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Abstract Background The relative contribution of the different components of mechanical power to mortality is a subject of debate and has not been studied in COVID-19. The aim of this study is to evaluate both the total and the relative impact of each of the components of mechanical power on mortality in a well-characterized cohort of patients with COVID-19-induced acute respiratory failure undergoing invasive mechanical ventilation. This is a secondary analysis of the CIBERESUCICOVID project, a multicenter observational cohort study including fifty Spanish intensive care units that included COVID-19 mechanically ventilated patients between February 2020 and December 2021. We examined the association between mechanical power and its components (elastic static, elastic dynamic, total elastic and resistive power) with 90-day mortality after adjusting for confounders in seven hundred ninety-nine patients with COVID-19-induced respiratory failure undergoing invasive mechanical ventilation. Results At the initiation of mechanical ventilation, the PaO2/FiO2 ratio was 106 (78; 150), ventilatory ratio was 1.69 (1.40; 2.05), and respiratory system compliance was 35.7 (29.2; 44.5) ml/cmH2O. Mechanical power at the initiation of mechanical ventilation was 24.3 (18.9; 29.6) J/min, showing no significant changes after three days. In multivariable regression analyses, mechanical power and its components were not associated with 90-day mortality at the start of mechanical ventilation. After three days, total elastic and elastic static power were associated with higher 90-day mortality, but this relationship was also found for positive end-expiratory pressure. Conclusions Neither mechanical power nor its components were independently associated with mortality in COVID-19-induced acute respiratory failure at the start of MV. Nevertheless, after three days, static elastic power and total elastic power were associated with lower odds of survival. Positive end-expiratory pressure and plateau pressure, however, captured this risk in a similar manner.

Introduction: Neutrophils are key players in the hyperinflammatory response during SARS-CoV-2 infection. The cytosolic proliferating cell nuclear antigen (PCNA) is a scaffolding protein highly dependent on the microenvironment status and known to interact with numerous proteins that regulate neutrophil functions. This study aimed to examine the cytosolic protein content and PCNA interactome in neutrophils from COVID-19 patients. Methods: Proteomic analyses were performed on neutrophil cytosols from healthy donors and patients with severe or critical COVID-19. In vitro approaches were used to explore the biological significance of the COVID-19-specific PCNA interactome. Results: Neutrophil cytosol analysis revealed a strong interferon (IFN) protein signature, with variations according to disease severity. Interactome analysis identified associations of PCNA with proteins involved in interferon signaling, cytoskeletal organization, and neutrophil extracellular trap (NET) formation, such as protein arginine deiminase type-4 (PADI4) and histone H3, particularly in critical patients. Functional studies of interferon signaling showed that T2AA, a PCNA scaffold inhibitor, downregulated IFN-related genes, including STAT1, MX1, IFIT1, and IFIT2 in neutrophils. Additionally, T2AA specifically inhibited the secretion of CXCL10, an IFN-dependent cytokine. PCNA was also found to interact with key effector proteins implicated in NET formation, such as histone H3, especially in critical COVID-19 cases. Conclusion: The analysis of the PCNA interactome has unveiled new protein partners that enhance the interferon pathway, thereby modulating immune responses and contributing to hyperinflammation in COVID-19. These findings provide valuable insights into interferon dysregulation in other immune-related conditions. Introduction: Neutrophils are key players in the hyperinflammatory response during SARS-CoV-2 infection. The cytosolic proliferating cell nuclear antigen (PCNA) is a scaffolding protein highly dependent on the microenvironment status and known to interact with numerous proteins that regulate neutrophil functions. This study aimed to examine the cytosolic protein content and PCNA interactome in neutrophils from COVID-19 patients. Methods: Proteomic analyses were performed on neutrophil cytosols from healthy donors and patients with severe or critical COVID-19. In vitro approaches were used to explore the biological significance of the COVID-19-specific PCNA interactome. Results: Neutrophil cytosol analysis revealed a strong interferon (IFN) protein signature, with variations according to disease severity. Interactome analysis identified associations of PCNA with proteins involved in interferon signaling, cytoskeletal organization, and neutrophil extracellular trap (NET) formation, such as protein arginine deiminase type-4 (PADI4) and histone H3, particularly in critical patients. Functional studies of interferon signaling showed that T2AA, a PCNA scaffold inhibitor, downregulated IFN-related genes, including STAT1, MX1, IFIT1, and IFIT2 in neutrophils. Additionally, T2AA specifically inhibited the secretion of CXCL10, an IFN-dependent cytokine. PCNA was also found to interact with key effector proteins implicated in NET formation, such as histone H3, especially in critical COVID-19 cases. Conclusion: The analysis of the PCNA interactome has unveiled new protein partners that enhance the interferon pathway, thereby modulating immune responses and contributing to hyperinflammation in COVID-19. These findings provide valuable insights into interferon dysregulation in other immune-related conditions.

Abstract Grape pomace is the main byproduct of the wine industry and an important source of dietary fiber and phenolic compounds. Grape pomace powder (GPP) partially substituted 8, 10, 12, 15, and 25% of the wheat flour in bread formulations. The proximate composition, total dietary fiber content, phenolic compounds, texture profile, color, and bioaccessibility of phenolic compounds in vitro were measured in the bread. Bread sensory acceptance by consumers was determined using a 9-point hedonic scale. Compared with the control bread (CB), the 8% GPB-substituted bread presented the best results and exhibited an increase in total protein content (7.5%) and total dietary fiber content (6.1%). The total phenolic content was greater in GPB (5.1 mg GAE/g) than in CB (2.1 mg GAE/g). Adding GPP to the bread affected the color, and the color of the GPB-treated bread was darker than that of the CB-treated bread. Still, no significant differences were detected regarding the texture profile or consumer sensory acceptance between the GPB-treated and CB-treated bread. The in vitro analysis of phenolic compound bioaccessibility revealed no differences between the two samples during gastrointestinal digestion. GPP is an interesting byproduct that can be used in bakery. The replacement of 8% of the bread with GPP increased the nutritional content of the bread, particularly the protein, total dietary fiber, and total phenolic content, without affecting the texture or sensory acceptance of the bread. To understand the possible beneficial effect of GPB on consumers, further research on the bioavailability of phenolic compounds and the impact of dietary fiber increment needs to be assessed. Graphical Abstract

Abstract BackgroundParkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms. Recently, dance has started to be considered an effective intervention for people with PD. Several findings in the literature emphasize the necessity for deeper exploration into the synergistic impacts of dance therapy and exergaming for PD management. Moreover, socially engaging robotic platforms equipped with advanced interaction and perception features offer potential for monitoring patients’ posture and enhancing workout routines with tailored cues. ObjectiveThis paper presents the results of the Social Robotics for Active and Healthy Ageing (SI-Robotics) project, aimed at designing an innovative rehabilitation program targeted at seniors affected by (early-stage) PD. This study therefore aims to assess the usefulness of a dance-based rehabilitation program enriched by artificial intelligence–based exergames and contextual robotic assistance in improving motor function, balance, gait, and quality of life in patients with PD. The acceptability of the system is also investigated. MethodsThe study is designed as a technical feasibility pilot to test the SI-Robotics system. For this study, 20 patients with PD were recruited. A total of 16 Irish dance–based rehabilitation sessions of 50 minutes were conducted (2 sessions per week, for 8 wks), involving 2 patients at a time. The designed rehabilitation session involves three main actors: (1) a therapist, (2) a patient, and (3) a socially interacting robot. To stimulate engagement, sessions were organized in the shape of exergames where an avatar shows patients the movements they should perform to correctly carry out a dance-based rehabilitation exercise. ResultsStatistical analysis reveals a significant difference on the Performance-Oriented Mobility Assessment scale, both on balance and gait aspects, together with improvements in Short Physical Performance Battery, Unified Parkinson Disease Rating Scale–III, and Timed Up and Go test, underlying the usefulness of the rehabilitation intervention on the motor symptoms of PD. The analysis of the Unified Theory of Acceptance and Use of Technology subscales provided valuable insights into users’ perceptions and interactions with the system. ConclusionsThis research underscores the promise of merging dance therapy with interactive exergaming on a robotic platform as an innovative strategy to enhance motor function, balance, gait, and overall quality of life for patients grappling with PD.

Beras analog adalah produk olahan yang berbentuk seperti butiran beras, tetapi terbuat dari bahan pangan non-beras seperti tepung kulit apel manalagi, tepung porang, dan tepung kacang merah. Pengeringan adalah tahap penting dalam pembuatan beras analog fungsional untuk memastikan kadar air bahan di bawah 15%, sehingga beras dapat disimpan dengan aman untuk waktu yang lebih lama. Tujuan dari penelitian ini adalah untuk menganalisa laju pengeringan dan sifat fisik beras analog yang dikeringkan pada suhu 40, 50, 60, dan 70°C serta menentukan suhu pengeringan paling optimal dalam memperoleh karakteristik terbaik dari beras analog. Tahapan penelitian meliputi pembuatan tepung kulit apel, pembuatan beras analog, dan pengeringan pada suhu 40, 50, 60, dan 70°C. Pengamatan meliputi perubahan kadar air, laju pengeringan, densitas kamba dan perubahan atribut warna (L, a*, b*). Hasil penelitian menunjukkan bahwa laju pengeringan tertinggi pada suhu 70°C. Suhu pengeringan optimal pada 70°C dengan kadar air beras analog 5,20%, densitas kamba 0,455 g/mL dan warna pada derajat kecerahan (L*) 66,50, derajat kemerahan (a*) 9,75, dan derajat kekuningan (b*) 24,90.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) requires innovative therapeutic strategies to counteract its progression and metastatic potential. Since the majority of patients are diagnosed with advanced metastatic disease, treatment strategies targeting not only the primary tumor but also metastatic lesions are needed. Tumor-Associated Macrophages (TAMs) have emerged as central players, significantly influencing PDAC progression and metastasis. Our objective was to validate an innovative therapeutic strategy involving the reprogramming of TAMs using lipid nanosystems to prevent the formation of a pro-metastatic microenvironment in the liver. Results In vitro results demonstrate that M2-polarized macrophages lose their M2-phenotype following treatment with lipid nanoemulsions composed of vitamin E and sphingomyelin (VitE:SM), transitioning to an M0/M1 state. Specifically, VitE:SM nanoemulsion treatment decreased the expression of macrophage M2 markers such as Arg1 and Egr2, while M1 markers such as Cd86, Il-1b and Il-12b increased. Additionally, the TGF-βR1 inhibitor Galunisertib (LY2157299) was loaded into VitE:SM nanoemulsions and delivered to C57BL/6 mice orthotopically injected with KPC PDAC tumor cells. Treated mice showed diminished primary tumor growth and reduced TAM infiltration in the liver. Moreover, we observed a decrease in liver metastasis with the nanoemulsion treatment in an intrasplenic model of PDAC liver metastasis. Finally, we validated the translatability of our VitE:SM nanosystem therapy in a human cell-based 3D co-culture model in vivo, underscoring the pivotal role of macrophages in the nanosystem’s therapeutic effect in the context of human PDAC metastasis. Conclusions The demonstrated effectiveness and safety of our nanosystem therapy highlights a promising therapeutic approach for PDAC, showcasing its potential in reprogramming TAMs and mitigating the occurrence of liver metastasis. Graphical abstract

Background: Several bacterial species belonging to the Gammaproteobacteria possess intrinsic class A β-lactamase genes that may represent a source of further dissemination and acquisition to other Gram-negative species. Here we characterised KSA-1 class A β-lactamase, the gene of which was identified within the chromosome of an environmental Enterobacterales species, namely Kosakonia sacchari, which was also recently identified as the progenitor of an MCR-like colistin-resistance determinant. Methods: In silico analysis using the GenBank database identified a class A β-lactamase gene within the chromosome of K. sacchari SP1 (GenBank accession no. WP_017456759). The corresponding protein KSA-1 shared 63% amino acid identity with the intrinsic CKO-1 from Citrobacter koseri and 53% with TEM-1. Using the K. sacchari DSM 100203 reference strain as a template, blaKSA-1 was amplified, cloned into the plasmid pUCp24 and expressed in Escherchia coli TOP10. Minimal inhibitory concentrations and kinetic parameters were obtained from the purified enzyme. Results: K. sacchari strain SP1 conferred resistance to amino-, carboxy- and ureido-penicillins only. Once produced within E. coli, KSA-1 showed a typical clavulanic acid-inhibited extended spectrum β-lactamase associated with a peculiar temocillin resistance profile. Kinetic assays were performed using a purified extract of KSA-1 and demonstrated a high hydrolysis rate for benzylpenicillin and piperacillin, as well as weakly extended spectrum cephalosporins. Determination of inhibitory constants showed 50% inhibitory concentration values of 2.2, 3 and 1.8 nM for clavulanic acid, tazobactam and avibactam, respectively. Analysis of sequences surrounding the blaKSA-1 gene did not reveal any mobile element that could have been involved in the acquisition of this β-lactamase gene in that species. Conclusion: KSA-1 is a class A extended spectrum β-lactamase distantly related to known extended spectrum or broad-spectrum Ambler class A β-lactamases, which is highly resistant to temocillin. The blaKSA-1 gene could be considered as intrinsic within the species.

Powdered honey represents a development from liquid honey to a powdered form. Product development is a critical component for businesses to be sustainable. Powdered honey processing is significant because it extends shelf life, facilitates transportation and storage, and makes it easier to utilize in a variety of food and beverage items. Furthermore, powdered honey can broaden market reach, provide value, and meet consumer desire for more practical and long-lasting products. Producers can use economic analysis to examine several components of their final product. By taking essential elements into account, business leaders can make better judgments about investments, machinery selection, and cost control to optimize earnings. The purpose of this study was to evaluate the economics of using vacuum drying equipment with a jet air system to produce powdered honey. The investigation was carried out at the Lastrindo Engineering Laboratory in Klojen, Malang, Indonesia. The results show that producing powdered honey with a vacuum drying machine and a jet air system has a positive NPV of IDR 640,134,063; a B/C Ratio of 1.22; and an IRR of 73.93%, making the investment plan for this machine economically viable. According to sensitivity analysis, increases in raw material prices and labor wages have a smaller impact than a loss in production, which has the greatest influence on the vacuum drying machine's profitability in powdered honey manufacturing. Keywords: economic analysis, powdered honey, vacuum dryer

Actinobacillus seminis is a gram-negative bacterium that affects reproductive organs, causing epididymitis, low fertility, and occasional abortions in sheep and goats. The virulence factors and the pathogenicity mechanisms of A. seminis have not been clearly elucidated yet. The aim of this study is to report a laboratory investigation performed on a sheep farm in the Basilicata region (southern Italy) following cases of abortion. Four samples of aborted fetuses taken from two sheep were analyzed to investigate the main pathogens causing abortions by bacterial isolation. In addition, serum samples belonging to the sheep have also been analyzed. Analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of the isolated colonies identified protein spectra referable to A. seminis. This result was also confirmed through the use of genome sequencing. Therefore, these data could explain cases of abortion that occurred on the farm and would confirm that MALDI-TOF MS technology is a rapid, accurate, and inexpensive method for identifying bacteria.

A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy resistance and relapse in CRC is associated with the formation of lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, the molecular mechanisms underlying the increase in DNL and the susceptibility to DNL-targeted therapies remain unclear. Our study demonstrates that colorectal drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), which facilitates the sequestration of free fatty acids into LDs. The increased expression is mediated by the ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking the conversion of free fatty acids into LDs by treatment with statins or inhibiting lipin1 expression disrupts lipid homeostasis, leading to lipotoxicity and ferroptotic cell death in both DTPs and patient-derived organoids (PDOs) in vitro. Ferroptosis inhibitors or N-acetylcysteine (NAC) can alleviate lipid ROS and cell death resulting from lipin1 inhibition. This strategy also significantly reduces tumor growth in CRC DTP mouse xenograft and patient-derived xenograft (PDX) models. Our findings highlight a new metabolic vulnerability in CRC DTPs, PDO, and PDX models and provide a framework for the rational repurposing of statins. Targeting the phosphatidic acid (PA) to diacylglycerol (DAG) conversion to prevent lipid droplet formation could be an effective therapeutic approach for therapy-resistant CRC.

Immune checkpoint inhibitors (ICIs) become integral in clinical practice, yet their application in cancer therapy is constrained by low overall response rates and the primary resistance of cancers to ICIs. Herein, this study proposes aggregation-induced emission (AIE)-based nanoparticles (NPs) for a more effective and synergistic approach combining immunotherapy and photodynamic therapy (PDT) to achieve higher responses than anti-PD-L1 monotherapy. The TBP@aPD-L1 NPs are constructed by functionalizing azide group-modified TBP-2 (TBP-N3) with anti-PD-L1 antibodies via the DBCO-S-S-PEG2000-COOH linker. The anti-PD-L1 target the tumor cells and promote the TBP-N3 accumulation in tumors for enhanced PDT. Notably, the TBP-N3, featuring aggregation-induced emission, boosts reactive oxygen species (ROS) generation through both type I and type II processes for enhanced PDT. The TBP@aPD-L1-mediated PDT induces more powerful effects of direct tumor cell-killing and further elicits effective immunogenic cell death (ICD), which exerts anti-tumor immunity by activating T cells for ICI treatment and reshapes the tumor immune microenvironment (TIME), thereby enhancing the efficacy of PD-L1 blockade of anti-PD-L1. Consequently, TBP@aPD-L1 NPs demonstrated significantly enhanced inhibition of tumor growth in the mouse model of malignant melanoma (MM). Our NPs act as a facile and effective drug delivery platform for enhanced immunotherapy combined with enhanced PDT in treating MM.

Foundation: adolescents who suffer from bullying are a cause for concern for global public health. Therefore, analyses are required that identify the presence of this phenomenon on a medium and large scale in the corresponding settings.Objective: to characterize bullying in ninth grade adolescents.Methods: A descriptive cross-sectional study was conducted at the Adolfo Ortiz Fonte Mixed School in Abreus, from September 2021 to June 2022. The sample consisted of 19 adolescent students from said school, who claimed to have been victims of bullying in the preceding six months. A questionnaire (validated by experts) was designed and applied that evaluated the particularities of perceived bullying through variables such as expression of bullying, precipitating factors and frequency, among others.Results: Females were more affected by the phenomenon of bullying. Psychological bullying was the most frequent (100%), followed by physical bullying (21.1%). Place of residence and skin color were identified as the main causes, while school hallways, backyards and bathrooms were listed as the most common places of aggression. The main perceived consequences were emotional (78.9%).Conclusion: The low perception of bullying within the studied universe, with psychological bullying being the most frequent form of expression, linked to the emotional consequences that arise from it.

Background Arginase-1 (Arg1) expressing tumor-associated macrophages (TAMs) may create an immune-suppressive tumor microenvironment (TME), which is a significant challenge for cancer immunotherapy. We previously reported the existence of Arg1-specific memory T cells among peripheral blood mononuclear cells (PBMCs) and described that Arg-1-based immune modulatory vaccines (IMVs) control tumor growth and alter the M1/M2 macrophage ratio in murine models of cancer. In the present study, we investigated how Arg1-specific T cells can directly target TAMs and influence their polarization.Methods Murine Arg1-specific CD4+T cells isolated from splenocytes of animals vaccinated with an Arg1-derived peptide in the adjuvant montanide were co-cultured with either in vitro M2-differentiated bone marrow-derived macrophages or ex vivo isolated F4/80+TAMs. Human Arg1-specific CD4+T cell clones were co-cultured with Arg1-expressing TAMs generated in vitro from either PBMC-derived CD14+cells or the myeloid cell lines MonoMac1 and THP-1. MHC class II-restricted Arg-1 peptide presentation by macrophages was confirmed by immunopeptidomics. T-cell-mediated changes in the macrophage immune phenotype and cytokine microenvironment were examined using flow cytometry, RT-qPCR and multiplex immunoassay. The effect of Arg1-derived peptide IMV on TAMs in vivo was assessed by multiplex gene analysis of F4/80+cells.Results We show that Arg1-based IMV-mediated tumor control was linked to a decrease in multiple immunosuppressive pathways in the TAM population of the treated animals. Tumor-conditioned media (TCM) derived from Arg1-vaccinated mice induced significantly higher upregulation of MHC-II on exposed myeloid cells compared with controls. Furthermore, murine CD4+Arg1-specific T cells were able to target TAMs and effectively reprogram their phenotype ex vivo by secreting IL2 and IFNγ. Next, we established that human Arg1+TAMs present Arg1-derived peptides and are directly recognized by proinflammatory CD4+Arg1-specific T cell clones. These CD4+Arg1-specific T cells were able to reprogram TCM-conditioned macrophages as observed by increased expression of CD80 and HLA-DR.Conclusions TAMs may be directly targeted and modulated by Arg1-specific CD4+T cells. These findings provide a strong rationale for future clinical development of Arg1-based IMVs to alter the immune-suppressive TME by reprogramming TAMs and promoting a proinflammatory TME.

Research has been carried out to analyze the ability of NaOH-activated rice husk Ash Silica to reduce Cl Ion Levels. This study aimed to determine the optimum mass, optimum pH, optimum contact time and apply NaOH-activated rice husk ash silica to reduce Cl ion levels in seawater. The method used in this study was an experimental method with the parameters studied, namely optimum mass, optimum pH, optimum contact time, and the ability of NaOH-activated rice husk ash silica to reduce Cl ion levels in seawater. The results showed that the optimum adsorbed percentage of Cl ions occurred at an optimum mass of 0.025 gram, optimum pH of 7, and optimum contact time of 30 minutes with an adsorbed percentage of 45.7% and an adsorption capacity of 9.14 mg/g. The Cl ion content of seawater samples that can be reduced using NaOH-activated rice husk ash silica is 16.925 ppm with an adsorbed percentage of 33.85%, so it can be concluded that NaOH-activated rice husk ash silica can be used to reduce Cl ion levels.

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Equine piroplasmosis is a worldwide tick-borne disease caused by the parasites Theileria equi sensu lato and Babesia caballi, with significant economic and sanitary consequences. These two parasites are genetically variable, with a potential impact on diagnostic accuracy.Our study aimed to evaluate the frequency of asymptomatic carriers of these parasites in France and describe the circulating genotypes. We developed a species-specific nested PCR protocol targeting the 18S small sub-unit (SSU) rRNA gene and used it on blood samples collected from 566 asymptomatic horses across four National Veterinary Schools.The carrier frequency varied from 18.7 % around Paris (central-north) to 56.1 % around Lyon (southeast), with an overall prevalence of 38.3 %. Theileria equi carriers were ten times more frequent (91.7 %; 209/228 isolates) compared to B. caballi carriers (8.3 %; 19/228 isolates). Notably, T. equi carrier frequency was significantly lower in the northern region (Ile de France) compared to the southeastern regions. A positive relationship was observed between the frequencies of asymptomatic carriers and the frequency of previous acute piroplasmosis reported from the owner across all four geographic areas. Neither horse gender nor age showed a significant effect on the frequency of asymptomatic carriers. In some areas, a substantial proportion of horses (22.2 % to 37.5 %) carried T. equi before the age of three years, indicating high infection pressure.Genotyping of 201 T. equi isolates revealed a predominance of genotype E (98 %) and few isolates belonging to genotype A (2 %). Notably, two of the four T. equi genotype A isolates were detected in horses originating from Spain. All 19 B. caballi isolates belonged to the genotype A.The discussion section explores the link between these results, the tick distribution and abundance, and the frequency of detection of T. equi and B. caballi in febrile cases attributed to piroplasmosis.

BackgroundIt has been widely demonstrated that siblings of children with autism spectrum disorder (ASD) have an increased risk of abnormal developmental trajectories. In response to this, early recognition protocols have been developed worldwide, aiming to promote early interventions that can positively impact the neurodevelopment of this population. This paper presents the protocol of a controlled trial: ERI-SIBS (Early Recognition and Intervention in SIBlingS at High Risk for Neurodevelopment Disorders) is an innovative and ecological early recognition and intervention program designed specifically for siblings of children with ASD.MethodsWe aim to recruit siblings at low risk and high risk of neurodevelopmental disorders. Based on clinical evaluation at T0, we will allocate the infants into three groups: Group 1, infants at low risk without any signs of neurodevelopmental disorders; Group 2, infants at high risk without any signs of neurodevelopmental disorders; Group 3: infants at low or high risk with signs suggestive of neurodevelopmental disorders. Children of Group 2 will undergo Active Monitoring (one 90 min session once a month for 6 months), while children of Group 3 will undergo Early Intervention (one 90 min session once a week for 6 months). In both cases, the ERI-SIBS contents are based on a multidimensional and naturalistic approach and always involve caregivers. All recruited children will be evaluated at three different time points (T0 within the 8 months of life of the child, T1 after 6 months and T2 after 12 months) using behavioural, technological, and biological techniques to assess infants’ neurodevelopmental functions, parent-infant interaction, and early ASD markers.DiscussionThe ERI-SIBS study will expand knowledge regarding the impact of early intervention on families of infants at risk of neurodevelopmental disorders for the presence of a child with a diagnosis of ASD. The study will have the potential to significantly contribute to future research and the scientific and clinical debate on the best way to implement early intervention in at-risk populations. Clinical Trial RegistrationClinicaltrials.gov identifier (NCT06512649).

Bullying is an important cause of depression in young people. Adolescents who are or were subject to bullying often have problems sleeping, eating, and focusing. Their academic performance can be negatively affected because they are angry, scared, and unmotivated. The present bibliographic review aims to systematize the knowledge about bullying in adolescence. The main technique for collecting information was a search in Scielo, PubMed, Dialnet, and Elsevier databases, using the Google Scholar search engine. The descriptors used were: bullying; adolescent; and mental health. 26 articles were selected based on their relevance and approach to the topic. Theoretical methods were used, such as analysis-synthesis for the introduction and development, and deduction-induction for structuring the conclusions. Despite being a phenomenon that has been studied for several decades, bullying is becoming more widespread and complex, a fact that researchers relate to behaviors arising from the growing attachment to technology, due to its strong impact at all levels of current existence in the world.

Traditional treatments against advanced non-small cell lung cancer (NSCLC) with high morbidity and mortality continue to be dissatisfactory. Given this situation, there is an urgent requirement for alternative modalities that provide lower invasiveness, superior clinical effectiveness, and minimal adverse effects. The combination of photodynamic therapy (PDT) and immunotherapy gradually become a promising approach for high-grade malignant NSCLC. Nevertheless, owing to the absence of precise drug delivery techniques as well as the hypoxic and immunosuppressive characteristics of the tumor microenvironment (TME), the efficacy of this combination therapy approach is less than ideal. In this study, we construct a novel nanoplatform that indocyanine green (ICG), a photosensitizer, loads into hollow manganese dioxide (MnO2) nanospheres (NPs) (ICG@MnO2), and then encapsulated in PD-L1 monoclonal antibodies (anti-PD-L1) reprogrammed exosomes (named ICG@MnO2@Exo-anti-PD-L1), to effectively modulate the TME to oppose NSCLC by the synergy of PDT and immunotherapy modalities. The ICG@MnO2@Exo-anti-PD-L1 NPs are precisely delivered to the tumor sites by targeting specially PD-L1 highly expressed cancer cells to controllably release anti-PD-L1 in the acidic TME, thereby activating T cell response. Subsequently, upon endocytic uptake by cancer cells, MnO2 catalyzes the conversion of H2O2 to O2, thereby alleviating tumor hypoxia. Meanwhile, ICG further utilizes O2 to produce singlet oxygen (1O2) to kill tumor cells under 808 nm near-infrared (NIR) irradiation. Furthermore, a high level of intratumoral H2O2 reduces MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further driving T cells. Taken together, the current study suggests that the ICG@MnO2@Exo-anti-PD-L1 NPs could act as a novel drug delivery platform for achieving multimodal therapy in treating NSCLC.

Abstract Background Recently, the development of advanced, noninvasive methods has allowed the study of respiratory function even in uncooperative infants. To date, there is still little data on the application of this technique in infants with suspected airway obstruction. The aims of our study were: - To evaluate the role of respiratory function testing (PFR) in the diagnosis and follow-up of infants with stridor - To evaluate the differences between patients with inspiratory stridor and expiratory stridor. - To evaluate the concordance between PFR and endoscopy. Methods We enrolled infants aged

Abstract Background There has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease. Methods Plasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile. Results High cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value

Abstract Background Equitable health service utilization is key to health systems' optimal performance and universal health coverage. The evidence shows that men and women use health services differently. However, current analyses have failed to explore these differences in depth and investigate how such gender disparities vary by service type. This study examined the gender gap in the use of outpatient health services by Mexican adults with non-communicable diseases (NCDs) from 2006 to 2022. Methods A cross-sectional population-based analysis of data drawn from National Health and Nutrition Surveys of 2006, 2011–12, 2020, 2021, and 2022 was performed. Information was gathered from 300,878 Mexican adults aged 20 years and older who either had some form of public health insurance or were uninsured. We assessed the use of outpatient health services provided by qualified personnel for adults who reported having experienced an NCD and seeking outpatient care in the 2 weeks before the survey. Outpatient service utilization was disaggregated into four categories: non-use, use of public health services from providers not corresponding to the user’s health insurance, use of public health services from providers not corresponding to the user’s health insurance, and use of private services. This study reported the mean percentages (with 95% confidence intervals [95% CIs]) for each sociodemographic covariate associated with service utilization, disaggregated by gender. The percentages were reported for each survey year, the entire study period, the types of service use, and the reasons for non-use, according to the type of health problem. The gender gap in health service utilization was calculated using predictive margins by gender, type of disease, and survey year, and adjusted through a multinomial logistic regression model. Results Overall, we found that women were less likely to fall within the “non-use” category than men during the entire study period (21.8% vs. 27.8%, P

Abstract Eucalyptus species play an important role in the global carbon cycle, especially in reducing the greenhouse effect as well as storing atmospheric CO₂. Thus, assessing the amount of CO₂ released by the soil in forest areas can generate important information for environmental monitoring. This study aims to verify the relation between soil carbon dioxide (CO₂) flux (FCO₂), spectral bands, and vegetation indices (VIs) derived from a UAV-based multispectral camera over an area of eucalyptus species. Multispectral imageries (green, red-edge, and near-infrared) from the Parrot Sequoia sensor, derived vegetation indices, and the FCO₂ data from a LI-COR 8100 analyzer, combined with soil moisture and temperature data, were collected and related. The vegetation indices ATSAVI (Adjusted Transformed Soil-Adjusted VI), GSAVI (Green Soil Adjusted Vegetation Index), and SAVI (Soil-Adjusted Vegetation Index), which use soil correction factors, exhibited a strong negative correlation with FCO₂ for the species E. camaldulensis, E. saligna, and E. urophylla species. A Multivariate Analysis of Variance showed significance (p

Abstract Background The term “sharenting” describes the increasingly popular habit of parents to share photos, videos, or other information regarding their children on their social profiles, through online platforms. It is highly likely that many parents are posting content about their underage children online with little knowledge of the risks associated with this practice. This study aims to investigate whether variables such as parents’ age, gender, marital status, occupation and educational level influence the practice of sharing child-related content and the degree of awareness. Methods We performed a pilot cross-sectional study, based on an anonymous questionnaire. The questionnaire was administered to parents of underage children attending the pediatric outpatient clinic of the Umberto I Hospital, Sapienza University, in Rome, Italy, by researchers, through the google forms platform; qualitative variables were generated on excel sheets and a statistical analysis was performed on SPSS Ibm-statistics using the chi-square test. Results Two hundred twenty-eight parents of children under 18 years of age completed the questionnaire (82% mothers, 18% fathers); 98% of the respondents used social media and 75% of them published their children’s related content online. Thirty-one percent of the compilers started their practice of sharenting in the first 6 months of life of their child. Our analysis showed that compared to parents who do not post online, parents who usually post online their children are significantly more likely to be partial employees or unemployed (p = 0,002), with lower educational level (p = 0,05), younger (less than 35 years of age (p = 0,01)) and have a higher number of followers (p

Within the last decade, one of the crucial efforts to reduce environmental impact and improve consumers' health has focused on shifting food choices. In our previous study, the authors developed a customizable and adaptable Dashboard for Improving Sustainable Healthy (DISH) food choices. DISH leverages nudge and traffic-light labels to enable consumers to compare and envision the potential environmental, nutritional, and health impacts of their food choices before purchasing. An initial test among 112 individuals through an online survey revealed the potential of the tool to shift purchase intentions among consumers on a university campus. As part of a second phase in a series of consumer evaluations, we provide a step-by-step protocol followed to investigate the effectiveness of a version of DISH (McGill DISH) in stimulating subtle dietary changes on another university campus. • Environmental nutrition information on DISH was communicated in simple but intuitive ways through multiple technological media (self-service kiosks and mobile applications) to stimulate dietary change. • The study participants were randomly separated into treatment and control groups. • We hypothesize that the participants in the treatment group are more likely to engage with food products that are more sustainable and healthier on the DISH application compared to the control group.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Background: Allergic rhinitis (AR) is a highly prevalent disease. We aimed to assess the symptoms that physicians who see patients with AR perceive as the most bothersome in their patients. Methods: We performed a cross-sectional study based on an online questionnaire sent to all members of the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative. The survey included questions on the physicians' perceptions of patients’ AR symptoms as well as of their own AR symptoms. Results: Among 401 respondents, 155 (38.7%) reported having AR. ARIA members reported nasal symptoms to be the most frequent (89.7%) and bothersome (80.0%) symptoms experienced by themselves. Likewise, nasal symptoms were reported by ARIA members as the most frequent (94.8% in members with AR vs 96.0% in members without AR) and bothersome (57.0% in members with AR vs 67.9% in members without AR) in their patients. We found a significant association (p = 0.001) between physicians’ own symptoms and those perceived as the most bothersome in their patients. Conclusion: Physicians perceive nasal symptoms to be the most frequent and the most bothersome symptoms in AR patients. The physicians' personal experiences with AR may influence their perception of patients’ symptoms.

Rationale & Objective: Hypokalemia is common and potentially life-threatening in patients undergoing peritoneal dialysis (PD). However, the current literature has produced varying results. This study aimed to evaluate the prevalence and adverse outcomes of hypokalemia and the role of potassium supplementation in patients receiving PD. Study Design: Systematic review and meta-analysis of randomized controlled trials and observational studies. Setting & Study Populations: Adults receiving maintenance PD. Selection Criteria for Studies: Studies that investigated the prevalence and adverse outcomes of hypokalemia and the effect of potassium supplementation. Data Extraction: Two independent reviewers evaluated studies for eligibility and extracted relevant data. Analytical Approach: Random effects meta-analysis was conducted to pool hazard ratios (HRs) and 95% CIs for the outcomes of interest. The certainty of findings was rated according to the Grading of Recommendations Assessment, Development and Evaluation criteria. Results: Of 3,632 reports identified, 24 studies involving 60,313 participants met the inclusion criteria. The prevalence of hypokalemia was 37.9% (95% CI, 27.2%-52.7%), 17.7% (95% CI, 12.0%-25.9%), and 4.4% (95% CI, 1.9%-10.2%) in patients with potassium level

Summary: The migratory culling hypothesis posits that infected individuals are less likely to survive long-distance migration due to physiological and behavioral effects, but this lacks empirical evidence. Here, we tested this hypothesis by sampling 357 passerines from 11 species during their autumn migration to wintering grounds in two different areas, i) at a stopover in southern Spain, and ii) in the Canary Islands, where they were drifted and preyed upon by Eleonora’s falcons while en route to the southern Sahara. Molecular detection of infections by Plasmodium, Haemoproteus, and Leucocytozoon was conducted on bird samples. A higher prevalence of both Plasmodium and Haemoproteus was observed in birds preyed upon by falcons. While a complete understanding of the mechanistic effects of haemosporidian infections on migration performance needs experimental validation, our approach suggests that infection reduces migration success by increasing mortality due to route deviations and/or predation.

Objetivo: Avaliar a associação de polimorfismos de base única (SNPs) do sistema endocanabinoide (ECS) com o subfenótipo de acidente vascular encefálico (AVE) em pacientes com anemia falciforme (AF). Materiais e métodos: O grupo amostral foi composto por 217 pacientes com AF, provenientes da Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope, PE), subdivididos em: (1) 73 com AVE (mediana do desenvolvimento de AVE de 8 anos [1-58 anos]) e (2) 144 pacientes como grupo controle, sem AVE (mediana de 29 anos [18-65 anos]). O fenótipo da AF foi diagnosticado por HPLC e confirmado por PCR-RE, e mutação da -α3,7kb talassemia foi detectada por GAP-PCR. Com base no impacto funcional e nas frequências alélicas mínimas (MAF) > 10%, selecionamos quatro SNPs do ECS que poderiam estar relacionados com o AVE na AF (FAAH rs324420, MAGL rs604300, CNR1 rs7766029 e CNR2 rs35761398) e a genotipagem foi realizada com ensaios TaqMan no PCR em Tempo Real, QuantStudio 5 (Thermo Fisher Scientific). Resultados: Os dados de gênero, hemoglobina total (Hb), contagem de reticulócitos, bilirrubina indireta, desidrogenase láctica, quantidade de crise vaso oclusivas (VOCs)/ano e o genótipo para -α3,7kb-talassemia não foram associados ao AVE, enquanto níveis mais baixos de Hb F (%) foram associados ao desenvolvimento de AVE (AVE, Hb F 5 ± 3,3 vs. grupo de controle, Hb F 9,6 ± 5,6, p < 0,0001). Em relação aos SNPs, todos encontraram-se dentro do Equilíbrio de Hardy Weinberg (p > 0,05), e o modelo de herança adotado foi o de dominância para o MAGL rs604300 e sobredominância para os demais. As frequências alélicas e genotípicas não diferiram estatisticamente entre os grupos, bem como a distribuição dos alelos não diferiu do MAF para a população adotada (NCBI's ALFA dataset, Latin America 1). Os modelos de regressão logística binária, ajustados para a Hb F como covariável, não demonstraram associação entre os SNPs e o desenvolvimento de AVE. Discussão: O AVE é um subfenótipo da AF relacionado à hemólise, à disfunção endotelial e à lesão vascular. No âmbito do ECS, estudos com modelos animais de AVE isquêmico já demonstraram a ação neuroprotetora do antagonismo de receptores CB1, codificados pelo gene CNR1, e do agonismo de receptores CB2 (CNR2), estes últimos ainda relacionados à neurogênese pós AVE. Portanto, ainda que nossos dados tenham revelado que os SNPs analisados não são bons preditores para o AVE, existem evidências crescentes para considerar estes genes como candidatos na modulação desse e de outros subfenótipos da AF. Além disso, nosso estudo fornece pela primeira vez um modelo de herança para os SNPs do ECS na AF e sua caraterização em uma coorte brasileira. O modelo de herança de um SNP pode ser vital para desvendar as características genéticas de doenças complexas, como a AF, e associar fenótipos da doença a genótipos específicos. Conclusão: Fornecemos aqui a primeira associação de SNPs do ECS com o subfenótipo da AVE na AF. Considerando os recentes avanços no sentido da utilização de canabinoides nessa e em diversas outras doenças, nossos resultados também abrem caminho para futuros estudos de caraterização dos polimorfismos genéticos do ECS nesta população.

Objetivo: Relatar um estudo familial de probando com hemoglobina (Hb) Korle-Bu e β talassemia. Material e métodos: Amostras de sangue total do probando, sexo masculino, 8 meses e de seus progenitores (mãe com 31 anos e pai com 26 anos), provenientes do ambulatório do Centro de Hematologia e Hemoterapia do Maranhão, foram enviadas ao Laboratório de Genética da UFMS/CPTL para diagnóstico molecular de perfil hemoglobínico inconclusivo. Foram realizados hemograma, reticulograma (ADVIA 2120i-Siemens Healthineers), análises bioquímicas (ARCHITECT ci4100-Abott), análises cromatográficas e análises moleculares (PCR-RE e sequenciamento do gene beta globina –HBB, sequenciador 3770xl DNA analyser). Resultados: O hemograma e reticulograma do probando, pai e mãe apresentaram respectivamente os seguintes parâmetros: E = 5.95, 5.71, 5.40 milhões/mm3; Hb = 11.2, 17.2, 12,0 g/dL; Ht = 33.8, 49.7, 38.6%; VCM = 56.8, 87.0, 71.4 fL; HCM = 18.8, 30.0, 22.2 pg; CHCM = 33.0, 34.5, 31.0%; RDW = 18.5, 13.5, 17.1%; Reticulócitos = 38.500, 34.300, 92.100/mm3; CHr = 20.4, 31.7, 25.4 pg; VCMr = 72.8, 106.3, 91.0 fL. Os resultados das dosagens de ferro sérico, ferritina, índice de saturação da transferrina do probando foram respectivamente: 57 ug/dL, 15.6 ng/mL, 21%. O perfil cromatográfico do probando indicou Hb Variante com tempo de retenção relativo (RRT) a Hb A2 (70.2%), Hb F (18.0%) e Hb A0 (5.7%). A cromatografia do pai apontou a presença de Hb A0 (47.9%) e Hb Variante (43.5%) com RRT de Hb A2. A sobreposição de picos entre Hb Variante e Hb A2 impossibilitou a quantificação da Hb A2 do probando e pai. A mãe apresentou Hb A0 (84.4%), Hb F (0.6%) e aumento de Hb A2 (5.3%). A análises moleculares detectaram a presença de um alelo com a mutação HBB:c.220G>A (Hb Korle Bu) para o pai e mutação HBB:c.92+5G>A (β+ grave talassemia IVS-I-5) em heterozigose para a mãe. Por fim, as análises moleculares do probando confirmaram a dupla heterozigose no gene HBB, formada pela presença de um alelo mutante para Hb Korle-Bu e de outro para talassemia β+ grave IVS-I-5. Discussão: A análise do hemograma do probando e da mãe não indicou anemia para a idade, mas revelou anisocitose com intensa microcitose. O hemograma do pai não apresentou alterações. O reticulograma do probando, pai e mãe não mostrou aumento absoluto na contagem de reticulócitos, no entanto, o VCMr do probando e da mãe estava diminuído. O perfil de ferro do probando não apresentou alterações, excluindo a possibilidade de deficiência de ferro e avaliado com o perfil do eritrograma, suspeitou-se de uma hemoglobinopatia quantitativa. A análise cromatográfica do probando revelou um perfil hemoglobínico inconclusivo. Contudo, com base na observação do eritrograma do probando e nos cromatogramas dos progenitores, em que a mãe possui um aumento de Hb A2 e o pai com presença de heterozigose para Hb Variante, concluiu-se tratar-se de uma provável β talassemia (herdada da mãe) em heterozigose composta com uma Hb Variante (herdada do pai) não identificável por HPLC. As análises moleculares foram realizadas para o diagnóstico confirmatório, com a presença de mutações correspondentes a Hb Korle-Bu e talassemia β+ grave IVS-I-5. Conclusão: A combinação de diferentes metodologias laboratoriais, especialmente as técnicas de biologia molecular, foi essencial para o diagnóstico preciso deste caso complexo, evitando interpretações errôneas e tratamentos inadequados.

Objectives: This study aims to compare clinical parameters and outcomes between patients with aplastic anaemia undergoing immunosuppressive treatment (IST) who received more than 10 units of blood components prior to IST and those who did not. Methods and materials: This cross-sectional study included patients diagnosed with aplastic anaemia and treated at Hospital Geral de Fortaleza. The treatment regimen comprised anti-thymocyte globulin, cyclosporine, and, in some cases, eltrombopag. Data were collected on various clinical parameters, including age, time to IST, haemoglobin (Hb), white blood cell count (Wbc), neutrophils (Neut), lymphocytes (Linf), platelet count (Plat), creatinine (Cr), urea (Ur), and lactate dehydrogenase (LDH). Patients were divided into two groups based on whether they received more than 10 transfusions before IST. Variables were summarised using medians and interquartile ranges (IQR). Comparisons between groups were evaluated using non-parametric tests, specifically the Mann-Whitney U-test, with p-values < 0.05 considered statistically significant. Overall survival (OS) was assessed using the Kaplan-Meier method, with a 95% confidence interval and p-values < 0.05 deemed statistically significant. Results: Between 2021 and 2024, 11 patients were diagnosed with aplastic anaemia and deemed suitable for IST. Patients who did not receive more than 10 transfusions had a median age of 20 years (IQR: 20-26.5), compared to 40.5 years (IQR: 35.5-42) for those who did. Time to IST was shorter for the transfusion group, with a median of 21 days (IQR: 11.5-25) versus 44 days (IQR: 34-54) for the non-transfusion group. The transfusion group had lower median levels of Hb (4.8 g/dL), WBC (1250 cells/μL), Neut (77 cells/μL), and plat (10500 cells/μL). Cr and urea levels were slightly higher in the transfusion group, with medians of 0.88 mg/dL and 35 mg/dL, respectively. LDH data were unavailable for the transfusion group. Only two patients received eltrombopag. There was no significant difference between the two groups in terms of age, blood count values at diagnosis, and sex (U-test > 0.05). Overall survival was 75%, with better outcomes in patients who had fewer than 10 transfusions, although this difference was not statistically significant (p-value: 0.257). Discussion: The analysis revealed significant clinical differences between the two groups. Patients who received more transfusions were older, had a shorter time to treatment initiation, and exhibited worse cytopenias. Although Cr and Ur levels were slightly higher in the group with more transfusions, LDH data were unavailable. Only two patients received eltrombopag, and there was no significant difference between the groups in terms of age, blood count values at diagnosis, and sex. The overall survival rate was 75%, with better outcomes in patients who had fewer transfusions, although this difference was not statistically significant. These findings suggest that multiple transfusions before IST may be associated with a more severe clinical profile, yet they do not significantly impact overall survival. Conclusion: The overall survival observed in this study was lower than international data. There was no significant difference between the groups analysed; however, the low patient count in the study should be considered when interpreting the lack of impact on outcomes. The use of IST with eltrombopag should be evaluated sequentially to determine its impact on individuals treated within the public health system.

Objetivo: Relatar um estudo de caso de uma hemoglobina (Hb) rara denominada Hb I-Interlaken, a qual foi recebido e diagnosticado pelo Laboratório de Genética e Biologia Molecular da UFMS/CPTL. Materiais e métodos: Amostra de sangue de uma paciente do sexo feminino de 64 anos de idade, procedente de Campinas/SP, foi encaminhada para Laboratório de Genética e Biologia Molecular (UFMS/CPTL) para análise laboratorial de perfil hemoglobínico inconclusivo, juntamente com exames hematológicos complementares. Para determinar as frações hemoglobínicas da paciente, a amostra foi submetida à Cromatografia Líquida de Alta Performance (HPLC-Premier Resolution, Trinity Biotech). Para confirmação molecular do genótipo, os genes da α-globina (HBA2 e HBA1) foram amplificados por PCR-Touchdown e sequenciados pelo método de Sanger (sequenciador 3730xl DNA Analyzer, Thermo Fisher Scientific). Resultados: Após análises por HPLC, o perfil cromatográfico da paciente apresentou Hb A (67,9%), Hb A2 (2,0%) e Hb variante (22,2%) com o tempo de retenção relativo (RRT) a Hb A de 0,84 (RRT/A = 0,84). O sequenciamento completo do gene HBA2 não demonstrou presença de mutações para Hb variantes, enquanto o sequenciamento do gene HBA1 demonstrou a presença da mutação HBA1:c.47G>A em heterozigose, correspondente à Hb I-Interlaken (genótipo αα/ααI-Interlaken). Em relação aos dados hematológicos, os seguintes parâmetros foram observados: Eritrócitos de 4,27 milhões/mm3, Hb de 13,3 g/dL, Hct de 39,7%, VCM de 93 fl, HCM de 31,2 pg, CHCM de 33,5 g/dL e RDW de 13,3 %. Discussão: A Hb I-Interlaken (também conhecida como Hb J Oxford) corresponde a uma Hb α-variante rara, caracterizada por uma substituição de glicina na posição 15 da cadeia α por um ácido aspártico (GlyAsp), e ocorre principalmente entre os indivíduos descendentes de ingleses e italianos. Relatamos aqui o segundo caso dessa Hb no Brasil, sendo seu primeiro relato curiosamente também em paciente proveniente de Campinas/SP, demonstrando o efeito da imigração europeia e da miscigenação na composição gênica dessa população. Apesar da alteração estrutural na proteína final, a Hb Interlaken não apresenta alterações funcionais, sendo estável e possuindo afinidade normal pelo oxigênio; portanto, seus portadores não apresentam manifestações clínicas, com parâmetros hematológicos dentro dos valores de referência. No entanto, mesmo assintomática, a detecção dessa e de outras variantes raras de Hb é imprescindível para a determinação de sua incidência e para o entendimento do fluxo dessas mutações na população brasileira. Além disso, a combinação de Hb α-variantes com outras mutações estruturais ou talassemias pode resultar em fenótipos clinicamente relevantes, realçando a importância da identificação dessas Hb. Nesse sentido, a associação de diferentes metodologias laboratoriais, como análises cromatográficas e moleculares, permite a detecção correta de Hb raras. Conclusão: A Hb I-Interlaken é uma Hb α-variante rara e tem pouco significado clínico. A presença de Hb anormais podem refletir o grau de miscigenação no Brasil e evidenciam a importância do estabelecimento de padrões e estratégias cromatográficas e moleculares para análises das amostras de Hb da população, além de desenvolver estudos com métodos combinados visando um diagnóstico preciso.

Objectives: This study aims to compare clinical parameters and outcomes between patients with high grade non-Hodgkin lymphomas undergoing intensive chemotherapy schedules. Material and methods: This cross-sectional study included patients diagnosed with High grade non-hogdkin lymphomas (HGNHL) and Burkitt's lymphoma (BL) treated at Hospital Geral de Fortaleza. The treatment regimen was R-CODOX-M/R-IVAC. Data were collected on various clinical parameters, including age, time to chemotherapy, haemoglobin (Hb), white blood cell count (Wbc), neutrophils (Neut), lymphocytes (Linf), platelet count (Plaq), creatinine (Cr), urea (Ur), and lactate dehydrogenase (LDH). Variables were summarised using medians and interquartile ranges (IQR). Comparisons between groups were evaluated using non-parametric tests, specifically the Mann-Whitney U-test, with p-values < 0.05 considered statistically significant. Overall survival (OS) was assessed using the Kaplan-Meier method, with a 95% confidence interval and p-values < 0.05 deemed statistically significant. Results: Between 2021 and 2024, 11 patients were diagnosed with high-grade non-Hodgkin lymphoma. The median age of the patients was 26 years, with an interquartile range (IQR) from 25.0 to 44.5 years. The time from diagnosis to admission at the Hospital Geral de Fortaleza (Time_dx_to_hgf) varied considerably, with a median of 19 days and an IQR from -10.5 to 36.5 days, indicating a wide range of delays and some instances of early intervention. The time from diagnosis to the initiation of treatment (Time_dx_treat) had a median of 48 days, with an IQR from 29.5 to 66.5 days, reflecting the varied timelines in starting therapy. The number of hospitalisations (N_internation) had a median of 3, with an IQR from 2.00 to 4.50, indicating the frequency of inpatient care required for these patients. The follow-up time in months (Time_months) showed a median of 9.33 months, with an IQR from 5.38 to 15.7 months, highlighting the duration over which these patients were monitored. The OS was 27.5% in two years, with no difference between HIV positive patients (p-value > 0,05). Discussion: The analysis reveals significant variability in clinical presentation and timing of treatment among patients with high-grade non-Hodgkin lymphoma and Burkitt lymphoma. Despite the urgent need for prompt intervention in these high-proliferative lymphomas, the median time to treatment initiation was 48 days, suggesting delays that could negatively impact outcomes. The overall survival rate of 27.5% at two years underscores the aggressive nature of these diseases. The lack of significant differences in survival between HIV-positive and HIV-negative patients indicates that timely and intensive treatment is crucial for all patients, regardless of HIV status. The study highlights the necessity for immediate and aggressive therapy to improve survival rates in these high-grade lymphomas. Conclusion: There are considerable variability in clinical presentation and timing of treatment among patients with high-grade lymphoma and Burkitt lymphoma. The time to iniate treatment was extremely harmful and this group of high proliferative lymphoma must start intensive treatment as soon as possible.

Objectives: This study assesses clinical outcomes for primary central nervous system lymphoma (PCNSL) patients, particularly focusing on the timelines from diagnosis to hospital arrival, treatment initiation, and overall survival. It examines the impact of these timelines on patient outcomes and evaluates the effectiveness of a treatment regimen that includes high-dose methotrexate, cytarabine, and rituximab on survival rates in first line. Material and methods: Conducted as a cross-sectional study in the hematology ward of Hospital Geral de Fortaleza, this research evaluates patients diagnosed with PCNSL. Clinical parameters such as age, time to chemotherapy initiation, and time to death are collected. Data are summarized using medians and interquartile ranges (IQR). Group comparisons are facilitated using non-parametric tests, specifically the Mann-Whitney U-test, with p-values < 0.05 considered statistically significant. Overall survival (OS) is assessed using the Kaplan-Meier method, maintaining a 95% confidence interval. Results: Median patient age is 45.5 years (IQR: 39.8 to 52.0), and the median time from diagnosis to hospital arrival is -7.00 days (IQR: -19.0 to 17.0), suggesting some patients were referred before formal diagnosis. The median time from diagnosis to treatment initiation is 36 days (IQR: 31.0 to 55.0). The median survival time post-diagnosis is 7.07 months (IQR: 3.22 to 18.6), with the primary treatment regimen consisting of high-dose methotrexate, cytarabine, and rituximab. The 2-year OS is 25%, with 66.7% of patients dying within one year of diagnosis. Discussion: The variability in the timelines from diagnosis to hospital arrival and treatment initiation among PCNSL patients highlights a critical need for more efficient care processes. The early referral of some patients indicates an urgent referral protocol for highly suspected cases, yet the substantial range in treatment initiation times could impact patient outcomes significantly. The aggressive nature of the disease is underscored by a median survival time of 7.07 months, with a significant percentage of patients dying within the first year post-diagnosis, suggesting potential inadequacies in the treatment protocol. Conclusion: The findings suggest an urgent need for more streamlined diagnostic and treatment protocols to improve the efficacy of lymphoma care. The significant mortality rate within a year of diagnosis and the low overall survival rate necessitate a re-evaluation of the standard treatment regimen to better meet patient needs. This study advocates for further research to optimize treatment timelines and regimen efficacy to enhance patient prognosis and combat the severity of lymphoma more effectively.

Objectives: This study aimed to analyze the clinical presentation of non-Hodgkin lymphoma (NHL) patients, focusing on age distribution, time to treatment initiation, and overall survival. It also sought to identify differences in these parameters across various NHL subtypes, including Burkitt lymphoma. Material and methods: We conducted a cross-sectional study involving NHL patients treated in the hematology ward at Hospital Geral de Fortaleza. Data on clinical parameters such as age, time to chemotherapy, and time to death were collected. We summarized these variables using medians and interquartile ranges (IQR). Non-parametric tests, specifically the Mann-Whitney U-test, were used for group comparisons, with p-values < 0.05 considered statistically significant. Overall survival (OS) was assessed using the Kaplan-Meier method, with a 95% confidence interval and p-values < 0.05 deemed significant. Results: The study included patients with various NHL subtypes, including Burkitt lymphoma (n = 5), diffuse large B-cell lymphoma (DLBCL, n = 11), high-grade B-cell lymphoma (n = 5), NK/T-cell nasal lymphoma (n = 1), plasmablastic lymphoma (n = 1), and primary CNS lymphoma (n = 6). Median ages were as follows: Burkitt lymphoma, 32 years (IQR: 25.0-50.0); DLBCL, 39 years (IQR: 35.0-49.5); high-grade B-cell lymphoma, 26 years (IQR: 20.0-39.0); NK/T-cell nasal lymphoma, 37 years; plasmablastic lymphoma, 26 years; and primary CNS lymphoma, 45.5 years (IQR: 39.8-52.0). These variations underscore the clinical heterogeneity and the need for tailored treatment strategies. Analysis showed significant variability in the median time to initiating chemotherapy among subtypes. Burkitt lymphoma patients had a median initiation time of 32 days, which was later than the 17 days for DLBCL patients. High-grade B-cell lymphoma patients had the longest median time to treatment initiation at 48 days, suggesting possible delays in diagnosis or treatment. These findings highlight the need for improved diagnostic and therapeutic strategies, especially for subtypes with longer initiation times. The overall survival rate was 37.5% at two years, which is lower compared to international data. Time to treatment initiation was particularly associated with worse outcomes in patients with primary CNS lymphoma (PNCSL), with delays in tissue evaluation contributing to challenges. Discussion: The study revealed significant differences in median ages across lymphoma subtypes, reflecting the clinical diversity and the need for personalized treatment approaches. Notably, patients with Burkitt lymphoma and high-grade B-cell lymphoma experienced delays in starting treatment. High-grade B-cell lymphoma patients had the longest median time to treatment initiation, highlighting potential diagnostic and treatment delays. The overall survival rate of 37.5% at two years was concerning, especially when compared to international data. Delays in initiating treatment were linked to poorer outcomes, particularly in PNCSL patients, with issues in tissue evaluation by stereotaxic samples being a significant hurdle. Conclusion: The findings emphasize the critical need for prompt diagnosis and timely treatment initiation to improve patient outcomes. The delays in treatment initiation, particularly for high-grade B-cell lymphoma and Burkitt lymphoma, underscore the importance of streamlining diagnostic and therapeutic processes.

Objetivos: A leucemia de células plasmocitárias (LCP) é uma doença rara e agressiva, que pode ser primária, surgindo sem antecedentes onco-hematológicos, ou secundária, iniciando após diagnóstico prévio de Mieloma Múltiplo (MM). Este estudo relata o caso de um paciente com LCP secundária no estado do Ceará. Materiais e métodos: Este estudo foi realizado através da consulta e coleta de dados dos prontuários do paciente com LCP no Hospital Geral de Fortaleza (HGF), mediante aprovação do comitê de ética da instituição (N°4.798.575). Relato de caso: Paciente masculino, cearense, 49 anos, foi admitido no HGF após diagnóstico de LCP, apresentando lesões líticas em arcos costais, corpos vertebrais e bacia. O hemograma apontou hemoglobina (Hb) de 9,6 g/dL, leucometria de 25.540/mm3, 28% de plasmócitos circulantes e 524.000/mm3 de plaquetas (PLT). A biópsia medular indicou neoplasia plasmocitária, enquanto a imunofenotipagem apresentou 58% de plasmócitos aberrantes e a eletroforese de proteínas (EPS) séricas apontou alterações associadas à região gamaglobulina. A conduta inicial foi o uso do protocolo VCD (Velcade, Ciclofosfamida e Dexametasona), permitindo o controle da doença durante alguns meses. Com o fim da terapia, o paciente ainda apresentou doença residual mínima (DRM) positiva. No final do ano de 2022 realizou novos exames, em que o mielograma apontou 76% de plasmócitos, β2-microglobulina (β2M) de 6,64 mg/L e hemograma com Hb de 10,1 g/dL, leucometria de 41.300/mm3, 81% de plasmócitos e 347.000/mm3 de PLT, sendo medicado com Decadron e Pamidronato Dissódico. No começo de 2023 fez uso de Dexametasona e ao realizar novos exames evidenciou-se recaída da doença. Seu mielograma apontou 88,2% de plasmócitos, β2M de 7,97 mg/L e a imunofenotipagem indicou 82,8% de plasmócitos clonais com expressão de CD38, CD138 e Lambda. Posteriormente, foram iniciados ciclos de VDT-PACE. Discussão: A LCP é uma doença rara, representando menos de 3% das neoplasias de células plasmáticas e relaciona-se com piores prognósticos. No caso relatado, apesar do paciente apresentar períodos de estabilidade com DRM, houve recaídas da doença e refratariedade ao tratamento. A alteração na região gamaglobulina identificada na EPS é comum em casos de MM, corroborando com o diagnóstico de LCP secundária. Nos momentos de auge da doença observou-se altos percentuais de plasmócitos no sangue e na medula óssea, além de anemia e leucocitose. Houve aumento nos níveis de β2M, que é um aspecto comum nessas neoplasias. Quanto aos resultados imunofenotípicos, a expressão de CD38 e CD138 são marcadores comuns de células plasmocitárias, enquanto a expressão de Lambda não é um aspecto tão frequente, apontando para uma infiltração medular de células plasmáticas restrita à cadeia leve Lambda. Conclusão: O relato de caso descrito neste estudo corrobora com os dados da literatura de que tal patologia apresenta-se de forma bastante agressiva, além da associação com prognósticos desfavoráveis e a alta complexidade diagnóstica e terapêutica. Apesar dos inúmeros esforços da equipe médica para o controle da doença do paciente em questão, o mesmo tem se mostrado refratário aos esquemas de tratamento. Ademais, o paciente está, atualmente, submetido ao tratamento com VDT-PACE, no qual ainda não há informações acerca da sua responsividade terapêutica.

The primary objective was to evaluate the association between the levels of BCR::ABL1 at diagnosis (BCR0), as measured by quantitative RT-qPCR, and the EUTOS score in patients with chronic myeloid leukemia (CML), and their association with BCR::ABL1 transcripts at 3 months after tyrosine kinase inhibitor therapy (BCRM3). We conducted a cross-sectional study evaluating 35 patients diagnosed with CML, using quantitative RT-qPCR to measure BCR0. The relationship between the EUTOS score, BCR0, and BCRM3 was evaluated using Spearman's rank correlation coefficient (Rho). Linear regression modelling was employed to examine the predictive capacity of the EUTOS score and BCR0 on BCRM3. Model fit was assessed using the adjusted coefficient of determination (R2). Statistical significance was determined for p-values less than 0.05. A total of 35 patients with CML were analyzed, with BCR::ABL1 activity assessed at diagnosis. Of these, 68.6% were male. The median age was 39.1 years (IQR: 23.5). The median EUTOS score was 58 (IQR: 69.5), the median percentage of blasts in the bone marrow at diagnosis was 6% (IQR: 8), and the median percentage of CD34 positive cells was 1.25% (IQR: 2). The median BCR0 level was 96% (IQR: 70.5). The correlation between BCR0 and BCRM3 was 0.63 (p-value < 0.01), demonstrating a strong positive correlation. Similarly, the correlation between EUTOS score and BCRM3 was 0.55 (p-value < 0.001), also indicating a strong positive correlation. In the linear regression analysis, using EUTOS and BCR0 as independent variables, the regression model for BCR0 had a slope coefficient of 0.05 with an R2 of 0.6 (p-value < 0.01), indicating that BCR0 significantly predicts BCRM3. The EUTOS regression model had a slope coefficient of 0.3 with an R2 of 0.45 (p-value < 0.01), also indicating a significant predictive value. In the multivariate model, the coefficients were 0.2 for EUTOS (p-value: 0.03) and 0.03 for BCR0 (p-value < 0.001). The multivariate model was more robust, with an R2 of 0.7 (p-value < 0.01), indicating that the combination of EUTOS and BCR0 provides a better prediction of BCRM3. The observed median BCR0 level of 96% underscores the high disease burden at diagnosis. The correlation analysis indicated a weak, non-significant association between BCR0 and EUTOS score (Rho = 0.317, p = 0.06), suggesting that while both are prognostic markers, they may reflect different aspects of disease biology. In contrast, the strong positive correlations between BCR0 and BCRM3 (Rho = 0.63, p < 0.01) and between EUTOS score and BCRM3 (Rho = 0.55, p < 0.001) underscore their relevance in predicting early treatment response. Linear regression analysis further demonstrated the predictive value of BCR0 and EUTOS scores. The BCR0 regression model, with a slope coefficient of 0.05 and R2 of 0.6, and the EUTOS model, with a slope coefficient of 0.3 and R2 of 0.45, both indicated significant predictive power. Notably, the multivariate model, incorporating both BCR0 and EUTOS scores, was more robust (R2 = 0.7), suggesting that a combined approach provides a superior predictive framework for assessing early response to imatinib therapy. These findings highlight the importance of integrating multiple prognostic markers to enhance predictive accuracy in CML management. The significant associations and robust multivariate model support the use of BCR0 and EUTOS scores as complementary tools in clinical practice.

Evaluate how TKIs affect the population dynamics of leukemic cells during treatment according an populational decaying model, with the goal of optimizing treatment strategies for CML. Using ELN guidelines, this study modeled BCR::ABL1 p210 decay over 12 months post-TKI treatment via logarithmic interpolation, yielding a predictive equation. Key assumptions included a closed population, non-overlapping generations, density-independent mortality, discrete time, and exponential decay. Wolfram Mathematica was used for curve fitting. This study uses ELN guidelines and logarithmic interpolation to model BCR::ABL1 decay in CML patients undergoing TKI therapy. Starting from month 3, the equation (y = 99.72e−0.766x), derived from RT-qPCR data, predicts BCR::ABL1 levels with an R2 of 0.99, indicating high accuracy. The model, reflecting the clinical timeline of BCR::ABL1 monitoring, demonstrates the efficacy of TKI therapy and offers a reliable framework for predicting BCR::ABL1 trajectories, aiding in treatment monitoring and decision-making. This study uses evolutionary and ecological modeling to evaluate BCR::ABL1 decline in CML patients undergoing TKI therapy. Initial BCR::ABL1 levels and decay rates are critical for predicting treatment success according to decaying model. This approach suggests more aggressive initial treatment for high BCR::ABL1 levels, using potent TKIs and combination therapies. This approach aims to overcome resistance, enhance treatment efficacy, and personalize therapy based on patient-specific characteristics. This research uses evolutionary, and population decline models to study CML treatment. Initial BCR::ABL1 levels could predict treatment response, suggesting personalized strategies could improve outcomes. Further validation is needed.

Objetivo: Relatar o primeiro caso no Brasil de interação da hemoglobina (Hb) variante Ottawa com alfa talassemia em um estudo familial. Materiais e métodos: Amostra de sangue total de uma criança do sexo feminino de dez meses, proveniente da APAE – Salvador/BA, foi recebida pelo Laboratório de Genética e Biologia Molecular (LGBM) da UFMS/CPTL, juntamente com as amostras de ambos os progenitores para confirmação diagnóstica de hemoglobinopatias. No hemograma do probando constava Hb (9,8 g/dL), VCM (78,6%), HCM (26,8%), CHCM (34,0%) e RDW (14,4%). Com base nesses dados, a amostra da criança, bem como a dos pais, foi submetida a Cromatografia Líquida de Alta Performance (HPLC), Trinity Biotech, e análises moleculares (PCR-RE, PCR-Multiplex e Sequenciamento de DNA por Sanger). Resultados: O perfil cromatográfico do probando indicou uma concentração incomum de Hb A (66,4%) e elevada concentração de Hb A2 (3,1%), acompanhadas de uma Hb variante no tempo de retenção relativo a Hb S de 1.06 (RRT/S 1.06) em uma concentração sugestiva de Hb alfa(α)-variante (18,9%), com possível presença de α-talassemia. A cromatografia do pai revelou a presença de Hb A (69,6%), Hb A2 (2,7%) e uma Hb variante (20,8%) de comportamento similar à encontrada no probando, enquanto a mãe apresentou um perfil cromatográfico sem sinais aparentes de hemoglobinopatias, com concentrações normais de Hb A (95,3%) e Hb A2 (2,7%). Os perfis cromatográficos guiaram as análises moleculares, onde identificou-se a mutação delecional de α-talassemia (-α3,7kb) em heterozigose tanto no probando quanto na mãe, e ausência de Hb S no probando e no pai. Devido às suspeitas de Hb α-variante, as amostras foram encaminhadas para sequenciamento dos genes HBA2 e HBA1 , no qual foi identificada a presença da mutação HBA1:c.46G>C (Hb Ottawa) em heterozigose tanto no probando, quanto no genitor. Discussão: Os resultados obtidos permitiram a conclusão do diagnóstico do probando como heterozigoto para Hb Ottawa e coerança de alfa talassemia (-α3,7kb) em heterozigose (-α3,7/ααOttawa). A Hb Ottawa (ou Siam) é uma variante rara de cadeia alfa, onde a mutação resulta na substituição de uma glicina por uma arginina no códon 15 do gene HBA2 ou HBA1 . Até o momento, essa variante não havia sido documentada no Brasil em coerança com alfa talassemia, tornando este o primeiro registro dessa associação. Em heterozigose, a Hb Ottawa é assintomática, sugerindo que a anemia microcítica e hipocrômica observada no hemograma do probando é decorrente da presença da α+talassemia, a qual acarreta na redução das sínteses de cadeias alfa, e portanto, no prejuízo, principalmente, da formação do tetrâmero Hb A. Apesar da sua baixa ocorrência e ausência de manifestações clínicas em heterozigose, a associação da Hb Ottawa com o traço falciforme (HbAS), pode desencadear crises vaso-oclusivas graves, e a não detecção dessa variante por análises moleculares pode levar ao falso diagnóstico de doença falciforme, considerando que seu perfil cromatográfico e padrão de migração eletroforética são similares a Hb S. Conclusão: Casos de Hb variantes raras acompanhadas de talassemias demonstram a relevância da associação das metodologias laboratoriais, bem como de laboratórios de apoio com profissionais especializados na identificação molecular de variantes globínicas para a determinação genotípica os pacientes, permitindo uma posterior orientação genética e acompanhamento clínico adequados aos familiares.