We identified a rare causal variant c.1691T>C p.I564T (rs745447480) in MTTP, encoding microsomal triglyceride transfer protein (MTP), associated with progressive NAFLD, unrelated to metabolic syndrome and without characteristic features of abetalipoproteinaemia. HLCs derived from a homozygote donor had significantly lower MTP activity and lower lipoprotein ApoB secretion than wild-type cells, while having similar levels of MTP mRNA and protein. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, and production of reactive oxygen species. Conclusions: We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP p.I564T is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia. Our findings provide insights into mechanisms driving progressive NAFLD. Impact and Implications: A rare genetic variant in the gene MTTP has been identified as responsible for the development of severe non-alcoholic fatty liver disease in a four-generation family with no typical disease risk factors. A cell line culture created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease. This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.

Summary: The Sicilian wolf remained isolated in Sicily from the end of the Pleistocene until its extermination in the 1930s–1960s. Given its long-term isolation on the island and distinctive morphology, the genetic origin of the Sicilian wolf remains debated. We sequenced four nuclear genomes and five mitogenomes from the seven existing museum specimens to investigate the Sicilian wolf ancestry, relationships with extant and extinct wolves and dogs, and diversity. Our results show that the Sicilian wolf is most closely related to the Italian wolf but carries ancestry from a lineage related to European Eneolithic and Bronze Age dogs. The average nucleotide diversity of the Sicilian wolf was half of the Italian wolf, with 37–50% of its genome contained in runs of homozygosity. Overall, we show that, by the time it went extinct, the Sicilian wolf had high inbreeding and low-genetic diversity, consistent with a population in an insular environment.

Purpose of Program: Glomerulonephritis (GN) is a group of rare kidney diseases that is increasingly being managed with higher cost immunosuppressive (IS) agents in Canada. Ontario Health’s Ontario Renal Network (ORN) oversees the management and delivery of GN services in the province. Stakeholder surveys previously conducted by ORN identified that both clinicians and patients do not perceive access to GN medications as comprehensive or timely. The program conducted a focused jurisdictional scan among 7 provinces to inform ORN initiatives to improve access to GN medications. Specifically, the program examined clinician experience with GN access, public drug coverage criteria, and timelines for public coverage for select IS agents (ie, tacrolimus, cyclosporine, mycophenolate mofetil [MMF], mycophenolate sodium, rituximab, and eculizumab) used to manage GN in adults who live in Canada. Methods: For the selected IS agents, a focused jurisdictional scan on medication access was conducted by ORN in 2018 and updated in July 2022. Information was obtained by searching the gray literature and/or credible online sources for public funding policies and eligibility criteria. Findings were supplemented by personal communications with provincial drug programs and consulting GN clinical experts from 7 provinces (ie, Alberta, British Columbia, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Quebec). Key Findings: Clinicians from different provinces prescribe IS agents similarly for GN indications, despite distinctions in public drug funding policies. While patients can obtain public funding for many IS agents, for GN, most provinces rely on case-by-case review processes. In addition, provinces can vary in their funding criteria and which IS agents are listed on the public formulary. For IS agents that require prior authorization or case-by-case review, timelines vary by province with decisions taking a few days to weeks. British Columbia, with a GN-specific drug formulary, had the most integrated and efficient system for patients and prescribers. Limitations: This scan primarily relied on publicly available information for drug coverage criteria and clinician experience with access in their province. Since this scan was conducted, public drug coverage criteria and/or application processes may have changed. Implications: While patients in most provinces have similar needs and nephrologists similar prescribing patterns, gaps still exist for publicly funded GN medications. Interprovincial differences in the drugs funded, funding criteria, and application process may affect timely and equitable access to GN medications across Canada. Given the rarity of GN, a pan-Canadian funding approach may be warranted to improve the current state.

During the first years of the HIV pandemic, the virus diffusion was responsible for discriminatory behavior from medical and dental care workers towards HIV-infected patients, as described by our research group in 2009. The aim of the current study was to provide an update on the previous data, investigating the presence of discriminatory behaviors, evaluating the level of dentists’ knowledge about the virus and proposing strategies to be implemented to avoid professional exposure and cross-infections. This study was a cross-sectional, online, national survey on dentists, members of the main national dental associations (ANDI and AIO). The questionnaire was divided into four major sections, with the same structure as the questionnaire administered in 2009. The differences between groups were analyzed using the software program IBM SPSS Statistic, version 21.0. A total of 1054 dentists filled out the questionnaire completely. Among them 0.04% revealed a discriminatory attitude towards HIV-infected patients. The univariate analysis showed that discrimination towards HIV + patients was statistically associated with personal experiences and the level of fear associated with treating them (p = 0.001) and with the type of dental treatments performed (p = 0.01). This cross-sectional study revealed the persistence of dentists who still discriminate against HIV + patients, and the percentage of these dentists was only slightly lower than that in the previous survey (4.3% in the present survey vs. 4.5%). The survey also depicted other information worthy of consideration, such as a perceived ability to detect HIV + patients based on their appearance, complaints about not having received adequate training for treating HIV + individuals, and a lack of scientific knowledge about the virus. From the evidence reported by the present survey, it can be argued that universities, professional boards, and training institutions must increase their efforts in spreading correct knowledge about HIV among all dental care workers.

To the Editor, Although postoperative pain associated with robot-assisted radical prostatectomy (RARP) is less than pain following the open technique, it remains a fundamental issue as it can be a significant source of discomfort for the patient and lengthen recovery times after surgery. The optimal management of pain after RARP is far from being fully elucidated and many factors have to be evaluated to choose the best analgesic approach. [...]

BackgroundReliable biomarkers for assessing the viability of the donor hearts undergoing ex vivo perfusion remain elusive. A unique feature of normothermic ex vivo perfusion on the TransMedics® Organ Care System (OCS™) is that the donor heart is maintained in a beating state throughout the preservation period. We applied a video algorithm for an in vivo assessment of cardiac kinematics, video kinematic evaluation (Vi.Ki.E.), to the donor hearts undergoing ex vivo perfusion on the OCS™ to assess the feasibility of applying this algorithm in this setting.MethodsHealthy donor porcine hearts (n = 6) were procured from Yucatan pigs and underwent 2 h of normothermic ex vivo perfusion on the OCS™ device. During the preservation period, serial high-resolution videos were captured at 30 frames per second. Using Vi.Ki.E., we assessed the force, energy, contractility, and trajectory parameters of each heart.ResultsThere were no significant changes in any of the measured parameters of the heart on the OCS™ device over time as judged by linear regression analysis. Importantly, there were no significant changes in contractility during the duration of the preservation period (time 0–30 min, 918 ± 430 px/s; time 31–60 min, 1,386 ± 603 px/s; time 61–90 min, 1,299 ± 617 px/s; time 91–120 min, 1,535 ± 728 px/s). Similarly, there were no significant changes in the force, energy, or trajectory parameters. Post-transplantation echocardiograms demonstrated robust contractility of each allograft.ConclusionVi.Ki.E. assessment of the donor hearts undergoing ex vivo perfusion is feasible on the TransMedics OCS™, and we observed that the donor hearts maintain steady kinematic measurements throughout the duration.

Objectives To better define the spectrum of new-onset post-COVID-19 and post-COVID-19 vaccine inflammatory rheumatic diseases (IRD) from a large multicentric observational study.Methods Consecutive cases of IRD encountered during a 12-month period and satisfying one of the following inclusion criteria: (a) onset of the rheumatic manifestations within 4 weeks from SARS-CoV-2 infection or (b) onset of the rheumatic manifestations within 4 weeks from the administration of one of the COVID-19 vaccines ws recruited.Results The final analysis cohort comprised 267 patients, of which 122 (45.2%) in the post-COVID-19 and 145 (54.8%) in the postvaccine cohort. Distribution of IRD categories differed between the two cohorts: the post-COVID-19 cohort had a higher percentage of patients classified as having inflammatory joint diseases (IJD, 52.5% vs 37.2%, p=0.013) while the post-vaccine cohort had a higher prevalence of patients classified as polymyalgia rheumatica (PMR, 33.1% vs 21.3%, p=0.032). No differences were detected in the percentage of patients diagnosed with connective tissue diseases (CTD 19.7% vs 20.7%, p=0.837) or vasculitis (6.6% vs 9.0%, p=0.467). Despite the short follow-up period, IJD and PMR patients’ response to first-line therapy was favourable, with both groups achieving a drop in baseline disease activity scores of ~30% and ~70% respectively.Conclusion Our article reports the largest cohort published to date of new-onset IRD following SARS-CoV-2 infection or COVID-19 vaccines. Although causality cannot be ascertained, the spectrum of possible clinical manifestations is broad and includes IJD, PMR, CTD and vasculitis.

To evaluate the influence of Fixed (FOA) and Removable Orthodontic Appliances (ROA) on oral Candida colonisation.

A large percentage of coronavirus disease 2019 (COVID-19) patients have taste dysfunction. Interleukin 6 (IL-6) levels in mild and moderate COVID-19 patients with the type (quantitative or qualitative) of taste disorders were compared in this observational study. The 208 COVID-19 patients (118 men and 90 women) revealing only taste dysfunctions as prodromic symptoms were classified as mild and moderate patients. Survey results were used to evaluate the taste disorder. The IL-6 levels were measured using a chemiluminescence assay. Statistical analysis was conducted using the Wilcoxon rank, Welch’s, and Mann–Whitney tests. The findings revealed that neither the presence of dysgeusia or phantogeusia nor the perception of sour and salty, differed statistically significantly between moderate and mild patients (P > 0.05). But between moderate and mild patients, there were statistically significant differences in how umami, bitter, sweet, and parageusia were perceived (P < 0.05). There was an impairment of multiple tastes up to ageusia in patients with high IL-6 levels. The findings demonstrated that parageusia and dysfunctions in umami, bitter, and sweet taste perception can be indicators of more severe forms of COVID-19.