A 68-year-old man with malignant metastatic melanoma in complete remission after Pembrolizumab treatment, developed 10 months after Pembrolizumab cessation due a grade 3 diarrhea, confusion, altered mental status, progressive memory loss, gait disturbance. He was admitted to the neurologic department and comprehensive neurological workup, brain magnetic resonance imaging, cerebral fluid analysis, EEG, blood test allowed the diagnosis of autoimmune encephalitis. The patient was treated with plasmapheresis, high dose of intravenous steroids and intravenous immunoglobulins. The patient improved and he is now well with a performance status 1. This case is interesting since the AE developed approximately 10 months after the cessation of immunotherapy, the underlying cancer was in complete remission and the AE showed a good response to the treatment done.

The German health authorities' guidelines for medical devices in 2012 highlighted the importance of cleaning ultrasound probes, emphasizing their validation and reliability. In addition to automated and validated options, alternative manual methods such as wipe disinfection have gained traction due to their independence from additional hardware. The study examines the effectiveness of manual disinfection methods, specifically the cleaning process, addressing concerns raised by the Robert Koch Institute regarding the lack of validation for wipe disinfection of semi-critical devices. The EQUINOS colored wipe disinfection kit identified wetting gaps in all cleanings across four probes tested. The results indicate significant challenges in ensuring complete surface wetting, particularly in complex body parts such as clip-on areas and shapes for additional biopsy attachments, suggesting that manual methods alone may not adequately mitigate the risk of infection transmission (p value .001). The study concludes that while manual disinfection methods are a viable alternative to automated reprocessing, there is a critical need for enhanced training and potentially the development of more effective manual disinfection techniques or colored wipes to ensure patient safety and compliance with healthcare hygiene standards.

Research indicates that brain region-specific synapse loss and dysfunction are early hallmarks and stronger neurobiological correlates of cognitive decline in Alzheimer’s disease (AD) than counts of amyloid plaques, neurofibrillary tangles, and neuronal loss. Even though the precise mechanisms underlying increased synaptic pruning in AD are still unknown, it has been confirmed that dysregulation of the balance between complement activation and inhibition is a crucial driver of pathology. The complement includes three distinct activation mechanisms, with activation products C3a and C5a, potent inflammatory effectors, and a membrane attack complex (MAC), leading to cell lysis. Besides pro-inflammatory cytokines, dysregulated complement proteins released by activated microglia bind to amyloid β at synaptic regions and cause microglia to engulf synapses. Additionally, research indicating that microglia-removed synapses are not always degenerating, and that suppression of synaptic engulfment can repair cognitive deficits point to an essential opportunity for intervention that can prevent the loss of intact synapses. In this study, we focus on the latest research on the role and mechanisms of complement-mediated microglial synaptic pruning at different stages of AD to find the right targets that could interfere with complement dysregulation and be relevant for therapeutic intervention at the early stages of the disease.

There has been significant increase of studies investigating plasma biomarkers of Alzheimer’s and their relationship to cognitive functioning. The impact of ethnicity on this relationship has not been extensively studied. The current research investigated the relationship between the plasma biomarkers of total tau, Aβ40, Aβ42 and NfL and neuropsychological test performance in a bi-ethnic sample of cognitively unimpaired, older community dwelling adults. The 1326 cognitively unimpaired participants drawn from The Health & Aging Brain Study – Health Disparities (HABS-HD) study included 765 Mexican American participants and 860 non-Hispanic White participants with complete plasma biomarkers and neuropsychological testing. Plasma samples were assayed using Simoa technology. Significant differences in concentrations were found for all of the plasma biomarkers. NHWs had significantly higher levels of each of the biomarkers with a lower Aβ42/ Aβ40. With none of the biomarkers related to performance on any of the neuropsychological tests. For MAs, Aβ40 was the only biomarker that was significantly related to neuropsychological test performance. Aβ40 levels were negatively related to performance on Trails A, Trails B and Digit Symbol Substitution. Results suggest that the relationship of these biomarkers to cognitive functioning is impacted by ethnicity and may be domain specific.

The therapeutic, attenuative, and morphological effects of proprietary neural stem cell-derived extracellular vesicles (NSC EVs, AB126) produced by Aruna Bio, Inc. were assessed in a range of in vitro and in vivo models of stroke. We emphasize that modulation of neuroinflammation is a key target and suggest further studies to advance our understanding of the mechanisms of action and ultimately how best to dose and monitor the benefits of AB126 in stroke patients.

Purpose: To evaluate the relationship between corneal nerve structure and function in a veteran population. Methods: 83 veterans (mean age: 55 ± 5 years) seen at the Miami Veterans Affairs (VA) eye clinic were included in the study. Each individual filled out questionnaires to evaluate ocular symptoms (5-Item Dry Eye Questionnaire, DEQ5, Ocular Surface Disease Index, OSDI) and ocular pain (Numerical Rating Scale, NRS, Neuropathic Pain Symptom Inventory modified for the Eye, NPSI-Eye). Individuals also underwent an ocular surface examination that captured functional nerve tests including corneal sensation, corneal staining, and Schirmer test for tear production. Corneal sub-basal nerve analysis was conducted using in vivo confocal microscopy (IVCM) images with corneal nerve density, length, area, width, and fractal dimension captured. IVCM and functional corneal metrics from the right eye were examined using correlational and linear regression analysis. Results: Most corneal structural metrics were not related to functional metrics, except for weak correlations between various IVCM metrics and tear production. In addition, corneal nerve fiber area was positively related to corneal sensation (r = 0.3, p = 0.01). On linear regression analyses, only corneal fractal dimension remained significantly related to tear production (β = -0.26, p = 0.02) and only corneal nerve fiber area remained significantly related to corneal sensation (β = 0.3, p = 0.01). Conclusions: Most corneal nerve structural metrics did not relate to functional metrics in our veteran population, apart from a few weak correlations between structural metrics and tear production. This highlights caution in using corneal nerve anatomy to predict corneal function.

Modern organic synthesis is majorly focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-Mass spectroscopy. Major highlights of the reported work include: atom economical process, extremely milder reaction conditions, operational simplicity, high isolated yields, and excellent catalyst turnover number. The molecular docking studies suggest that the compound 4n has the hydrogen bonding, hydrophobic and π-pair interactions with the active site of active sites of CXT M 15 receptor.

The gut-brain axis (GBA) represents a complex, bidirectional communication network that intri-cately connects the gastrointestinal tract with the central nervous system (CNS). Understanding and intervening in this axis opens a pathway for therapeutic advancements. In light of this, the current review assesses the effectiveness of neuromodulation techniques in treating neurological and gastrointestinal disorders by modulating the GBA, involving key elements such as gut micro-biota, neurotrophic factors, and proinflammatory cytokines. Through a comprehensive literature review encompassing PubMed, Google Scholar, Web of Science, and the Cochrane Library, and analyzing 182 relevant articles, this research highlights how neuromodulation can positively impact the management of functional gastrointestinal disorders (FGIDs), chronic pain, inflammation, and a range of GI disorders like Crohn's disease and ulcerative colitis. Despite existing challenges, the ability of neuromodulation to adjust disrupted neural pathways, alleviate pain, and mitigate in-flammation is significant in improving the quality of life for patients, thereby offering exciting prospects for future advancements in patient care.

Berberis vulgaris (L.) has remarkable ethnopharmacological properties and is widely used in traditional medicine. The present study investigates B. vulgaris stem bark (Berberidis cortex) by extraction with 50% ethanol. The main secondary metabolites were quantified, resulting in a polyphenols content of 17.6780 ± 3.9320 mg Eq Tannic acid / 100 g extract, phenolic acids amount of 3.3886 ± 0.3481 mg Eq Chlorogenic acid / 100 g extract and 78.95 µg/g berberine. The dried hydro-ethanolic extract (BVE) was thoroughly analyzed using Ultra-High Performance Liquid Chromatography coupled with High-Resolution Mass Spectrometry (UHPLC–HRMS/MS) and HPLC and 40 bioactive phenolic constituents were identified. Then, the antioxidant potential of BVE was evaluated using three methods; our results could explain the protective effects of Berberidis cortex EC50FRAP = 0.1398 mg/mL, IC50ABTS = 0.0442 mg/mL, IC50DPPH = 0.2610 mg/mL compared to ascorbic acid (IC50 = 0.0165 mg/mL). Next, the acute toxicity and teratogenicity of BVE and Berberine - Berberine sulfate hydrate (BS) - investigated on Daphnia sp reported significant BS toxicity after 24 h; BVE revealed considerable toxicity after 48 hours and induced embryonic developmental delays. Finally, the anticancer effects of BVE and BS were evaluated on different tumor cell lines after 24 and 48 hours of treatments. The MTS assay evidenced a dose- and time-dependent antiproliferative activity, higher on BS than BVE. The strongest diminution of tumor cell viability was recorded on breast (MDA-MB-231), colon (LoVo) cancer, and OSCC (PE/CA-PJ49) cell lines after 48 h of exposure (IC50 < 100 µg/mL). However, no cytotoxicity was reported on normal epithelial cells (HUVEC) and hepatocellular carcinoma (HT-29) cell lines. Extensive data analysis supports our results, showing a significant correlation between the BVE's concentration, phenolic compounds content, antioxidant activity, exposure time, and the viability rate of various normal cells and cancer cell lines.

Prostate cancer lung metastasis represents a clinical conundrum due to their implication of advanced disease progression and the complexities they introduce in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, the review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, the review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Acute kidney injury (AKI) following surgery with cardiopulmonary bypass (CPB-AKI) is common in pediatrics. Urinary liver-type fatty acid binding protein (uL-FABP) increases in some kidney diseases and may indicate CPB-AKI earlier than current methods. The aim of this systematic review with meta-analysis was to evaluate the potential role of uL-FABP in early predicting CPB-AKI. Databases Pubmed/MEDLINE, Scopus, and Web of Science were searched on November 12th, 2023, using the MeSH terms “Children”, “CPB”, “L-FABP”, and “Acute Kidney Injury”. Included papers were revised. AUC values from similar studies were pooled by meta-analysis, performed using random- and fixed-effect models, with p

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), and nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres, 100-300 nm in size, loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than nonspecific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study shows the potential for anticancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labelling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier for precisely targeting tumors. This combination has the potential to produce anti-tumor effects in active targeted therapy of GBM.

Background: The aim of this experimental work was to confirm the individual uniqueness of lip prints, to verify the presence of recurrent patterns according to the Suzuki and Tsuchihashi classification and to search for characteristics that can be used in establishing the sex of a subject. Methods: Lip prints were taken from a sample of 172 volunteers using liquid lipstick and transparent adhesive tape and were digitally analyzed. Results: 59 prints (35.3%) were not considered for Suzuki and Tsuchihashi classification due to quality errors and the impossibility of visualizing lip wrinkles in one or more sextants, all the digitized prints revealed themselves to be unique after having been analyzed using superimposition. Qualitatively valid prints indicated a prevalence of Type II in both male and female and the presence of sex-linked features. A major problem was that the analysis of the same print by different operators often resulted in a different attribution of a Type. Conclusions: The potential of cheiloscopy lies mainly in the matching of prints, given their uniqueness, and can be a valid tool in gender determination but the absence of a database greatly limits its use. It is necessary to establish an acquisition protocol for taking and analyzing prints that could reduce the errors committed by the operator.

Severe cancer pain significantly diminishes patients' quality of life, leading to increased reliance on caregivers. Although opioid analgesics are effective, they may induce opioid-induced bowel dysfunction (OIBD) with symptoms such as nausea, vomiting, drowsiness, and constipation. While controlled-release oxycodone is a viable option, its prolonged use can lead to opi-oid-induced constipation (OIC). Addressing this, a relative novel formulation - a fixed 2:1 ratio of oxycodone and naloxone in prolonged release - aims to provide analgesia while alleviating OIC. This review critically assesses the evidence on the efficacy, safety, and patient experience of ox-ycodone/naloxone prolonged release in managing severe cancer pain, emphasizing the necessity for a targeted approach in this patient population.

Abstract: This study aims to evaluate the effectiveness of plant-based diets and supplement interventions in mitigating the severity and mortality of COVID-19 patients. Observational research suggests that a diet high in plant-based foods may decrease the likelihood and severity of SARS-CoV-2 infection. However, several studies have faced criticism regarding the accuracy of obtaining dietary questionnaires and the insufficient intake of essential vitamins and minerals in such diets. To address these issues, this study employed a prospective interventional design that strictly controlled the quality, quantity, and processing of plant-based foods provided. Furthermore, the study incorporated supplementation, which enhanced the anti-viral, anti-inflammatory, antioxidant, antithrombotic, and immunomodulatory properties of a plant-based diet against the SARS-CoV-2 virus. Of the 3,470 COVID-19 elderly patients, half already followed a plant-based diet, and the other half new patients, both with various comorbidities, were intervened with a plant-based diet and supplementation. The results showed that the participants in the non-plant-based diet group were twice as likely to have experienced moderate disease (with 95% confidence limit: 1.42-3.12) and 2.4 times more likely to have experienced severe disease (with 95% confidence limit: 1.2-5.0) with a significant p-value of less than 0.0005 and 0.016 respectively, compared to those in the PBD group. During the interventions, none of the participants experienced disease progression or hospitalization, and there were no reported deaths by the end of the study. The outcome was highly favorable and aligned with the researchers' expectations, as COVID-19 morbidity and mortality rates in Indonesia were among the highest in Asia. This research may provide significant insights into the prevention and management of COVID-19 and aid in better preparation for future pandemics.

Menin inhibitors are new and promising agents currently in clinical development that target the HOXA/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemia. The mechanism of action of this new class of agents is based on the disruption of menin-KMT2A complex (constitute of chromatin remodelling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or mutated NPM1. This new class of drugs has been tested alone, or in combination with synergistic drugs, in phase I and II clinical trials (AUGMENT-01 and 02, KOMET-01 and 07, SAVE, COVALENT trial and others), showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this review, we summarise the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data of this emerging and promising class of agents, in particular revumenib and ziftomenib.

Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knockout on the development of intestinal polyps using Collaborative Cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knockout mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knockout males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knockout, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-Nearest Neighbours and Linear Regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides a comprehensive understanding of the intricate genetic interplay in the context of Smad4 knockout, offering valuable insights into potential therapeutic targets for juvenile polyposis and related diseases.

: Image guided superficial radiation therapy (IGSRT) combines superficial radiation therapy (SRT) with full dermal visualization (FDV) via high resolution dermal ultrasound (HRDUS) for the treatment of non-melanoma skin cancer (NMSC). The gold standard for IGSRT delivery includes a comprehensive cancer care model with support for the dermatologists by a multidisciplinary team. When delivered in this model, IGSRT can achieve cure rates of 99% for treatment of NMSC. This paper focuses on the benefits of IGSRT during therapy. Medical records from 7 dermatology clinics of 883 patients with 1,507 cases of NMSC treated with IGSRT be-tween 2017 and 2018 were retrospectively reviewed. 92% of the NMSC lesions showed daily depth fluctuations, 60.32% of lesions did not require changes during therapy, and nearly 40% of lesions required at least one compensatory change during therapy. 83% of NMSC lesions were labeled high-risk based on the 2024 NCCN guidelines. Increasing and decreasing tumor depth measurements during IGSRT inform dermatologists when adaptive changes in energy (kV), TDF and dose will result in more efficacy and less toxicity, respectively.

This review aims to explore the intricate relationship between epigenetic mechanisms, stress, and affective disorders, focusing on how early life experiences and coping mechanisms contribute to susceptibility to mood disorders. Epigenetic factors play a crucial role in regulating gene expression without altering the DNA (deoxyribonucleic acid) sequence, and recent research has revealed associations between epigenetic changes and maladaptive responses to stress or psychiatric disorders. A scoping review of 33 studies employing the PRISMA-S (Preferred Reporting Items for Systematic Reviews and Meta-Analyses – Statement) guidelines investigates the role of stress-induced epigenetic mechanisms and coping strategies in affective disorders' occurrence, development, and progression. The analysis encompasses various stress factors, including childhood trauma, work-related stress, and dietary deficiencies, alongside epigenetic changes such as DNA methylation and altered gene expression. Findings indicate that specific stress-related genes frequently exhibit epigenetic changes associated with affective disorders. Moreover, the review examines coping mechanisms in patients with bipolar disorder and major depressive disorder, revealing mixed associations between coping strategies and symptom severity. While active coping is correlated with better outcomes, emotion-focused coping may exacerbate depressive or manic episodes. Overall, this review underscores the complex interplay between genetic predisposition, environmental stressors, coping mechanisms, and affective disorders. Understanding these interactions is essential for developing targeted interventions and personalized treatment strategies for individuals with mood disorders. However, further research is needed to elucidate specific genomic loci involved in affective disorders and the clinical implications of coping strategies in therapeutic settings.

Background/Objectives: In the efficacy of L-Prf on complications in lower impacted third molar surgery, it's not known which method increases the effect of L-Prf on postoperative complications when using primary and secondary closure methods with L-Prf. The aim of this study was to compare the effect of using L-PRF in patients undergoing impacted lower third molar surgery with either primary or secondary closure techniques. Methods: This prospective, randomised, double-blind, split-mouth clinical trial was conducted in patients with bilateral lower impacted third molars of similar position. The study had 2 groups. Primary closure was performed in group 1 and secondary closure in group 2. Group 1 closure technique was applied to one side of the patients and group 2 closure technique was applied to the other side at different times. A total of 45 patients were evaluated during the study period. 9 of these patients were excluded from the study due to alveolitis and failure to attend regular control visits. Results: Of the 36 patients included in the study, 23 were female and 13 were male and the mean age was 22.42±3.36 years. The secondary closure group had lower VAS scores at hour 6 (p<0.05). Pain decreased more in the primary closure group when comparing changes between the VAS scores at 6 hours and 7 days (p<0.05). Conclusions: The results of this study, showing that both secondary and primary closure are effective with similar outcomes in terms of pain, swelling and trismus, should be supported by future prospective clinical trials.

As the most serious of the many worse new pathological changes caused by diabetes, there are many risk factors for the occurrence and development of DR. It mainly includes hyperglycemia, hypertension, hyperlipidemia and so on. Among them, hyperglycemia is the most critical cause, which plays a key role in the pathological changes of DR.High-sucrose diets(HSDs) lead to elevated blood glucose levels in vivo, which, through oxidative stress, inflammation, the production of AGEs and VEGF, causes plenty of pathological damages to the retina and ultimately bring about loss of vision. The existing therapies for DR primarily target the terminal stage of the disease, when irreversible visual impairment has appeared. Therefore, early prevention is particularly critical. Early prevention of DR-related vision loss requires adjustments to dietary habits, mainly by reducing sugar intake. This article primarily discusses the risk factors, pathophysiological processes, and molecular mechanisms associated with the development of DR caused by HSDs. It aims to raise awareness of the crucial role of diet in the occurrence and progression of DR, promote timely changes in dietary habits, prevent vision loss, and improve the quality of life. The aim is to make people aware of the importance of diet in the occurrence and progression of DR. According to the dietary modification strategies we give, patients can change their poor eating habits timely, avoid the retinopathy that can be avoided theoretically, and obtain a excellent outcome.

The shortage of physicians in rural communities contributes to increased mortality rates among Medicare beneficiaries. This increase in mortality risk is commonly due to diseases such as heart disease and cancer, including melanoma and non-melanoma skin cancer (NMSC). Mohs micrographic surgery (MMS) is considered the gold-standard treatment for NMSC tumors, however, due to a shortage of dermatologists and Mohs surgeons in rural areas, access to MMS is limited. In these areas, image guided superficial radiation therapy (IGSRT) serves as a viable option for the treatment of NMSC lesions, with fewer recurrences and 99% cure rates, which are comparable to MMS cure rates. IGSRT is performed in dermatology clinics with support from a multidisciplinary team, including radiation therapists, medical physicists, radiation oncologists, and dermatologists. As IGSRT is able to be performed by general dermatologists, Medicare beneficiaries in rural communities will have an increase in access to treatment options and a decrease in delayed skin cancer treatment.

In this report we describe the case of a healthy, young, athletic woman who developed acute lymphoblastic leukaemia (ALL)/lymphoblastic lymphoma (LBL) after receiving the second dose of the Pfizer/BioNTech modified mRNA (modRNA) COVID-19 genetic vaccine (marketed as Comirnaty^®). The first dose of the genetic vaccine did not appear to illicit any noticeable side effects, but within 24 hours of the second dose the patient suffered widespread and intensifying bone pain, fever, vomiting, and general malaise. Due to the persistence of the symptoms, the patient underwent a series of tests and examinations including a full laboratory workup, a consult with a clinical immunologist and rheumatologist, a Positron Emission Tomography (PET) imaging, as well as an osteomedullary biopsy. These together led to a definitive diagnosis of ALL. A time interval of 16 weeks from the second vaccination to the diagnosis of cancer was noted. Several similar cases with identical pathology which developed after the modRNA COVID-19 vaccination, are described in case reports in the scientific literature. The massive and indiscriminate use of genetic vaccines to fight COVID-19 is raising serious concerns about their safety and about the technology platform as a whole for this purpose. Growing evidence is accumulating regarding the biodistribution and persistence of the modRNA which can reach, thanks to the lipid nanoparticles, a multitude of tissues and organs of the body, including the bone marrow and other blood-forming organs and tissues. Moreover, there is evidence that the modRNA vaccines display a particular tropism for the bone marrow, influencing the immune system at multiple levels and being able to trigger not only autoimmune-based pathologies, but also neoplastic mechanisms. The aim of this article is to assess, on the basis of the available scientific literature, the risk of developing haematopoietic cancers after modRNA vaccination, and to investigate the potential genetic mechanisms involved in the pathogenesis of disease.

Pulmonary hypertension (PH) is a progressive and potentially fatal complication of sickle cell disease (SCD) affecting 6-10% of adult SCD patients. Various mechanisms and theories have been evaluated to explain the pathophysiology of the disease. However, questions remain, particularly regarding the clinical heterogeneity of the disease in terms of symptoms, complications, and survival. Beyond the classical mechanisms that have been thoroughly investigated and include hemolysis, nitric oxide availability, endothelial disorders, thrombosis, and left heart failure, attention is focused nowadays on the potential role of the genes involved in such processes. Potential candidate genes are investigated through next-generation sequencing, with the TGF-β pathway being the initial target. This field of research may also provide novel targets for pharmacologic agents in the future as is already the case with idiopathic PH. The collection and processing of data and samples from multiple centers can yield safe results that will allow a better understanding of SCD-related PH as a part of the disease’s clinical spectrum. The following review attempts to capture the most recent findings of studies on gene polymorphisms that have been associated with PH in SCD patients.

Background: This study aimed to assess the impact of a nutrition-care bundle on growth and neurodevelopmental outcomes of micro-preterm infants born in a level III neonatal intensive care unit (NICU) by two years corrected age. Methods: A nutrition-care bundle emphasizing the prompt initiation of parenteral nutrition at birth, initiation of enteral feeds within 6 hours after birth, and early addition of human milk fortifiers was implemented in 2015 for infants born <26 weeks gestation. This before-and-after study evaluated growth and neurodevelopmental outcomes in infants born between 2012-2013 (before-nutrition-bundle BNB) and 2016-2017 (after-nutrition-bundle ANB). Results: A total of 145 infants were included in the study. Infants in the ANB group (n=73) were smaller (birthweight and gestational age), and there were more male infants and multiples included compared to the BNB group (n=72). Enteral feeds and fortifiers started earlier in the ANB group. Growth velocity and weight-z-score changes were similar in both groups during NICU stay and post-discharge. Systemic steroid use, but not cohort, was linked to lower Bayley scores across all domains. Conclusions: Implementing a nutrition-care bundle was not consistently associated with improved weight-gain and neurodevelopmental outcomes in the micro-preterm infant population, likely due to ongoing high-quality nutritional care by the clinical team.

Based on screening in computational biology and biological in vitro assays, five natural products isolated from extracts of the herbal medicine toad skin, such as cinobufagin (CBFi), bufalin (BFi), arenobufagin (ABFi), telocinobufagin (TBFi), bufotalin (BFTi), were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (PDB 6LU7 and 7BTF) and top-scoring ligand-receptor complexes were obtained. The results showed that the binding energy of ABFi to the 3CL protein was -17.044kcal/mol, which was higher than CBFi and TBFi. However, the binding energy of ABFi to the RdRp protease was -23.250 kcal/mol, which was much lower than that of CBFi and TBFi, EVEN lower than that of ABFi to the 3CL protein. ABFi also has polar interactions with amino acids such as Glu811, Ser814, Ser681 and Thr680 of RdRp enzyme. The results revealed that ABFi had a moderate inhibitory effect on the cell proliferation of SARS-CoV-2 in vitro, with an inhibition rate of 61.12%, even weaker than Remdesivir. This new discovery provides us with new ideas for in-depth studies on the development of natural products with this class of structural generalizations as inhibitors of SARS-CoV-2, and provides an experimental basis for the next step of mechanistic studies.

Objective: We report a case of acute pancytopenia and liver injury after concomitant administration of low-dose methotrexate (MTX), and high-dose esomeprazole and metamizole. Case summary: A 71-year-old patient with chronic systemic idiopathic erosive arthritis was admitted after a pelvic ring fracture. After hospital admission, she received MTX in addition to esomeprazole and metamizole. Subsequent laboratory tests revealed pancytopenia and elevated liver enzymes. The follow-up clinical examinations were unremarkable, with the exception of sub-febrile temperatures. Further investigations did not detect a definitive etiology. Due to the suspicion of methotrexate-induced hematotoxicity and hepatotoxicity, antagonizing therapy with calcium folinate was administered, after which the blood counts and liver parameters normalized. Discussion: Due to the administration of high-dose metamizole immediately before the administration of low-dose MTX, the pre-existing hematotoxic pharmacodynamic effect of MTX was acutely enhanced by that of metamizole, although folic acid was administered preemptively. In addition, the concomitant administration of high-dose esomeprazole and normal dose torasemide resulted in a pharmacokinetic interaction with MTX by decreasing its renal secretion and elimination, further enhancing the concentration-dependent hematotoxic and hepatotoxic side effects of MTX. Conclusions: The relatively high demand for analgesics in patients with chronic rheumatic diseases already being treated with MTX and proton pump inhibitors necessitates that clinicians consider drug-drug interactions as potential causes of adverse drug reactions after the administration of metamizole or nonsteroidal anti-inflammatory drugs. In this category of patients, it is strongly recommended to switch to analgesics of other classes.

Rheumatoid arthritis (RA) is a well-known autoimmune inflammatory disease that affects the diarthrodial joints. Inflammation increases the production of reactive oxygen species (ROS), which may explain why RA is one of the diseases that induce oxidative stress. This study aimed to evaluate potential differences in biochemical, hematological and oxidative stress markers in early stages of RA and after different treatment regimens. The study involved 111 patients, 28 men and 83 women, aged 34 to 59 years who were divided based on their c-reactive protein (CRP) levels into inactive RA patients (IRA) with CRP < 1.3 (n = 57, 22 men and 35 women) and active RA patients (ARA) with CRP ≥ 1.3 (n = 54, 6 men and 48 women). The study participants were divided into two groups, A and B, based on their treatment regimen. Group A, which comprised 90% IRA, received methotrexate (MTX) monotherapy. Group B, which comprised 90% ARA, received a combination of leflunomide, a conventional disease-modifying antirheumatic drug (DMARD), and a biologic DMARD. Hematological, biochemical, oxidative stress and RA-specific biomarkers were measured twice in groups A and B, in the early stage in the disease, before and 3 months post-treatment, using conventional colorimetric, fluorometric and immunological assays. According to the results of our study, glutathione peroxidase (GPx), ROS, calcium (Ca) and phosphorus (P) ions, vitamin C and D, and lipid profile could serve as potential diagnostic markers in the early stages of the disease. Both treatment options were equally effective in improving the overall health of the patients. However, treatment resulted in a further increase in ROS levels and a decrease in antioxidant markers.

Bladder cancer (BC) diagnosis is reliant on cystoscopy, an invasive procedure associated with urinary tract infections. This has sparked interest in identifying non-invasive biomarkers in body fluids such as blood and urine. A source of biomarkers in these biofluids are extracellular vesicles (EVs), nanosized vesicles that contain a wide array of molecular cargo, including small non-coding RNA such as microRNA and transfer RNA-derived fragments (tRF). Here we performed small-RNA next-generation sequencing for urine EVs, serum EVs and serum supernatant from 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. Serum and urine samples were collected before transurethral resection of bladder tumors (TUR-b) and at routine postsurgery check-ups. Expression levels of tRFs in presurgery samples were compared to those at postsurgery check-ups and to NCPs. To strengthen the reliability of our results, samples from 10 patients with stage T1 disease were resequenced. When comparing tRF expression in urine EVs between BC patients with stage T1 disease and NCPs, 14 differentially expressed tRFs (DEtRFs) were identified. In serum supernatant, six DEtRFs were identified among stage T1 patients when comparing presurgery to postsurgery samples, and four DEtRFs were found when comparing presurgery samples to NCPs. By performing a blast search, we found that sequences of DEtRFs aligned with genomic sequences pertaining to processes relevant to cancer development, such as enhancers, regulatory elements and CpG islands. Our findings display a number of tRFs that may hold potential as biomarkers for the diagnosis and recurrence-free survival of BC.

The KOSovan Acute Coronary Syndrome (KOS-ACS) Registry is established as a prospective, continuous, nationwide, web-based registry that is operated online. The KOS-ACS registry is designed with the following objectives: 1) to obtain data on the demographic, clinical, and laboratory characteristics of ACS patients treated in Kosovo; 2) to create a national database with information on health care in ACS patients treated in Kosovo; 3) to identify the national features of associations between ACS characteristics and clinical outcomes, including mortality, complications, length of hospital stay, and quality of clinical care; and 4) to propose a practical guide for improving the quality and efficiency of ACS treatment in Kosovo. The Kosovo Society of Cardiology and University of Prishtina will be responsible for the development of the KOS-ACS registry and centralized data analysis at the national level. The KOS-ACS Registry will enroll all patients admitted, at any of the registered clinical centers, with the diagnosis of ACS and who will be clinically managed at any of the Kosovo hospitals. Data on patient demographics, clinical characteristics, previous and hospital drug treatment, and reperfusion therapy will be collected. The type of ACS (Unstable angina, NSTEMI or STEMI) will also be clearly defined. The time from first medical contact to balloon inflation (FMC-to-balloon) and door-to-ballon time will be registered. In-hospital death and complications will be registered. Data on post-hospital primary outcome (MACE: cardiac death, all-cause mortality, hospitalization, stroke, need for coronary revascularization) of patients, at 30 days and 1 year, will be included in the Registry.

Background Apolipoprotein E (APOE) gene polymorphism has been implicated in the pathogenesis of various metabolic disorders, including type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a major public health concern worldwide, including in Pakistan. Cardiovascular problems linked with T2DM have a significant impact on people and society. The study's goal is to investigate the relationship between Apolipoprotein E (ApoE) genotypes, lipid profiles, and cardiovascular complications such as ischemic heart disease (IHD) and stroke. Methods: This study was carried out on 260 subjects, divided into control D1: Diabetics without cardiovascular issues. D2: Diabetics with heart disease. D3: Diabetics with stroke. D4: Diabetics with both heart disease and stroke. Anthropometric parameters (age, BMI) and risk factors (smoking, diabetes duration, hypertension) were assessed in all groups. Serum levels of TC, TG, LDL, HDL, VLDL, creatinine, BSF, and HbA1c were measured. Apolipoprotein E gene polymorphism was determined using PCR-RFLP. Results: Hypertension, BMI, and dyslipidemia, defined as elevated levels of total cholesterol, triglycerides, LDL, HDL, and VLDL, as well as uncontrolled hyperglycemia (elevated fasting blood sugar and glycated hemoglobin) in T2DM, were linked to vascular complications such as IHD and stroke. Hypertension was prevalent in 75.4% of the population, with greater rates among the elderly. Stage 2 hypertension was more prevalent in all age groups. Apolipoprotein E gene polymorphism was discovered, with genotypes 3/3, 4/4, 2/3, and 3/4 being the most prevalent. Genotype 3/4 was more common in diabetics who had IHD/stroke or both problems, whereas genotype 2/3 was linked to DM and stroke. Conclusion: It is concluded that BMI, hypertension, hyperglycemia, atherosclerosis, and dyslipidemia are linked with cardiovascular complications of type 2 diabetes. Apolipoprotein E gene polymorphism is associated with cardiovascular disease in diabetic patients by affecting the lipid profile.

The brown pelican (Pelecanus occidentalis) is a species often affected by natural and man-made disasters such as hurricanes and oil spills as well as general human activities; that subsequently receives medical care and rehabilitation. During rehabilitation, blood may be collected for various testing to help with diagnosis, treatment, and monitoring. Reference intervals for this species are limited, dated, and typically from small sample sizes. Seventy one presumed healthy brown pelicans were sampled as a part of their pre-release examination from rehabilitation at the Wildlife Center of Texas after a large volume stranding in December 2014 to January 2015, and various venous analytes were measured to establish updated reference intervals for Brown Pelicans. Fibrinogen was measured via heat precipitation and the Abaxis VSPro equine Fibrinogen cartridge to determine reference intervals, and in an attempt to validate the VSPro for use in avian species. Abaxis VS2 Avian/Reptile Chemistry panel, iSTAT CG4+, and iSTAT Chem8+ results in addition to body condition score, spun PCV, cloacal temperature and fibrinogen were measured. Proposed reference intervals for brown pelicans are presented. Fibrinogen results were not comparable between the gold standard method and the VSPro, indicating that the VSPro is not appropriate for use in brown pelicans.

Objective: The COVID-19 pandemic inferred on neuro-oncological patients (PTS) and the caregivers regarding tumor care and emotional functioning. This study aimed to understand how COVID-19 affects their psychological state and relations between PTS and health personnel in neuro-oncology. Methods: A cross-sectional study on neuro-oncological PTS and their caregivers. Results: A total of 162 PTS and 66 caregivers completed the questionnaire. The 37.5% of PTS perceived greater risk of contracting the COVID-19 compared to the general population. On the 0-10 scale, PTS tumor-related anxiety score was 5.8 and COVID-related 4.6. The caregivers reported 7.7 and 5.5 respectively. The QoL was described at least as good in 75% of both PTS and caregivers; the caregivers’ care burden increased in 22.7% during the pandemic, with no correlation with QoL. Future perception often changed both in PTS and in the caregivers. Cancer treatment schedule was changed in 18.5%, including for PTS decision. However, the 93.5% of PTS was satisfied with the overall care. Conclusion: A considerable proportion of PTS and caregivers still perceived the tumor disease as more burdensome than the pandemic, and perceived their future as more uncertain. Such data rinforce the need to build a proficient alliance between PTS and health personnel.

Abstract: Congenital cytomegalovirus (cCMV) infection poses significant risks to fetal development, particularly affecting the nervous system. This study reports a fetal autopsy case, examining cCMV infection and focusing on CMV DNA measurements in various fetal organs before formalin fixation, a novel approach for comprehensive CMV DNA evaluations in fetal organs affected by cCMV. A 20-week-old male fetus was diagnosed with cCMV following the detection of CMV DNA in ascites obtained via abdominocentesis in utero. After termination of pregnancy, multiple organs of the fetus, including the cerebrum, thyroid gland, heart, lungs, liver, spleen, kidneys, and adrenal glands, were extracted and examined for CMV DNA loads using real-time polymerase chain reaction. Histopathological examination involved hematoxylin-eosin and CMV-specific immunostaining. A correlation was found between CMV DNA loads and pathology, with higher CMV-infected cell numbers observed in organs positively identified with both staining methods, exhibiting CMV DNA levels of ≥1.0 × 104 copies/mL, compared to those detected solely by CMV-specific immunostaining, where CMV DNA levels ranged from 1.0 x 103 to 1.0 x 104 copies/mL. These results highlight a quantifiable relationship between organ infection extent and CMV DNA concentration, providing insights into cCMV pathogenesis and potentially informing future diagnostic and therapeutic strategies for cCMV infection.

Study of alterations in Osteoarthritis (OA) of Glypicans 1 to 6 (GPCs) and Notum in plasma, bone marrow mesenchymal stromal cells (BM-MSCs) and osteoblasts. Plasma levels of GPCs and Notum were measured of 25 patients and 24 healthy subjects. In addition, BM-MSCs from eight OA patients and eight healthy donors were cultured during 21 days with culture me-dium and osteogenic medium. Protein and gene expression levels of GPCs and Notum were de-termined by ELISA and qPCR at 0, 7 ,14 and 21 days. GPC5 and Notum have been found de-creased in OA patients’ plasma. OA BM-MSCs showed downexpression of GPC6 and upregula-tion of Notum. A decrease in GPC5 and Notum proteins and an increase in GPC3 were found. During osteogenic differentiation, elevated GPC2, 4, 5, 6 and Notum mRNA levels and decreased GPC3 were observed in OA. Furthermore, the protein levels of GPC2, GPC5 and Notum de-creased and GPC3 increased. Glypicans and Notum are altered in BM-MSCs and during osteo-genic differentiation from patients with OA. Furthermore, GPC5 and Notum can be proposed as new biomarkers of the pathology. The alterations found indicate that Notum could be a prom-ising therapeutic strategy for Osteoarthritis.

Certain micronutrients exhibit immunomodulatory effects. However, no intervention has yet investigated the effect of an individualized supplementation on the severity of upper respiratory tract infections (URI). Therefore, we investigated whether a personalized supplementation moderates the incidence and severity of URI. Selenium, zinc, and vitamin D was measured from 59 healthy participants ) in dried blood spots. Accordingly, a personalized supplement was provided with or without the respective micronutrients. We used WURSS-21 questionnaires to assess the disease status. The blood values converged during the intervention and micronutrients no longer differed at the end of the intervention period between treated and untreated volunteers. The incidence and severity of the illness did not significantly differ between the groups. However, when analyzing the WURSS-21 score by the intention to treat, the initially randomized treatment arm revealed a significantly higher score than the placebo arm. Upon acute administration, individualized combination of selenium, zinc and vitamin D does not reduce the number or contribute to a milder course of URIs. Therefore, supplementation in acute infectious situations seems questionable. Further studies must address the habitual diet in more detail to better understand the impact of individual micronutrient status on the prevention of URI.

(1) Background: Globally, about 600 million people are afflicted with diabetes, and one of its most prevalent complications is neuropathy, a debilitating condition. At present, the exploration of novel therapies for alleviating diabetic neuropathy-associated pain is genuinely captivating, considering that current therapeutic options are characterized by poor efficacy and significant risk of side effects. In the current research, we evaluated the antihyperalgesic effect of sildenafil (phosphodiesterase-5 inhibitor) – metformin (antihyperglycemic agent) combination and its impact on biochemical markers in alloxan-induced diabetic neuropathy in rats; (2) Methods: The study comprised a cohort of 70 diabetic rats and 10 non-diabetic rats which were submitted to hot, cold, and tactile stimulus tests. Morover, we investigated the influence of this combination on TNF-α, IL-6 nitrites and thiols levels in brain and liver tissues; (3) Results: The results demonstrated that all sildenafil-metformin combinations decreased the pain sensitivity in von Frey test, Hot-plate test and Cold-plate test. Furthermore, alterations in nitrites and thiols concentrations and pro-inflammatory cytokines (specifically TNF-α and IL-6) were noted following a 15-day regimen of various sildenafil-metformin combinations. (4) Conclusions: The combination of sildenafil and metformin has a synergistic effect in alleviating pain in alloxan-induced diabetic neuropathy rats. Additionally, the combination effectively decreased inflammation, inhibited the rise in NOS activity, and provided protection against glutathione depletion.

The vast majority of antibodies generated against a virus will be non-neutralising1. However, this does not denote an absence of protective capacity. Yet, within the field there is typically a large focus on antibodies capable of directly blocking infection (neutralising antibodies, nAbs) of either specific viral strains or multiple viral strains (broadly-neutralising antibodies, bnAbs). More recently, a focus on non-neutralising antibodies (nnAbs), or neutralisation-independent effects of nAbs, has emerged. These can have additive effects on protection or in some cases, be a major correlate of protection. As their name suggests, nnAbs do not directly neutralise infection but instead, through their Fc domains, may mediate interaction with other immune effectors to induce clearance of viral particles or virally infected cells. nnAbs may also interrupt viral replication within infected cells. Developing technologies of antibody modification and functionalisation may lead to innovative biologics that harness the activities of nnAbs for antiviral prophylaxis and therapeutics. In this review, we discuss specific examples of nnAb actions in viral infections where they have known importance. We also discuss the potential detrimental effects of such responses. Finally, we explore new technologies for nnAb functionalisation to increase efficacy or introduce favourable characteristics for their therapeutic applications.

This study aimed to introduce a novel machine learning (ML) model designed to predict the need of interventions during endoscopy in patients with upper gastrointestinal bleeding (UGIB). The risk stratification tools in current use, such as the Glasgow Blatchford Score (GBS) and pre-endoscopic Rockall score, have limitations in accurately predicting the need for endoscopic interventions. All patients diagnosed with UGIB from January 2013 to October 2023 who underwent endoscopy were included in the study. Variables extracted included demographics, social history ,clinical history, clinical presentation and symptoms, drug history, management prior to endoscopy, findings during endoscopy, laboratory variables and vitals, and post-endoscopic results. Three machine learning models including Random Forest Classifier (RFC), Gradient Boosting Classifier (GBC), and AdaBoost Classifier were used to evaluate the need for intervention during endoscopy in our study. A total of 1372 patients were included from three major hospitals in Jordan, of whom 242 underwent endoscopic intervention. The GBC outperformed all other models and pre-endoscopic scores in predicting the need for endoscopic intervention with an area under the curve of 0.861. Findings during endoscopy, platelet count, pulse rate and systolic blood pressure during admission were the most contributing features in predicting the need for the need of endoscopic intervention. This study highlights the potential of machine learning models in enhancing decision making for UGIB management.

We conducted a pilot study to analyze the differential methylation status of 20 primary acinar adenocarcinomas of the lungs. These adenocarcinomas had to be wild type in mutation analysis and had either high (TPS>50%; n=10) or low (TPS<1%; n=10) PD-L1 status to be integrated into our study. To examine the methylation of 866,895 specific sites, we utilized the Illumina Infinium EPIC bead chip array. Both hypermethylation and hypomethylation play significant roles in tumor development, progression, and metastasis. They also impact the formation of the tumor microenvironment, which plays a decisive role in tumor differentiation, epigenetics, dissemination, and immune evasion. The gained methylation patterns were correlated with PD-L1 expression. Our analysis has identified distinct methylation patterns in lung adenocarcinomas with high and low PD-L1 expression. After analyzing the correlation between methylation results of genes and promoters with their pathobiology, we found that tumors with high expression of PD-L1 tend to exhibit oncogenic effects through hypermethylation. On the other hand, tumors with low PD-L1 expression show loss of their suppressor functions through hypomethylation. The suppressor functions of hypermethylated genes and promoters are ineffective compared to simultaneously activated dominant oncogenic mechanisms. The tumor microenvironment supports tumor growth in both groups.

Obstructive sleep apnea (OSA) may be linked to various factors that narrow the upper airways, such as obesity, adenotonsillar hypertrophy and craniofacial abnormalities. Hypothyroidism has also been described as a risk factor for OSA. However, the implication of goiter independently of thyroid function in the occurrence of OSA remains unclear. We present the case of a 66-year-old patient, with a large compressive multinodular goiter for whom total thyroidectomy was indicated. During the preoperative assessment, the patient showed a body mass index (BMI) of 37.8 kg/m2 with symptoms of OSA. Respiratory polygraphy confirmed the diagnosis of severe OSA (apnea hypopnea index: AHI=32) and treatment with continuous positive airway pressure (CPAP) was initiated prior to thyroid surgery. Surprisingly, after total thyroidectomy, OSA symptoms disappeared and the patient abandoned CPAP therapy. Subsequent respiratory polygraphy after thyroidectomy showed a decrease in AHI to a normal value (AHI < 5). Interestingly, there was no change in BMI or other factors explaining the resolution of OSA, except for thyroidectomy. This case report suggests that goiter can be considered a risk factor for OSA. However, prospective studies are needed to accurately assess the effects of goiter on occurrence of OSA according to its dimensions and local extension.

Abstract: The Willows, belonging to the genus Salix, encompass a vast array of species and hybrids, totaling between 330 to 500 species along with approximately 200 hybrids. These plants are found across continents such as Africa, North America, Europe, and Asia, exhibiting diverse forms ranging from trees to shrubs and prostrate plants. Traditionally, Willows have been utilized in folk medicine due to their rich reservoir of biologically active compounds, with salicin being a notable example, serving as a prodrug for salicylic acid.The chemical composition of Willows is highly diverse, with 322 secondary metabolites identified thus far. These include various classes such as flavonoids (94 types encompassing flavonols, flavones, flavanones, isoflavones, flavan-3-ols like catechins and procyanidins, chalcones, dihydrochalcone, anthocyanins, and dihydroflavonols), phenolic glycosides (76), organic acids (28), non-phenolic glycosides (17), sterols, and terpenes (17), simple phenolics (13), lignans (7), as well as volatiles and fatty acids (69). This rich chemical di-versity underpins the various pharmacological activities exhibited by Willows. The pharmacological properties attributed to Willows are extensive and include analgesic, an-ti-inflammatory, antioxidant, anticancer, cytotoxic, antidiabetic, antimicrobial, antiobesity, neuroprotective, and hepatoprotective effects. These properties make Willows a subject of con-siderable interest in the fields of medicine and pharmacology. In summary, Willows represent a valuable natural resource with a diverse chemical composition and a wide range of pharmacological activities. This study aimed to enhance our comprehension of the medicinal characteristics of willow bark extract, focusing on its antimicrobial properties. This investigation holds significance in validating the traditional usage of willow bark and investi-gating its potential utility in contemporary medicine.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI) resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in fetal programming of the hypothalamus-pituitary-adrenal (HPA) axis, leading to adverse fetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on fetal HPA axis function and postnatal offspring development, hence this study. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone were measured in all dams and pups. Glucose tolerance and expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase in pups ACTH and corticosterone concentrations, impaired glucose tolerance and dysregulated MR and GR expression in the PD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Chikungunya virus (CHIKV), a single-stranded RNA virus transmitted by Aedes mosquitoes, poses a significant global health threat, with severe complications observed in vulnerable populations. The only licensed vaccine, IXCHIQ, approved by the USFDA, is insufficient to address the growing disease burden, particularly in endemic regions lacking herd immunity. Monoclonal antibodies (mAbs), explicitly targeting structural proteins E1/E2, demonstrate promise in passive transfer studies, with mouse and human-derived mAbs showing protective efficacy. The article explores various vaccine candidates, including live attenuated, killed, nucleic-acid-based (DNA/RNA), virus-like particle, chimeric, subunit, and adenovirus vectored vaccines. RNA vaccines emerge as promising candidates due to their rapid response capabilities and enhanced safety profile. The review underscores the importance of E1 and E2 proteins as immunogens, emphasising their antigenic potential. Several vaccine candidates, such as CHIKV/IRES, measles vector (MV-CHIK), synthetic DNA-encoded antibodies, and mRNA-lipid nanoparticle vaccines, demonstrate encouraging preclinical and clinical study results. In addition to identifying potential molecular targets for antiviral therapy, the study looks into the roles played by Toll-like receptors, RIG-I, and NOD-like receptors in the immune response to CHIKV. It also offers insights into novel tactics and promising vaccine candidates.

We describe an interesting case report about a patient with hemophilia A with severe chronic elbow arthropathy who underwent multiple surgical because of his condition. We collected all the clinical and imaging findings, and we compared the decision-making flow chart and the surgery performed with the most recent indications, treatments and complications reported in the literature. The aim of this case report is to show how usually the hemophilic patient even if young usually comes to our attention from the beginning with complex and advance musculoskeletal disease. Elbow hemophilic arthropathy is a complex disease and the management in these patients could be more difficult than others because of the higher risk of complications rate after all surgical procedures, for this reason it’s very important to treat these patients in hub centers with expertise in well-coordinated multidisciplinary teams. The path from diagnosis to surgical treatment of hemophilic elbow arthropathy can be a risky one, as it happened in this case.

Due to bacterial contamination, natural medicinal preservatives may be an alternative to enhance the quality of milk. Besides, thorough biocompatibility testing is deemed essential before integrating natural extracts into food products. To address this matter, our research focused on evaluating the antimicrobial potential of Plectranthus amboinicus, Flueggea leucopyrus, Cymbopogon citratus, and Bacopa monnieri against prevalent foodborne pathogens, including Staphylococcus aureus, Escherichia coli, Salmonella spp, and Pseudomonas aeruginosa and investigating the efficacy of plant extracts as natural preservatives along with biocompatibility and toxicity assessments. The methanolic extracts of plant materials were used for measuring antimicrobial activity using the agar well diffusion method, Minimum Inhibitory Concentration (MIC) and Minimum bactericidal concentration (MBC) assays. The preservative activity was tested by isolating pathogenic organisms in a sterilized milk medium and toxicity and biocompatibility was assessed using zebrafish embryo and brine shrimp lethality assays. At a concentration of 400 mg/ml, all plant extracts demonstrated notable activity against bacterial strains. B. monnieri at 400 mg/ml exhibited particularly significant effects on S. aureus (30.3 mm ± 0.6), surpassing the positive control, gentamicin (28.3 mm ± 0.6), while also displaying pronounced activity against E. coli. F. leucopyrus, at the same concentration, showed antimicrobial activity comparable to the positive control against both S. aureus (28.0 mm ± 1.0) and E. coli (27.0 mm ± 1.0). However, as there’s weak-mild toxicity in these herbs, prior to consumption, careful consideration of their toxicity and biocompatibility is imperative for ensuring their safe use.

The term `motor control´ encompasses a wide range of mechanisms thought to be implicated in the organization of movements. Their study, like that of any other scientific field, must use specific notions to get to grips with them. This review is therefore organized along a series of notions that are frequently used in motor control, and we will discuss them with particular emphasis on neurological conditions, which may disrupt normal motor functioning. We will start with a short description of the roles of space and time, in which movements take place. Subsequently we will deal with kinematics and kinetics (dynamics) of movements. Then, we will list the inputs to motoneurons (MNs), which, in different forms, convey signals from the central nervous system (CNS) to skeletal muscles and muscle spindles, including central pattern generators (CPGs), sensory inputs and supraspinal descending fiber systems. Some helpers in movement organization will be introduced, such as internal models and neuronal network models. A relatively brief section on sensory-motor learning will follow because learning abilities are required to endow the sensory-motor system with flexibility and adaptability. The major emphasis is placed on neurological processes, which result from genetic modifications, autoimmune diseases, neurodegenerative diseases, infections in the nervous system as well as vascular and traumatic lesions. These neurological diseases lead to a variety of impairments and symptoms, particularly movement derangements including cerebellar ataxia, spasticity, and (other) movement disorders such as Parkinson’s syndromes. The conclusion is that there is no unique top controller that controls ´motor control`.

Dipeptidyl peptidase 9 (DPP9) is a multifunctional intracellular protease with roles in tumour growth, inflammation and mitochondrial function. We developed a hepatocyte-specific DPP9 knockout mouse (DPP9-KO) to explore DPP9 in a mouse model of hepatocellular carcinoma (HCC). DPP9-KO mice were generated by crossing Albumin-Cre mice (Wt/Wt Cre+/+) with DPP9 floxed mice (Fl/Fl Cre-/-). Mice were treated with Diethylnitrosamine and Thioacetamide then an atherogenic High Fat Diet until 28 weeks of age. DPP9-KO mice had reduced liver and subcuta-neous adipose tissue mass and lower fasting plasma glucose, fewer small macroscopic liver nod-ules compared to DPP9-WT mice. However, there were no differences in the total number of mac-roscopic liver nodules, tumour burden, inflammation score and steatosis score. Consistent with the known ability of DPP9 to suppress NLRP1 activation, activated caspase-1 protein was ele-vated in DPP9-KO mouse liver. Additionally, Nfkbib, Cxcl10 and Ccl5 mRNA and protein levels of autophagy marker beclin1 and tumour suppressor p53 were increased. In conclusion, DPP9 de-pletion in hepatocytes may reduce liver cancer initiation, via mechanisms that may include in-creased autophagy and innate tumour suppression in this experimental model. Finally, the data supports DPP9 having a role in glucose regulation by the liver.

Abstract: Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset hyperinsulinemic hypoglycemia caused by ABCC8 gene mutations. In the first patients, which presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330- 1)del] correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C&gt;T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) PET/CT was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance and of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.

Background: Spinal schwannomas and meningiomas are the most common spinal cord benign tumors in adults and total excision is the goal of the treatment. The traditional surgical approach is performed by total laminectomy, but recently unilateral hemilaminectomy has been recognized as a valuable surgical alternative. We report the clinical results of patients affected by spinal schwannoma and meningioma in whom total laminectomy or unilateral hemilaminectomy were performed. Material and Methods: A retrospective study of patients who underwent resection of spinal meningioma or schwannoma by laminectomy or unilateral hemilaminectomy approaches in our Institute from January 2013 to January 2023 was made. The baseline data of these patients, operative approach and postoperative outcome were compared. Results: The study was performed on 41 patients with mean age of 62.5 ±14.6 years. Our series included 24 (59%) cases of schwannomas and 17 (41%) cases of meningiomas, with a prevalent location in the thoracic spine. The average schwannomas volume was 3,6 ±2,7 cm3, whereas the average meningiomas volume was 1.1 ±0.5 cm3. Total excision was achieved in all cases. Operative time of schwannomas was longer (p=0.001) respect to meningiomas with higher intra-operative blood loss (p=0.000). Total laminectomy approach was performed in 24 out of 41 patients (59%) and unilateral hemilaminectomy approach in 17 out of 41 (41%) patients. Unilateral hemilaminectomy was associated with shorter postoperative bed rest (p=0.003), shorter hospitalization (p=0.028) and lower postoperative pain (p=0.02) respect to total laminectomy. Conclusions: Both spinal schwannomas and spinal meningiomas in various size can be safely and effectively treated with unilateral hemilaminectomy approach. This approach grants more advantages compared with standard total laminectomy, including shorter postoperative bed rest, shorter hospitalization and reduced postoperative pain.

Gestational diabetes mellitus (GDM) is a hyperglycemia state that is typically diagnosed by an oral glucose tolerance test (OGTT), which is unpleasant, time-consuming, poorly reproducible, and tardy. The machine learning (ML) predictive models that have been proposed to improve GDM diagnosis are usually based on instrumental methods that take hours to get a result. Near-infrared (NIR) spectroscopy, a simple, fast and low-cost analytical technique has never been assessed for the prediction of GDM. This study aims to develop ML predictive models for GDM based on NIR spectroscopy, and to evaluate their potential as early detection or alternative screening tools according to their predictive power and time of analysis. Serum samples from the first (before GDM diagnosis) and the second (at the time of GDM diagnosis) trimester of pregnancy were analyzed by NIR spectroscopy. Four spectral ranges were considered, and 80 pretreatments were tested for each. NIR data-based models were built with single- and multi-block ML techniques. Every model was subjected to double cross-validation. The best first and second trimester models got areas under the receiver operating characteristic curve of 0.5768 ± 0.0635 and 0.8836 ± 0.0259, respectively. This is the first study reporting NIR spectroscopy-based methods for the prediction of GDM. The developed methods allow to predict GDM from 10 µL of serum in only 32 minutes. They are simple and fast, and have a great potential to be applied in clinical practice, especially as alternative screening tools to the OGTT at the time of GDM diagnosis.

Differential diagnosis of solid pancreatic lesions (SPLs) using B-mode endoscopic ultrasonography (EUS) is challenging. Detective flow imaging (DFI) offers the potential for detecting low-flow vessels in the pancreas, thus enhancing diagnostic accuracy. This study aimed to investigate DFI-EUS findings of SPLs and analyze their differential diagnostic accuracy for pancreatic cancer. This retrospective study included patients with pathologically confirmed SPLs who underwent EUS between April 2021 and June 2023. Expert endosonographers, blinded to the patients’ clinical data, evaluated images obtained through B-mode, eFLOW, and DFI-EUS. Frame rate and vessel detection sensitivity between eFLOW and DFI were compared, and diagnostic criteria for pancreatic cancer were established. This study included 104 patients, most diagnosed with pancreatic cancer. DFI-EUS demonstrated a significantly higher vessel visualization rate (96%) in SPLs compared to eFLOW (27%). Additionally, DFI showed a superior frame rate, sensitivity (99%), and accuracy (88%) in detecting pancreatic cancer, although with a modest specificity (43%). On DFI-EUS, characteristics such as hypovascular, peritumoral, or spotty vessel findings were suggestive of pancreatic cancer. DFI-EUS significantly improved the visualization of vascular structures within the SPLs, highlighting its efficacy as a diagnostic modality for pancreatic cancer.

Introduction Urolithiasis, a prevalent urological condition (8-13% globally) exhibits regional variations, influenced by water quality, climate, health factors and diet. Sri Lanka with its tropical climate and dietary patterns is part of the "Stone Belt" of Asia. This study in Northern Sri Lanka examines urinary stone compositions and assesses the prevalence of metabolic disorders among urolithiasis patients. Methods This prospective cross-sectional study, conducted at tertiary urology centre from July 2022 to June 2023, focused on surgically treated urolithiasis patients. Institutional ethical clearance was obtained. Patient details and investigational findings were collected through questionnaires and data extraction forms. Stone analysis utilized Fourier transform infrared spectroscopy and detailed metabolic evaluation of 24 hour urine collection sample is carried out. Results This study followed 153 surgically treated urolithiasis patients, primarily male (64.3%), mean age 48.64. Ureteric colic (48.4%) was common, with kidney stones (45.8%) prevalent; 57.52% had recurrent stones. Diabetes mellitus (DM=23.5%) was the top comorbidity. Calcium oxalate monohydrate (COM) stones (78.4%) were most frequent, followed by uric acid (12.4%). COM predominated in 40-59 age group. No significant gender-stone type association. 86.9% had metabolic abnormalities, notably hypocitraturia (60.1%). 23% had both hypocitraturia and hypomagnesuria. Some metabolic disorders showed gender differences, with a marginal age-metabolic disorders association (p < 0.061). Urine oxalate levels were normal with higher variability in males. Conclusion Middle-aged males with urolithiasis commonly presented with ureteric colic and predominantly had calcium oxalate monohydrate stones. Recurrent stones were common, often accompanied by metabolic abnormalities such as hypocitraturia and hypomagnesuria, with diabetes mellitus as the primary comorbidity.

Xinjiang, as a climate-sensitive region in northwest China, holds significant importance in studying extreme weather events for agricultural production and socioeconomic development. Based on data from 52 meteorological stations and 23 extreme climate indicators in Xinjiang from 1960 to 2021, the 5a moving average, linear trend estimation, climate tendency rate, and GIS spatial analysis methods are used to analyze the distribution and change characteristics of extreme climate. The results revealed that from 1960 to 2021, TXx, TNx, TXn, TNn, FD, ID, TN10p, TX10p, and WSDI showed a significant upward trend, while SU, TR, TN90p, TX90p, and CSDI showed a significant downward trend. What is more, the range of changes in the extreme temperature indexes from 1990 to 2021 is higher than that of 1960 to 1989. The high-value areas of extreme indexes are primarily concentrated in the northern part, while the high-value areas of cold event indexes are mainly distributed in the southern part. The upward/downward trends all accounting for over 80.00% of the entire region. The Rx1day, Rx5day, PRCPTOT, R95p, R99p, R10, R20, and R25 showed a significant growth trend from 1960 to 2021, and the range of change in the extreme precipitation indexes from 1990 to 2021 was lower than that from 1960 to 1989. Moreover, their high-value areas and high climate tendency areas are mainly concentrated in the northern and western parts of Xinjiang, with upward trends all accounting for over 71.00% of the entire region. The research results provide theoretical foundations for formulating climate risk strategies in the northwest region of China.

Introduction: Parameters used for neonatal mortality calculation vary among publications. Mortality in < 33 weeks gestational age at birth display global variations across different healthcare units. Objective: This study aims to explore trends in neonatal mortality among infants born preterm in the different units in Latin America and the Caribbean utilizing the EpicLatino Network Database in comparison to Canadian Neonatal Network (CNN) 2022. Materials and Methods: This study focused on an eight-year period, with a particular attention to mortality rates during the pre-pandemic (2015-2019) and pandemic/post pandemic (2020-2022) periods. Survival rates from CNN 2022 were included in the comparison analysis. Logistic regression analysis was confined to the 2020-2022 period. Adjustments were made for factors including gestational age, small for gestational age (SGA), Snape II score, inborn/outborn status, and center. As major malformations could account for mortality differences among units. The incidence of major congenital malformations, as defined by CNN, was compared among deceased patients. Results: A total of 15,454 records from 2015-2019 and 10,711 records from 2020-2022 were scrutinized. Overall, there were no significant differences in mortality rates between the two time periods (p=0.22). Moreover, the originating unit during the 2020-2022 period significantly influenced all statistical computations. Conclusions: Survival rates among infants < 26 weeks of gestation in Latin America and the Caribbean are on an upward trajectory, with the healthcare unit playing a pivotal role in this outcome within the EpicLatino database. Major malformations do not seem to be a significant contributing factor. These findings underscore the imperative of implementing quality improvement initiatives to elevate neonatal care standards in Latin America and the Caribbean.

Mosquitoes are a family of the order Diptera, which includes more than 3500 species. Two groups able to suck human blood and transmit diseases: the anophelines and the culicines comprise several genera such as Culex, Aedes and Aedes communis (Ac). Previous study has demonstrated a significant relationship between Ac sensitization and either extract or single bee venom components suggesting a “bee-mosquito syndrome” occurrence. It is well known that CCD can interference with the measurement of quantitative IgE results. Hence, it has been hypnotized that the presence of sIgE to CCD could have a role in the Bee-Mosquito syndrome. Method Serum from 21 different Mosquito and Ape melifera allergic individuals were combined with extracts of Mosquito (in house) and Apis melifera. SDS-PAGE and Immunoblot (IB) were carried out without and with with CCD-Inhibitor. Results The data would suggest IgE binding to common bands between Culex male, Culex female and Aedes species mosquitos of approximate molecular weight ~21kDa, ~35kDa, ~40kDa and ~55kDa. Whilst IgE binding has been observed to protein bands from the Apis melifera extract, these bands do not align with any present in the mosquito extracts. The use of a CCD-Inhibitor results in differences in IgE binding. Specifically, bands that were previously observed in the Apis melifera venom sample without use of CCD-Inhibitor at 40kDa and 90kDa are no longer observed when CCD-Inhibitor is used. Two bands of the Apis melifera venom remain present between 15-20kDa. No major differences in banding pattern were observed for the mosquito samples with or without CCD-Inhibitor, although the blot appears cleaner with less background when CCD-Inhibitor is used. Conclusion Further experiments have to be done to determine whether the reactive bands from Apis melifera are unrelated proteins or whether the proteins are related homologues of varying molecular weight.

Introduction the outbreak of the Israel-Gaza conflict, initiated by a major attack on the civilian population in Israel provided a tragic opportunity to study the community wide association between severe emotional stressors related to acts of war and the incidence and clinical characteristics of Takotsubo cardiomyopathy (TCM) in this scenario. Methods Eight consecutive cases of TCM diagnosed during the first 50 days of the Israel-Gaza conflict were retrospectively collected from two southern medical centers who provided care to most of the war victims throughout the period of monitoring. The medical records were thoroughly reviewed and analyzed. Results During the monitoring period, the incidence of TCM increased substantially compared to the control period. Eight patients were included in the analysis. All patients were female and 100% of patients presented within the first 3 weeks of conflict whereas after this initial phase, despite the continuing war, the incidence of TCM reverted to pre-conflict levels. Two patients (25%) were under 50 years of age. All patients had hazardous clinical characteristics including severe left ventricular (LV) dysfunction (≤35%) and prolonged QTc interval (>500 ms). Five patients (62.5%) experienced complications. Nevertheless, no in-hospital mortality was reported. Conclusions Repeated exposure to severe emotional stress, on both personal and national level, due to mass crisis such as war is associated with an increased incidence of TCM potentially with high-risk phenotype in comparison to TCM following other, less potent, psychological insults.

Background: With its impressive natural language processing and comprehension skills, ChatGPT-4 (Chat Generative Pre-Trained Transformer) is a technology that shows great promise for use in a number of medical fields. This article provides a thorough description of the possible uses of OpenAI's state-of-the-art language model, ChatGPT-4, in musculoskeletal imaging. Purpose for review: MSK Radiologists need to evolve about their knowledge and understanding of the roles of ChatGPT and its implications in daily practice. We aim to emphasize the advantages of ChatGPT-4 on the musculoskeletal imaging field and its potential to enhance radiologist working checklist review items, and the overall productivity of radiology reports. Recent findings: The fact of that specialists in radiology, rheumatology, orthopedic surgery, and other fields are conversant with ChatGPT. Furthermore, opinions are generally well, despite the fact that many people have reservations about the new technology, which is still developing ^[1]. Compared to GPT-4V based ChatGPT, GPT-4 based ChatGPT showed noticeably better diagnostic accuracy. Although ChatGPT, which is based on GPT-4, performed diagnostically on par with radiology residents, however, it demonstrated lower performance than a musculoskeletal radiologist ^[2].

Cancer being a multi-factorial disease, a multi-target approach is needed to treat it with minimal side-effects. Therefore, combined use of a proven herbal formula with chemo-therapy could be the better therapeutic. It may maintain homeostasis by synergistically targeting multiple signaling pathways involved in tumorigenesis, thus circumventing recurrence, resistance, and immunosuppression. Here we aim to determine the effectiveness and safety of an FDA-approved herbal formula, SR033 in combination with 5-fluorouracil (5FU) and paclitaxel (PTX). We report chemo-sensitization and chemo-synergy in HeLa and MCF-7 cell lines, immunomodulation of COX-2, PD-L1, VEGF and TGFβ and overall survival in-vitro and in-vivo via oral and topical delivery of SR033. In-vitro, SR033/5FU significantly reverses 5FU and PTX-resistance, lower COX-2, and PD-L1, resulting in TGFβ/ VEGF axis modulation. Furthermore, the study suggests that due to anti-oxidative potential of SR033, oral administration exerts chemo-preventive activity and restores cellular compartment in solid tumor and ascites-bearing mice models. Furthermore, the topical application, SR033L with low-dose 5FU increases survival rate, reduces tumor growth, and completely restores local and peripheral neutrophil-lymphocyte ratio in solid tumor mice model. The study indicates that SR033 could be a strong candidate in combination with low-dose 5FU and PTX for a holistic approach to cancer management.

Background and Objectives: The healing of bone defects is a serious challenge worldwide. One branch of dentistry deals with bone defects. capsaicin has anti-inflammatory, anti-oxidative and cholesterol-reducing effects. The aim of this study is to evaluate the effects of systemic capsaicin administered at different doses on bone healing. Materials and Methods: A total of 32 male wistar rats was used, their weight varying between 250 and 300 g. The rats were randomly divided into four groups of eight rats each. The analyses served to evaluate the effect on healing of different doses of capsaicin and grafts. A significant increase was observed in the number of osteoblasts in the capsaicin-applied groups compared to the control group. Conclusions: As a result of the analyses, positive effects on bone healing were observed when capsaicin 0.25 mg/kg and 0.50 mg/kg was administered intraperitoneally. However, more studies are needed for more accurate information.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

Abstract For the past 70 years, dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling, antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there was limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal, senescence, brain volume loss, attenuation of gamma oscillations on electroencephalogram and oxidation of lipids in plasma and mitochondrial membranes. We surmise that aberrant activation of aryl hydrocarbon receptor by toxins derived from the gut microbes or the environment drives premature cellular, including neuronal, senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: 1. To summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders. 2. To discuss novel strategies for improving long-term outcome in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor.

Introduction: Anterior Lumbar Interbody Fusion (ALIF) and Posterior Spinal Fusion (PSF) play pivotal roles in restoring lumbar lordosis in spinal surgery. Debates persist between combined single-position surgery and traditional prone-position PSF for optimizing segmental lumbar lordosis. Research Question: The study investigates the impact of performing ALIF in the supine position followed by PSF in the prone position on segmental lumbar lordosis. Material and Methods: A cohort of 59 patients underwent ALIF and PSF at a single institution. Preoperative, post-ALIF supine, and post-PSF prone Cobb angles were assessed using x-ray imaging. Statistical analyses, including one-way repeated measures ANOVA and Post-hoc analyses with Bonferroni adjustment, were employed for mean comparisons within subjects. Results: The mean Cobb angle for the entire cohort showed significant variations over different time points (p).

The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and potently attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine secretion, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals.

Abstract: Purpose: High-grade isthmic spondylolisthesis (HGISL) is a severe condition, associated with low-back pain (LBP) and radiculopathies. The present study is a monocentric prospective observational study investigating the clinical-radiological outcomes of a bilateral minimally invasive TLIF (bm-TLIF) for HGISL. Material and Methods: Patients who underwent bm- TLIF for HGISL at our institution, were considered for inclusion. Clinical-radiological outcomes and complications were collected. Results: Twenty-one patients (14M:7F) were included and the mean clinical follow-up (FU) time was 27(±6) months. There was a significative improvement of the mean VAS-back, VAS-legs, ODI, and SF-36 PCS scores, comparing pre- and last FU measurements. The mean pelvic tilt (p0,05). The univariate analysis showed that residual slip angle (> or  10°) may independently influence VAS-b (p

Background/Aim: Baricitinib (BAR) is the first oral selective Janus kinase inhibitor approved in Europe for rheumatoid arthritis (RA). Real-world data are still needed to clarify its long-term benefit/risk profile. This study aimed to evaluate the effectiveness, persistence, adherence, and safety of BAR in a real-world setting. Methods: An ambispective study was conducted between October 2017 and December 2021 in RA patients starting BAR. Effectiveness was evaluated by change from baseline in the Disease Activity Score using 28-joint counts-C reactive protein (DAS28CRP), and achievement of low disease activity/remission. Drug persistence was evaluated by Kaplan-Meier analysis. Adherence was estimated by medication possession ratio (MPR) and the 5-item Compliance Questionnaire for Rheumatology. Safety was assessed by global incidence proportion and adjusted incidence rates of adverse events. Results: 61/64 recruited patients were finally analyzed, 83.6% female, 78.7% seropositive, mean age of 58.1 (15.4) years, and disease duration of 13.9 (8.3) years. 32.8% were naïve to biologics and 16.4% received BAR on monotherapy. After a median exposure to BAR of 12.4 (6.6-31.2) months (range 3.1-51.4), a significant change in DAS28CRP was observed (difference -1.2, p=0.000). A total of 70.5% and 60.7% patients achieved low disease activity or remission, respectively and 50.8% (31/61) patients remained on BAR during follow-up with a median persistence of 31.2 (9.3-53.1) months. The average MPR was 0.96 (0.08) and all patients were “good adherents” by questionnaire. 21.3% patients discontinued baricitinib due to toxicity. Conclusion: In our real-world practice, BAR demonstrated effectiveness, large persistence, high adherence to treatment and acceptable safety profile.

Background: Renal cancers are among the top ten causes of cancer-specific mortality, of which the ccRCC subtype is responsible for most cases. The grading of ccRCC is important in determining tumour aggressiveness and clinical management. Objectives: The objectives of this research were to predict the WHO/ISUP grade of ccRCC pre-operatively and characterise the heterogeneity of tumour sub-regions using radiomics and ML models, including comparison with pre-operative biopsy-determined grading in a sub-group. Methods: Data were obtained from multiple institutions across two countries, including 391 patients with pathologically proven ccRCC. For analysis, the data were separated into four cohorts. Cohorts 1 and 2 included data from the respective institutions from the two countries, cohort 3 was the combined data from both cohort 1 and 2, and cohort 4 was a subset of cohort 1, for which both the biopsy and subsequent histology from resection (partial or total nephrectomy) were available. 3D image segmentation was carried out to derive a voxel of interest (VOI) mask. Radiomics features were then extracted from the contrast-enhanced images, and the data were normalised. The Pearson correlation coefficient and the XGBoost model were used to reduce the dimensionality of the features. Thereafter, 11 ML algorithms were implemented for the purpose of predicting the ccRCC grade and characterising the heterogeneity of sub-regions in the tumours. Results: For cohort 1, the 50% tumour core and 25% tumour periphery exhibited the best performance, with an average AUC of 77.9% and 78.6%, respectively. The 50% tumour core presented the highest performance in cohorts 2 and 3, with average AUC values of 87.6% and 76.9%, respectively. With the 25% periphery, cohort 4 showed AUC values of 95.0% and 80.0% for grade prediction when using internal and external validation, respectively, while biopsy histology had an AUC of 31.0% for the classification with the final grade of resection histology as a reference standard. The CatBoost classifier was the best for each of the four cohorts with an average AUC of 80.0%, 86.5%, 77.0% and 90.3% for cohorts 1, 2, 3 and 4 respectively. Conclusion: Radiomics signatures combined with ML have the potential to predict the WHO/ISUP grade of ccRCC with superior performance, when compared to pre-operative biopsy. Moreover, tumour sub-regions contain useful information that should be analysed independently when determining the tumour grade. Therefore, it is possible to distinguish the grade of ccRCC pre-operatively to improve patient care and management.

Laser in situ keratomileusis (LASIK) is the gold standard in the surgical correction of refractive errors on the cornea. It entails the creation of a superficial hinged corneal flap by a femtosecond laser, ablation of the underlying stromal bed by an excimer laser, and reposition of the flap. The corneal flap can be build in a 2-dimension (2D) fashion with tapered edges, or in a 3-dimension (3D) fashion, with angled sidecut. The latter reduces the risk of flap dislocation and infiltration of epithelial cells. This retrospective study compares with optical coherence tomography 3D and 2D flaps, and respective intra- and early post-operative complications. Four hundred consecutive eyes were included, 200 for each group. In the 3D group, the mean edge angle was 92°. The procedure was in average 5.2 seconds slower in the 3D group (p=0). Non visually significant flap folds were found in 13 eyes of the 2D group and in 7 eyes of the 3D group (p= 0.17). An intracorneal opaque bubble layer induced by laser photodisruption was more commonly observed in the 3D group (9 eyes vs. 2; p=0.03). In conclusion, the creation of a LASIK flap by a 3D-femtosecond laser cut was safe and effective.

Lung cancer is one of the leading causes of cancer-related mortality globally. Pulmonary nodules are one of the risk factors and their discovery rate has been increasing. Based on the nodule size and growth rate, their malignancy propensity is determined; however, it is very challenging to distinguish between benign and cancerous nodules. Many tumour-associated antigens (TAA) have been studied as blood biomarkers for lung cancer, most commonly the Cytokeratin 19 fragment (CYFRA 21-1), squamous cell carcinoma antigen (SCC Ag), carbohydrate antigen (CA19-9) and carcinoembryonic antigen (CEA). Due to their low sensitivity, TAAs are not recommended as tools for the early detection of lung cancer. However, cancer testis antigens (CTAs) are highly specific for carcinomas but their expression is more commonly associated with advanced stages of cancer and poor prognosis. Despite the fact that TAAs may provide useful insights for the diagnosis and prognosis of early lung cancer, their potential to do so has yet to be demonstrated.

Scedosporium species are human pathogenic fungi, responsible for chronic, localised, and life-threatening disseminated infections in both immunocompetent and immunocompromised individuals. Diagnosis of Scedosporium infections currently relies on non-specific CT, lengthy and insensitive culture from invasive biopsy, and time-consuming histopathology of tissue samples. At present, there are no rapid antigen tests that detect Scedosporium-specific biomarkers. Here we report the development of a rapid (30 min) and sensitive (pmol/L sensitivity) lateral-flow device (LFD) test, incorporating a Scedosporium-specific IgG1 monoclonal antibody (mAb), HG12, which binds to extracellular polysaccharide (EPS) antigens of between ~15 kDa and 250 kDa secreted during hyphal growth of the pathogens. The test is compatible with human serum, and allows the detection of the Scedosporium species most-frequently reported as agents of human disease (Scedosporium apiospermum, Scedosporium aurantiacum, and Scedosporium boydii), with limits of detection (LOD) of the EPS biomarkers in human serum of ~0.81 ng/mL (S. apiospermum), ~0.94 ng/mL (S. aurantiacum), and ~1.95 ng/mL (S. boydii). The Scedosporium-specific LFD (ScedLFD) test therefore provides a potential novel opportunity for the detection of infections caused by different Scedosporium species.

Berberis vulgaris L. (Berberidaceae) is a shrub that has been widely used in European folk medicine as an anti-inflammatory and antimicrobial agent. The purpose of our study was to elucidate the mechanisms of antiproliferative action of the plant’s methanolic root extract (BVR) against colon cancer cells. Cytotoxicity and pro-apoptotic activity were determined in human colon adenocarcinoma cell lines (LS180 and HT-29) and control colon epithelial CCD841 CoN cells. According to the MTT assay, after 48 h of cell exposure, the IC50 values were as follows: 4.3; 46.1 and 50.2 µg/mL for LS180, HT-29, and CCD841 CoN cells, respectively, showing the greater sensitivity of cancer cells to BVR. The Cell Death Detection ELISAPLUS kit demonstrated that BVR induced programmed cell death only against HT-29 cells. RT-qPCR with relative quantification method showed significant changes in the expression of genes related to apoptosis in both colon cancer cell lines. The genes BCL2L1 (126.84-366.66%), BCL2L2 (277.08-330.12%), CASP3 (180.36-261.36%) and CASP9 (158.08-213.46%) had significantly elevated expression, while BCL2 (23.08-52.06%) had reduced expression. Furthermore, in a panel of antioxidant tests, BVR showed positive effects (63.93±0.01, 122.92±0.01, and 220.29±0.02 mg Trolox equivalents (TE)/g in the DPPH•, ABTS•+ and ORAC assays, respectively). In the lipoxygenase (LOX) inhibition test, BVR revealed 62,60±0.87% of enzyme inhibition. The chemical composition of BVR was determined using UHPLC-UV-CAD-MS/MS analysis and confirmed the presence of several known alkaloids, including berberine, as well as other alkaloids and two derivatives of hydroxycinnamic acid (ferulic and sinapic acid hexosides). This is the first such extensive assessment of the biological activity of BVR. The results are very promising and encourage for the use of BVR as a comprehensive chemopreventive agent (anti-inflammatory, antioxidant, and pro-apoptotic) in colorectal cancer.

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

Immune responses to influenza (flu) antigens reflect memory to prior infections or vaccinations, which might influence immunity to new flu antigens. Memory of past antigens has been termed “original antigenic sin” or more recently “immune imprinting” and “seniority”. We have researched a comparison between the immune response to live flu infections and inactivated flu vaccina-tions. A brief history of antibody generation theories is presented culminating in new findings about the immune-network theory suggesting that a network of clones exists between an-ti-idiotypic antibodies and T cell receptors. Findings regarding the 2009 pandemic flu strain and immune responses to it are presented, including memory B cells and conserved regions within the hemagglutinin protein. The importance of CD4+ memory T cells and cytotoxic CD8+ T cells responding to both infections and vaccinations are discussed and compared. Innate immune cells like natural killer (NK) cells and macrophages are discussed regarding their roles in adaptive immune responses. Antigen presentation via macroautophagy processes are described. New vaccines in development are mentioned along with the results of some clinical trials. The manu-script concludes with how repeated vaccinations are impacting the immune system and a sketch of what might be behind the imprinting phenomenon, including future research directions.

This study investigated the influence of single nucleotide polymorphisms (SNPs) in genes asso-ciated with the interferon pathway (IFNAR2 rs2236757), antiviral response (OAS1 rs10774671, OAS3 rs10735079), and viral entry (ACE2 rs2074192) on COVID-19 severity and their association with non-alcoholic fatty liver disease (MAFLD). We did not observe a significant association between the investigated SNPs and COVID-19 severity. While the IFNAR2 rs2236757 A allele correlated with higher creatinine levels upon admission and the G allele with lower band neu-trophils upon discharge, these findings require further investigation. The distribution of OAS gene polymorphisms (rs10774671, rs10735079 did not differ between MAFLD and non-MAFLD patients. Our study population's distribution of ACE2 rs2074192 genotypes and alleles differed from the European reference population. Overall, our findings suggest that these specific SNPs may not be major contributors to COVID-19 severity in our patient population, highlighting the potential role of other genetic factors and environmental influences.

Badminton is one of the most popular racket sports played by children up to the elderly worldwide. Everyone can practice and play badminton as a leisure or competitive sport, regardless of age, experience, or skill level. It does not require physical contact among players and expensive equipment. Compared with closed-skill exercise (e.g., running, swimming), open-skill exercise (e.g., badminton, table tennis) has been reported to intervene more with cognitive function and prevent cognitive decline. In this review, we outline the characteristics of badminton’s beneficial effects on physical and cognitive aspects. The characteristics presented here indicate that intervention with regular badminton exercise could effectively improve cognitive function and prevent cognitive decline in the elderly.

This study unveils verapamil's compelling cytoprotective and proliferative effects on pancreatic β-cells amidst diabetic stressors, spotlighting its unforeseen role in augmenting cholecystokinin (CCK) expression. Through rigorous investigations employing MIN6 β-cells and zebrafish models under type 1 and type 2 diabetic conditions, we demonstrate verapamil's capacity to significantly boost β-cell proliferation, enhance glucose-stimulated insulin secretion, and fortify cellular resil-ience. A pivotal revelation of our research is verapamil's induction of CCK, a peptide hormone known for its role in nutrient digestion and insulin secretion, which signifies a novel pathway through which verapamil exerts its therapeutic effects. Furthermore, our mechanistic insights reveal that verapamil orchestrates a broad spectrum of gene and protein expressions pivotal for β-cell survival and adaptation to immune-metabolic challenges. In vivo validation in a zebrafish larvae model confirms verapamil's efficacy in fostering β-cell recovery post-metronidazole inflic-tion. Collectively, our findings advocate for verapamil's reevaluation as a multifaceted agent in diabetes therapy, highlighting its novel function in CCK upregulation alongside enhancing β-cell proliferation, glucose sensing, and oxidative respiration. This research enriches the therapeutic landscape, proposing verapamil not only as a cytoprotector but also as a promoter of β-cell re-generation, thereby offering fresh avenues for diabetes management strategies aimed at pre-serving and augmenting β-cell functionality.

Conclusions: Our findings suggest that the NMS-E represents a valuable preoperative diagnostic tool for endometriosis, effectively correlating with the disease's severity and surgical outcomes. Incorporating the NMS-E into clinical practice could significantly enhance the management of endometriosis by addressing current diagnostic limitations and guiding surgical planning.

Background: to analyze the impact of COVID-19 pandemic on characteristics and management of uveal melanoma (UM) in National Referral Center in Poland. Materials and Methods: the retrospective analysis of 1336 patients who were newly diagnosed with UM at Department of Ophthalmology and Ophthalmic Oncology, Jagiellonian University Collegium Medicum Krakow, Poland between January 1, 2018 and December 31, 2021. The demographic and clinical data were compiled including localization, size and treatment methods of tumors. Results: In total, 728 patients with UM were included before COVID-19 pandemic in years 2018-2019 and 608 were included during COVID-19 pandemic in years 2020-2021. Fixed-base dynamics indicators for the incidence of uveal melanoma (base year 2018) in the national referral center in Poland were 80.22% and 86.81% in year 2020 and 2021, respectively. UMs were statistically significantly larger and more frequently localized anterior to the equator of the eye globe in year 2021 than in year 2018 (Chi^2 Pearson test p= 0.0001 and p= 0.0077, respectively). The rate of patients treated with enucleation increased from 15.94% in year 2018 to 26.90% in year 2021 (Chi^2 Pearson test p=0.0005). Conclusions: statistically significant differences were found in the management of uveal melanoma in National Referral Center in Poland during COVID-19 pandemic with tumors being larger, more frequently localized anterior to the equator of the eye globe and more often enucleated.

In this report we describe the case of a healthy, young, athletic woman who developed acute lymphoblastic leukaemia (ALL)/lymphoblastic lymphoma (LBL) after receiving the second dose of the Pfizer/BioNTech modified mRNA (modRNA) COVID-19 genetic vaccine (marketed as Comirnaty^®). The first dose of the genetic vaccine did not appear to illicit any noticeable side effects, but within 24 hours of the second dose the patient suffered widespread and intensifying bone pain, fever, vomiting, and general malaise. Due to the persistence of the symptoms, the patient underwent a series of tests and examinations including a full laboratory workup, a consult with a clinical immunologist and rheumatologist, a Positron Emission Tomography (PET) imaging, as well as an osteomedullary biopsy. These together led to a definitive diagnosis of ALL. A time interval of 16 weeks from the second vaccination to the diagnosis of cancer was noted. Several similar cases with identical pathology which developed after the modRNA COVID-19 vaccination, are described in case reports in the scientific literature. The massive and indiscriminate use of genetic vaccines to fight COVID-19 is raising serious concerns about their safety and about the technology platform as a whole for this purpose. Growing evidence is accumulating regarding the biodistribution and persistence of the modRNA which can reach, thanks to the lipid nanoparticles, a multitude of tissues and organs of the body, including the bone marrow and other blood-forming organs and tissues. Moreover, there is evidence that the modRNA vaccines display a particular tropism for the bone marrow, influencing the immune system at multiple levels and being able to trigger not only autoimmune-based pathologies, but also neoplastic mechanisms. The aim of this article is to assess, on the basis of the available scientific literature, the risk of developing haematopoietic cancers after modRNA vaccination, and to investigate the potential genetic mechanisms involved in the pathogenesis of disease.

Background: Glucose 6-phosphate dehydrogenase (G6PD) deficiency increases the risk of neonatal hyperbilirubinemia. The aim of the study is to evaluate the clinical findings of glucose 6 phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) deficiency, to prevent further examinations for prolonged jaundice, and to contribute by regulating its treatment. At the same time, it is to determine whether systemic-immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) can be used in addition to conventional complete blood count (CBC) parameters in the diagnosis of neonatal prolonged jaundice. Methods: In full term neonates with hyperbilirubinemia who were admitted to Medicine Hospital between January 2019 and January 2024 with the complaint of jaundice, 167 infants with a serum bilirubin level above 5 mg/dL, whose jaundice persisted after the 10th day, were included in the study. Results: 63.5% of the patients were male and the mean age was 31±6 days. G6PD was negatively perfectly correlated with NLR (r: -1; p

Reactive oxygen species (ROS) play an important role in biological processes and offer hope for the development of effective treatments for ROS-dependent diseases, including cancer. The interaction of hydrogen peroxide with proteins stimulates the creation of chemical molecules that can weaken or stop the pathological process in cancer. However, reliable drugs have not yet been described. To understand the reason for the failure, we studied the behavior of ROS-containing compounds in cancer cells. The epidermal growth factor receptor (EGFR) is activated by interaction with a ligand protein, as well as by binding the chemical structure of hydrogen peroxide to the catalytic cysteine in the intracellular domain. Both mechanisms trigger signaling pathways in cells. The EGFR can be inactivated by protein tyrosinase phosphatase PTP-1B, which itself is activated by hydrogen peroxide. A simple in-gel fluorescence technique was used to demonstrate the rapid binding of hydrogen peroxide to a large number of proteins, including both activating and inactivating target proteins. Natural defense systems take longer to action and apparently cannot prevent hydrogen peroxide from binding to protect cells from exposure to unwanted proteins. Therefore, superoxide dismutase, which produces hydrogen peroxide, is not a suitable target for disease therapy.

Background/Objectives: Vitamin B12 deficiency can cause variable symptoms, which may be irreversible if not diagnosed and treated in a timely manner. We aimed to develop a widely accepted expert consensus to guide the practice of diagnosing and treating B12 deficiency. Methods: We conducted a scoping review of the literature published in PubMed since January 2003. Data were used to design a two-round Delphi survey to study the level of consensus among 42 experts. Results: The panelists agreed on the need for educational and organizational changes in the current medical practices for diagnosing and treating B12 deficiency. Recognition of clinical symptoms should receive the highest priority in establishing the diagnosis. There is agreement that the serum B12 concentration is useful as a screening marker, whereas methylmalonic acid or homocysteine can support the diagnosis. Patient lifestyle, disease history and medications can provide clues to the cause of B12 deficiency. Regardless of the cause of the deficiency, initial treatment with parenteral B12 was regarded as the first choice for patients with acute and severe manifestations of B12 deficiency. The use of high-dose oral B12 at different frequencies may be considered for long-term treatment. Prophylactic B12 supplementation should be considered for specific high-risk groups. Conclusions: There is a consensus that clinical symptoms need to receive more attention and weight in establishing a diagnosis. B12 laboratory markers can support the diagnosis. The severity of clinical symptoms, the causes of B12 deficiency and the treatment goals govern decisions regarding the route and dose of B12 therapy.

Background: Critical states present scale-free dynamics, optimizing neuronal complexity. We explored electroencephalogram (EEG) criticality in amnesic Mild Cognitive Impairment (aMCI) patients with clinical improvement in working memory, verbal memory, verbal fluency and overall executive functions after the completion of a 6-month prospective memory training. (2) Methods: We compared “before” and “after” stationary resting-state EEG records of right-handed MCI patients (n = 17; 11 females), using the method of critical fluctuations and Haar wavelet analysis. (3) Results: Significant criticality enhancement was present in frontotemporal electrodes [mean dif: 0.10; Z = 7, p = .019] and isolated electrodes T6 [mean dif: 0.204; t (10) = - 2.3, p = .044] and F4 [mean dif: 0.0194; t (10) = - 2.82; p = .018]. (4) Conclusions: EEG criticality agreed with clinical improvement, consisting a possible monitoring biomarker in MCI and Alzheimer’s disease. Further evaluation is needed in patients under cognitive training or even drug-modifying therapies.

In voice analysis, the electroglottographic (EGG) signal has long been recognized as a useful complement to the acoustic signal, if only when the vocal folds are actually contacting, such that this signal has an appreciable amplitude. However, phonation can occur also without vocal fold contacting, as in breathy voice, in which case the EGG amplitude is low, but not zero. It is of great interest to identify the transition from non-contacting to contacting, because this will substantially change the nature of the vocal fold oscillations; yet that transition is not in itself audible. The magnitude of the normalized peak derivative of the EGG signal is a convenient indicator of contacting, but no current EGG hardware has a sufficient signal-to-noise ratio of the derivative. The textbook techniques of spectral thresholding and static notch filtering are straightforward to implement, can run in real time, and can mitigate several noise problems in EGG hardware.

In chronic myeloid leukemia (CML), a clonal proliferative disorder of granulocytic lineage, the 90%‐95% of cases are characterized by t(9;22) (q34.1;q11.2) translocation, leading to the Philadelphia chromosome (1). Rarely, CML patients directly present a blast crisis, mostly of myeloid origin (2, 3). Herein, we describe one rare CML case, showing an unusual early T lymphoid blastic crisis.

Introduction: This study aims to elucidate the clinical diagnostic value of S100 Calcium Binding Protein beta (S100B) in epilepsy, a topic of ongoing debate among European and Asian epilepsy research centres.Methods and analysis: A structured long-term research plan was developed, comprising three phases. Phase one involves observational studies investigating the correlation between S100B levels in serum or cerebrospinal fluid and epilepsy. Phase two integrates observational and randomised controlled data to establish baseline S100B levels across diverse epilepsy demographics, underpinning the predictive value of S100B for epilepsy. Phase three focuses on randomised controlled trials to evaluate the diagnostic accuracy of S100B as an epilepsy biomarker.Ethics and dissemination: All enrolled patients will provide written consent. The ethics committee of the Second People’s Hospital of Gansu Province, Affiliated Hospital of Northwest Minzu University, China, approved the study (GSSEY2022-KY009-01).Registration: The study is registered with PROSPERO (CRD42023425431).

Drug hypersensitivity reactions (DHR) to platinum-based compounds (PC) are on the rise, and their personalized and safe management is essential to enable first-line treatment of these cancer patients. This study aimed to evaluate the usefulness of basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PC. 24 patients with DHR to PC (20 oxaliplatin and four carboplatin) were evaluated: 13 patients diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients diagnosed as non-allergic with negative STs and DPTs, and five patients classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarrays were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control group were negative for the sIgE- and BAT-microarrays. Our experience indicates that sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PC and may provide an advance in decision-making for drug provocation testing.

Rhodotorula mucilaginosa fungaemia is rare and highly resistance to antifungal therapy. We herein report a case involving a 31-year-old male admitted after a high-velocity road traffic accident. He sustained a grade IV liver injury with right hepatic vein thrombosis, necessitated an urgent laparotomy. Post-operatively, repeated imaging of the abdomen revealed presence of biloma. Percutaneous subdiaphragmatic drainage was done but appeared ineffective, prompting second surgery for a urgent hemi-hepatectomy. Patient then was nursed in the intensive care unit (ICU) however during his stay in the ICU he became more sepsis evident by worsening ventilatory support and rise in septic parameters from the biochemistry parameters. Despite on intravenous piperacillin-tazobactam and fluconazole, his septic parameters did not improve and a full septic workup was done and was found to be positive for Rhodotorula mucilaginosa from the blood cultures. After discussion with the infectious disease physicians and clinical microbiologist, it was decided to initiate a course of intravenous meropenem and amphotericin B based on minimum inhibitory concentration (MIC) values, considering the patient's extended ICU stay and catheter use. Eventually, successful weaning off mechanical ventilation was discharge from ICU care. This case underscores the necessity of individualized approaches, combining timely imaging, appropriate drainage techniques, and tailored treatments to optimize outcomes for such intricate post-traumatic complications.

This retrospective study examines 248 test-bolus examinations preceding contrast-enhanced magnetic resonance angiography (CE-MRA) to extract clinically relevant data for critical limb ischemia (CLI) management. Methods involved a retrospective review of test-bolus exams, analysing 60 graphs for time-to-peak (TTP), full-width half-maximum (FWHM) time, and time to continual rise in signal intensity. These values were correlated with heart function parameters (ejection fraction, ASA-Classification, Lee-Index, and MET-Score). Results indicate a mean TTP of 31.2 ± 7.3s, showing a correlation between ejection fraction and ASA classification. Patients with atrial fibrillation exhibited prolonged TTP compared to those without. Despite population heterogeneity, findings facilitate risk stratification for limb-saving interventions in CLI. TTP emerges as a potential clinical cardiovascular parameter and a risk factor for vascular interventions. Given the variation in injection protocols across centres, this study underscores the importance of precise bolus arrival time documentation for future multicentre studies.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

Aim: To evaluate the panmacular subthreshold micropulse laser treatment results among patients with central serous chorioretinopathy (CSC) and their correlation with functional and morphological parameters. Material and methods: The examined group included 10 non-treated and 41 treated patients with acute, recurrent, and chronic CSC (13 F, 38 M, mean age 44.11±6.5) and 14 healthy controls (6 F, 8 M, mean age 45±9.3). The BCVA examination, ophthalmoscopy, microp-erimetry, angio-OCT and OCT were performed. The medical history regarding chronic general disorders and known risk factors were recorded. Results: Complete resorption of SRF was obtained in 100% aCSC, 86.66% cCSC, and 63.63% r CSC. BCVA and RetSens significantly improved most of the patients treated in aCSC. The lowest BCVA and RetSens, but the largest pachyvessel and disease duration, were found in rCSC. A strong negative correlation between final BCVA and disease duration was found. No patient demonstrated laser lesions following treatment. Conclusions: The panmacular MPLT therapy leads to long-term enhancement of functional and morphological parameters in all CSC patients. The acute CSC patients showed the most significant improvement. The procedure is safe and could be considered a preferred treatment option for all active CSC cases. Timely treatment is crucial for beneficial outcomes.

In pediatric burn care, achieving swift healing with minimal complications remains paramount. This investigation assesses polyhexamethylene biguanide (PHMB)'s role in managing superficial partial-thickness burns in children, focusing on the effects of various patient-specific factors on recovery. Through a retrospective analysis of 27 pediatric cases treated with PHMB, we explored the impact of age, burn size, dressing frequency, treatment delay, cold therapy application, and analgesic usage on the duration until reepithelialization. Notably, the majority of patients benefited from early cold therapy, yet only 1 in 3 patients received analgesics. The study reveals a mean healing time of 8.78 days, with the extent of the burn showing a strong correlation to recovery speed. Most treatments were managed outpatient, evidenced by a negligible average hospital stay. Impressively, the intervention recorded no complications. Our findings endorse PHMB as a promising treatment for second-degree burns in young patients, offering healing efficiency on par with or surpassing traditional methods, without increasing complication risks. This investigation underscores the necessity for continued exploration into the optimal application of prehospital interventions and the comprehensive benefits of PHMB in pediatric burn management, advocating for future research aimed at assessing long-term outcomes, including scar quality and patient satisfaction.

Introduction: Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental condition in children in Saudi Arabia based on the results of the national mental health survey. ADHD significantly impacts the child and their family dynamics, particularly causing increased stress and diminished life quality for parents. In Saudi Arabia, there is a research gap regarding the quality of life and coping mechanisms of parents managing children with ADHD. This study assesses levels of depression and anxiety, quality of life, and coping strategies used by parents of children diagnosed with ADHD. Methods: We conducted a cross-sectional online survey with 151 parents of ADHD-diagnosed children, utilizing the WHOQOL-BREF for life quality, the brief-COPE for coping strategies, and the Patient Health Questionnaire (PHQ): depression (PHQ9-9 items) and generalized anxiety (GAD7-7 items) modules. Results: Among the parents surveyed, 36% reported moderate to severe depression, while 39.1% experienced moderate to high anxiety levels. Quality of life positively correlated significantly with higher household monthly income (HHI), employment status, sibling count, and effective coping strategies. Conversely, a parent's age, educational level, and particularly maternal status were inversely related to anxiety levels, with fathers displaying higher maladaptive coping scores. Conclusion: The study sheds light on the considerable anxiety and depression experienced by parents of children with ADHD, significantly affecting their quality of life. Lower parents' quality of life is associated with high levels of depression, anxiety, and ineffective coping strategies. These insights highlight the critical need for interventions to aid parental mental health, thereby improving their overall quality of life amidst ADHD challenges.

Aim: To investigate the effects of intensive physical exercise on retinal microvascular regulation in healthy volunteers by the adaptive optics retinal camera measurement. Methods: We included healthy volunteers (11 men and 14 women) aged 20.6± 0.9. Heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) were recorded before and after a submaximal physical exertion of continuously riding a training ergometer. The superior temporal retinal artery measurements were captured using the adaptive optics (AO) camera rtx1TM (Imagine Eyes, Orsay, France) without pupil dilatation. We compared measures of vessel diameter (VD), lumen diameter (LD), two walls (Wall 1, 2), wall-to-lumen ratio (WLR), and wall cross-sectional analysis (WCSA) before and immediately after the cessation of exercise. Results: Cardiovascular parameters: After exercise, SBP, DBP and HR changed significantly from 130.2±13.2 to 159.7±15.6 mm Hg, 81.2±6.3 to 77.1±8.2 mm Hg and 80.8±16.1 to 175.0±6.2 bpm, respectively (p < 0.002). Retinal microcirculation analysis: Before the exercise, the mean LD was 96.0±6.8, VD 118.5±8.3, WLR 0.234±0.02, WCSA 3802.8±577.6. The mean LD and Wall 1 did not change significantly after exercise but slightly decreased. The VD, Wall 2, WLR and WCSA decreased significantly (p

Keywords: leptophages; Cas system; bacteriophages; Leptospira interrogans

Abstract Background: Periodontitis is associated with systemic chronic inflammatory diseases. There is limited evidence on the influence of anti-cytokine therapies on the periodontal condition and microbiome in the tooth pocket of such patients, so the aim of this study was to elucidate this issue. Methods: In this observational trial, the periodontal status and the gingival crevicular fluid of 13 patients with different chronic inflammatory diseases were obtained before initiation of anti-cytokine treatment and 14 weeks after. Gingival crevicular fluid was collected for 16S rRNA gene sequencing from a clinically healthy tooth and the deepest measured pocket. Results: In participants with advanced attachment loss at baseline, the clinical attachment level significantly decreased from 2.9 (2.3-3.4) to 2.4 (1.3-3.0) mm (p = 0.04), and the bleeding- on-probing index dropped from 19.4 (10.0-21.0) to 7.3 (6.9-9.9) mm (p = 0.02) without any further periodontal treatment. Shannon’s diversity index significantly increased in the deepest pockets of patients (p = 0.039). Conclusion: The data showed alterations in diversity of the subgingival microbiome and improvement of periodontal parameters over the course of the study, implying a shift towards a healthier condition after starting anti-cytokine therapy. Additional investigations are needed to analyze whether the administration of selective biologicals can improve periodontal conditions in patients with or without chronic inflammatory diseases.

Cardiovascular diseases (CVDs) remain the leading cause of mortality. Traditional approaches to diagnosing and treating CVDs often involve interpretation, which can lead to errors. The emergence of Artificial Intelligence (AI) and Machine Learning aids the management of CVDs. AI examines amounts of data and identifies patterns offering solutions for disease detection, risk prediction, and patient care. The American Heart Association's 2023 Scientific Sessions (AHA23) showcased studies that highlight AIs potential to revolutionize cardiac healthcare. This article presents a review of these cutting-edge studies exploring how AI is applied in health, the outcomes of these applications, and their implications for clinical practice. The insights gained from this review will contribute to the discussion on AI's role in healthcare and its capacity to enhance outcomes.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a specific subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was safe and well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is safe and well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

In all mammals, the circulating pool of MLT is synthesized in the pineal gland, during the night darkness hours. Its main function is that of synchronizing the organism in the photoperiod. In contrast, extra-pineal MLT is synthesized in peripheral organs, does not follow any circadian rhythm nor circulates and plays a detoxifying and cytoprotective action. Circulating MLT may stimulate both innate and acquired immune responses by its circadian action and by activating high affinity receptors on immunocompetent cells. Extra-pineal MLT may have anti-oxidant and anti-inflammatory effects dampening the innate immune response. These two seemingly divergent roles may be considered as two faces of the same coin. In fact, the integration of both circulating and extra-pineal MLT functions might generate a balanced and effective immune response against microbial pathogens. The studies described in this review investigated the effect of exogenous MLT in various models of infectious diseases using extremely different doses and treatment schedules. None of them evaluated the possibility to integrate the non-circadian anti-inflammatory effect with the circadian immunoenhancing action of MLT. As a consequence, in spite that most studies agree that MLT has a beneficial effect against infections, it seems difficult to draw any definite conclusion about its possible therapeutic use.