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Chun-Yu Lin,1,2 Chiung-Hung Lin,1,2 Yu-Lun Lo,1,2 Chun-Yu Lo,1,2 Hung-Yu Huang,1,2 Meng-Heng Hsieh,1,2 Yueh-Fu Fang,1,2 Tsu-Chuan Li,1,2 Shu-Min Lin,1,2 Yu-Tung Huang,3 Po-Jui Chang,1,2 Horng-Chyuan Lin1,2,4 1Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; 2College of Medicine Chang Gung University, Taoyuan, Taiwan; 3Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 4Department of Respiratory Therapy, Chang Gung Memorial Hospital at Linkou, Taoyuan, TaiwanCorrespondence: Horng-Chyuan Lin, Department of Thoracic Medicine, Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Kweishan, Taoyuan, 33305, Taiwan, Tel +886-3-3281200 ext. 8470, Fax +886-3-3282474, Email lin53424@gmail.comBackground: Non-pharmaceutical interventions (NPIs) were widely used during the coronavirus disease 2019 (COVID-19) pandemic, however their impact on acute asthma exacerbations (AEs) is not well studied.Methods: We had retrospectively collected patients with asthma AEs between 2019 and 2020 and retrieved data from the Chang Gung Research Database, including clinical manifestations, medications, pulmonary function, clinic and emergency department visits and hospitalizations.Results: A total of 39,108 adult patients with asthma were enrolled, of whom 1502 were eligible for analysis. The prevalence of acute AEs significantly decreased throughout 2020 compared with 2019 after implementation of the NPI policy. The patients were categorized into four groups: Group 1, acute AEs in 2019 with influenza infection (n=692); Group 2: acute AEs in 2019 without influenza infection (n=328); Group 3: acute AEs in 2020 with influenza infection (n=268); Group 4: acute AEs in 2020 without influenza infection (n=214). The patients in group 4 were significantly older (73.3± 29.1 vs 65.5± 29.2, 69.7± 26.2 years, p< 0.01) and had significantly worse forced expiratory volume in one second/forced vital capacity ratio (70.5± 13.9 vs 79.6± 15.5, 72.9± 18.0, p< 0.01) than those in group 1 and 2, and the highest rate of oral corticosteroid prescriptions (17%, p< 0.01). The patients in group 3 and 4 had significantly lower rates of oxygen therapy, ventilator use and mortality at 3 and 12 months of follow-up than those in group 1 and 2.Conclusion: The use of NPIs during the COVID-19 pandemic in Taiwan may reduce the frequency and severity of asthma AEs. This may provide some cost-effective strategies to attenuate acute asthma AEs.Keywords: non-pharmaceutical interventions, asthma, COVID-19

Giuliano Lo Bianco,1 Michael E Schatman,2,3 Silvia Natoli,4,5 Christopher L Robinson6 1Anesthesiology and Pain Department, Foundation 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, USA; 4Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; 5IRCCS Policlinico San Matteo, Pavia, Italy; 6Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USACorrespondence: Giuliano Lo Bianco, Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Via Pietrapollastra, Cefalù, Palermo, 90015, Italy, Email giulianolobianco@gmail.com

Sayed E Wahezi,1 Ugur Yener,1 Tahereh Naeimi,1 Heejung Choi,2 Yashar Eshraghi,3 Scott G Pritzlaff,4 Trent Emerick,5 Corey W Hunter,6 Moorice Caparo,1 Michael E Schatman,7 Farshad Ahadian,8 Charles Argoff,9 Timothy Deer,10 Dawood Sayed,11 Miles Day,12 Alaa Abd-Elsayed,13 Giuliano Lo Bianco14 1Department of Physical Medicine & Rehabilitation, Montefiore Medical Center, Bronx, NY, USA; 2Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3Department of Anesthesia, Ochsner Medical Health Center, New Orleans, LA, USA; 4Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA; 5Division of Chronic Pain, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 6Ainsworth Institute of Pain Management, Department of Rehabilitation & Human Performance, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7Department of Anesthesiology, Perioperative Care and Pain Medicine, Department of Population Health - Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA; 8Department of Anesthesiology, Center for Pain and Palliative Medicine, University of California, San Diego Medical Center, San Diego, CA, USA; 9Department of Neurology, Albany Medical Center, Albany, NY, USA; 10The Spine and Nerve Center of the Virginias, West Virginia University Hospitals, Charleston, WV, USA; 11Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS, USA; 12Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; 13Department of Anesthesiology, University of Wisconsin, Madison, WI, USA; 14Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, ItalyCorrespondence: Sayed E Wahezi, Department of Physical Medicine and Rehabilitation, Montefiore Medical Center, 1250 Waters Place, Tower &num;2 8th Floor, Bronx, NY, 10461, USA, Tel +1 718-920 7246, Fax +1 929-263-3950, Email swahezi@montefiore.orgBackground: Pain medicine care has expanded to encompass a wider range of conditions, necessitating updated education and training for pain specialists to utilize emerging technologies effectively. A national survey was conducted through several verified Pain organizations regarding pain physician employers’ perspectives on pain medicine fellowship training and education. The survey aimed to gather insights from a diverse range of geographic locations, practice types (academic and private practice), and practice settings. The findings emphasize the need for educational programs to adapt to the evolving landscape of pain medicine.Methods: A survey was disseminated through several national professional pain societies, including the AAPM, ASIPP, NANS, and ASPN, and Pain DocMatters forum, an online verified pain physician forum to ensure a wide reach among potential respondents. The survey received responses from 196 participants, 39 from the Pain DocMatters forum and 157 through pain societies’ channels.Results: Most survey respondents reported a need for additional training and experience beyond what is offered during the one-year ACGME-approved fellowship. Professionalism and basic interventional skills were identified as the highest valued attributes of pain physician candidates by potential employers. Employers rated spinal cord stimulator (SCS) trials as the most important advanced procedure for trainees to learn. Other advanced procedures such as SCS implants, PNS implants, interspinous spacers, and percutaneous procedures involving the vertebral body were also rated as either very important or somewhat important by most respondents. A significant gap in training has been identified, with only 7% of respondents feeling that fellows were adequately prepared to independently practice in the current educational model. A vast majority of respondents stated that fellows need additional training following graduation from fellowship to practice independently.Conclusion: Training programs should provide more robust education to prepare their graduates for independent practice.Keywords: graduate medical education, fellowship training, analysis, multidisciplinary, independence

Marco Cascella,1 Mohammed Naveed Shariff,2 Giuliano Lo Bianco,3 Federica Monaco,4 Francesca Gargano,5 Alessandro Simonini,6 Alfonso Maria Ponsiglione,7 Ornella Piazza1 1Anesthesia and Pain Medicine, Department of Medicine, Surgery and Dentistry “scuola Medica Salernitana”, University of Salerno, Baronissi, 84081, Italy; 2Department of AI&DS, Rajalakshmi Institute of Technology, Chennai, TN, India; 3Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, Italy; 4Anesthesia and Pain Medicine, ASL NA1, Napoli, Italy; 5Anesthesia and Intensive Care, U.O.C. Fondazione Policlinico Campus Bio-Medico, Roma, Italy; 6Pediatric Anesthesia and Intensive Care Unit, Salesi Children’s Hospital, Ancona, Italy; 7Department of Electrical Engineering and Information Technology, University of Naples “federico II”, Naples, 0125, ItalyCorrespondence: Giuliano Lo Bianco, Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, Italy, Email giulianolobianco@gmail.comIntroduction: Effective pain management is crucial for patient care, impacting comfort, recovery, and overall well-being. Traditional subjective pain assessment methods can be challenging, particularly in specific patient populations. This research explores an alternative approach using computer vision (CV) to detect pain through facial expressions.Methods: The study implements the YOLOv8 real-time object detection model to analyze facial expressions indicative of pain. Given four pain datasets, a dataset of pain-expressing faces was compiled, and each image was carefully labeled based on the presence of pain-associated Action Units (AUs). The labeling distinguished between two classes: pain and no pain. The pain category included specific AUs (AU4, AU6, AU7, AU9, AU10, and AU43) following the Prkachin and Solomon Pain Intensity (PSPI) scoring method. Images showing these AUs with a PSPI score above 2 were labeled as expressing pain. The manual labeling process utilized an open-source tool, makesense.ai, to ensure precise annotation. The dataset was then split into training and testing subsets, each containing a mix of pain and no-pain images. The YOLOv8 model underwent iterative training over 10 epochs. The model’s performance was validated using precision, recall, and mean Average Precision (mAP) metrics, and F1 score.Results: When considering all classes collectively, our model attained a mAP of 0.893 at a threshold of 0.5. The precision for “pain” and “nopain” detection was 0.868 and 0.919, respectively. F1 scores for the classes “pain”, “nopain”, and “all classes” reached a peak value of 0.80. Finally, the model was tested on the Delaware dataset and in a real-world scenario.Discussion: Despite limitations, this study highlights the promise of using real-time computer vision models for pain detection, with potential applications in clinical settings. Future research will focus on evaluating the model’s generalizability across diverse clinical scenarios and its integration into clinical workflows to improve patient care.Keywords: pain, artificial intelligence, automatic pain assessment, computer vision, action units

Background: Tuberculosis (TB) remains a Global Health challenge, with diagnostic delays contributing significantly to its spread. This study investigates the differences in diagnostic delays between native and migrant TB patients in Italy, examining patient-related diagnostic delay (PDD), health system-related diagnostic delay (HDD), and total diagnostic delay (TDD). Methods: We conducted a retrospective, multicenter, cross-sectional study of TB cases in 10 Italian hospitals from 2018 to 2023. We compared PDD, HDD, and TDD between native and migrant populations. Socio-demographic data and clinical histories were analyzed to identify factors contributing to diagnostic delays. Results: We included 669 TB patients (390 migrants and 279 natives). Migrants experienced significantly longer PDD (median 90 vs 10 days, P < 0.0001) but shorter HDD (median 5 vs 40 days, P < 0.0001) compared to natives, resulting in a longer TDD (median 96 vs 65 days, P < 0.0001). Furthermore, migrants had higher Timika scores, longer sputum conversion times, and were more frequently lost to follow-up. Conclusion: Migrants face longer PDD, emphasizing substantial barriers to healthcare access. Natives experience longer HDD, reflecting neglect of TB in low-endemic regions. Future research should focus on the impact of social determinants and training for healthcare providers on TB diagnosis and develop strategies to reduce diagnostic delays.

Background Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse.Methods This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y. Individual patient-level data (IPD) from the experimental arm of the KEYNOTE-024 trial were extracted (KN024 IPD cohort) to compare the long-term outcomes between the two cohorts. To further assess the reproducibility of clinical trial results, we reconstructed the “KN024 look-alike” cohort by excluding patients with an Eastern Cooperative Oncology Group-performance status (ECOG-PS)≥2, those requiring corticosteroids with doses ≥10 mg of prednisolone/equivalent, patients with positive/unknown epidermal growth factor receptor/anaplastic lymphoma kinase genotype, and those with pre-existing autoimmune disease. We additionally provided a hierarchical organization of determinants of long-term benefit through a conditional inference tree analysis.Results The study included 1050 patients from 61 institutions across 14 countries, with a median follow-up of 70.3 months. The 5-year survival rate was 26.9% (95% CI: 23.8% to 30.2%), and median OS was 21.8 months (95% CI: 19.1 to 25.7), while 32 (3.0%) patients who achieved a complete response remained progression-free at the data cut-off. The KN024 look-alike cohort had a 5-year survival rate of 29.3% (95% CI: 25.5% to 33.6%) and a median OS of 27.5 months (95% CI: 22.8 to 31.3). Neither the overall study population nor the KN024 look-alike cohort exhibited significantly different OS compared with the KN024 IPD cohort. By the data cut-off, 1015 patients (96.7%) had permanently discontinued treatment: 659 (64.9%) due to progressive disease, 156 (15.4%) due to toxicity, 77 (7.6%) due to treatment completion, and 106 (10.4%) due to other reasons. Overall, 222 participants (21.1%) were treated for a minimum period of 24 months, among them the 5-year survival rates were: 31.7%, 72.7%, 78.6%, 84.2% for patients who discontinued treatment due to progressive disease, toxicity, treatment completion, and other reasons, respectively.Conclusion This study provides valuable real-world evidence that confirms the long-term efficacy of pembrolizumab outside of clinical trials. Hierarchical organization indicates ECOG-PS, age and PD-L1-TPS as the most important predictors of 5-year survival, potentially informing clinical practice.

ABSTRACT Objectives One of the primary objectives in endodontics is to achieve thorough cleaning and disinfection of the root canal system during an endodontic procedure. This aims to reduce microbial contamination and prevent the development of endodontic lesions. To attain this goal, it is imperative to establish access to the endodontic space that allows for the complete removal of pulp tissue and the accurate identification of canal orifices while preserving the anatomical integrity of the root floor and pulp chamber as much as possible. In this scoping review, we aim to explore aspects related to the identification of canal orifices and the presence of pulp debris and residues during endodontic treatment. Specifically, we aim to assess whether and to what extent the design of the access cavity impacts these factors. Material and Methods The scoping review was conducted and prepared following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines (PRISMA Extension for Scoping Reviews [PRISMA‐ScR]). Results The search yielded a total of 3697 bibliographic sources. After eliminating duplicates and applying eligibility criteria, only 10 studies were included. Conclusions In conclusion, our review, conducted following PRISMA guidelines, includes 10 studies and suggests a potential trend: conservative techniques may generate more debris, whereas guided techniques exhibit superior precision in locating canal openings.

(1) Background: Head and neck cancer (HNC) is a major public health challenge worldwide, with oral squamous cell carcinoma (OSCC) being the predominant form. Despite advances in treatment, OSCC remains a major cause of morbidity and mortality due to delayed diagnosis and limited therapeutic efficacy. This study reviews omics technologies to assess new salivary biomarkers for the early detection of OSCC. (2) Methods: A comprehensive literature search in the last 20 years identified four relevant studies focusing on salivary biomarkers in OSCC. (3) Results: Proteomic and genomic analyses revealed significant changes in salivary composition between OSCC patients and healthy controls, suggesting promising diagnostic and prognostic biomarkers. However, studies showed varying degrees of bias, indicating the need for further research and improved standardization. (4) Conclusions: Saliva, with its advantages of ease of collection, minimal invasiveness, and potential for large-scale screening, is an emerging promising substrate for non-invasive biomarker research. Nonetheless, there is a need for improved biomarker sensitivity and specificity; currently, histological examination remains the golden standard.

Matthew Slitzky,1 R Jason Yong,2 Giuliano Lo Bianco,3 Trent Emerick,4 Michael E Schatman,5,6 Christopher L Robinson2 1Burke Rehabilitation, Montefiore Health System, White Plains, NY, USA; 2Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA; 3Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, Italy; 4Department of Anesthesiology and Perioperative Medicine, Chronic Pain Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 5Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 6Department of Population Health-Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Christopher L Robinson, Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women’s Hospital, 75 Francis Street Boston, Boston, MA, 02118, USA, Email crobinson48@bwh.harvard.edu

Abstract Arctic amplification (AA), the greater Arctic surface warming compared to the global average, has been widely attributed to increasing concentrations of greenhouse gases (GHG). However, less is known about the impacts of other forcings - notably, anthropogenic aerosols (AER) - and how they may compare to the impacts of GHG. Here we analyze sets of climate model simulations, specifically designed to isolate the AER and GHG effects on global climate. Surprisingly, we find stronger AA produced by AER than by GHG during the 1955–1984 period, when the strongest global AER increase. This stronger AER-induced AA is due to a greater sensitivity of Arctic sea ice, and associated changes in ocean-to-atmosphere heat exchange, to AER forcing. Our findings highlight the asymmetric Arctic climate response to GHG and AER forcings, and show that clean air policies which have reduced aerosol emissions may have exacerbated the Arctic warming over the past few decades.

Matthew Slitzky,1 R Jason Yong,2 Giuliano Lo Bianco,3 Trent Emerick,4 Michael E Schatman,5,6 Christopher L Robinson2 1Burke Rehabilitation, Montefiore Health System, White Plains, NY, USA; 2Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA; 3Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, Italy; 4Department of Anesthesiology and Perioperative Medicine, Chronic Pain Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 5Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 6Department of Population Health-Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Christopher L Robinson, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02118, USA, Email crobinson48@bwh.harvard.edu

Abstract Objectives Historically, the prevalence of caries has undergone significant changes, particularly increasing with the industrialization of sugar consumption. When examining ancient populations, lower caries rates are discovered, attributed in part to dietary factors. These populations consumed abrasive foods, leading to occlusal wear and reduced non-axial occlusal forces, potentially influencing Non-Carious Cervical Lesions (NCCLs). Although some attribute NCCLs to abfraction, the mechanism remains debated. This systematic review aims to evaluate the presence of NCCLs in ancient populations, shedding light on the factors contributing to their occurrence. Materials and Methods The present systematic review was registered on PROSPERO, and the manuscript was prepared following PRISMA guidelines. Results After the literature search and article screening, data from 6 studies were included in the meta-analysis, with only 2 reporting NCCLs in ancient skulls, encopassing 17 subjects in 805 examined skulls, suggesting their presence even before the widespread use of toothbrushes. This finding indicates a potential etiopathogenic mechanism linked to abfraction, but the cause is complex and involves abrasive and erosive factors closely tied to dietary habits. Conclusions In summary, NCCLs were present in ancient populations, albeit with a much lower prevalence. Their occurrence cannot be solely attributed to wear mechanisms but must be connected to abrasive factors related to diet or practices with religious and cultural significance, such as the use of labrets. Clinical relevance: Th the knowledge of NCCLs presence in acient sculls is crucial today for better understand the associated risk factors. In this context, the analysis of ancient skulls allows us to discern the role that tooth brushing and diet played in the formation of NCCLs, over the past century.

Introdução: A quantificação de linfócitos T, B e Natural Killer (NK) por citometria de fluxo é o confiável para avaliar a imunocompetência do organismo, crucial para a homeostase e defesa contra patógenos e células danificadas. Alterações nas populações de linfócitos no sangue periférico estão associadas a diversas doenças, incluindo imunodeficiências primárias e secundárias, doenças autoimunes, infecções e câncer. A citometria de fluxo, utilizando anticorpos monoclonais conjugados a fluorocromos, permite a detecção e quantificação dessas subpopulações celulares. Esta tecnologia está em constante avanço, com melhorias contínuas nos equipamentos e procedimentos laboratoriais que aumentam a eficiência e precisão das análises. No entanto, é crucial que os resultados das análises laboratoriais sejam comparáveis independentemente da metodologia e da instrumentação diagnóstica utilizadas. Objetivo/Justificativa: Este estudo teve como objetivo validar e comparar a consistência e a precisão dos resultados da análise de linfócitos T, B e NK utilizando os citômetros de fluxo BD FACSCanto II e BD FACSLyric. Essa validação é fundamental para assegurar que a introdução do novo citômetro BD FACSLyric não comprometa a precisão diagnóstica e o acompanhamento do tratamento clínico, mantendo a qualidade dos diagnósticos realizados. Métodos: Foi realizada uma pesquisa experimental utilizando amostras de sangue periférico de 20 pacientes. As amostras foram marcadas com anticorpos para detecção de linfócitos T, B e NK e suas subpopulações, adquiridas simultaneamente em ambos os citômetros de fluxo. A análise da porcentagem parcial das populações celulares foi realizada utilizando o software Infinicyt. Foram conduzidas análises de correlação e de Bland-Altman. Resultados/Discussão: Todos os coeficientes de correlação de Pearson (r) na Análise de Correlação mostraram-se muito próximos de 1, indicando uma correlação positiva perfeita entre as medições dos dois citômetros de fluxo, com valor de p < 0,001 em todos os casos, o que indica significância estatística. A análise de Bland-Altman revelou pequenas diferenças nas medições entre os equipamentos, demonstrando alta concordância entre as medições dos dois citômetros para a quantificação das células. Os resultados obtidos neste estudo são consistentes com a maioria dos estudos comparativos realizados em outros contextos, evidenciando forte correlação e excelente comparabilidade entre os resultados obtidos na avaliação das subpopulações de linfócitos pelos dois citômetros de fluxo analisados. Conclusão: Este estudo demonstrou que os equipamentos BD FACSCanto II e BD FACSLyric são capazes de fornecer resultados consistentes e comparáveis para a maioria das subpopulações analisadas. Esses achados são cruciais para a validação e padronização dos métodos de análise, especialmente em ambientes clínicos e de pesquisa.

A Leucemia Linfoide Aguda (LLA) é uma neoplasia hematológica caracterizada pela proliferação descontrolada de células progenitoras linfoides B ou T, comprometendo o processo de hematopoese. Representando mais de 80% das leucemias agudas, a LLA de linhagem B é responsável por aproximadamente 85% dos casos, sendo mais comum em crianças. A imunofenotipagem por citometria de fluxo multiparamétrica (CFMP) desempenha um papel crucial na identificação e caracterização das leucemias, permitindo a detecção precisa de marcadores de diferenciação celular. Compreender os perfis de imunofenotipagem em LLA-B pode orientar o desenvolvimento de novas terapias direcionadas. Portanto, o presente estudo teve como objetivo avaliar o perfil de pacientes com LLA-B utilizando a CFMP. A análise de coorte retrospectiva foi realizada por meio da revisão dos prontuários eletrônicos dos pacientes, onde foram coletados dados demográficos e resultados da CFMP no momento do diagnóstico. Este estudo retrospectivo analisou os perfis de imunofenotipagem em 116 pacientes com LLA-B, coletando dados demográficos e de CFMP ao diagnóstico ao longo de cinco anos (jan/2018 a jan/2023). A análise da expressão de CD45 revelou intensidades dim, dim/negativo e negativo em 57, 52 e 6 pacientes, respectivamente. Entre os subtipos de LLA-B, a positividade para CD34 foi associada ao subtipo Comum. Todos os pacientes apresentaram positividade para CD19, e outros marcadores comumente expressos, como CD79a (97,4%), CD22 (81,8%) e CD10 (83,6%), foram positivos na maioria dos casos, ressaltando a importância da identificação alternativa das células B leucêmicas para terapias alvo-específicas. A análise dos subtipos revelou uma prevalência do tipo Comum (75,7%), seguido pelo subtipo Pró-B (14,8%) e Pré-B (9,6%). Observou-se uma predominância do sexo masculino nos subtipos Pró-B e Comum. No subtipo Pré-B, 54,5% dos pacientes eram do sexo feminino, enquanto 45,5% eram do sexo masculino. No subtipo Pró-B, 64,7% dos pacientes eram adultos e 35,3% eram pediátricos. Para o subtipo Comum, 37,9% eram adultos e 62,1% eram crianças. No subtipo Pré-B, associado a uma maior maturação das células leucêmicas, houve uma incidência de 45,5% de adultos e 54,5% de crianças. A variabilidade na expressão de CD45 e a associação de CD34 com o subtipo Comum sublinham a necessidade de uma identificação precisa para o desenvolvimento de estratégias terapêuticas personalizadas. A capacidade da CFMP em detectar e caracterizar de maneira detalhada os marcadores de diferenciação celular oferece uma base sólida para a criação de terapias direcionadas. A interpretação dos resultados reforça a importância clínica da investigação dos marcadores por CFMP, fornecendo informações valiosas para o avanço das estratégias terapêuticas e sugerindo novas direções para pesquisas futuras. A continuidade da pesquisa na área é essencial para aprimorar o tratamento e melhorar os desfechos clínicos para os pacientes com LLA-B.

Normal karyotype in Acute Myeloid Leukemia (NK-AML) occurs in 40-50% of patients. Leukemic Stem Cells (LSC) persistence is known to trigger relapse, but the prognostic impact of their identification is understudied. We correlated LSC frequency at diagnosis with mutational profile and clinical outcomes in a Brazilian NK-AML cohort. Bone marrow samples (n = 93) were submitted to LSC quantification by multiparametric flow cytometry (MPFC). Patients were categorized based on LSC percentage as lower (LSClow) or higher (LSChigh) than 0.1%. Regarding risk stratification, the LSClow group was composed by 19 favorable, 13 intermediate and no adverse-risk. In the LSChigh group, the patients were classified as 25 favorable, 28 intermediate, and 6 adverse, thus suggesting that lower LSC frequency is associated with favorable risk, although statistical significance was not reached. In the LSClow group, 12.5%had the FLT3 mutation whereas in 33.3% of the LSChigh samples FLT3 mutation was detected. Of note, LSChigh samples presented lower FLT3allelic ratio as compared to LSClow (0.47 ± 0.28 vs 0.87 ± 0.53). When associating LSC frequency with NPM1 gene status, 65.62% of LSClow group and 40% of LSChigh group were NPM1 mutated. When the co-mutational status was considered, among individuals with LSClow, 81.8% (n = 18) was FLT3 wtNPM1 mut, 13.64% (n = 3) was FLT3 mutNPM1 mut, and 4.56% (n = 1) FLT3 mutNPM1 wt. In the LSChigh group, 37.5% (n = 12) was FLT3 wtNPM1 mut,37.5% (n = 12) was FLT3 mutNPM1 mut, and 25% (n = 8) FLT3 mutNPM1 mut. Overall, complete remission (CR/CRi) rate was 64.5% (n = 60) after 2 cycles of chemotherapy. No significant difference was observed between groups:59.4% (n = 19) in the LSClow and 67.2% (n = 41) in the LSChigh group achieved CR. After remission, 15.6% (n = 5) of the patients relapsed in the LSClow group as compared to 16.2% (n = 16) of the LSChigh patients. The LSClow group had a mean overall survival (OS) and event-free survival (EFS) of 568 and 541days, respectively, whereas the LSChigh group had both mean OS and EFS of466 days. We also assessed outcomes according to ELN2017 risk stratification. Favorable-risk patients with low LSC levels had a mean OS of 130 days, compared to 182 days for those with high LSC levels. Intermediate-risk patients with low LSC levels had a mean OS of 174 days, while the high LSC group had a mean OS of 228 days. Adverse-risk patients with low LSC levels had no measurable mean OS, whereas those with high LSC levels had a mean OS of 216 days. No significant differences in survival distributions between the groups. Our data indicated that FLT3 mutation was more prevalent in patients with higher frequency of LSCs indicating that cases with high LSC content at the flow cytometry initial examination should be quickly assessed for FLT3 mutation, especially considering that target therapy with FLT3 inhibitors can be included in the induction regimen. In agreement, ELN2017 favorable-risk patients had lower LSC quantification at diagnosis. The implication of LSC quantification in survival was not statistically demonstrated due to technical limitations including the number of patients with available data, but remission and survival rates suggested that LSChigh group present worse outcomes. The findings suggest that LSC identification is a potential biomarker that can guide clinicians, particularly for assessment of AML with out karyotypic abnormalities that rely only on mutational profiles, not always available in low and middle-income countries.

Acute Myeloid Leukemia (AML) alters immune profiles of T and NK cells, suppressing cell-mediated responses and potentially aiding tumor evasion. NK cells are crucial in anti-tumor defense by eliminating malignant cells without specific antigens. However, immunosuppressive cytokines in the tumor microenvironment can impair NK cell function, allowing neoplastic cell survival and progression. NK cell activity is regulated by a complex network of receptors and ligands (NKRLs). NK receptors interact with HLA class I molecules on target cells, providing inhibitory signals or allowing tumor cell elimination in their absence. The prognostic impact of NKRL expression in AML blasts and the combined effect of NKRLs still require thorough investigation. We aimed to investigate how receptor and ligand expression influences NK cell function in AML pathogenesis. In silico approaches were used to analyze immune cell transcriptomic signatures with bulk RNA-seq data from BeatAML 1.0. The analysis focused on mononuclear cell transcriptomic profiles from AML patient samples at diagnosis, emphasizing gene modulation. Statistical analysis was performed on the R platform using the limma-voom algorithm with Benjamini-Hochberg adjustment. The analysis revealed that variable expression of NKRLs significantly influenced critical clinical outcomes in AML. In the overall survival analysis, high expression levels of ULBP1 were associated with improved survival compared to lower levels (p = 0.016). The interaction between ULBP1 and receptors such as NKG2D on NK cells and T cells can trigger anti-tumoral immune responses, enhancing the elimination of tumor cells. Additionally, some tumor cells express HLA class I ligands like HLA-C, binding inhibitory receptors such as KIR2DL on NK cells, inhibiting their anti-neoplastic activity. Decreased NKG2D ligand expression or increased HLA class I ligand expression may promote leukemogenesis and disease aggressiveness, aiding tumor survival. These findings highlight the complexity and adverse effects of immune response modulation in AML, stressing the importance of understanding NKRLs’ mechanisms and clinical implications for personalized treatment. The study identified high expression of genes like HLA-E, HLA-C, MICAB, KLRK1, KLRC1, KIR2DL2, CD226, MICA, and PVRL2, associated with inflammation-related gene enrichment in AML samples. A coordinated pattern of inflammatory gene expression was often seen in AML samples with high gene expression, suggesting a potential causal relationship that needs further functional investigation. Heatmap analysis indicated that samples with high MICA and PVRL2 gene expression showed negative enrichment relative to genes positively enriched in other samples, implying complex molecular interactions influencing NKRL expression in AML. These results show how inflammatory gene expression patterns influence NK cell behavior and the immune response against AML, offering valuable insights for understanding this hematological disease. The findings suggest that assessing NKRL expression may serve as a prognostic biomarker in AML. Understanding this interaction is crucial for developing therapies to reverse immune escape and improve outcomes in myeloid leukemias.

Acute Myeloid Leukemia (AML) is a severe hematopoietic disorder marked by uncontrolled proliferation of immature myeloid progenitors due to differentiation arrest, with significant immunophenotypic diversity. FLT3-ITD mutations’ prognostic impact varies with NPM1 mutation presence and the FLT3 allelic ratio. While cytogenetic and molecular features are well-established for risk stratification by European LeukemiaNet (2017 ELN), the role of leukemia arrest stages in prognosis remains unclear. This study classified the maturation arrest stages of leukemic blasts in a Brazilian AML cohort, analyzing its association with genetic risk and clinical data. Bone marrow from 148 de novo AML patients (Sep-2015-Jul-2024) was evaluated for FLT3 and NPM1 mutations, FLT3 allelic ratio, and immunophenotyping. MPO cytochemistry stains and phenotypic markers by flow cytometry defined six stages of leukemia arrest (SLA): Hematopoietic Stem Cells-like (HSC-L:CD34+ CD117±CD13-CD33-HLA-DR+MPO-); Multipotent Progenitors-like (MPP-L:CD34+CD117+CD13±CD33±HLA-DR+MPO-); Common Myeloid Progenitors-like (CMP-L:CD34±CD117+CD13+CD33± HLA-DR+MPO+); Granulocyte-Monocyte Progenitors-like (GMP-L:CD34±CD117±CD13±CD33+HLA-DR+MPO+); Monocyte Progenitors-like (MP-L:CD34-CD117±CD13+CD33+HLA-DR+MPO+); and Granulocyte Progenitors-like (GP-L:CD34-CD117±CD13+ CD33+HLA-DR-MPO+). SLA showed highest frequency in MP-L (n = 57, 38.5%) and GP-L (n = 53, 35.8%), followed by GMP-L (n = 23, 15.5%), CMP-L (n = 7, 4.7%), MPP-L (n = 6, 4.1%), and HSC-L (n = 2, 1.4%). Predominance of FLT3wt/NPM1mut patients (n = 80, 54.1%) was observed, with similar distribution among FLT3mut patients (FLT3mut /NPM1mut:n = 32, 21.6%; FLT3mut/NPM1wt:n = 36, 24.3%). CMP-L and GMP-L frequencies were increased in FLT3low/NPM1wt and FLT3high/NPM1wt vs. FLT3wt/NPM1mut (CMP-L:13.33%, 14.28% vs 1.25%, p < 0.05; GMP-L:40%, 42.85% vs 7.5%, p < 0.05). GP-L frequency was decreased in FLT3low/NPM1wt and FLT3 high/NPM1wt vs. FLT3wt/NPM1mut (0%, 9.52% vs 43.75%, p < 0.05). Response to treatment (CR/CRi, CR/CRiMRD+ and PD–Persistence disease) was evaluated after 1st and 2nd cycles of Induction of Remission (1IR, 2IR). GMP-L was increased in PD after 1IR (OR:6.09, 95% CI:1.22–30.19, p < 0.05). Immature (HSC+MPP+CMP) SLA was higher in MRD+ patients compared to MRD- (OR:6.81, 95% CI:0.86–47.05, p < 0.05). Overall survival (p = 0.81) and relapse-free survival (p = 0.27) analyses showed that GMP-L patients relapsed sooner. In 2017 ELN risk assessment, FLT3-ITD stratification was based on allelic ratio and NPM1 mutation status. A high FLT3-ITD allelic ratio with NPM1 mutation indicated intermediate risk, and with wild-type NPM1, it indicated unfavorable risk. The 2022 ELN guidelines classify FLT3-ITD alone as intermediate risk, regardless of NPM1 status. Mutated NPM1 is favorable only when FLT3-ITD is absent. Supporting these findings, FLT3 mutation, regardless of allelic ratio, in the absence of NPM1, led to immature SLA and increased GMP-L frequency. This SLA was linked to PD after the 1IR. Immature SLA significantly impacts prognosis with lower survival rates, higher relapse risks, and increased post-induction remission failure. Our findings enhance the understanding of the cell of origin in AML, and further investigation of the SLA-dependent mechanisms that contribute to leukemia resistance are warranted.

Myelofibrosis (MF), driven by JAK/STAT signaling mutations in hematopoietic stem cells, has the worst survival rates among myeloproliferative neoplasms (MPNs), worsening from pre-fibrotic MF (PFMF) to overt MF (OMF) that often precedes acute myeloid leukemia. Natural Killer (NK) cells have phenotypical alterations that predominate in MF when compared to other MPNs, suggesting that the immune content may contribute to disease burden. We hypothesized that the cytotoxic immune cell profile, along with fibrosis and mutations, drives MF progression. Aiming test this, peripheral blood mononuclear cells (PBMC) from 9 PFMF and 9 OMF, and 9 healthy donors (controls: CT) were analyzed by flow cytometry to profile: NK cell frequency and subtypes (CD45hiCD3-CD19-CD56brightCD16-; CD45hiCD3-CD19-CD56dimCD16+; NK maturation [CD11b-CD27- tolerant (DN), CD27+CD11b- immature secretory (IS), CD27+CD11b+ mature secretory (MS), CD11b+CD27- cytotoxic]; T lymphocytes (CD45hiCD3+) frequency and subtypes (CD4, CD8) and maturation [CD45RO-CD45RA+CD27+ Naïve (N), CD45RO+CD45RA+CD27+ intermediate (INT), CD45RO+CD45RA+CD27- Central Effector (CE), CD45RO+CD45RA-CD27+ Central Memory (CM)]. Immune evasion was assessed by CD62L, and Treg cells (CD4+CD25hiCD127lowFOxp3+) were also quantified. NK cytotoxic capacity was measured by quantifying dead/K562 target cells and NK degranulation (CD107a) after PBMC co-culture. Top of FormBottom of Form Total NK frequency was similar in MF vs CT or OMF vs PFMF. CD56bright (CT 3.4 ± 2.6%, MF 17.7 ± 17.9%, p < 0.05) were increased and CD56dim (CT 82.7 ± 7.6%, MF 53.4 ± 25%, p < 0.05) decreased in MF vs CT. MF showed higher DN (CT 4.5 ± 3.5%, MF 13.9 ± 8.7%, p < 0.05) and IS (CT 0.2 ± 0.3%, MF 1.2 ± 1.2%, p < 0.05), and lower cytotoxic NK cells (CT 92.1 ± 3.8%, MF 77.3 ± 11.2%, p < 0.05). When compared to PFMF, OMF presented higher frequency of cytotoxic NK cells (PFMF 72.2 ± 12%, OMF 82.4 ± 7.9%, p = 0.09). In agreement, reduced NK cytotoxic capacity was observed despite no degranulation changing in MF (death: CT 81.8 ± 4.2%, MF 30.1 ± 7.76%, p < 0.05) and slightly increased cytotoxicity (PFMF 28 ± 6.4%, OMF 31.4 ± 9.9%, p = 0.7) and degranulation (PFMF 10.1 ± 8.8%, OMF 32.17 ± 9.9%, p = 0.1) accompanied fibrosis. No changes in total T lymphocytes or CD4/CD8 frequencies were seen between CT and MF or PFMF and OMF. However, INT and CE reduced in MF (CT 19.8 ± 9.9%, MF 7.3 ± 12.2%, p < 0.05; CT 19.1 ± 16.4%, MF 8.1 ± 13.8%, p < 0.05) and CM decreased in OMF (PFMF 18.9 ± 11.9%, OMF 10.6 ± 9.5%, p < 0.05). CD62L+ CM decreased in MF (CT 21.5 ± 12.8%, MF 6.8 ± 6.8%, p < 0.05) and in OMF (PFMF 9.4 ± 8%, OMF 3.9 ± 3.7%, p = 0.2). Treg frequency decreased in MF (CT 1.9 ± 1.7%, MF 0.25 ± 0.22%, p < 0.05) but increased in OMF (PFMF 0.2 ± 0.13%, OMF 0.3 ± 0.2%, p = 0.5). More advanced MF has a higher degree of fibrosis, which leads to an inflammatory profile. This, in turn, may activate NK cells and result in a more mature but cytotoxic-deficient profile probably due to exhaustion. On the other hand, increased Treg cells found in OMF negatively regulate cytotoxic T cells and its memory compartment, specifically leading to immune evasion via a decrease in CD62L+ CM (associated with better anti-tumor response). The results shed light on the mechanisms involved in MF progression, suggesting that changes in the maturation profile of cytotoxic cells is associated with disease progression, thus inspiring new therapies that target antitumoral cells from the leukemic environment.

Patients with Chronic Myeloid Leukemia (CML) who achieve sustained deep molecular response (DMR) to Tyrosine Kinase Inhibitors (TKIs) are eligible for treatment discontinuation, but only 50% of those achieve long-term treatment-free remission (TFR). Current biomarkers that predict resistance to TKIs as well as loss of the molecular response after TKI interruption have not been defined. We hypothesized that antitumoral immunity mediated by Natural Killer (NK) and T cells may contribute to TFR success and result in distinct responses during treatment and after discontinuation. NK and T cells phenotype were correlated with BCR::ABL1 kinetics and TFR success in a cohort of CML Brazilian patients included in the DES-CML study (Study of treatment discontinuation in CML treated at the Unified Health System), multicenter, prospective, open-label, single-arm, phase 2, non-randomized, ongoing trial, with current data from two Brazilian centers. Using flow cytometry, we evaluated frequency, subtypes, maturation, and receptors expression of NK and T cells from diagnosis to TKI discontinuation. Peripheral blood samples from 20 healthy controls and 68 CML patients were analyzed at different time points: 14 diagnosis (DX), 13 Imatinib failure (F), 7 major molecular response (MMR), 9 DMR, 20 TFR and 5 TFR loss (TFRL). Patients in discontinuation cohort had TKI dose reduced to 50% for 6 months before total suspension. NK cell subtypes were defined as secretory (CD56brightCD16-) or cytotoxic (CD56dimCD16+). We assessed NK maturation markers (CD57 and NKp80), activation (NKG2D,NKp46,DNAM-1), and inhibition receptors (KIR2DL1,TIGIT,NKG2A). PD-1 checkpoint inhibitor was assessed in CD8 T cells. The frequencies of cytotoxic (p < 0.05) and mature (CD57+ and NKp80 p < 0.05) NK cells as well as NKG2D and DNAM-1 (p < 0.05) were lower in the DX, F, and TFRL groups as compared to patients under TKI treatment with DMR, TFR, and healthy individuals. Patients in TFR exhibited a distinct immune profile from TFRL patients that were not influenced by gender, TKI drug, ELTS or SOKAL score. TFR patients presented higher frequency of cytotoxic (p < 0.05) and mature (CD57+ p < 0.05) NK cells, and also NKG2D, DNAM-1,NKp46 (p < 0.05) compared with TFRL. Frequency of PD-1 (p < 0.05) in T cells was decreased in TFR. At the TKI dose reduction timepoint,TFRL patients already had decreased frequency of cytotoxic (p < 0.05) and mature (CD57+ p < 0.05) NK cells as well as of the activating receptor NKG2D (p < 0.05) compared with TFR cases. Conversely, T-cell PD-1 (p < 0.05) expression was higher in TFRL than in TFR patients at the dose reduction point. In conclusion, our study indicates that impaired NK cell function and PD-1 T-cell inhibition are major contributors to molecular responses in CML. Patients with sustained TFR exhibit higher frequencies of cytotoxic, mature and activated NK cells, along with lower PD-1 expression in T cells. These profile contrasts with patients who have persistent disease or lose molecular response post-treatment suspension, who demonstrate impaired NK cell function and increased PD-1 expression. Monitoring parameters such as mature NK content and activating receptors, particularly NKG2D, and PD-1 expression during the de-escalation phase of TKI potentially predicts TFR relapse and can be useful for decision-making in TKI interruption.

Objetivos: O objetivo deste estudo é analisar publicações acerca da lesão tecidual ocasionada pela hemocromatose hereditária levando ao desenvolvimento de diabetes mellitus como manifestação clínica, a fim de elucidar e gerar atenção para as amplas complicações e apresentações associadas a essa doença crônica. Metodologia: A seguinte revisão literária foi realizada por meio da análise de artigos publicados entre os anos de 2015 e 2024, na língua inglesa, obtidos através da base de dados MedLine via PubMed. Os termos para a pesquisa utilizados estão de acordo com o MeSH e foram “haemochromatosis”, “diabetes” e “pathogenesis”. Resultados: A hemocromatose é uma doença genética caracterizada pelo aumento na absorção de Ferro pelo intestino, levando ao seu acúmulo excessivo, o que resulta em lesões teciduais diversas. É uma doença autossômica recessiva, causada por mutações no gene HFE em cerca de 80% dos casos. Geralmente é diagnosticada após os 20 anos de idade, devido ao seu aspecto crônico e silencioso, com maior incidência entre os 40 e 50 anos. Acomete principalmente o fígado, tendo em vista seu importante papel no metabolismo do Ferro, e a doença recebeu seu nome originalmente pela coloração observada no órgão ao ser realizada a biópsia hepática, antigo método diagnóstico. Contudo, atualmente sabe-se que a sobrecarga de Ferro pode afetar diversos outros órgãos e sistemas, trazendo um alerta para o que se pode esperar das manifestações clínicas da doença. Nesse cenário, um dos importantes órgãos que podem ser acometidos pela doença é o pâncreas, com a deposição de Ferro podendo levar a o desenvolvimento de diabetes pela lesão tecidual em até 50% dos pacientes sintomáticos. Nesses casos, além da disfunção pancreática, frequentemente pode ser vista, na pele do paciente, uma coloração acinzentada, ou, por vezes, bronzeada, devido ao excessivo acúmulo de ferro. Tal observação de hiperpigmentação, aliada a níveis glicêmicos elevados característicos de diabetes mellitus, deve elevar a suspeição da doença, a qual deve, então, ser investigada por meio da coleta de história familiar, assim como pela procura de mutações prevalentes para a avaliação da hemocromatose, como a C282Y e a H63D no gene HFE. Discussão: Embora a maioria dos pacientes com diabetes tenha Diabetes Mellitus Tipo 1 (DM1) ou Diabetes Mellitus Tipo 2 (DM2), existem outras etiologias de diabetes que ocorrem com menos frequência. É clinicamente importante reconhecer essas causas incomuns, pois o tratamento direcionado à etiologia subjacente pode ser necessário para evitar outras complicações futuras. A hemocromatose é uma doença hematológica causadora de diabetes por disfunção orgânica que pode também levar a doenças hepáticas graves e insuficiência cardíaca congestiva, caso não haja controle adequado. O excesso de ferro causando um grau de escurecimento da pele deve servir como sinal clínico para a doença. O diagnóstico definitivo requer a realização de testes genéticos, os quais substituíram a necessidade de uma biópsia hepática para confirmação da doença em casos de rastreamento positivo para a doença. Conclusão: A Hemocromatose é uma doença sistêmica com potencial de acometer diversos órgãos em diferentes graus, podendo levar a complicações irreversíveis. É, portanto, essencial o diagnóstico precoce pelo rastreamento em pacientes com histórico familiar e sinais compatíveis para que haja um melhor manejo clínico que reduza o seu impacto, com o intuito de avançar o cuidado dessa condição.

Introduction: Pregnancy loss, which occurs in approximately 10 to 15% of all gestations, has been linked to many blood-related changes which take place during pregnancy. Some of these changes have proven to lead to life-threatening conditions, particularly in patients who already present with hematologic conditions. Objectives: This review aims to point out the most prevalent hematological disorders found in clinical practice that may favor the event of a single or of multiple spontaneous abortions in women, as well as to highlight the need for a prompt diagnosis and early treatment in these scenarios, as to avoid maternal complications and pregnancy loss. Methods: This study is a literature review. We searched the PubMed/Medline database to identify studies related to pregnancy loss in patients with various hematological disorders. The primary search was conducted using the terms: “Hematological” and “Miscarriage”. We included 12 articles in the English language, published from 2013 to 2024. Results: The most common hemostasis-related cause of Recurrent Pregnancy Loss (RPL) is antiphospholipid syndrome (APLS), accounting for about 8 to 42 percent of patients with RPL. APLS causes an increased risk of thrombosis and placental insufficiency, causing the miscarriages. Thrombophilia is a condition in which the blood has a tendency to form clots, which can predispose women to RPL due to placental thrombosis and impaired blood flow. Pregnant women with Von Willebrand Disease are especially susceptible to having significant bleeding complications. Thrombocytopenia is another prevalent bleeding problem during pregnancy, affecting approximately 10% of all pregnancies. The American Society of Hematology recommends that treatment should be initiated for platelet counts below 30,000/mm3 or in cases of bleeding within the second or third trimesters of pregnancy. A less common, yet worth mentioning, disorder that influences the incidence of miscarriages is Sickle Cell Disease (SCD), a disease which causes reduced oxygen delivery to the placenta and fetal tissues, increasing the risk of adverse outcomes during gestation. Furthermore, other hemoglobinopathies, such as Thalassemia, may lead to anemia and intrauterine growth restriction due to inadequate oxygen supply. Discussion: Hematological disorders can significantly contribute to pregnancy loss through a wide spectrum of mechanisms, ranging from abnormal clotting disorders to excessive bleeding. This depicts the fact that each patient must be individually evaluated for a broader understanding and safer conduct in clinical practice. Finally, of utmost importance, if properly screened, the cause for recurrent pregnancy losses (RPL) can be found in almost all women. The main importance of a thorough evaluation is that, if a cause for the RPL is found, most women will be able to achieve normal-term delivery. Conclusion: Pregnancy can aid to cause and/or exacerbate underlying hematologic disorders, as well as predispose to life-threatening hematologic emergencies. Therefore, it's essential that women receive specialized care during pregnancy to optimize its outcomes and minimize any risks related to hematologic problems, which commonly require comanagement by obstetrics, hematology, and other subspecialties.

Objetivos: O objetivo dessa revisão de literatura é analisar a relação da hemocromatose hereditária e seus efeitos osteoarticulares, com a finalidade de identificar os mecanismos patológicos envolvidos e discutir as implicações clínicas para o manejo dos pacientes. Métodos: Trata-se de uma revisão literária realizada mediante análise de artigos publicados entre os anos de 2015 a 2022, escritos na língua inglesa, obtidos por meio da base de dados MedLine via PubMed. Para isto, utilizou-se os descritores: “Haemochromatosis”e “Osteoarthritis”. Resultados: A hemocromatose é uma doença de perfil hematológico hereditário relacionado ao metabolismo do ferro, que causa diversas consequências sistêmicas. Atualmente, entende-se que a hemocromatose hereditária (HH) é uma condição genética que resulta de anomalias em genes responsáveis pela regulação do ferro, especialmente o gene HFE. Isso provoca uma absorção intestinal excessiva desse micronutriente, aliada a uma diminuição na concentração de hepcidina. Cerca de 40% a 80% dos pacientes portadores de hemocromatose em sua forma hereditária (HH) apresentam alterações no sistema osteoarticular. É necessário destacar que muitos pacientes com essa condição podem permanecer assintomáticos por muitos anos. Contudo, quando presentes, os sintomas do acúmulo excessivo de ferro no organismo podem incluir manifestações como a osteoartrite, dores articulares e a redução da densidade mineral óssea. O excesso de ferro acarreta em estresse oxidativo e inflamação, levando à degeneração da cartilagem articular e à alteração da remodelação óssea. Assim, pacientes portadores de hemocromatose apresentam uma incidência significativamente maior de artrite e dor crônica nas articulações, principalmente nas articulações das mãos e joelhos. O acometimento mais característico da HH é o de segunda e terceira metacarpofalangeanas, com redução do espaço articular e formação de osteófitos em formato de gancho. Discussão: As alterações osteoarticulares associadas à hemocromatose são complexas e multifatoriais. O acúmulo de ferro nos tecidos pode interferir na função osteoblástica e osteoclástica, resultando em uma desregulação do metabolismo ósseo. Além disso, a presença de ferro livre no tecido conjuntivo pode causar inflamação local e dano celular, contribuindo para o desenvolvimento de condições como a osteoartrite. A flebotomia, considerado o tratamento padrão para a hemocromatose hereditária, possui papel pequeno na progressão de doença articular, sendo o tratamento mais usual com medicações de ação sintomática, como analgésicos simples e anti-inflamatórios não esteroidais. Conclusão: A hemocromatose é uma doença com diversas implicações sistêmicas, podendo manifestar alterações que contribuem para uma deterioração da saúde óssea e articular. É importante que o profissional da saúde reconheça os sinais e sintomas precoces desses acometimentos para que se possa minorar o impacto sistêmico e localizado da hemocromatose por meio de prevenções e intervenções terapêuticas adequadas e individualizadas.

Objetivos: O objetivo deste estudo é, por meio de uma revisão de literatura, analisar e discutir as principais alterações hematológicas observadas em pacientes portadores de HIV. Serão destacadas tanto as alterações clínicas quanto a necessidade de um monitoramento regular e mais rigoroso desse grupo, dada a sua vulnerabilidade a complicações. Métodos: Esta revisão literária foi realizada com base na análise de artigos publicados entre os anos de 2017 e 2021, todos redigidos na língua inglesa, e obtidos a partir da base de dados PubMed. Para a busca, foram utilizadas as palavras-chave “Anemia”, “HIV” e “Hematological”. Resultados: A infecção pelo HIV compromete significativamente o sistema imunológico, deixando os portadores suscetíveis a infecções oportunistas e a diversas alterações laboratoriais. As principais anormalidades hematológicas observadas em pacientes HIV-positivos incluem anemia, citopenia e trombocitopenia. Estima-se que cerca de 50% dos pacientes em estágios avançados da infecção apresentem níveis de hemoglobina baixos, que estão frequentemente associados à resposta inflamatória e à toxicidade dos antirretrovirais utilizados no tratamento. Além disso, o HIV é considerado uma condição pró-trombótica, aumentando o risco de tromboembolismo venoso (TEV) e levando a desequilíbrios nos fatores de coagulação. Por isso, a vigilância para TEV e citopenias em pacientes HIV-positivos torna-se crucial. Discussão: Nos pacientes portadores de HIV, a contagem de linfócitos TCD4+ emerge como um indicador vital da resposta imunológica. A redução na contagem desses linfócitos está diretamente relacionada com alterações hematológicas, como anemia, leucopenia e trombocitopenia, que contribuem para o surgimento de doenças oportunistas e complicações. Portanto, é imperativo aumentar a monitorização periódica do perfil hematológico em clínicas que atendem pacientes HIV+, o que pode ajudar na redução de complicações hematológicas e facilitar um tratamento mais precoce e direcionado. Além disso, a avaliação regular dos parâmetros hematológicos é fundamental para a adequação das terapias antirretrovirais. Fatores socioeconômicos e demográficos, como nível educacional e qualidade de vida, também influenciam a gravidade das alterações hematológicas em pacientes HIV positivos, comprometendo a eficácia do tratamento. Portanto, é necessária uma abordagem que considere aspectos clínicos e sociais a fim de otimizar o cuidado e promover a saúde desses pacientes. Conclusão: As anomalias hematológicas associadas ao HIV são frequentes e têm um impacto significativo na saúde dos pacientes, prejudicando a resposta ao tratamento. Fatores como deficiências hematínicas, efeitos adversos dos medicamentos e infiltração da medula óssea devem ser cuidadosamente considerados na avaliação clínica. A terapia antirretroviral (HAART) é crucial, mas o manejo clínico deve ser adaptado às complicações específicas apresentadas por cada paciente. É vital que futuras pesquisas se concentrem em estratégias que visem mitigar essas complicações e melhorar os desfechos clínicos em populações vulneráveis, promovendo uma abordagem mais holística e integrada no cuidado dos pacientes portadores de HIV.

Objetivos: Este estudo tem como objetivo realizar uma revisão da literatura para analisar a relação entre hemofilia e artropatia hemofílica. A pesquisa focou na identificação das principais manifestações clínicas, fatores de risco e estratégias de manejo que visam prevenir a progressão da artropatia. Além disso, busca-se compreender os avanços terapêuticos recentes que impactam a qualidade de vida dos pacientes hemofílicos. Métodos: A revisão será realizada por meio da análise de artigos publicados entre 2018 e 2023, todos escritos em inglês e obtidos na base de dados PubMed. As palavras-chave utilizadas na busca incluirão: “hemophilia”, “hemophilic arthropathy”, “joint bleeding”, “treatment advances” e “quality of life”. Essa abordagem garantirá uma coleta abrangente de dados relevantes e atualizados sobre o tema. Resultados: As hemofilias A e B são distúrbios hemorrágicos hereditários raros, resultantes da deficiência dos fatores de coagulação VIII ou IX, respectivamente. A hemartrose é a manifestação clínica mais comum, especialmente em pacientes com hemofilia grave (níveis de fator < 1 U/dl), mas também pode ocorrer em formas moderadas (1-5 U/dl) e leves (> 5 U/dl). Nos últimos 30 anos, os avanços terapêuticos, como a introdução de fatores de coagulação recombinantes e medicamentos inovadores como o eculizumab, melhoraram significativamente tanto a expectativa quanto a qualidade de vida dos pacientes. Esses tratamentos possibilitaram a implementação de regimes profiláticos mais abrangentes, visando a prevenção de danos articulares. Discussão: Apesar dos avanços terapêuticos, muitos pacientes ainda enfrentam episódios hemorrágicos, que podem ser manifestos de forma clínica ou subclínica, contribuindo para a progressão do dano articular. A hemartrose repetida é um fator crítico que resulta em artropatia hemofílica, afetando principalmente articulações como joelhos, cotovelos e tornozelos. Portanto, a vigilância deve ser ampliada para abranger todas as formas da doença. A educação dos pacientes sobre a prevenção e o manejo das hemorragias é fundamental. Medidas educativas, juntamente com a orientação adequada sobre os tratamentos disponíveis, são essenciais para melhorar os desfechos clínicos e, consequentemente, a qualidade de vida dos pacientes hemofílicos. Conclusão: A artropatia hemofílica continua a representar um desafio significativo para a qualidade de vida dos pacientes, apesar dos recentes avanços nos tratamentos. A compreensão aprofundada da fisiopatologia subjacente é essencial para o desenvolvimento de intervenções terapêuticas mais eficazes. Os esforços de prevenção devem se concentrar em uma abordagem multidisciplinar, envolvendo terapia de reposição de fatores de coagulação, uso de medicamentos inovadores como o eculizumab e programas de fisioterapia. Além disso, a motivação para a prática de atividade física é vital na gestão da saúde dos pacientes. A colaboração contínua entre equipes de saúde em centros de tratamento abrangentes é fundamental para melhorar os desfechos clínicos e a qualidade de vida dos indivíduos afetados pela hemofilia. A implementação de estratégias de manejo integradas e a promoção de um estilo de vida saudável são passos cruciais para enfrentar os desafios que a hemofilia e a artropatia hemofílica impõem.

IntroductionCerebrovascular stroke, a leading cause of global morbidity and mortality, is influenced by several modifiable risk factors such as hypertension, diabetes, and smoking. Emerging evidence highlights the significant role of inflammation in stroke pathogenesis, with conditions like periodontitis potentially exacerbating this risk. The aim of this systematic review was to identify and quantify the real impact of periodontal disease in individuals with cerebral stroke through the analysis of inflammatory periodontal indicesMethodsFollowing PRISMA guidelines, we conducted a systematic review and meta-analysis of case-control studies assessing periodontal indices in stroke patients. Data sources included PubMed, Scopus, and Cochrane Library, with searches extended to grey literature. The review protocol was registered on PROSPERO (CRD42024529767). Studies were evaluated using the Newcastle-Ottawa Scale to assess risk of bias, and meta-analyses were conducted using Review Manager 5.4 and TSA software.ResultsThe review included seven case-control studies, comprising 723 stroke patients and 787 controls. Meta-analyses revealed significant differences between stroke and control groups in clinical attachment loss [MD 1.04 mm, 95% CI (0.54, 1.54)], probing pocket depth [MD 0.68 mm, 95% CI (0.31, 10.6)], and radiological bone loss (MD 2.15 mm, 95% CI [−1.58, 5.89]. These findings indicate that stroke patients exhibit worse periodontal health compared to controls, supporting a potential link between periodontal inflammation and stroke.ConclusionThis study confirms the significant impact of periodontal disease on stroke patients and highlights the importance of oral health in preventing adverse cerebrovascular events.Systematic Review RegistrationPROSPERO, identifier (CRD42024529767).

Abstract Objectives Odontogenic keratocysts exhibit frequent recurrence, distinctive histopathological traits, a tendency towards aggressive clinical behavior, and a potential linkage to the nevoid basal cell carcinoma syndrome. The aim of this systematic review is to compile insights concerning the control of this condition and assess the effectiveness of various treatment approaches in reducing the likelihood of recurrence. Materials and methods The following systematic review adhered to the PRISMA guidelines. The systematic revision was registered on PROSPERO and structured around the questions related to the population, intervention, control, outcome and study design (PICOS). Results After conducting a search on the PubMed database, we initially identified 944 records. After using end-note software to remove duplicate entries, results totally with 462 distinct records. A thorough review of the titles and abstracts of these articles led to the selection of 50 papers for in-depth examination. Ultimately, following the application of our eligibility criteria, we incorporated 11 articles into our primary outcome analysis. Conclusion Among the studies examined, the most common location for these lesions was found to be in the area of the mandibular ramus and the posterior region of the mandible. In cases where the exact location wasn’t specified, the mandible emerged as the predominant site. When we considered the characteristics of these lesions in studies that mentioned locularity, most were described as unilocular in two studies, while in two other studies, the prevalence of multilocular lesions was observed. Risk factors associated with keratocyst recurrence include younger patient age, the presence of multilocular lesions, larger lesion size, and a longer anteroposterior dimension. Certain treatment methods have demonstrated a lack of relapses. These include the use of 5-fluorouracil, marsupialization, enucleation with peripheral ostectomy or resection, enucleation and curettage, as well as resection without creating continuity defects. However, it is important to note that further research is essential. Prospective studies and randomized trials are needed to collect more comprehensive evidence regarding the effectiveness of various treatment approaches and follow-up protocols for managing odontogenic keratocysts. Clinical relevance Odontogenic keratocysts still enter into differential diagnoses with other lesions that affect the jaw bones such as ameloblastama and other tumor forms, furthermore it is not free from recurrence, therefore the therapeutic approach to the lesion aimed at its elimination can influence both the possible recurrence and complications, knowledge of the surgical methods that offer the most predictable and clinically relevant result for the management of follow-up and recurrences.

Matthew Slitzky,1 R Jason Yong,2 Giuliano Lo Bianco,3 Trent Emerick,4 Michael E Schatman,5,6 Christopher L Robinson2 1Burke Rehabilitation, Montefiore Health System, White Plains, NY, USA; 2Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA; 3Anesthesiology and Pain Department, Fondazione Istituto G. Giglio Cefalù, Palermo, Italy; 4Department of Anesthesiology and Perioperative Medicine, Chronic Pain Division, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 5Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 6Department of Population Health-Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Christopher L Robinson, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02118, USA, Email crobinson48@bwh.harvard.edu

IntroductionSurgical-related injuries are frequent, in fact the reported percentage of musculoskeletal disorders in surgeons is between 47% and 87%. These conditions are caused by long periods of standing, incorrect postures, repeated movements, little rest between operations, the lack of integrated operator rooms, the correct number and arrangement of monitors and the use of non-ergonomic instruments. This survey aims to assess the Italian overview both highlighting how prevalent surgical-related injury is in our surgeons and whether there is an operating room ergonomics education program in Italian surgical specialty schools.MethodsAn anonymous questionnaire was designed through SurveyMonkey© web application. This survey was composed of 3 different sections concerning the general characteristics of the participants, their surgical background and any training performed, and any injuries or ailments related to the surgical activity. The survey was carried out in the period 1th of December 2022 and the 6th of February 2023.ResultsAt the close of our survey, 300 responses were collected. Among the participants, the two most represented specialties were Gynecology and Obstetrics (42.3%) and General Surgery (39.7%) and surgeons were mainly employed in the Northern regions of Italy (54.8%). Analyzing the participants’ background, 61.7% of the respondents had laparoscopic training during their training and only 53.1% had a pelvic trainer during their residency. In accordance with 98.7% of the respondents, during surgery we have the feeling of being in an uncomfortable position that causes discomfort or muscle pain, and regarding the frequency of these discomforts, the majority of our study population experiences these problems monthly (46.2%), while in 29.6% it is experienced weekly, 12.1% annually and finally 12.1% daily. The surgical approach that is most correlated with these disorders is laparoscopy (62.7%) while the one that causes the least discomfort is robotic surgery (1.4%). These discomforts cause 43.9% of our population to take a break or do short exercises to reduce pain during surgery, and the body areas most affected are the back (61.6%), neck (40.6%) and shoulders (37.8%).ConclusionDespite this, our survey allows us to highlight some now-known gaps present in the surgical training program of our schools and the lack of protection toward our surgeons during their long career.

Objectives: Heavily treatment-experienced (HTE) people living with HIV (PLWH) pose unique challenges due to limited antiretroviral treatment (ART) options. Our study aimed to investigate the prevalence and features of HTE individuals followed up in the Italian Cohort Naïve Antiretrovirals (ICONA) cohort as of December 31, 2021. Methods: HTE were defined based on meeting specific conditions concerning their current ART and their ART history up to December 31, 2021. Descriptive statistics were performed by HTE status. Regression analyses explored factors associated with becoming HTE based on pre-ART patients' characteristics. Cluster dendrogram analysis provided insights into subgroups with inadequate responses based on clusters of differentiation (CD4) counts and viral load (VL) trajectories. Results: Among the 8758 PLWH actively followed in our cohort, 163 individuals (1.9%), mainly female, younger, Italian, and infected through heterosexual contact, met the HTE criteria. A lower CD4 count at ART initiation (odds ratio [OR] 1.60 per 100 cells/mmc lower CD4, 95% confidence interval [CI] 1.06-2.41, P = 0.03) and hepatitis C virus antibody positivity (OR 1.90, 95% CI 1.16-3.11, P = 0.01) were associated with higher HTE risk. Thirty PLWH exhibited ongoing immune-virological failure (18% of the HTE subgroup and 0.003% of the total population). Thirty PLWH exhibited ongoing immune-virological failure (i.e., with a current CD4 count 200 copies/mL). A cluster analysis identified 13 (43%) with a current CD4 count

Abstract Background Hunter–Schreger bands (HSB) are optical phenomena observed on tooth surfaces under polarized light, resulting from the intersection of enamel prisms. Anthropological studies demonstrate the prevalence of HSB in large mammals, contributing to enamel resistance. Historically, John Hunter and Schreger depicted HSB in dental literature. In dentistry, HSB play a role in non-carious cervical lesions (NCCL) and internal dental perikymata, suggesting their potential for personal identification. Personal identification, crucial in both daily and professional life, involves biometric characteristics, such as fingerprints or facial recognition. The need for non-invasive, rapid, and user-friendly methods has prompted the exploration of using HSB dental images for personal identification. The review aimed to consolidate studies employing HSB for personal identification. Methods The scoping review was carried out strictly following the PRISMA–ScR checklist; the search was carried out on tree databases (PubMed, Scopus, Science Direct,) and a register (Cochrane library). Results The research produced a number of bibliographic sources totaling 410. With the removal of duplicates, 334 were obtained; potentially eligible articles amounted to 14, of which only 4 fully complied with the criteria of eligibility. Conclusions From the data in the literature, we can assert that HSB could be used in personal identification, as they are characteristics that are difficult to change and easily detectable.

Abstract Background COVID-19 is generally milder in children than in adults, however severe infection has been described in some patients. Few data are available on use of Remdesivir (RDV) in children, as most clinical trials focused on adult patients. We report a multicenter study conducted in 10 Italian Hospitals to investigate the safety of RDV in children affected by COVID-19. Methods We collected the clinical data of children with COVID-19 treated with RDV between March 2020 and February 2022 in 10 Italian hospitals. Clinical data were compared according to a duration of RDV therapy more or less than 5 days. Linear regression model was used to determine the association of significant variables from the bivariate analysis to the duration of RDV therapy. Results A total of 50 patients were included, with a median age of 12.8 years. Many patients had at least one comorbidity (78%), mostly obesity. Symptoms were fever (88%), cough (74%) and dyspnea (68%). Most patients were diagnosed with pneumonia of either viral and/or bacterial etiology. Blood test showed leukopenia in 66% and increased C-reactive protein (CRP) levels in 63% of cases. Thirty-six patients received RDV for 5 days, nine patients up to 10 days. Most children who received RDV longer were admitted to the PICU (67%). Treatment with RDV was well tolerated with rare side effects: bradycardia was recorded in 6% of cases, solved in less than 24 h after discontinuation. A mild elevation of transaminases was observed in 26% of cases, however for the 8%, it was still detected before the RDV administration. Therefore, in these cases, we could not establish if it was caused by COVID-19, RDV o both. Patients who received RDV for more than 5 days waited longer for its administration after pneumonia diagnosis. The presence of comorbidities and the duration of O2 administration significantly correlated with the duration of RDV therapy at the linear regression analysis. Conclusion Our experience indicates that RDV against SARS-CoV-2 is safe and well-tolerated in pediatric populations at high risk of developing severe COVID-19. Our data suggest that delaying RDV therapy after diagnosis of pneumonia may be associated with a longer duration of antiviral therapy, especially in patients with comorbidities.

Abstract The heart coordinates its functional parameters for optimal beat-to-beat mechanical activity. Reliable detection and quantification of these parameters still represent a hot topic in cardiovascular research. Nowadays, computer vision allows the development of open-source algorithms to measure cellular kinematics. However, the analysis software can vary based on analyzed specimens. In this study, we compared different software performances in in-silico model, in-vitro mouse adult ventricular cardiomyocytes and cardioids. We acquired in-vitro high-resolution videos during suprathreshold stimulation at 0.5-1-2 Hz, adapting the protocol for the cardioids. Moreover, we exposed the samples to inotropic and depolarizing substances. We analyzed in-silico and in-vitro videos by (i) MUSCLEMOTION, the gold standard among open-source software; (ii) CONTRACTIONWAVE, a recently developed tracking software; and (iii) ViKiE, an in-house customized video kinematic evaluation software. We enriched the study with three machine-learning algorithms to test the robustness of the motion-tracking approaches. Our results revealed that all software produced comparable estimations of cardiac mechanical parameters. For instance, in cardioids, beat duration measurements at 0.5 Hz were 1053.58 ms (MUSCLEMOTION), 1043.59 ms (CONTRACTIONWAVE), and 937.11 ms (ViKiE). ViKiE exhibited higher sensitivity in exposed samples due to its localized kinematic analysis, while MUSCLEMOTION and CONTRACTIONWAVE offered temporal correlation, combining global assessment with time-efficient analysis. Finally, machine learning reveals greater accuracy when trained with MUSCLEMOTION dataset in comparison with the other software (accuracy > 83%). In conclusion, our findings provide valuable insights for the accurate selection and integration of software tools into the kinematic analysis pipeline, tailored to the experimental protocol.

Background: Sleeve lobectomy with bronchoplasty is a safe surgical technique for the management of lung cancer and endobronchial localization of extrapulmonary cancers. However, anastomotic complications can occur, and treatment strategies are not standardized. Methods: Data from 280 patients subjected to bronchoplasty were retrospectively analyzed, focusing on surgical techniques, anastomotic complications, and their management. Multivariate analysis was performed, and Kaplan–Meier curves were used to determine survival. Results: Ninety percent of 280 surgeries were for lung cancer. Anastomotic complications occurred in 6.42% of patients: late stenosis in 3.92% and broncho-pleural fistula in 1.78%. The median survival was 65.90 months (95% CI = 41.76–90.97), with no difference (p = 0.375) for patients with (51.28 months) or without (71.03 months) anastomotic complications. Mortality at 30 days was higher with anastomotic complications (16.7% vs. 3%, p = 0.014). Multivariable analysis confirmed pathological stage (N+) as a risk factor for anastomotic complications (p = 0.016). Our mortality (3.93%) and morbidity rate (41.78%) corresponded to recent series results. Conclusions: In our experience, surgery is preferred to avoid life-threatening complications in bronchopleural fistulas. Bronchoscopic balloon dilatation is preferred for benign strictures. The nodal stage is related to complications (p = 0.0014), reflecting the aggressiveness of surgery, which requires extended radical lymphadenectomy.

Solenopsis invicta, a South American ant species from the Formicidae family (subfamily Myrmicinae), has recently established a stable settlement in Europe, raising public health concerns due to its venomous stings. The venom of S. invicta is rich in bioactive molecules, particularly piperidine alkaloids such as solenopsin A and peptides (Sol 1–4). These compounds have been implicated in various health applications, including antimicrobial, anti-inflammatory, and antitumour activities. While previous reviews have focused on the ecological and allergenic risks posed by S. invicta, this scoping review aims to evaluate the potential therapeutic uses of S. invicta venom by summarizing existing scientific evidence and providing a novel synthesis of recent research on its bioactive components. Furthermore, this study, by describing the unique biological aspects of S. invicta, provides an overview of its direct impact on public health, highlighting new findings on the venom’s role in inhibiting bacterial biofilm formation and modulating cancer growth pathways through gene regulation. A search of databases (PubMed, Scopus, Science Direct, and Cochrane Library) identified 12,340 articles, from which 11 studies met the eligibility criteria. These studies included seven microbiological investigations and four studies on tumour cell lines and animal models. The findings suggest that S. invicta venom could inhibit biofilm formation, combat fungal infections, and suppress tumour growth. However, further research, including clinical trials, is required to fully elucidate the safety and efficacy of these bioactive molecules in human medicine, for their potential use in drug discovery to counteract several diseases, including cancer.

Background and Objectives: The purpose of this case report is to examine the management of vestibular bone fenestration during alveolar socket preservation using the Periosteal Inhibition (PI) approach. Here, for the first time, the PI technique, which has been shown to be successful in maintaining intact cortical bone, is examined in the context of a bone defect. Materials and Methods: After an atraumatic extraction of a damaged tooth, a vestibular bone fenestration was discovered in the 62-year-old male patient. To shield the defect, a non-resorbable PTFE membrane (OSSEO GUARD by Zimmer Biomet) was positioned between the mucosa and the fenestration site. A resorbable porcine gelatin sponge (SPONGOSTANTM) was used to achieve hemostasis, and a 5/0 PGCL absorbable suture was used to close the wound. A CBCT scan was performed, and a dental implant was inserted after 4 months. Results: After 4 months, the case demonstrated positive results, with full cortical remodeling and preservation of the original bone proportions. The fenestration completely healed, proving that the PI approach works even in the presence of bone flaws in cortical bone that is still intact. Conclusions: This is the first case report that shows that vestibular bone fenestration can be successfully treated with the PI approach. It has now been demonstrated that the procedure, which hitherto needed an undamaged cortical bone to work, can help bone abnormalities to repair completely. These results imply that the PI technique is a flexible and useful approach that provides predictable results in dental surgery for treating different types of alveolar bone abnormalities. Its use might be expanded with more study to include bone dehiscence treatment.

Background: The surgical removal of impacted mandibular third molars is routine in oral and maxillofacial surgery and common postoperative complications are widely reported in the literature. Therefore, this prospective split-mouth study aims to compare the postoperative sequelae of piezoelectric surgery versus conventional surgery of the lower third molar, focusing on pain and swelling. Methodology: In total, 41 patients were treated under local anesthesia and surgical removal on one side of their mouth was performed using conventional rotary surgery (micromotor) while the other side’s was by piezosurgery, with an interval of 15 days from the previous procedure (82 extraction sites); in addition, pain and swelling analyses were conducted. Results: The pain analysis demonstrated a median of one day of pain in patients treated with piezoelectric surgery compared to two days with conventional surgery (p < 0.001). The probability of not feeling pain was greater in sites treated with experimental surgery on the first and second days (p < 0.001). The swelling was worse in places treated with the conventional method, with the most significant difference being the distance between the angle of the mandible and the upper lip vermilion on both days and the more subtle difference between the angle of the mandible and the anterior nasal spine on the seventh day. Conclusions: When a piezosurgical unit is used, according to the literature, is well known that it takes more time to perform the surgical extraction of third molars. Despite that, our results show that it causes less pain postoperatively, with faster improvement and a quicker reduction in swelling compared to conventional surgery.

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence in relation to sex- differentiation and their association with gender-specific factors are limited. Aims: The primary objective of the G-DEFINER study is to compare the irAEs incidence in female and male patients who undergo ICI treatment. Secondary objectives are: to compare the irAEs incidence in pre- and postmenopausal female patients; to compare the irAEs incidence in female and male patients according to different clinical and gender-related factors (lifestyle, psychosocial, and behavioral factors). Exploratory objectives of the study are to compare and contrast hormonal, gene-expression, SNPs, cytokines, and gut microbiota profiles in relation to irAEs incidence in female and male patients. Methods and Results: The patients are recruited from Fondazione IRCCS Istituto Nazionale dei Tumori, Italy, St Vincent’s University Hospital, Ireland, Oslo University Hospital, Norway, and Karolinska Insitutet/Karolinska University Hospital, Sweden. The inclusion of patients was delayed due to the Covid pandemic, leading to a total of 250 patients recruited versus a planned number of 400 patients. Clinical and translational data will be analyzed. Interpretation: The expected outcomes are to improve the management of cancer patients treated with ICIs, leading to more personalized clinical approaches that consider potential toxicity profiles. The real world nature of the trial makes it highly applicable for timely irAEs diagnosis.

Giuliano Lo Bianco,1 Sean Li,2 Miles Day,3 Michael E Schatman4,5 1Anesthesiology and Pain Department, Fondazione Istituto ”G. Giglio”, Cefalù, Palermo, Italy; 2National Spine and Pain Centers, Shrewsbury, NJ, USA; 3Pain Research, The Pain Center at Grace Clinic, Department of Anesthesiology, Texas Tech University HSC, Lubbock, TX, USA; 4Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA; 5Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USACorrespondence: Michael E Schatman, Department of Anesthesiology, Perioperative Care & Pain Medicine, NYU Grossman School of Medicine, 550 First Avenue, New York, NY, 10016, USA, Tel +1 425-647-4880, Email Michael.Schatman@NYULangone.org

Abstract Background The gut microbiome is a critical modulator of host immunity and is linked to the immune response to respiratory viral infections. However, few studies have gone beyond describing broad compositional alterations in severe COVID-19, defined as acute respiratory or other organ failure. Methods We profiled 127 hospitalized patients with COVID-19 (n = 79 with severe COVID-19 and 48 with moderate) who collectively provided 241 stool samples from April 2020 to May 2021 to identify links between COVID-19 severity and gut microbial taxa, their biochemical pathways, and stool metabolites. Results Forty-eight species were associated with severe disease after accounting for antibiotic use, age, sex, and various comorbidities. These included significant in-hospital depletions of Fusicatenibacter saccharivorans and Roseburia hominis, each previously linked to post-acute COVID syndrome or “long COVID,” suggesting these microbes may serve as early biomarkers for the eventual development of long COVID. A random forest classifier achieved excellent performance when tasked with classifying whether stool was obtained from patients with severe vs. moderate COVID-19, a finding that was externally validated in an independent cohort. Dedicated network analyses demonstrated fragile microbial ecology in severe disease, characterized by fracturing of clusters and reduced negative selection. We also observed shifts in predicted stool metabolite pools, implicating perturbed bile acid metabolism in severe disease. Conclusions Here, we show that the gut microbiome differentiates individuals with a more severe disease course after infection with COVID-19 and offer several tractable and biologically plausible mechanisms through which gut microbial communities may influence COVID-19 disease course. Further studies are needed to expand upon these observations to better leverage the gut microbiome as a potential biomarker for disease severity and as a target for therapeutic intervention.

Jonathan B Lin,1 Kristen M Pitts,1 Hani El Helwe,1 Cameron Neeson,1 Nathan E Hall,1 Henisk Falah,1 Stephanie A Schultz,2 Silas L Wang,1 Kristine Lo,1 Christian Song,1 Milica A Margeta,1,&ast; David Solá-Del Valle1,&ast; 1Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear, Boston, MA, USA; 2Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA&ast;These authors contributed equally to this workCorrespondence: David Solá-Del Valle; Milica A Margeta, Assistant Professor of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA, Email david_sola-delvalle@meei.harvard.edu; milica_margeta@meei.harvard.eduPurpose: Neurofilament light chain (NfL) is a neuronal cytoskeletal protein that has been identified as a marker of neurodegeneration in diseases of the central nervous system. In this study, we investigated whether NfL in the aqueous humor (AH) can serve as a marker of neurodegeneration in glaucoma in a racially diverse North American population.Design: Single-center, case–control study.Participants: We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract.Methods: We collected AH from 39 glaucoma patients and 10 patients without glaucoma. AH NfL was quantified using the Single-Molecule Array (Simoa)® NF-light assay (Quanterix). Demographic information, such as age, body mass index, sex, and self-reported race, as well as clinical information, such as pre-operative intraocular pressure (IOP), maximum IOP, and number of pre-operative glaucoma medications, was obtained by reviewing the medical record.Main Outcome Measures: Levels of AH NfL.Results: In a model controlling for age and body mass index (BMI), NfL was significantly elevated in AH from glaucoma patients (mean: 429 pg/mL; standard deviation [SD]: 1136 pg/mL) compared to AH from patients without glaucoma (mean: 3.1 pg/mL; SD: 1.9 pg/mg): P = 0.002. Higher AH NfL was associated with higher maximum IOP (R = 0.44, P = 0.005), higher pre-operative IOP (R = 0.46, P = 0.003), and more pre-operative glaucoma medications (Rs = 0.61, P < 0.001). There was no association between AH NfL and Humphrey visual field mean deviation (R = − 0.20, P = 0.220), retinal nerve fiber layer thickness as measured with optical coherence tomography (R = 0.07, P = 0.694), or glaucoma stage (Rs = 0.015, P = 0.935).Conclusion: Our findings suggest that AH NfL may have clinical utility as a marker of glaucomatous neurodegeneration.Keywords: neurofilament light chain, glaucoma, neurodegeneration, biomarker