Background: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with a rapidly increasing prevalence. Current therapeutic options primarily manage symptoms, not modifying the disease. Secretome-based therapies have emerged as a promising avenue for AD treatment in targeting multiple pathways and promoting neuroprotection and regeneration. This systematic review evaluated the preclinical and clinical evidences for secretome-based therapies in AD.Methods: A systematic search was conducted across Scopus, PubMed, ScienceDirect, and Cochrane Library. The SYRCLE risk of bias (RoB) tool was used for preclinical studies and Cochrane RoB 2.0 for clinical studies. We performed qualitative analysis of study results.Results: Included 21 in vivo studies and 2 clinical trials revealed promising outcomes of treatments involving secretomes, exosomes, and extracellular vesicles from different cell sources. The therapies could reduce amyloid plaque load, reactive gliosis, and enhance neuronal density. These findings suggested the treatments reveal mechanism of action in neuroprotection, neuroregeneration, and inflammation modulation, which are critical in AD pathology. Ongoing trials also supported the safety and efficacy of the treatment strategies. However, translational medical study faces several challenges regarding large-scale production, optimization of protocols, and understanding biomarkers. The heterogeneity in secretome-based therapies administration have complicated the comparison of study outcomes and the translation of preclinical findings into clinical settings. Deeper understanding of the secretome's mechanisms of action, optimal dosing, and delivery methods are needed to maximize therapeutic outcomes.Conclusion: Despite secretome-based therapies hold significant promise for AD treatment, addressing the identified gaps and limitations is crucial for advancing these therapies from preclinical research to clinical practice.

Background: Commensal Neisseria species are part of the oropharyngeal microbiome and important for health, but also serve as a reservoir for antimicrobial resistance. Little is known about the prevalence of these species in the general population, how this varies by age and how antimicrobial susceptibility varies between species. Methods: We assessed the prevalence and antimicrobial susceptibility of commensal Neisseria species in the parents (n=38) and children (n=50) of 35 families in Belgium.Results: Various commensal Neisseria (n=5) could be isolated from the participants. Most abundant were N. subflava and N. mucosa. N. subflava was detected in 77 of 88 (87.5%) individuals and N. mucosa in 64 of 88 (72.7%). N. mucosa was more prevalent in children (41/50 [82%]) than parents (23/38 [60.5%]; P<0.05), while N. bacilliformis was more prevalent in parents (7/36 [19.4%]) than children (2/50 [4%]; P<0.05). N. bacilliformis showed high ceftriaxone minimum inhibitory concentrations (MICs; median MIC 0.5mg/L; IQR 0.38-0.75) and these high MICs explained the higher ceftriaxone MICs of all Neisseria isolates from the parents than the children. The median azithromycin MIC of all Neisseria isolates per individual was positively correlated with the median family MIC (rho=0.24; P=0.033). The same association was found for the analysis limited to N. subflava (rho=0.36; P=0.004) and N. mucosa (rho=0.30; P=0.027). Interpretation: The most abundant commensal Neisseria species found in this population were N. subflava and N. mucosa, of which the prevalence of N. mucosa varied by age. The prevalence of N. bacilliformis also varied by age and showed concerningly high ceftriaxone MICs which warrant further investigation. We found evidence of clustering of azithromycin, but not ceftriaxone, MIC by family.

Chronic rhinosinusitis (CRS) is a complex inflammatory condition affecting the nasal and paranasal sinus mucosa. Gastroesophageal reflux disease (GERD) has been implicated as a potential exacerbating factor in CRS, but the specific endoscopic features of nasopharyngeal pathology in this context remain poorly understood. Background and Objectives: CRS is a multifactorial disease with various underlying etiologies, including inflammation, anatomical factors, and environmental triggers. While GERD has been suggested as a potential contributor to CRS, the specific endoscopic features indicative of nasopharyngeal pathology in CRS patients with GERD symptoms have not been clearly elucidated. Our aim is to identify specific endoscopic features of nasopharyngeal pathology in patients with CRS associated with GERD symptoms, and to propose a method for assessing the influence of GERD on the mucosal layer of the nose and nasopharynx. Materials and Methods: We conducted a cross-sectional observational study involving 521 adult patients presenting with symptoms suggestive of CRS. From this cohort, 95 patients with the highest scores on the Reflux Symptom Index (RSI) and Reflux Symptom Score-12 (RSS-12) questionnaires were selected as the main group. Endoscopic examinations were performed to assess the nasal and nasopharyngeal mucosa. Results: Our study revealed significant alterations in the nasopharyngeal mucosa of patients with CRS associated with GERD symptoms. Increased vascularity of the nasopharyngeal mucosa was observed in 91 patients (95.7%), while hypertrophy was noted in 83 patients (87.4%). Mucus was present in the nasopharynx of 77 patients (81.1%), exhibiting varying characteristics of color and consistency. Asymmetric hypertrophy of the oropharyngeal mucosa was noted in 62 patients (65.3%). Conclusions: We propose a method for assessing the influence of GERD on the mucosal layer of the nose and nasopharynx, which may aid in diagnostic and management decisions. Further research is warranted to explore the potential impact of GERD symptoms on the course and severity of CRS exacerbations.

To clarify the risk factors for aggravation of esophagogastric varices (EGV) after hepatitis C virus (HCV) eradication with direct-acting antiviral (DAA) therapy, we enrolled 167 consecutive patients with HCV-related compensated cirrhosis who achieved a sustained virological response (SVR) after DAA therapy. During a median of 69 months, EGV was aggravated in 42 (25%) patients despite SVR. The cumulative 1, 3, 5, and 10-year aggravated EGV rates were 7%, 23%, 25%, and 27%, respectively. Multivariate analysis identified platelet count <11.0×10⁴/μL, LSM ≥18.0 kPa, total bile acid ≥33.0 μmol/L, and diameter of left gastric vein (LGV) ≥5.0 mm at HCV eradication as independent risk factors for EGV aggravation post-SVR. In groups that meet all of these risks, the cumulative EGV aggravation rates at 1, 3, and 5 years were 27%, 87%, and 91%, respectively. However, none of the patients who had only one or none of the risk factors experienced EGV aggravation. Platelet count, LSM, total bile acid, and diameter of LGV at HCV eradication were associated with aggravated EGV post-SVR. EGV tends to worsen as two or more of these risk factors increase.

Indocyanine Green (ICG) has significantly advanced minimally invasive surgery. It is widely recognized for its ability to visualize blood vessel patency in real-time across various surgical specialties. While its primary use in colorectal surgery is to evaluate anastomoses for leaks, nu-merous other applications have been documented in the literature. In this review, we aim to explore both established and emerging applications of ICG fluorescence in colorectal surgery, with the goal of improving patient outcomes. This includes preoperative tumor marking and the detection of metastatic disease. Some applications, such as lymphatic mapping, require further research to determine their impact on clinical practices. Conversely, oth-ers, like the intraoperative localizations of ureters, necessitate additional procedures and are not yet widely accepted by the surgical community. However, the development of alternative com-pounds could offer better solutions. Future research should focus on areas like quantitative ICG and protocol standardization in prospective multicenter studies.

A ~3-kb deletion-type DNA copy-number variation (CNV, esv3587290) located at intron 7 of the VANGL1 gene (1p13.1, MIM*610132) has been proposed as a genetic factor for developing lupus nephritis (LN) in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: cSLE patients with (N=39) or without (N=27) LN, as diagnosed by renal biopsy (N=17), proteinuria (N=33), urinary protein:creatinine ratio >0.2 (N=34), and erythrocyturia and/or granular casts in urinary sediment (N=16). For esv3587290 CNV genotyping, we performed an end-point PCR assay with breakpoint confirmation by Sanger sequencing. We also determined the allelic frequencies of the esv3587290 CNV in 181 deidentified ethnically-matched individuals (reference group). The obtained genotypes were tested for Hardy-Weinberg equilibrium (HWE) by c2 test. Associations between LN and esv3587290 CNV were tested by calculating the Odds Ratio (OR) and using Pearson's c² tests with a 95% confidence interval and P≤0.05. The esv3587290 CNV allele (OR 0.108, 95% CI 0.034-0.33, P=0.00003) and the heterozygous genotype (OR 0.04, 95% CI 0.119-0.9811, P=0.002) showed a significant protective effect against LN development. Finally, we characterized the precise breakpoint of the esv3587290 CNV as NG_016548.1(NM_138959.3):c.1314+1339_1315-897del (https://databases.lovd.nl/shared/variants/0000918418#00025811) in our population. This report supports the notion that a broad genetic heterogeneity underlies the susceptibility for developing LN.

Background: Our study investigates the prevalence and causes of injuries among undergraduate dental students during clinical sessions. Methods: The study was conducted at the Department of Dentistry, National and Kapodistrian University of Athens, focusing on injuries reported from 2021 to 2024. Data were collected through self-reported questionnaires and clinical records. The primary variables assessed included the type of injury, the instrument involved, the clinical procedure being performed, and the immediate actions taken post-injury. Serological testing was conducted on both students and patients to assess the risk of bloodborne pathogen transmission. Results: The findings revealed a high prevalence of injuries, with needles being the most common cause, followed by burs and dental probes. The most frequent injury type was piercing, primarily affecting the fingers. Periodontal treatments, restorative procedures, and endodontic treatments were the main activities leading to injuries. Despite normal medical records for most patients treated by injured students, serological testing showed significant positivity rates for HCV and HBV. It is noteworthy that most injured students demonstrated their commitment to safety by adhering to recommended post-exposure protocols, including wound cleaning, disinfecting, and serological testing. Our study highlights the critical need for enhanced biosafety awareness and training among dental students to reduce injury risks. Conclusions: These findings underline the necessity for integrated safety protocols and continuous education to improve clinical practices and ensure student safety.

Parkinson-like events are side effects that may persist for an extended period even after drug administration is discontinued. Although these events can be triggered by various drugs, the mechanisms underlying their diverse symptoms remain largely unclear. To investigate this, we used the Japanese Adverse Drug Event Reporting Database, which is maintained by the Phar-maceuticals and Medical Devices Agency, to analyze the risk factors associated with Parkinson-like events along with associated drug trends and characteristics. Our findings indicate that similar to　Parkinson’s disease, age-related differences affect the onset of these events, with older individuals being more susceptible. Hierarchical clustering and principal component analysis revealed that the mechanisms triggering these Parkinson-like events are consistent across reports, suggesting a common underlying cause. However, even with a consistent mechanism, side effects can vary depending on the site of action. These insights underline the importance of swift identification of the drugs suspected of causing these events and implementation of measures to reduce their side effects.

Total hip arthroplasty (THA) is a preferred treatment for primary osteoarthritis (OA) or secondary due to developmental hip dysplasia (DDH). Gait analysis is considered a golden standard for evaluating post-arthroplasty walking patterns. This study compared post-THA spatiotemporal gait parameters (SGPs) between OA and DDH patients and explored correlations with demographic and clinical variables. Thirty patients (15 per group) were recorded during gait, and their SGPs were analyzed. Functionality was evaluated with the Oxford Hip Score (OHS). The OA patients were significantly older than DDH (pr< 0.51, all p< 0.05). The preoperative gait alterations associated with OA or DDH were improved to similar levels in both groups after THA. Post-arthroplasty SGPs and OHS correlations indicate limitations in certain activities. These find-ings must be correlated with kinetic gait analysis data to fully evaluate gait and functionality dif-ferences among patient groups.

Background: Patterns of humoral immune responses represent a major hurdle in terms of pig-to-human xenotransplantation approaches. The best-known xenogeneic glycan antigens pre-sent in pigs are the αGal (Galili-antigen) and the non-human sialic acid Neu5Gc. As there are further differences between porcine and human cellular surface glycosylation, a much broader range of glycan epitopes with xeno-reactive relevance can be anticipated. Therefore, we set-out to chemically modify porcine cellular surface glycans in a global approach by applying sodium peri-odate (NaIO4) oxidation. Methods: Porcine endothelial cells were exposed to oxidation with 1 to 5 mM NaIO4 for different time periods at 37°C or 4°C and under static or dynamic conditions. The impact on cellular sur-vival was determined applying live/dead-assays. Oxidation of αGal-epitopes was assessed by flu-orescence microscopy-based quantification of isolectin-B4 (IL-B4) staining. Overall immunogenic-ity of porcine cells was determined by human serum antibody binding. Results: Treatment of porcine endothelial cells and tissues with NaIO4 led to a reduced binding of the αGal-specific IL-B4 and/or human serum antibodies. NaIO4 revealed to be cytotoxic when performed at elevated temperature and for prolonged time. However, by applying 2 mM NaIO4 for 60 min at 4°C a high extent of cellular viability and a relevant reduction of detectable αGal epitope were observed. No differences were detected irrespectively on whether the cells were oxi-dized under static or flow conditions. Conclusion: Glycan epitopes on living cells can be oxidized with NaIO4 while maintaining their viability. Accordingly, this strategy holds promise to prevent immune reactions mediated by pre-formed anti-glycan antibodies.

Background: Studies have tried to identify predictors of functional markers of keratoconus progression, whereas structural outcomes of collagen cross-linking have not been properly investigated. Objective: find and set up a combination of diagnostic modalities and measurements to reliably reflect CXL efficiency. Material and methods: We retrospectively reviewed the medical histories of 107 KC patients (131 eyes) who underwent CXL in a medical center from January 2018 to December 2022. The dataset included preoperative examinations and follow-up results, which provided a total of 796 observations. The cases of other corneal diseases, repeated CXL, pregnancy, and observations without follow-up examinations were excluded. Results: The study findings revealed a significant drop in the central and corneal thickness during 14.01±9.98 months of observations. Linear and polynomial equations suggested different trends in pachymetry change after CXL. The linear model showed corneal thinning, and according to the polynomials, pachymetry findings return to baseline values two years after CXL. Conclusion: The most reliable prognosis of postoperative corneal thickness is achieved with the models trained on keratometry readings and topography indices. BAD indices are also reliable predictors of the corneal thickness after CXL. A combination of the aforementioned structural parameters and their derivatives can reliably predict CXL efficiency.

The disruption of brain energy metabolism, leading to alterations in synaptic signaling, neural circuitry, and neuroplasticity, has been implicated in severe mental illnesses such as schizophrenia, bipolar disorder, and major depressive disorder. The therapeutic potential of ketogenic interventions in these disorders suggests a link between metabolic disturbances and disease pathology; however, the precise mechanisms underlying these metabolic disturbances and the therapeutic effects of metabolic ketogenic therapy remain poorly understood. In this study, we conducted an in silico analysis of transcriptomic data to investigate perturbations in metabolic pathways in the brain across severe mental illnesses via gene expression profiling. We also examined dysregulation of the same pathways in rodent or cell culture models of ketosis, comparing these expression profiles to those observed in the disease states. Our analysis revealed significant perturbations across all metabolic pathways, with the greatest perturbations in glycolysis, the tricarboxylic acid (TCA) cycle, and the electron transport chain (ETC) across all three disorders. Additionally, we observed some discordant gene expression patterns between disease states and ketogenic intervention studies, suggesting a potential role for ketone bodies in modulating pathogenic metabolic changes. Our findings highlight the importance of understanding metabolic dysregulation in severe mental illnesses and the potential therapeutic benefits of ketogenic interventions in restoring metabolic homeostasis. This study provides insights into the complex relationship between metabolism and neuropsychiatric disorders and lays the foundation for further experimental investigations aimed at appreciating the implications of the present transcriptomic findings as well as developing targeted therapeutic strategies.

More than 20 lines of independent evidence from clinical observations, studies in laboratory animal models, pharmacokinetic considerations, and numerous temporal and spatial associations previously indicate that numerous genetic and environmental factors leading to inflammation and oxidative stress confer vulnerability to aberrant metabolism of acetaminophen during early development, leading to autism spectrum disorder (ASD). Contrary to this conclusion, multivariate analyses of cohort data adjusting for inflammation-associated factors have tended to show little to no risk of acetaminophen use for neurodevelopment. To resolve this discrepancy, here we use in-silico methods to create an ideal (virtual) population of 120000 individuals in which 50% of all cases of virtual ASD are induced by oxidative stress-associated cofactors and acetaminophen use. We demonstrate that Cox regression analysis of this ideal data set shows little to no risk of acetaminophen use if cofactors which create aberrant metabolism of acetaminophen are adjusted for in the analysis. Further, under-reporting of acetaminophen use is shown to be a considerable problem for this analysis, leading to large and erroneously low calculated risks of acetaminophen use. In addition, we argue that factors which impart susceptibility to acetaminophen-induced injury, and propensity for acetaminophen use itself, can be shared between the prepartum, peripartum, and postpartum periods, creating additional difficulty in analysis of existing datasets to determine risks of acetaminophen exposure for neurodevelopment during a specific time frame. It is concluded that risks of acetaminophen use for neurodevelopment obtained from multivariate analysis of cohort data depend on underlying assumptions in the analyses, and that other evidence, both abundant and robust, demonstrate the critical role of acetaminophen in the etiology of ASD.

Objective: Meningococcal meningitis (MM) is an acute, severe respiratory infectious disease caused by Neisseria meningitidis and remains an important cause of morbidity/mortality in children. Immunization with meningococcal vaccine (MV) is the most effective measure to control and prevent the transmission of MM. In this study, in order to support the appropriate use of various MVs in the prevention of MM, the effects of MVs, especially single-dose and inter-booster administered, on inflammatory parameters in

This study aims to provide an updated overview of the systematic evaluation and management of Post-Traumatic trigeminal neuropathic pain (PTTN) resulting from dental procedures or trauma. PTTN arises following an injury to the trigeminal nerve, which is responsible for sensory and motor functions in the maxillofacial region. The etiology encompasses various dental procedures and craniofacial trauma, leading to a spectrum of symptoms, from tingling to severe pain. Diagnostic challenges stem from the absence of standardized criteria and the overlap with focal neuralgia, necessitating comprehensive evaluation. Misdiagnosis can result in prolonged suffering and unnecessary procedures. Successful management hinges on prompt diagnosis and interdisciplinary collaboration, with early intervention crucial in mitigating chronicity. While nerve recovery post-trauma is challenging, preventive measures through accurate evaluation and treatment are paramount.  Management for PTTN includes non-invasive and surgical interventions. Non-invasive intervention includes systematic and local pharmacological management. This review enhances uniformity in PTTN evaluation and treatment approaches despite standardized study limitations.

The hyperactivation of the sympathetic nervous system (SNS) is linked to obesity, hypertension, and type 2 diabetes, with elevated norepinephrine (NE) levels being a key feature. Previous research has shown increased sodium-glucose cotransporter 1 (SGLT1) protein in kidneys of hypertensive rodents, prompting investigation into SGLT1 expression in other tissues such as skeletal muscle. This study aimed to assess: i) whether skeletal muscle cells and tissue express SGLT1 and SGLT2 protein; ii) if NE increases SGLT1 in skeletal muscle cells and iii) whether skeletal muscle of neurogenically hypertensive mice exhibits increased SGLT1 expression. We found that i) skeletal muscle cells and tissue are a novel source of SGLT2 protein and ii) NE significantly elevated SGLT1 in skeletal muscle cells. As SGLT2 inhibition (SGLT2i) with Empagliflozin increased SGLT1, in vivo studies with the dual SGLT1/2i, Sotagliflozin were warranted. Treatment of neurogenically hypertensive mice with Sotagliflozin significantly reduced blood pressure. Our findings suggest that SNS activity upregulates the therapeutic target, SGLT1 in skeletal muscle, potentially worsening cardiometabolic control. As clinical trial data suggests cardiorenal benefits with SGLT2i, future studies should aim to utilize sole SGLT1i which may offer a therapeutic strategy for conditions with heightened SNS activity, such as hypertension, diabetes and obesity.

Spontaneous splenic rupture (SSR) is a relatively rare, but potentially lethal complication of infectious mononucleosis (IM). While SSR is extremely rare in patients with proven IM, it is the most lethal complication of the infection (9% mortality rate) and can present completely asymptomatically or with abdominal pain and hemodynamic instability. As adolescents and young adults are the most affected population group, with this case report we intend to raise the vigilance of any doctor treating those patients in the emergency department. We present the case of a 16-year-old patient with an atraumatic splenic rupture and hemoperitoneum secondary to an Epstein-Barr virus (EBV) infection. The patient underwent an exploratory laparotomy, and a splenectomy was performed. This case demonstrates that even if the SSR in patients with IM is extremely rare, it should be always considered in a patient with relevant clinical presentation.

Diagnosing congenital heart disease (CHD) remains challenging because of its complex morphology. Representing the intricate structures of CHD on conventional two-dimensional flat screens is difficult owing to wide variations in the pathologies. Technological advancements, such as three-dimensional printed heart models (3DPHM) and virtual reality (VR), could potentially address the limitations of viewing complex structures using conventional methods. This study aimed to investigate the usefulness and clinical value of four visualization modalities across three different cases of CHD, including ventricular septal defect, double outlet right ventricle, and tetralogy of fallot. Seventeen cardiac specialists were invited to participate in this study, which was aimed at assessing the usefulness and clinical value of four visualization modalities, namely, DICOM images, 3DPHM, VR, and 3D PDF. Of these modalities, 76.4% of the specialists ranked VR as the best for understanding the spatial associations among cardiac structures and for presurgical planning. Meanwhile, 94.1% ranked 3DPHM as the best modality for communicating with patients and their families. Of the various visualization modalities, VR was the best tool for assessing anatomical locations and vessels, comprehending the spatial relationships among cardiac structures, and for presurgical planning. The 3DPHM models were the best tool for medical education as well as communication. In summary, both 3DPHM and VR have their own advantages and outperform the other two modalities, i.e., DICOM images and 3D PDF, in terms of visualizing and managing CHD.

Objective. To test the hypothesis that a session of unilateral tSMS over the dominant primary motor cortex (M1) in healthy subjects produces a transient decrease in manual dexterity. Methods. A triple-blinded randomized control trial was conducted in 40 healthy participants who were allocated to real- or sham-tSMS group. Each participant underwent one session of tSMS and were assessed before, immediately after, 15 minutes, and 40 minutes after stimulation. Outcome measures were Finger Tapping Test (FTT), 5-seconds FTT, nine Hole Peg Test, and the hand grip assessment. Results: Significant differences were found between groups 15 minutes after stimulation in favor of the tSMS group in the FTT (2.2 ± 0.99; CI= .18-4.22; d= .84p=.034), and 5-second FTT (4.2 ± 1.98; CI= .199-8.2, d= .68; p=.04). In the intragroup analysis, a significantly lower number of taps 15 minutes after stimulation was observed in sham group (3.3 ± 1.01; CI= .47-6.13; d= .42; p=.015), but not in the real stimulation group. Conclusion: A unilateral session of tSMS in the M1 of the dominant hemisphere of healthy individuals does not reduce manual dexterity or grip strength. This technique could have benefits on the motor performance of the arm contralateral to the stimulated motor cortex

Background Main treatment modality for spinal meningiomas (SM) is gross total resection (GTR). However, optimal timing of surgery, especially in cases with absent or mild neurological symptoms remains unclear. The aim of this study is to assess the impact of early-stage resection on neurological outcome, quality of life (QoL) and quality of care. The primary objective was a favorable neurological outcome (McCormick scale 1); Methods: We retrospectively analyzed data from patients operated on SM between 2011 and 2021. Patients with mild neurological symptoms preoperatively (McCormick scale 1 and 2) were compared to those with more severe neurological symptoms (McCormick scale 3-5). Disabilities and QoL were assessed according to validated questionnaires (SF36, ODI, NDI). Results: Age, spinal cord edema, thoracic localization, and spinal canal occupancy ratio were associated with more severe neurological symptoms (all p<.05). Patients presented with mild symptoms were associated with favorable neurological outcome (OR: 14.778 (95%CI 3.918-55.746, p<.001), which is associated with shorter hospitalization, better QoL and less disabilities (p<.05). Quality of care was comparable in both cohorts; Conclusions: Early surgical intervention of SM, before the development of severe neurological deficits, should be considered as it is associated with a favorable neurological outcome and quality of life.

Androgenetic alopecia, the most common cause of hair loss affecting both men and women, is typically treated using pharmaceutical options such as minoxidil and finasteride. While these medications work for many individuals, they are not suitable options for all. To date, the only non-pharmaceutical option that the United States Food and Drug Administration has cleared as a treatment for androgenetic alopecia is low-level laser therapy (LLLT). Various clinical trials utilizing LLLT devices of various types are available. However, a myriad of other physical treatments for this form of hair loss are reported in the literature. This review evaluated the effectiveness of microneedling, pulsed-electromagnetic field (PEMF) therapy, low-level laser therapy (LLLT), fractional laser therapy, and non-ablative laser therapy for the treatment of androgenetic alopecia (AGA). It also explores the potential of multimodal treatments combining these physical therapies. LLLT has the majority of evidence in the literature as a physical therapy for androgenetic alopecia. However, other physical treatments, such as non-ablative laser treatments, and multimodal approaches, such as PEMF-LLLT, seem to have the potential to be equally or more promising and merit further exploration.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.

Depression is the most common chronic mental illness and is characterized by low mood, insomnia, and affective disorders. However, the pathological mechanisms of depression remain unclear. Numerous studies have suggested that the ghrelin/GHSR system may be involved in the pathophysiologic process of depression. Ghrelin plays a dual role in the experimental animals, increasing depressed behavior and decreasing anxiety. By combining several neuropeptides and traditional neurotransmitter systems to construct neural networks, it modifies signals connected to depression. The present review emphasizes the role of ghrelin in neuritogenesis, astrocyte protection, inflammatory factor production, and endocrine disruption in depression. Furthermore, ghrelin/GHSR can activate multiple signaling pathways to produce antidepressant effects, including cAMP/CREB/BDNF, PI3K/Akt, Jak2/STAT3, and p38-MAPK. Given the antidepressant effects of ghrelin/GHSR1a system, it is expected to become a potential therapeutic target for the treatment of depression.

(1) Background : When placing implants in the maxillary posterior region with insufficient alveolar bone, a maxillary sinus elevation is necessary. Autogenous bone, though biologically ideal, poses risks and discomfort due to donor site harvesting. Block-type autogenous tooth bone graft material, made from the patient’s own extracted tooth, offers similar biological stability without these drawbacks; (2) Methods : This study observed the progress of 19 implant patients who were treated with maxillary sinus elevation procedures using block-type autogenous tooth bone graft material at the Daegu Catholic University Medical Center. Extracted teeth were processed into demineralized tooth block bone. After elevating the sinus membrane, implants and the tooth bone graft material were placed in the space, and the bony window was repositioned. Postoperative evaluations through clinical observation and radiographic imaging assessed sinus membrane elevation, alveolar bone height increase, and implant osseointegration; (3) Results : Results showed proportional increases in alveolar bone height to the graft material size, with long-term stability. No postoperative complications occurred, even with sinus membrane perforation, and implants remained stable; (4) Conclusions : The study concludes that maxillary sinus lifts using block-type autogenous tooth bone graft material provide excellent bone induction and biocompatibility, making it a highly beneficial method for both dentists and patients.

Background and Objectives: Pulmonary Hypertension (PH) is a clinical condition with high mortality rates, particularly in patients over 65. Current guidelines recommend assessing the Probability of Pulmonary Hypertension (PHP) using advanced echocardiography, before pro-ceeding to right heart catheterization. This study proposes using the common femoral vein (CFV), an accessible vein that reflects right atrial pressure, as an alternative method to assess the like-lihood of severe PHP. Materials and Methods: This prospective observational study included 175 emergency patients from three hospitals. Ultrasound assessed the Pulsed Wave Doppler (PW-Doppler) morphology of the CFV. This diagnostic yield for high PHP was evaluated along-side traditional ultrasound parameters (right-to-left ventricular basal diameter ratio greater than 1 (RV>LV), septal flattening, right ventricular outflow acceleration time of less than 105 ms and/or mesosystolic notching, pulmonary artery diameter greater than the aortic root diameter or over 25 mm, early pulmonary regurgitation maximum velocity >2.2 m/s, TAPSE/PASP less than 0.55, in-ferior vena cava (IVC) diameter over 21 mm with decreased inspiratory collapse, and right atrial (RA) area over 18 cm²). Results: The CFV's PW-Doppler cardiac pattern correlated strongly with high PHP, showing a sensitivity (Sn) of 72% and a specificity (Sp) of 96%. RA dilation and TAPSE/PASP < 0.55 also played significant diagnostic roles. Conclusions: The CFV's PW-Doppler cardiac pattern is an effective indicator of high PHP, allowing reliable exclusion of this condition when absent. This approach could simplify initial PHP evaluation in emergency settings or where echocardiographic resources are limited.

Background/Objectives Bowel endometriosis (BE) is defined as the presence of endometrial-like tissue in the muscular layer of the bowel wall. When BE does not cause severe obstruction to fecal transit, not leading to (sub)occlusive symptoms, the decision to operate becomes challenging as intestinal surgery is associated with higher complication rates and long-term bowel dysfunction. The aim of this cross-sectional study is to evaluate the quality of life (QoL) in patients with BE undergoing medical therapy or expectant management, investigating the impact of characteristics of BE nodules on QoL and intestinal function. Methods A retrospective cross-sectional analysis was conducted on 580 patients with BE who did not undergo surgery but were treated conservatively by medical therapy or expectant management between January 2017 and August 2022. The diagnosis of BE was done by transvaginal ultrasound and confirmed at double contrast barium enema. After at least one year of follow-up, QoL and intestinal function of patients were evaluated by the Endometriosis Health Profile-5 (EHP-5) questionnaire and Bowel Endometriosis Symptom score (BENS), whereas pain symptoms were assessed by the Visual Analogic Scale (VAS 0-10). Statistical analysis was performed to investigate possible associations between QoL and characteristics of bowel nodules (dimension, location, and evidence of stenosis) as well as type and length of eventual medical therapy. Results Patients with BE had a satisfying overall QoL with a mean EHP-5 score of 105.42 ± 99.98 points and VAS lower than 3 for all pain domains; additionally, they did not show a significant impartment of bowel function with mean BENS score of 4.89 ± 5.28 points. Notably, patients under medical therapy had a better QoL than patients without therapy (p

The regulatory approvals of tumor agnostic therapies have led to reevaluation of the drug development process. Conventional models of drug development are histology-based. On the other hand, tumor agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. Basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently 8 tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and 5 targeted therapy agents. Pembrolizumab is an anti-PD-1 antibody that was the first FDA approved tumor agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, Dostarlimab was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for Rearranged During Transfection (RET) fusion-positive solid tumors. FDA approved the first combination therapy of dabrafenib, a B-Raf Proto-Oncogene Serine/Threonine Kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying BRAFV600E mutation. The most recent FDA tumor agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

Limited research has been conducted on the metabolites present in the essential oils (EOs) of Phlomoides rotata (Benth. ex Hook. f.) Mathiesen (PR, syn. Lamiophlomis rotata (Benth.) Kudô), and their potential pharmacological activities, such as antioxidant properties, are often overlooked. We conducted a metabolomics-based screening to identify the characteristic metabolites (CMs) in the EOs extracted from PR. Meanwhile, we evaluated their in vitro antioxidant activities (AOAs). The EOs obtained through hydro-distillation are characterized by a light yellow color and a fresh, elegant fragrance. Cryoprecipitation was used to separate the crystals (Crs) from the EOs, resulting in the crystal-free EOs (CFs). A total of 121 components are identified and quantified in the EOs, Crs, and CFs. Among them, 84 were reported for the first time from such EOs. The major compounds include long-chain fatty acids (LCFAs) and their esters, such as palmitic acid (PA), myristic acid (MA), linoleic acid (LA), oleic acid (OA), stearic acid, and methyl palmitate (MP). Furthermore, 11 kinds of apocarotenoids (also called norisoprenoids) were first systematically investigated. Among them, eight C13-norisoprenoids, with trans-β-damascenone (DN) being particularly notable for its flavor, were identified. A sum of 11 CMs are screened , including PA, MA, LA, OA, MP, hexahydrofarnesyl acetone, phytol (PT), DN, stearic acid, linalool, and hexanal. These CMs are biosynthesized through FAs and 2-C-Methyl-D-erythritol 4-phosphate/1-Deoxy-D-xylulose 5-phosphate pathways. The in vitro AOAs of EOs, Crs, CFs, and seven selected CMs (PA, MA, LA, OA, MP, PT, and DN) were evaluated. Generally, PA and MA exhibited pro-oxidant activities (POAs) or weak AOAs. LA and OA demonstrated POAs or weak AOAs at lower concentrations, but at higher concentrations, they displayed medium to strong AOAs. Importantly, the CFs typically exhibited stronger AOAs compared to the corresponding EOs and Crs, potentially due to variations in their PA content. Overall, this study provides valuable insights into the potential utilization of EOs from PR.

Malignant melanoma (MM) is the most fatal form of skin cancer, accounting for 90% of all skin cancer deaths. Multiple dysregulated cellular pathways are involved in MM, including the MAPK/ERK and PI3K/PTEN/AKT pathways, which can be targeted with novel targeted inhibitors. However, these blockades can be overcome through the activation of alternative pathways, leading to treatment resistance. The high immunogenicity of MM has been exploited using checkpoint inhibitors resulting in improved survival outcomes of patients with advanced MM. However, their side effect profile and prohibitive cost remain a challenge and the survival outcomes for patients with metastatic MM remain poor. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, metastasis, and treatment resistance. CSCs reside within the MM tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system (RAS), expressed in many cancer types, including MM. This article reviews the current treatment of advanced MM with targeted therapy and immune checkpoint blockers, highlights the emergence of mRNA vaccine. It also discusses the MM TME and its relationship with CSCs, and the local immune system and the paracrine RAS. It highlights the regulation of the MAPK/ERK and PI3K/AKT/mTOR pathways by the RAS via prorenin receptor and angiotensin II receptor 1, and how this relates to the CSCs and treatment resistance. This underscores the potential multi-modal therapeutic strategy by concurrent targeting of multiple components of the TME.

Despite the effectiveness of insulin injections in managing hyperglycemia in Type 1 Diabetes, they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential of various treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, and pancreatic islet cell transplantation. Results: MSCs demonstrate efficacy in T1DM treatment through immunomodulation and tissue regeneration, although further research is warranted to optimize their therapeutic potential. Gene therapy presents a promising approach despite challenges such as donor shortage and immune rejection. Pancreatic islet cell transplantation emerges as a viable option, albeit with associated risks including graft rejection and the need for immunosuppression. Teplizumab, an FDA-approved humanized monoclonal antibody, revolutionizes the treatment landscape of Type 1 Diabetes by significantly delaying its onset, offering a paradigm shift since the discovery of insulin Conclusion: Ongoing studies and technological advancements in T1DM management offer a promising outlook for improved treatments and possibly even eradication on a global scale. MSCs, MSC-derived exosomes, gene therapy, and pancreatic islet transplantation hold considerable potential.

Background: Gram-negative bacteremia, especially from Klebsiella spp., Escherichia coli, and Pseudomonas aeruginosa, poses a significant public health threat due to multidrug resistance and high mortality rates. Cost-effective treatments are essential in low-middle income countries as Colombia. Methods: This descriptive, phase IV study was conducted in a tertiary care hospital in Colombia. Adult patients with Gram-negative bacteremia treated with generic piperacillin/tazobactam (Penibactam®) were evaluated. Clinical and microbiological responses were assessed over 12 months. Results: The study included 30 critically ill patients with an average APACHE II score of 22.12. The clinical response at day 7 was 66% (n = 20), and the microbiological response was 56.7% (n = 17). By the end of follow-up, clinical improvement was observed in 63.3% (n = 19), with a mortality rate of 23% (n = 7). The cardiovascular system was the most common infection site. Conclusions: Generic piperacillin/tazobactam demonstrated effectiveness and safety comparable to existing literature in treating Gram-negative bacteremia, offering a viable, cost-effective alternative for critically ill patients in real-world settings.

This review article delves into the multifaceted nature of primary ovarian insufficiency (POI), a condition marked by diminished ovarian function before age 40, underscoring the complexity of its aetiology encompassing genetic, autoimmune, infectious, and environmental factors. A significant focus is placed on the potential role of single-gene mutations, such as those in FMR1, BMP15, and GDF9, in the pathogenesis of POI, highlighting the intricate interplay between genetics and ovarian health. The article also explores innovative therapeutic avenues, including the activation of dormant follicles in vitro, offering hope for fertility restoration in affected individuals. Despite the prevalence of traditional treatments, such as Chinese medicine and hormone therapy, in China, these approaches often need to meet therapeutic needs, underscoring the urgency for advanced research and tailored treatment strategies. The discovery of a pituitary tumour-associated POI case further complicates the diagnostic landscape, suggesting a broader diagnostic lens and more in-depth research to unravel the complex underpinnings of POI and enhance patient care.

Mitochondria play a significant role in the functioning of the cell, acting both as an intracellular energy source and a signaling organelle. In the heart, mitochondria produce more than 95% of the ATP in addition to regulating the redox state, calcium homeostasis, apoptosis, and lipid synthesis. However, there is also evidence that mitochondria exist outside of cells where they have been observed to mediate cell-to-cell communication, repair, and participate in the immune response. Cardiometabolic disease (CMD) has a complex pathogenesis closely associated with mitochondrial dysregulation, inflammation, and metabolic abnormalities. Because of this metabolic interdependence between the myocardium and the intracellular mitochondria, circulating extracellular mitochondria (CEMI) are being identified as possible regulators of CMD. Outside of the cell, mitochondrial functions are determined by the mitochondrial form, either as whole functional structures (e.g., small extracellular mitochondria) or as mitochondrial components with or without membrane encapsulation. Here, we explore the different forms of CEMI, their role in CMD pathogenesis, their potential therapeutic utility in treating diseases, and their role as biomarkers.

We present a case of adult-onset systemic chronic active EBV disease (CAEBV) in a 40-year-old woman with chronic HBV hepatitis. Initial symptoms resembled a viral illness, progressing to recurrent fever, transaminitis, and anasarca. Investigations revealed high-level EBV viremia and an abnormal T-cell population in liver and bone marrow, indicative of CAEBV. Liver biopsy showed CD3+ T-cells lacking TCRbeta and displaying dim/negative CD5, with elevated EBV-infected T-cells. Next-generation sequencing identified rare variants in CREBBP, SPEN, TP73, and PLCG2, suggesting potential contributions to disease pathogenesis. This case underscores diagnostic challenges and management complexities of adult-onset CAEBV, particularly with underlying chronic HBV infection. Genomic profiling offers crucial insights into the molecular landscape of rare lymphoid malignancies, highlighting the importance of personalized treatment strategies. The distinct immunophenotypic features underscore the heterogeneity in EBV-associated T-cell LPDs, urging further research for optimized clinical management

Beta thalassemia is an inherited blood disorder that results in inefficient erythropoiesis due to genetic mutation that leads to reduction or absence of the hemoglobin beta-globulin protein. Approximately 8.5% of UAE residents suffer from β-thalassemia, a significant health and financial problem. The treatment options available for β-Thalassemia major are limited and associated with a wide range of complications. β-thalassemia gene therapy is emerging as a potential novel treatment option that eliminates the complications caused by the current long-term treatment modalities and the associated economic burden. This paper reviews the scientific literature related to emerging gene-therapy for β-Thalassemia by analyzing all the articles published from January 2010 to December 2023 in the English language on Databases like PubMed, Scopus, ProQuest, and CINAHL. The use of gene therapy has demonstrated promising outcomes for a permanent cure of β-Thalassemia. ZYNTEGLO (Betibeglogene autotemcel) is the only cell-based gene therapy which was approved by the FDA on 19th August, 2018. To conclude, Gene therapy is an innovative solution. It demonstrates a promising future, but does come with its own set-backs and is something that must be tackled in-order to revolutionize it in the medical world. FDA approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost; a price of $2.8million per patient.

Recent studies have shown that the endogenous cannabinoid system (ECS) of the brain is essentially involved in the pathogenesis of Parkinson's disease (PD), influencing its symptoms by regulating the level of endogenous cannabinoids and altering the activation of cannabinoid receptors (CBR). Therefore, modulation of ECS with new drugs developed for this purpose may prove to be a promising strategy in the treatment of PD. However, fine regulation of ECS is quite a challenge due to the functional diversity of CBR in the basal ganglia. Our review analyses the effects of ECS modulators on experimental PD models and in patients with PD, as well as presents the outlooks for the development of new cannabinoid drugs for the treatment of motor and non-motor symptoms in PD.

Abstract: Background: In 2021, two randomized controlled trials (RCTs), TheraP and VISION, demonstrated that 177Lu-PSMA-617 as monotherapy was more effective for enhancing the decline of PSA than the comparator third-line treatments. Methods: Our review summarizes new RCTs that add to the use of radioligand therapy (RLT) for patients with high-risk prostate cancer (PCa). Results: Five past and present RCTs include 1139 patients. A RCT, ENZA-p, studied first-line treatment of patients with metastatic castration-resistant PCa (mCRPC). A combination of enzalutamide (ENZA) and 177Lu-PSMA-617 gave longer progression-free survival than ENZA as monotherapy. Other RCTs of patients with mCRPC, including the PSMAfore, and SPLASH trials, showed 177Lu-PSMA-617 as second-line treatment gave better progression-free survival than androgen receptor pathway inhibitors (combined p value 6 x 10-8). Conclusion: Patients with PCa may gain if they are given PSMA-RLT early in the treatment of PCa and as part of combination therapies.

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Interrupting the vicious cycle within neuron-microglia interactions may be a therapeutic goal in DE by limiting the inflammatory response.

Isokinetic testing of the knee joint is the “gold standard” in strength assessment in sport especially in soccer, where it is part of pre-season screening to establish norms in case of injuries. There are many devices on the market that make it difficult to use of normative data. Isokinetics literature in females’ soccer players is scarce in comparison to males. Furthermore, evaluation protocols strongly differ from each other, using different ranges of speeds, movement patterns and output data. Thus, it is difficult for the researcher and the clinician to choose a correct protocol for isokinetic evaluation in female soccer players. The indexes of isokinetic performance that are widely accepted are the hamstring/quadriceps (H/Q) ratio and dominant/non-dominant (D/ND) ratio as reference. In this review are highlighted some common features of isokinetic testing in female soccer players of different levels of qualification. From this study, it emerges that, for a reliable test, 3 reps at the speed of 60°/sec in knee flexion/extension is preferable due to the high reliability and that an optimal H/Q ratio in healthy female soccer players of different level of qualification and age is 50%, while the interlimb differences (D/ND) should be below 10%.

Candida albicans is an opportunistic fungus that becomes pathogenic and problematic under certain biological conditions. C.albicans may cause painful and uncomfortable symptoms, as well as deaths in immunocompromised patients. Therefore, early detection of c.albicans is essential. However, conventional detection methods are costly, slow and inaccessible to women in remote or developing areas. To address these concerns, we have developed a wearable and discrete naked-eye detectable, colorimetric platform for c.albicans detection. With some modification, this platform is designed to be directly adhered to existing feminine hygiene pads. Our platform is rapid, inexpensive, user-friendly, disposable and only requires three steps: i) addition of vaginal fluid onto sample pads; ii) addition of gold nanoparticle gel and running buffer, and iii) naked eye detection. Our platform is underpinned by selective thiolated aptamer-based recognition of 1,3-β-D glucan molecules- a hallmark of c.albicans cell walls. In the absence of c.albicans, wearable sample pads turn bright pink. In the presence of c. albicans, the wearable pads turn dark blue due to significant nanoparticle target-induced aggregation. We demonstrate naked eye colorimetric detection of 4.4 ×106 c.albicans cells per ml. We believe that this proof-of-concept platform has the potential to have a significant impact on women’s health, globally.

Poverty has long been associated intricately with neurological disorders. Majority of the previous studies designed to describe the effects of poverty on neurological ailments have mostly linked the association of hypoxic ischemic encephalopathy and nutritional deficiency disorders with poverty. Authors herein try to delve deeper into this issue. The association of begging with neuropsychiatric disorders is robust. The burden of probable autosomal dominant neurological ailments is very common among beggars; followed by neurological disorders with social stigma like abnormal movements, facial dysmorphism and gait unsteadiness. Dearth of support from family members in autosomal dominant neurological disorders (as family members are likely to be suffering from similar neurodegenerative disorder ) and poor perception about neurological diseases, misconceptions, myths and low educational attainment at large in the society can be implicated as the often overlooked but important factors underneath this association of begging and neurological disorders.

Background Endometrial cancer is the fourth most common type of cancer in the world. Due to the prevalence and high morbidity, it is of key importance to make a quick and accurate diagnosis and effective therapy. The use of photodynamic therapy (PDT) in the treatment of endometrial cancer is a significant challenge in conducting clinical trials. PDT is non-invasive, with few side effects, damaging only neoplastic tissue, leaving healthy adjacent structures intact. Thanks to numerous experiments (also in vitro), PDT is gaining more and more recognition as a potential tool in endometrium cancer treatment. Objective The aim of the study was to analyze the effectiveness of photodynamic therapy on endometrial cancer tissue samples Methods In the in vitro experiment of PDT, sections of endometrial cancer tissue taken from female patients were subjected to. Rose Bengal was used as a photosensitizer in order to assess the usefulness of the applied PDT and to introduce these solutions into the in vivo test procedure. Results Changes on the cellular substrate, such as: chromatin condensation, disturbed structure and shape of cell nuclei were observed in all tissues subjected to PDT. Conclusions The PDT experiment in vitro offers opportunities and hopes for using the chosen procedure also in vivo. Keywords endometrial cancer; photodynamic therapy; in vitro; treatment; rose bengal

Hearing loss (HL) is a major clinical, population and public health leading to serious disorders and often early mortality. However, there is a significant paucity in high quality data. Saudi Arabia has a genetically uniform and young population; however factors and estimates on prevalence of HL remains unknown. Background/Objectives: we aimed to determine the frequency, factors, and patterns of HL in different regions. Methods: this study was a descriptive cross-sectional design using a web-based online public questionnaire sent out simultaneously to different regions of Saudi Arabia; namely Eastern, Western, Northen, and Southern as self-administered non-probability sample of social media users mainly WhatsApp, Twitter, and others. Results: Among 789 responses, 6.6 % reported HL, 62.4% were from the Eastern province of which 41.2% were employed and 31.7% were students. Many (36.5%) reported HL &gt; 5-years while 21.2% had programmed and fitted with hearing aids or cochlear implants implying negligence. 19.2% reported diabetes and 51.9% had family history. Ages (11– 50 years) were examined with a slight female predominance (females 59.1%, males 41%). Age was significantly associated with HL (P &lt;0.001) irrespective of gender (males 6.8%, females 6.4%, P value =0.838) reaching peaks at 17.2% in age groups 51-60 years and 25% in 71-80 indicating a risk for HL (OR = 1.43, 95% CI: 0.78-2.81, p = 0.032). Genetic diseases reported as leading cause in 34.6% (OR = 2.23, 95% CI: 1.34-3.58, p = 0.432) followed by noise (26.9%), while other factors including infections, stroke, and fevers made 19.2%. Work involving air or sea travels reported (7.7%) with no significant association (P = 0.628) while history of head injury or trauma (11.5%), or relocation between low- and high-altitudes showed 21.2%. However, frequent noise pollution (OR = 1.54, 95% CI: 0.83-3.01, p = 0.048), regular use of medications (OR = 2.15, 95% CI: 1.03-3.32, p = 0.017), and history of inflammatory disorders (OR = 0.72, 95% CI: 0.32-1.87, p = 0.229) were also associated with higher odds of HL. Conclusion: thus, these findings have significant clinical implications in early diagnosis and management of HL in genetic disorders, diabetes, geriatrics, as well as awareness on family history and occupational health and safety. The study was limited in size and use of online questionnaires. Future large cohort multicenter study would gain more insights.

In patients with heart failure, the evaluation of left ventricular (LV) diastolic function is vital, offering crucial insights into hemodynamic impact and prognostic accuracy. Echocardiography stands as the primary imaging modality for diastolic function assessment, and using it effectively requires a profound understanding of the underlying pathology. This review covers four main topics: first, the fundamental driving forces behind each phase of normal diastolic dynamics, along with the physiological basis of two widely used echocardiographic assessment parameters, E/e' and mitral annulus early diastolic velocity (e'); second, the intricate functional relationship between the left atrium and LV in patients with varying degrees of LV diastolic dysfunction (LVDD); third, the role of stress echocardiography in diagnosing LVDD and the significance of parameter changes in this context; and fourth, the clinical utility of evaluating diastolic function from echocardiography images across diverse cardiovascular care areas.

In the frame of our diversity-oriented research on multitarget small molecule anticancer agents, utilizing convergent synthetic sequences terminated by Sonogashira coupling reactions, a preliminary selection of representative alkyne-tethered vindoline hybrids was synthesized. The novel hybrids with additional pharmacophoric fragments of well-documented anticancer agents, including FDA-approved tyrosine-kinase inhibitors (imatinib and erlotinib) or ferrocene or chalcone units, were evaluated for their antiproliferative activity on malignant cell lines MDA-MB-231 (triple negative breast cancer), A2780 (ovarian cancer), HeLa (human cervical cancer) and SH-SY5Y (neuroblastoma) as well as human embryonal lung fibroblast MRC-5 served as reference non-malignant cell line for the assessment of the therapeutic window of the tested hybrids. The biological assays identified a trimethoxyphenyl-containing chalcone-vindoline hybrid (36) as a promising lead compound exhibiting submicromolar activity on A2780 cells with a marked therapeutic window. These results suggest that ovarian cancer might be considered as a prioritized target of treatment with 36.

Curcumin has attracted attention for its nontoxic chemopreventive effects; however, the specific pathways underlying its anticancer effects in colon cancer remain unclear. This study investigated the potential interplay between curcumin and integrin β1 in colon cancer. HCT116 and fibroblast cells were treated with curcumin, and cell proliferation was assessed using MTT assay and western blotting. We analyzed integrin β1 expression after curcumin treatment of HCT116 cells using western blotting and confocal microscopy. The roles of talin and rab25 in integrin β1 activation by curcumin were investigated using the same methods. Curcumin treatment significantly decreased the survival of HCT 116 cells but did not significantly affect the survival of fibroblast cells. Moreover, curcumin significantly increased integrin β1 expression in HCT 116 cells, which was primarily mediated by talin. In contrast, rab25 expression remained unchanged after curcumin treatment. Using rab25-specific siRNA knockdown experiments, we confirmed that curcumin increased integrin β1 expression even in the absence of rab25. Confocal microscopy revealed a dose-dependent increase in integrin β1 and talin expression, with consistent spatial distribution patterns in response to curcumin. This study highlights the clinical significance of curcumin as a selective anticancer agent in colon cancer by modulating integrin β1 expression through a talin-mediated pathway rather than through rab25.

Background and objectives: Main aim of the study is to analyze the outcomes of NSTEMI admissions and testing the relevance of TIMI as a risk score in a real-world setting. Also looking at any potential social or health care disparities involved with outcomes of NSTEMI admissions. The study also investigates factors associated with mortality in NSTEMI admissions and correlation between in-hospital mortality and heart catheterization. . Materials and Methods: NSTEMI admissions were analyzed using the National Inpatient Sample. TIMI scores were calculated in the admissions and association between all-cause mortality and calculated TIMI score >=2 was analyzed. Difference in outcomes based on heart catheterization was studied in the subgroup with TIMI score >=2. Correlation between time to heart catheterization and all-cause mortality in NSTEMI admissions were analyzed. Results: No significant social or healthcare disparities were noted amongst outcomes for NSTEMI admissions. NSTEMI admissions with a calculated TIMI score >=2 had a statistically significant association with all-cause mortality during the admission. Prevalence of mortality among NSTEMI admissions with calculated TIMI score >2, who did not undergo heart catheterization was higher with statistical significance when compared to admissions that underwent heart catheterization. NSTEMI admissions with a calculated TIMI score >2 who underwent catheterization on or beyond the 4th day of hospitalization had statistically significant association with all-cause mortality during the admission. Age at admission, presence of CKD and CHF were associated with mortality in NSTEMI admissions, with statistical significance. Keywords: NSTEMI; TMI score; heart catheterization

The study examines the integration of postbiotics in food products through the use of attenuated probiotics, specifically lactic acid bacteria (LAB) in bread. Postbiotics, non-viable microorganisms or their metabolites, offer health benefits similar to probiotics without the risks associated with live bacteria. This research evaluates the regulatory aspects and safety of LAB in sourdough bread production, highlighting their historical and significant use in Europe before 1997. The study includes microbial quantification and Next-Generation Sequencing (NGS) to identify LAB in traditional sourdough, comparing them with historical and current EFSA Qualified Presumption of Safety (QPS) lists. Findings show that the LAB present in sourdough have been extensively and safely used in bread making, supporting their classification as non-novel foods under EU regulations. The stability and consistency of LAB metabolites in sourdough bread are also confirmed, ensuring quality and safety in each batch. The study concludes that LAB in sourdough, when inactivated through bread-making processes, are not considered novel foods, aligning with historical, scientific, and regulatory evidence.

Cardiovascular diseases are one of the most common causes of death in the United States of America and the sudden rise of patients having cancer are suffering from cardiovascular side effects of Chemotherapeutics drugs. Trastuzumab is a potent targeted agent for HER2-positive cancers though despite its excellent efficacy, the cardiotoxic effects of Trastuzumab restrict its usage globally. The most severe adverse effect is cardiotoxicity presents as contractile dysfunction that is reduction in left ventricular systolic function but the electrophysiological side effects are still not known. Due to these severe life-threatening side effects, it routinely results in the cessation of Trastuzumab. This review aims to provide a comprehensive overview of Trastuzumab-induced cardiomyopathy, offering insights into the mechanisms through which Trastuzumab exerts its cardiotoxic effects, clinical manifestations, diagnostic strategies, and potential cardioprotective interventions. By shedding light on the multifaceted aspects of this condition, we hope to emphasize the importance of early detection and effective management, while highlighting the urgent need for continued research to optimize the balance between oncological success and cardiovascular well-being. Cardiologists, oncologists, and researchers stand at the forefront of this critical intersection between oncology and cardiology, collectively striving to improve patient outcomes in the era of Trastuzumab therapy.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (&gt;12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.

Background and Objectives: This study aimed to evaluate the histological and biochemical ef-fects of capsaicin on implant osseointegration and oxidative stress. Materials and Methods: Male Wistar albino rats weighing between 250 and 300 grams were used in this study. Twenty-four rats were randomly divided into three equal groups: implant + control (n= 8), implant + capsai-cin-1 (n= 8), and implant + capsaicin-2 (n= 8). 2.5 mm diameter and 4 mm length titanium im-plants were surgically integrated into the corticocancellous bone parts of the femurs. In the treatment groups, rats were injected intraperitoneally with 25 mg/kg (implant + capsaicin-1) and 50 mg/kg (implant + capsaicin-2) of capsaicin. No additional applications were made in the con-trol group. Three rats in totally were died during and after the experiment, as a result of the an-alyzes performed on 21 animals. Results: The highest total antioxidant status value was found in capsaicin dose 2, according to the analysis. The control group had the highest total oxidant status and oxidative stress index values, while group 2 of capsaicin had the lowest. After analysis, we found that there was no observed positive effect on osteointegration in this study (p> 0.05), alt-hough the bone implant connection was higher in the groups treated with capsaicin. Conclusi-ons: A positive effect on osteointegration was not observed in this study. This may be due to os-teaclast activation. However it was found that it has a positive effect on oxidative stress. Osteo-clast activation may be the cause of this phenomenon. Capsaicin was found to have a positive effect on oxidative stress (p

The mutation in NF2 is the most common alteration associated with meningioma oncogenesis, and it is related to the loss of a suppressing protein called merlin. At the same time, alterations in energy production are visible in cancer cells where increased demand for energy is observed. Fatty acid oxidation could be one of the ways cancer cells obtain energy. This metabolic pathway uses the acylcarnitine shuttle system, which is responsible for the acylation of fatty acids and their transport through mitochondria. Therefore, this study aimed to profile acylcarnitines with short-, medium- and long-acyl chain length in meningiomas to assess their changes in tumors with different NF2 mutation statuses. For the analysis, solid-phase microextraction (SPME) coupled with liquid chromatography high resolution mass spectrometry (LC-HRMS) was used. The presented sampling method enables low invasive and easy collection of the analytes from the studied lesions, which can be crucial for future analysis of potential biomarkers in the surgery room. It was observed that higher levels of these analytes characterized meningiomas with NF2 mutation. Moreover, increased energy consumption and elevated levels of acylcarnitines show that these analytes can be considered as a marker of increased fatty acid oxidation in NF2 mutated cells.

Background: The transversus abdominis plane (TAP) block has gained increasing importance as a very effective pain relief in for caesarean section. This study aimed to compare bupivacaine (Group B), bupivacaine with dexmedetomidine (Group BD) and bupivacaine with dexamethasone (Group BDx) applied in ultrasound-guided TAP block in the treatment of CS postoperative pain. Material and Method: American Society of Anesthesiologists I and II pregnant women who underwent cesarean section were included in the study. Forty patients were admitted in each group. All patients were applied TAP block with ultrasound guidance by administering the medications of the group in which they were included. Results: Body mass index (BMI) and operation duration were higher in Group B (p*=0.01 and 0.004, respectively). Instant tramadol requirement and amount were higher in Group B at some of follow up times. Patient satisfaction scale were better in Group BD and Group BDx. Conclusion: TAP block significantly reduces pain after cesarean section, prolongs the time to first analgesic request, and reduces the need for additional opioid analgesics. The addition of adjuvant to the TAP block usually improves the postoperative clinical condition. However, some special conditions such as body mass index (BMI) may negatively affect the clinical situation. Comprehensive, standardized, randomized controlled studies are needed to compare results under different conditions.

Lung cancer (LC) is the second most common cancer and the leading cause of cancer deaths in the U.S. Insulin therapy, a key treatment for managing Type 2 Diabetes Mellitus (T2DM), may increase LC risk. The impact of non-insulin antidiabetic drugs, particularly GLP-1 receptor agonists (GLP-1RAs), on LC risk is not well understood. This study evaluated LC risk in T2DM patients comparing seven non-insulin antidiabetic agents to insulin. Using the TriNetX Analytics platform, we analyzed de-identified electronic health records of 1,040,341 T2DM patients treated between 2005-2019, excluding those with prior antidiabetic use or LC diagnoses. We calculated hazard ratios and confidence intervals for LC risk and used propensity score matching to control for confounding factors. All non-insulin antidiabetic drugs, except alpha-glucosidase inhibitors, significantly reduced LC risk compared to insulin, with GLP-1RAs showing the greatest reduction (HR: 0.49, 95% CI: 0.41, 0.59). GLP-1RAs were consistently associated with lowered LC risk across all histological types, races, genders, and smoking statuses. These findings suggest that non-insulin antidiabetic drugs, particularly GLP-1RAs, may be preferable for managing T2DM while reducing LC risk.

: Carcinoma-associated fibroblasts (CAFs) are highly accumulated in the tumor surrounding stroma of primary epithelial ovarian cancer (OC). CAFs exert important functions for the vascularization, growth and progression of ovarian tumor cells. However, no attention has been shown to their origin so far. It has been mainly assumed that CAFs in primary OC arise from the activation of resident fibroblasts. Here, we compare CAFs with ovarian location to CAFs found in peritoneal implants from patients with advanced OC. Our findings show that CAFs from primary tumors and peritoneal metastases share the expression of mesothelial-related markers. Therefore, as in peritoneal carcinomatosis, CAFs in primary ovarian carcinomas could be originated via a mesothelia-to-mesenchymal transition (MMT) process. The detection of mesothelial-derived CAFs in tumors confined to the ovary and associated biomarkers could be the key to early detection of peritoneal spread in affected patients.

The emergence of antimicrobial resistance have represented a serious threats for public health and infections due to multidrug-resistant (MDR) microorganisms represent one of the most important causes of death worldwide. The renew of old antimicrobials, such as colistin, have been proposed as valuable therapeutic alternative to the emergence of the MDR microorganisms. Although colistin is well known to presents several adverse toxic effect, its usage in clinical practice have been reconsidered due to the broad spectrum of activity to gram-negative (GN) bacteria and to the important role of “last resort” agent against MDR-GN. Despite the revolutionary prospective of treatment of this old antimicrobial molecule, many questions remain open regarding the emergence of novel phenotypic traits of resistance and the optimal usage of the colistin in clinical practice. In the last years, several forward steps have been done in the understanding of resistance determinants, clinical usage and pharmacological dosage of this molecule, however, different points regarding the role of colistin in clinical practice and the optimal pharmacokinetic/pharmacodynamic targets are not well defined yet. In this review, we summarize the mode of action, the emerging resistance determinants and its optimal administration in the treatment of difficult-to-treat infections due to MDR Gram-negative bacteria.

Previous studies show that women with a history of high-grade CIN have a greater risk of subsequent high-grade anogenital intraepithelial neoplasia or cancer, and the risk is greater for vaginal cancer than for anal and vulvar cancers. It is hypothesized that the laparoscopic hysterectomy procedure may cause a higher incidence of VaIN in hysterectomized women. There are few studies addressing this issue and they show mixed results. This study aimed to investigate the incidence of high-grade or worse VaIN in the population of women undergoing hysterectomy for CIN3 or benign uterine disease, illustrate treatment options and follow-up. Methods: This retrospective study was conducted on 170 women who underwent laparoscopic hysterectomy for high-grade cervical intraepithelial neoplasia (CIN3) or benign gynecological disease. The follow-up strategy included performing a cotest and colposcopy with biopsy if necessary. The median time between primary treatment and diagnosis of high-grade VaIN was 18 months. Results: High grade or worse VaIN was found in 8 patients after hysterectomy (4.7%). All cases of high-grade VaIN occurred in women with persistent HPV infection. The most frequent genotype was 16. Women hysterectomized for CIN3 showed an 8-fold greater risk than women hysterectomized for benign disease of developing high-grade VaIN. The risk of VaIN is low in women hysterectomized for benign disease. The risk of developing VaIN is greater in women with viral persistence Conclusion. All these elements suggest that it is the history of HPV-related disease of the lower genital tract and viral persistence, rather than hysterectomy itself, that should be considered a risk factor for the development of high-grade VaIN. After hysterectomy, patients with a history of CIN should undergo annual screening with vaginal dome cytology and HPV testing.

Respiratory Syncytial Virus (RSV) continues to pose a significant challenge, contributing to elevated hospitalization rates among children up to 5 years old, with a disproportionate burden on newborn and infants under 6 months old. The unique characteristics of the young immune system make it prone to altered responses to infections and vaccinations, requiring a tailored approach to disease prevention. The recent approval of the maternal RSV vaccine, (brand name ABRYSVO), represents a pivotal advancement in preventive strategies among newborns and infants, marking a milestone in RSV research as the first market-approved maternal vaccine. The present review examines clinical trial data on both recent and previous vaccine candidates, as well as the licensed vaccine, focusing on the prevention of RSV disease in newborns and young infants through the passive acquisition of antibodies following maternal immunization. Additionally, it evaluates the safety profile of these vaccines.

The accurate identification of bacterial infections is critical for effective treatment in intensive care units (ICUs), yet current diagnostic methods face limitations in sensitivity and specificity, along-side cost and accessibility issues. Consequently, there's a pressing need for a marker that is economically feasible, rapid, and reliable. Presepsin (PSP), also known as soluble CD14 subtype (sCD14-ST), has emerged as a promising biomarker for early sepsis diagnosis. PSP, derived from soluble CD14, reflects the activation of monocytes/macrophages in response to bacterial infec-tions. It has shown potential as a marker of cellular immune response activation against patho-gens, with plasma concentrations increasing during bacterial infections and decreasing post-antibiotic treatment. Unlike traditional markers such as procalcitonin (PCT) and C-reactive protein (CRP), PSP specifically indicates monocyte/macrophage activation in bacterial infections. While limited studies in critical illness have explored PSP's role in sepsis, its diagnostic accuracy varies with threshold values, impacting sensitivity and specificity. Recent meta-analyses suggest PSP's diagnostic potential for sepsis, yet its standalone effectiveness in ICU infection management remains uncertain. This review provides a comprehensive overview of PSP's utility in ICU set-tings, including its diagnostic accuracy, prognostic value, therapeutic implications, challenges, and future directions.

Evaluation of drug permeability using cell monolayers is an important in vitro assay in the process of drug development, to identify compounds with favourable pharmacokinetics that may proceed to in vivo studies. When allowed to differentiate on permeable filters for at least 21 days, monolayers of Caco-2 cells develop morphological and functional properties similar to those of the intestinal epithelium. Permeability through Caco-2 monolayers is thus particularly relevant to assess drug absorption after oral administration. The major drawback of this assay is its very low throughput, with the cell monolayers being used in a single permeability assay. We have previously proposed a protocol to allow the re-use of the Caco-2 monolayer on additional permeability assays during the stable period and shown that cell monolayer integrity is maintained. In this work we evaluate the effect of re-use on the permeability of several reference compounds that permeate through passive pathways and show that the cell monolayers can be re-used twice in additional permeability assays. Preliminary results were also obtained regarding active transport pathways, and a new methodology is proposed to quantify the contribution from passive and active transport. This is a major step towards the full validation of the re-use methodology proposed, which at least triplicates the throughput of this important in vitro assay.

We report an unusual case of Terson's syndrome that resulted in the di-agnosis of a right posterior communicating artery aneurysm. Interest-ingly Terson's syndrome presented with Roth spot resembling features accompanied by third nerve palsy in a patient without any disturbance of consciousness. To our knowledge, the association of Terson's syndrome with third nerve palsy has not been described before in the absence of radiologically diagnosed subarachnoid haemorrhage. We present the case of a 48-year old woman who presented in the De-partment of Emergencies of the University Hospital of Patras with right-sided complete pupil-involving third nerve palsy combined with bilateral Terson's syndrome. More precisely, fundoscopy revealed multi-ple scattered intra- and pre-retinal haemorrhages in both eyes while some retinal haemorrhages had a white-centered pattern resembling Roth spots. Neurological examination revealed no nuchal rigidity or any other neurological signs. The Glasgow coma scale was 15/15. A cerebral computed tomography angiography revealed a 5mm aneurysm of the right posterior communicating artery and the patient underwent a mi-crovascular clipping operation after craniotomy. The significant contribution of the ophthalmological consultation to the appropriate and timely diagnosis and management of a life-threatening condition is highlighted.

Serum neurofilament light chain (sNfL) levels have been proposed as a biomarker of the clinical activity, disability progression, and response to treatment of people with multiple sclerosis (PwMS); however, questions remain about its implementation in clinical practice. Ocrelizumab (OCR) has proven effective to improve clinical and radiological outcomes and to reduce sNfL levels. This real-life study followed the sNfL levels of 30 PwMS treated for 12 months with OCR and evaluated the usefulness of this biomarker for the short-term prognosis, considering expanded disability status scale (EDSS), annualized relapse rate (ARR), radiological activity, and NEDA-3 values. OCR reduced the ARR in 83% of PwMS and the radiological activity in 80%. Their EDSS was maintained, while NEDA-3 was achieved in 70% at 12 months. OCR produced an early reduction in sNfL levels (at 3 months). At baseline, greater MRI-evaluated radiological activity was associated with higher sNfL levels. sNFL levels over the first 12 months of treatment did not predict a suboptimal response or sustained control of the disease. Longer-term studies are needed to explore the predictive usefulness of sNfL levels in PwMS treated with high-efficacy drugs

Abstract: Physicians, physical therapists, and occupational therapists have traditionally assessed hand motor function in hemiplegic patients but often struggle to evaluate complex hand move-ments. To address this issue, in 2019, we developed Fahrenheit, a device and algorithm that uses infrared camera image processing to estimate hand paralysis. However, due to Fahrenheit's de-pendency on specialized equipment, we conceived a simpler solution: developing a smartphone app that integrates MediaPipe. The objective of this study was to measure hand movements in stroke patients using both MediaPipe and Fahrenheit and to assess their criterion-related validity. The analysis revealed moderate-to-high correlations between the two methods. Consistent results were also observed in the peak angle and velocity comparisons across severity stages. Because Fahrenheit determines finger recovery status based on these measures, it has the potential to transfer this function to MediaPipe. This study highlighted the potential use of MediaPipe in pa-ralysis estimation applications.

Background: Electrical Impedance Tomography (EIT), combined with variable ventilation strate-gies and Artificial Intelligence (AI), is poised to revolutionize critical care by transitioning from reactive to predictive approaches. This integration aims to enhance patient outcomes through personalized interventions and real-time monitoring. Methods: This narrative review explores the principles and applications of EIT, variable ventilation, and AI in critical care. EIT’s impedance sensing creates dynamic images of internal physiology, aiding in the management of conditions like Acute Respiratory Distress Syndrome (ARDS). Variable ventilation mimics natural breathing variability to improve lung function and minimize ventilator-induced lung injury. AI enhances EIT through advanced image reconstruction techniques, neural networks, and digital twin technology, offering more accurate diagnostics and tailored therapeutic interventions. Conclu-sions: The confluence of EIT, variable ventilation, and AI represents a significant advancement in critical care, enabling a predictive, personalized approach. EIT provides real-time insights into lung function, guiding precise ventilation adjustments and therapeutic interventions. AI inte-gration enhances EIT's diagnostic capabilities, facilitating the development of personalized treatment plans. This synergy fosters interdisciplinary collaborations and sets the stage for in-novative research, ultimately improving patient outcomes and advancing the future of critical care.

Renal cell carcinoma (RCC) accounts for approximately 90-95% of all kidney cancers in adults, with the clear cell RCC (ccRCC) the most frequently identified subtype. RCC is known for its responsiveness to immunotherapy, making it an area of significant research interest. Immune checkpoint (IC) molecules, which regulate immune surveillance, are established therapeutic targets in RCC. The aim of this study was to analyze the influence of polymorphisms in genes HVEM and CD160 on susceptibility to ccRCC and patient overall survival (OS) with over a ten-year period of observation. We genotyped three HVEM single nucleotide polymorphisms (SNPs): rs1886730, rs2234167, and rs8725, and two CD160 SNPs: rs744877 and rs2231375, in 238 ccRCC patients and 521 controls. Our findings indicated that heterozygosity within rs2231375 and/or rs2234167 increases ccRCC risk. Furthermore, in women, heterozygosity within additional HVEM SNPs, rs8725 and rs1886730, is associated with an increased ccRCC risk. The presence of a minor allele for rs1886730, rs2234167, rs8725, and rs2231375 was also correlated with certain clinical features of the disease. Moreover, the rs1886730 SNP was found to be associated with patients' OS. In conclusion, our study highlights an association between HVEM and CD160 polymorphisms and the risk of developing ccRCC as well as patient’s OS.

With around one billion of the world's population affected, the era of Metabolic-associated fatty liver disease (MAFLD) pandemic has entered the global stage. MAFLD is a chronic progressive liver disease with accompanying metabolic disorders such as type 2 diabetes mellitus and obesity which can progress asymptomatically to liver cirrhosis and subsequently to hepatocellular carcinoma (HCC), and for which, to date there is almost no approved pharmacologic options. Because MAFLD has a very complex etiology and it affects also extrahepatic organs, a multidisciplinary approach is required when it comes to finding an effective and safe active substance for MAFLD treatment. The optimal drug for MAFLD should diminish steatosis, fibrosis and inflammation in the liver, and the winner for MAFLD drug authorisation seems to be the one that significantly improves liver histology. Saroglitazar (Lipaglyn®) was approved for Metabolic dysfunction associated steatohepatitis (MASH) in India in 2020; however, the drug is still being investigated in other countries. Despite that a pharmaceutical industry is still lagging behind to develop an ap-proved pharmacologic therapy for MAFLD, research has been recently intensified and many molecules which are underway in the final stages of clinical trials are expected to be approved in the coming few years. Already this year, the first drug (Rezdiffra™) in the United States was ap-proved via accelerated procedure for treatment of MAFLD, i.e. of MASH in adults. This review underscores the most recent information related to the development of drugs for MAFLD treatment, focusing on the molecules that have come furthest towards approval.

Liver cancer is the fourth leading cause of cancer-related death worldwide. In Mexico, there is a high burden of liver cancer mortality in rural states, which affects both women and men equally. Thus, we aimed to describe the demographic and clinical characteristics of hepatocellular cancer (HCC) by sex in Mexico. Demographic and clinical information were extracted retrospectively from the medical records of patients with HCC initially treated (2015-2022) at participating institutions of a national survey across the country. The male-to-female ratio was calculated at the national and regional levels and the results were stratified by sex. Among 697 HCC patients, the age at diagnosis was 65.4±11.9y and 20% were diagnosed at ≥75y. The male-to-female ratio was 1.4:1, ranging from 1:1 in the northwestern and southwestern regions to 2.1:1 in the western region. The proportion of cirrhosis was similar between sexes; however, the etiologies for cirrhosis differed: cryptogenic cirrhosis was higher in women and alcohol consumption was higher in men. Men had a higher proportion of advanced HCC, poor/undifferentiated tumors, and ≥4 nodules than women. HCC in the Mexican population affects men and women at a 1.4:1 male-to-female ratio. This unique proportion by sex could be explained by the differences in the prevalence of risk factors across our heterogeneous country.

This study examines the relationship between semantic memory and social cognition in schizophrenia, addressing how these cognitive domains intersect. Semantic memory, which includes general world knowledge and word meanings, was evaluated using verbal fluency tasks and the Camels and Cactus Test. Social cognition, essential for social interaction, was assessed through emotion recognition (Faces Test) and Theory of Mind (Hinting Task). Participants included 50 individuals with schizophrenia and 30 controls. The schizophrenia group showed significantly lower performance on both semantic memory and social cognition tasks. Notably, strong correlations were found between the Camels and Cactus Test and social cognition measures, suggesting that social cognition deficits in schizophrenia may be linked to semantic memory impairments. Regression analyses highlighted that the Camels and Cactus Test significantly predicted social cognition performance, independent of symptomatology. These findings underscore the interconnectedness of semantic memory and social cognition in schizophrenia, suggesting that semantic memory deficits, particularly in non-categorical associations, play a important role in social cognitive impairments. This study provides new insights into the cognitive underpinnings of schizophrenia, emphasizing the need for further research to explore these relationships and their implications for cognitive models and therapeutic interventions.

: Cytokine storm is usually described as one of the main reasons behind COVID-associated mor-tality. Cytokines are essential protein molecules engaged in immune responses; they play a critical role in protection against infections. However, they also contribute to inflammatory reactions and tissue damage, becoming a double-edged sword in the context of COVID-19. Recent studies have suggested various cytokines and chemokines that play a crucial role in the immune response to SARS-CoV-2 infection. One such cytokine is Interleukin 27 (IL-27), which has been found to be elevated in the blood plasma of patients with COVID-19. Within this study, we will explore the role of IL-27 in immune responses and address our own findings concerning this cytokine in COVID-19. It affects a wide variety of immune cells; regardless of the pathological process it is involved in, IL-27 is critical for upholding the necessary balance between tissue damage and cytotoxicity against in-fectious agents and/or tumors. In COVID-19, it is involved in multiple processes, including antiviral cytotoxicity via CD8+ cells, IgG subclass switching, and even the activation of Tregs.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

Copper (Cu) is a critical element for cancer cell proliferation and considerably accumulates in the nucleus. 64Cu2+ is an anticancer radiopharmaceuticals targeting the copper requirement of cancer cells. However, intravenously injected 64Cu2+ ions primarily accumulate in the liver. Ligand complexation of 64Cu2+ would be a promising method for increasing tumor delivery by reducing liver uptake. Herein, we used three tripodal amine ligands [tris(2-aminoethyl)amine (Tren), diethylenetriamine (Dien), and tris(2-pyridylmethyl)amine (TPMA)] to enclose 64Cu2+ ions and compared their in vivo tumor and liver uptake using a tumor-bearing xenograft mouse model of the extrahepatic bile duct carcinoma cell line TFK-1. We examined intracellular Cu distribution using microparticle-induced X-ray emission (micro-PIXE) analysis for these compounds. 64Cu2+-Tren and 64Cu2+-Dien showed higher tumor uptake than 64Cu2+-TPMA and 64Cu2+ ions in TFK-1 tumors. Among the three 64Cu2+ complexes and 64Cu2+ ions, liver uptake was inversely correlated with tumor uptake. Micro-PIXE analysis showed that in vitro cellular uptake was similar to in vivo tumor uptake and nuclear delivery was the highest for 64Cu2+-Tren. Conclusively, an inverse correlation between tumor and liver uptake was observed using three 64Cu2+ complexes of tripodal amine ligands and 64Cu2+ ions. These results provide useful information for the future development of anticancer 64Cu radiopharmaceuticals.

Porcine pleuropneumonia (PPP) is one of the main causes leading to massive losses in the pig industry, with high economic impacts. Among different etiological agents, Actinobacillus pleuropneumoniae (APP) is responsible for severe fibrinous-necrotizing pleuropneumonia. A total of 19 different APP serotypes are currently recognized. This study aimed to identify APP serotypes isolated from pneumonic lesions in naturally infected and dead pigs in the Piedmont Region and to describe lesions. A total of 107 dead pigs with a suspected PPP diagnosis were included in this study. Lungs were evaluated using gross pathology scoring systems, APP isolation and serotypes identification by multiplex PCR were conducted. Gross lung lesions were mainly represented by fibrinous pneumonia and pleuropneumonia. APP was isolated in 21/107 (19.6%) samples. On the contrary, PCR indicated APP DNA presence in 53/107 (49.5%) of lung samples. The most observed serotypes were serotype 2 in 24/53 (45.3%) and serotype 6 in 13/53 (24.5%) samples. Moreover, multiplex PCR results suggested a coinfection of different serotypes in 5 samples. This study highlights the relevance of the different techniques application (i.e. bacteriological culture, PCR, gross and histopathology) for improving the identification of APP infections.

Multiple myeloma (MM) is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse, therefore advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which is typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract and encompasses two main subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). IBD is frequently accompanied by extraintestinal manifestations (EIMs), with axial and peripheral spondyloarthritis (SpA) being the most common. Enthesitis, an inflammation of the bone insertions of capsules, ligaments, and tendons, represents an initial lesion in SpA. However, enthesitis remains an underestimated and often obscured EIM. The early detection of subclinical enthesial involvement in IBD patients using ultrasound (US) could provide an opportunity for timely intervention. While previous meta-analyses have reported on the incidence and prevalence of SpA in IBD, specific attention to enthesitis has been lacking. Therefore, this narrative review aims to resume the current knowledge on existing IBD-SpA cohorts, focusing specifically on enthesitis.

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development, and addresses some of the major limitations that previously hindered the development of therapies for rare diseases.

Expression of the breast cancer resistance protein (BCRP/ ABCG2) transporter is downregulated in placentas from women with preeclampsia (PE) and in an immunological rat model of PE, which closely resembles human PE. While many drugs are substrates of this important efflux transporter, the impact of BCRP downregulation on maternal and fetal drug exposure has not been investigated. Using the PE rat model, we performed a pharmacokinetic study with rosuvastatin (RSV), a BCRP substrate, to investigate this impact. PE was induced in rats during gestational days (GD) 13 to 16 with daily low-dose endotoxin. On GD18, RSV (3 mg/kg) was administrated intravenously, and rats were sacrificed at time intervals between 0.5-6 hours. Placental expression of Bcrp and Oatp2b1 significantly decreased in PE rats. A corresponding increase in RSV levels was seen in fetal tissues and amniotic fluid of the PE group (p&lt;0.05), while maternal plasma concentrations remained unchanged. An increase in Bcrp expression and decreased RSV concentration, was seen in the livers of PE dams. This suggests that PE-mediated transporter dysregulation leads to significant changes in the maternal and fetal RSV disposition. Overall, our findings demonstrate that altered placental expression of transporters in PE can increase fetal accumulation of their substrates.

Objective: This study aimed to assess the impact of artificial intelligence (AI)-driven noise reduction algorithms on metal artifacts and image quality parameters in cone-beam computed tomography (CBCT) images of the oral cavity. Materials and Methods: This retrospective study included 70 patients, 61 of whom were analyzed after excluding those with severe motion artifacts. CBCT scans, performed using a Hyperion X9 PRO 13 × 10 CBCT machine, included images with dental implants, amalgam fillings, orthodontic appliances, root canal fillings, and crowns. Images were processed with ClariCT. AI deep learning model (DLM) for noise reduction. Objective image quality was assessed using metrics such as the differentiation between voxel values (ΔVVs), the artifact index (AIx), and the contrast-to-noise ratio (CNR). Subjective assessments were performed by two experienced readers, who rated overall image quality and artifact intensity on predefined scales. Results: Compared with native images, DLM reconstructions significantly reduced the AIx and increased the CNR (p<0.001), indicating improved image clarity and artifact reduction. Subjective assessments also favored DLM images, with higher ratings for overall image quality and lower artifact intensity (p<0.001). However, the ΔVV values were similar between the native and DLM images, indicating that while the DLM reduced noise, it maintained the overall density distribution. Orthodontic appliances produced the most pronounced artifacts, while implants generated the least. Conclusion: AI-based noise reduction using ClariCT. AI significantly enhances CBCT image quality by reducing noise and metal artifacts, thereby improving diagnostic accuracy and treatment planning. Further research with larger, multicenter cohorts is recommended to validate these findings.

Rabies is a viral zoonotic disease caused by the lyssavirus and endemic to most tropical and sub-tropical areas of the world. This study reports on the occurrence of rabies in dogs and relates the results to the vaccination status of the dogs. A total of each of the 50 brain and 50 saliva samples from 100 dogs were tested for Lyssavirus using RT-PCR and visualized using gel electrophoresis. Additionally, a histopathological diagnosis of rabies was made on the brain samples. A lyssavirus positivity of 34 % was realized with 29/50 from brain and 5/50 from saliva being positive for rabies. Statistical significance was associated with vaccination (p=0.011) and health (p=0.0) statuses and attack by a stray dog prior to exhibition of signs of rabies (p=0.002). The rabid positive dogs had bitten at least 15 humans and a dog before their demise. This study confirms vaccination as an effective tool for the prevention of rabies. However, elimination of the disease is possible if there is an established and effective collaboration between veterinary and human medicine through one health.

Background: We evaluate the genetic and phenotypic features of a cohort of 12 Italian patients affected by Retinitis Pigmentosa (RP) associated with RP1 sequence variants.; Methods: Retrospective, single center study (Careggi Hospital, Florence), including a cohort of twelve Italian patients (Five male and seven female) affected by RP carrying pathogenic variants of the RP1 gene. A complete ophthalmic assessment and pedigree analysis was conducted with focus on the onset of disease symptoms, the patient’s age at the first diagnosis, the follow up duration and the possible presence of comorbidities; Results: The mean age at onset of symptoms was 31,0 ± 24,1 years old, with a mean follow-up period of 9,1± 2,4 years. The main symptoms at presentation were hemeralopia and visual field constriction. Fundus evaluation revealed a classic type of RP. Fundus autofluorescence (FAF), Optical Coherence Tomography (OCT), Electroretinogram (ERG), and visual field confirmed in most of the cases the typical features of classic retinitis pigmentosa.; (4) Conclusions: This single-center cohort of Italian patients provided information on the clinical and genetic features of RP1-associated RP. By comprehensively clarifying the genetic variations and their associated clinical manifestations, we can better tailor therapeutic interventions aimed at targeting specific genetic abnormalities. This ultimately promises to improve the prognosis and quality of life for individuals with RP-associated RP1.

This study examines the association between dietary saturated fatty acid (SFA) intake and leukocyte telomere length (LTL) using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Telomeres, protective repeats of DNA at the ends of chromosomes, play a crucial role in cellular aging. Their length is shortened over time and is influenced by various factors, one of which is diet. The present study's objective was to evaluate whether increased SFA consumption is associated with shorter LTL. The analysis, conducted on a large, nationally representative sample of 6646 adults, revealed an inverse association between dietary SFAs and LTL. When examined further, this association was found to be significant in women, but not in men. Serum C-reactive protein (CRP) levels were tested as a potential mediator in this relationship, but no such mediation was found. These findings support the role of dietary factors in modulating cellular aging. However, further research is warranted to elucidate the underlying mechanisms driving the overall association, as well as the gender-specific effects observed.

The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic in 2020, following which a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, it has been reported worldwide that the modified mRNAs encoding spike proteins and lipid nanoparticles, which are used as drug delivery systems, not only cause thrombosis and cardiovascular disorders post vaccination, but might also cause diverse diseases involving all organs and systems, including the nervous system. Furthermore, the toxicity and pathogenicity of spike proteins may necessitate defining these proteins as nonbiological infective material. Based on these reports and the abundant evidence that has come to light in the past few years, this paper aims to draw the attention of medical professionals to the various risks associated with transfusion using blood products derived from long COVID patients or from genetic vaccine recipients, and to make proposals regarding specific inspection items, testing methods, regulations, etc. This paper provides insights to address the post-vaccination syndrome and its consequences following such genetic vaccination programs.

Identifying the primary site of origin of metastatic cancer is vital for guiding treatment decisions, especially for patients with cancer of unknown primary (CUP). Despite advanced diagnostic techniques, CUP remains difficult to pinpoint and is responsible for a considerable number of cancer-related fatalities. Understanding its origin is crucial for effective management and potentially improving patient outcomes. This study introduces a machine learning framework ONCOfind-AI that leverages transcriptome-based gene set features to enhance the accuracy of predicting the origin of metastatic cancers. By ensuring compatibility between RNA-sequencing and micro-array data, we were able to construct a more comprehensive training dataset. Integrating data from different platforms improved the accuracy of our machine learning models for predicting cancer origins. Our method was validated using external data from clinical samples collected through Kangbuk Samsung Medical Center and the Gene Expression Omnibus. The external validation results demonstrated a top-1 accuracy ranging from 0.80 to 0.86, with a top-2 accuracy of 0.90. This study highlights that incorporating biological knowledge through curated gene sets can merge gene expression data from different platforms, enhancing the compatibility needed for more effective machine learning prediction models.

Reducing under-five mortality is a key indicator of a country's overall development, yet in Angola, understanding the factors contributing to hospital deaths in this vulnerable demographic remains incomplete despite improvements in healthcare infrastructure and public health policies. With one of the highest under-five mortality rates in Sub-Saharan Africa, Angola grapples with significant challenges, including malaria, malnutrition, pneumonia, neonatal conditions, and intestinal infectious diseases, as leading causes of death among children. This study aimed to identify factors associated with these hospital deaths in children aged 28 days to five years admitted to DBPH in Luanda between May 2022 and June 2023. Utilizing a hospital-based case-control design, a total of 1020 children were studied, with 340 cases of hospital deaths. Notably, distal and intermediate determinants emerged as primary predictors of hospital mortality, revealing significant associations with maternal education status, maternal alcohol consumption during pregnancy, short hospital stays (≤24h), poor nutritional status, short interbirth intervals, maternal age ≤19 years, and maternal age ≥35 years. These findings underscore the preventable nature of most under-five hospital deaths and emphasize the urgent need to address social inequities and enhance the quality of primary healthcare services to effectively mitigate child mortality.

The objective of this study is to investigate how different therapies modulating insulin resistance, either causally or consequently, affect metabolic parameters in treatment-naive subjects with T2DM. A total of 212 subjects were assigned to receive either a tight Japanese diet (n=65), pioglitazone at doses ranging from 15-30 mg/day (n=70), or canagliflozin at doses ranging from 50-100 mg/day (n=77) for a duration of three months. Correlations and changes (Δ) in metabolic parameters relative to insulin resistance were investigated. Across these distinct therapeutic interventions, ΔHOMA-R exhibited significant correlations with ΔFBG and ΔHOMA-B, while demonstrating a negative correlation with baseline HOMA-R. However, other parameters such as ΔHbA1c, ΔBMI, ΔTC, ΔTG, Δnon-HDL-C, or ΔUA displayed varying patterns depending on the treatment regimens. Participants were stratified into two groups based on the median value of ΔHOMA-R: the lower half (X) and upper half (Y). Group X consistently demonstrated more pronounced reductions in FBG compared to Group Y across all treatments, while other parameters including HbA1c, HOMA-B, TC, TG, HDL-C, non-HDL-C, TG/HDL-C ratio, or UA exhibited distinct regulatory responses depending on the treatment administered These findings suggest that 1) regression to the mean is observed in the changes of insulin resistance across these therapies. 2) modulation of insulin resistance with these therapies, either causally or consequentially, results in differential effects on glycemic parameters, beta-cell function, specific lipids, body weight or UA.

Recently Candida auris has emerged as a multi-resistant fungal pathogen, with a significant clinical impact, and has become a critical issue in WHO fungal priority list, due to its unique ability to persist for long time on human skin and hospital environments. It is therefore fundamental to reinforce hospital surveillance protocols to limit nosocomial outbreaks. The study purpose was the Fourier-Transform Infrared Spectroscopy (FT-IR) application to investigate the phylogenetic relationships between isolated strains within the C. auris outbreak at the university Intensive Care Unit of a Tertiary University hospital in Turin (Italy). In order to calculate a clustering cut-off, intra- and inter-isolates distance values were analysed. Data showed the presence of a major cluster Alfa and a minor cluster Beta with a defined C. auris clustering cut-off. The results were validated by an external C. auris strain and Principal Component and Linear Discriminant Analysis. The application of FT-IR technology had allowed to obtain important information about the phylogenetic relationships between the analysed strains, defining for the first time a “not WGS-based” clustering cut-off with a statistical-mathematical approach. FT-IR could represent a valid alternative to molecular methods for rapid and cost saving typing of C. auris strains with important clinical implications.

Omicron SARS-CoV-2 variants have dominated the strains of COVID-19 circulating worldwide for the last two years. Although the mortality rate of the COVID-19 Omicron variants is only approximately half that of previous variants, vaccines effective against Omicron are needed. Demonstrating that a SARS-CoV-2 vaccine can protect against Omicron in an in vivo infection model, particularly in that of Syrian hamsters, is important for the preclinical characterization of SARS-CoV-2 vaccines. Here, we report on the evaluation of W-PreS-O for its ability to protect Syrian hamsters against infection by Omicron. W-PreS-O is a chimeric vaccine based on a single fusion protein (W-PreS-O), combining RBDs from Wuhan hu-1 wild-type and Omicron adsorbed to aluminum hydroxide. The Syrian hamsters were immunized three times at three-week intervals with W-PreS-O or with aluminum hydroxide (placebo), and then they were infected with Omicron BA.1. Non-infected and non-vaccinated animals served as controls. Neutralizing antibody (nAB) titers, weight, lung symptoms (i.e., edema and pneumonia index), and viral loads, as measured using RT-PCR in the upper and lower respiratory tracts, were determined. In addition, infectious virus titers from the lungs were measured using a plaque-forming assay. W-PreS-O-vaccinated hamsters developed robust nABs against Omicron, showed almost no development of pneumonia, and had significantly reduced infectious virus titers in the lungs. Importantly, the viral loads in the nasal cavities of W-PreS-O-vaccinated hamsters were close to or above the PCR cycle threshold considered to be non-infectious. Our data provide compelling evidence demonstrating that the W-PreS-O vaccine has protective effect against Omicron in a Syrian hamster in vivo infection model. W-PreS-O is therefore a highly promising candidate vaccine for Omicron infections, and it should be further evaluated in clinical studies.

Background and Aim: It is generally accepted that oxidative stress mediators play an important role in ischemia-reperfusion injury(I/R), although the exact mechanism is not fully elucidated. While the impact of silymarin on I/R injury in several tissues, including the myocardial, cerebral, gastric and liver tissue, has been examined, the present state of research on this topic remains insufficient to provide a widely accepted understanding. For this purpose, our objective was to examine the effect of silymarin on muscle tissue in rats subjected to lower extremity I/R injury. Method: After ethics committee approval, 18 male Wistar albino rats weighing between 225-275 g were used. The rats were divided into three groups containing six mice each, Control,Ischemia-Reperfusion and Silymarin-Ischemia/Reperfusion groups. Silymarin was administered intraperitoneally 30 minutes before the procedure.( 100 mg/kg-1 ) In the I/R groups, an atraumatic microvascular clamp was placed in the infrarenal abdominal aorta. After 120 minutes, the clamp was removed and reperfusion was achieved for 120 minutes. In muscle tissue samples taken at the end of the reperfusion period; Malondialdehyde (MDA) levels, catalase (CAT) enzyme activity levels and histopathological parameters were compared. Results: In the histopathological examination, no degeneration was observed in the muscle fibers in the control group, while findings of striated muscle damage such as muscle atrophy hypertrophy, muscle degeneration-congestion, internal of the muscle nucleus-oval-central nucleus, fragmentation-hyalinization and leukocyte cell infiltration were observed in the I/R group. In the S-I/R group, muscle atrophy hypertrophy, internal of the muscle nucleus-oval-central nucleus, fragmentation-hyalinization and leukocyte cell infiltration were observed to improve these damaged areas compared to the I/R group. MDA levels in the I/R group were found to be significantly higher than in the control and S-I/R groups. CAT enzyme activity was found to be significantly higher in the I/R group than in the control group. Conclusion:Our study revealed that the administration of silymarin at a dosage of 100 mg/kg-1 by intraperitoneal injection 30 minutes before ischemia in rats effectively decreased lipid peroxidation and oxidative stress. Additionally, it successfully reduced the injury caused by ischemia/reperfusion in muscle histology.

Chelating gels may assist initially in root canal preparations to help establish a glide path. While irrigation surveys have investigated liquid chelators, and gels to a minor extent, no endodontic survey has focused on EDTA gels, and why clinicians use them. All 395 members of the Australian Society of Endodontology (ASE) were emailed an 11-question survey concerning chelation gel usage via Qualtrics. Paper copies were also distributed at ASE events. Descriptive statistics was performed for practitioner and chelating gel data. Cross-tabulations of practitioner type with case percentage usage of gels were analyzed with the chi square test (adjusted P value <0.0083). The overall response rate was 181/395 (46%). For 174 eligible responses, those who never/rarely used a gel was: endodontic residents 12/14 (86%), endodontists 53/71 (75%), general dentists 39/86 (45%), and other members 0% (0/3). Most gel users said that gels helped establish a glide path. Those who never/rarely used chelating gels commented that they held no benefits over liquid EDTA. Endodontists were less likely to use a chelation gel than general dentists (P <0.0083). Older members had higher gel usage than younger members (P <0.0083), indicating a possible trend to diminished gel usage over time amongst ASE members.

Cardiac arrhythmias are among the leading causes of morbidity and mortality worldwide. While antiarrhythmic drugs traditionally represent the first-line management strategy, their use is often limited by profound proarrhythmic effects. Several studies, including randomized control trials (RCTs), have demonstrated the antiarrhythmic efficacy of ranolazine, registered as an antianginal agent while also establishing its safety profile. This review compiles clinical evidence investigating the antiarrhythmic properties of ranolazine, focusing primarily on ventricular tachycardia (VT) and atrial fibrillation (AF), as common rhythm abnormalities with serious complications. Data from RCTs indicate that ranolazine reduces VT incidence, although this effect is not universal. Therefore, we attempt to better describe the patient population that gains the most benefit from ranolazine by VT suppression. Additionally, ranolazine is known to enhance the conversion rate of AF to sinus rhythm when combined with other antiarrhythmic drugs such as amiodarone, highlighting its synergistic effect in the atrium without provoking ventricular dysrhythmias. Despite the heterogeneity in currently available data, ranolazine appears to be an effective and safe option for the management of various arrhythmias.

Background and Objectives: The complications seen after lower impacted third molar surgery affect the quality of life of the patients. The aim of the study was to investigate the efficacy of a single preoperative dose of deflazacort on pain, swelling and trismus following impacted lower third molar surgery. Materials and Methods: This randomised, prospective, double-blind, split-mouth clinical study included 30 healthy individuals with bilaterally impacted lower third molars that was removed for orthodontic purposes between September 2017 and September 2018. Group 1 was given a placebo (single dose vitamin C tablet) and group 2 was given a single 30 mg dose of deflazacort 1 hour prior to the surgery. Pain was evaluated using the visual analog scale for 1 week postoperatively. Edema (in mm) and trismus (in mm) were evaluated preoperatively and on postoperative days 2 and 7. The Mann-Whitney U test was applied for group analysis. p values < 0.05 were considered statistically significant. Results: When postoperative pain scores were evaluated, a significant difference was found between the groups only at the 6th and 12th hours (p0.05). Even high trismus values were recorded on the 2nd day, it was observed that the trismus resolved on the 7th day. There were no significant differences in trismus between the groups at any time point (p>0.05). Evaluation of swelling showed that there was no statistically significant difference between the study and control groups at any time point (p>0.05). No side effect was detected in both the study and the control groups. Conclusions: This was the first split-mouth study evaluating the anti-inflammatory effect of deflazacort after lower impacted third molar surgery. A single dose of 30 mg deflazacort was shown to be effective in reducing pain at 6 and 12 hours postoperatively.

Leptospirosis is a worldwide zoonotic disease, most common in tropical and rural settings. It's a public health problem in most of the French tropical overseas territories. The primary objective of this study was to describe severe forms of leptospirosis admitted to the intensive care unit (ICU) on Mayotte, a French island in the Indian Ocean. The secondary objective was to compare the characteristics of these patients with those admitted to the ICU in other French tropical territories and in mainland France. We conducted a retrospective study among adult patients admitted to the ICU of Mayotte hospital between 2009 and 2017. The diagnosis mainly relied on a positive PCR in blood or urine samples. The results were compared to the similar and available studies carried out in mainland France and in the other French tropical overseas territories. On the study period, 55 patients were admitted in the ICU for leptospirosis (18% of the leptospirosis admitted in the hospital). Among them, 45 (82%) were male and the median age was 44 years (25-75 IQR: 33-55). The median time between first symptoms and ICU admission was 3.5 days (2-5). The median duration for antibiotic treatment, hospital stay, and ICU stay were 7 days (7-8), 9 days (6-13) and 5 days (3-9) respectively. The main acute organ impairments were acute renal failure (87%), followed by circulatory failure (58%), acute liver failure (45%) and neurological failure (22%). The most frequently used supportive cares were: vaso-active drugs (56%) and renal replacement (56%), and mechanical ventilation (27%). The case-fatality rate was low (5%). Genotype identification could be performed on 19 patients’ isolates. The strain L. borgpetersenii serogroup Mini cgMLST CG78 was predominant (n=14), followed by L. interrogans serogroup Pyrogenes cgMLST CG 81 (n=4). No L. interrogans serogroup Icterohemorrhagiae was identified. We publish here the first series of severe patients admitted in the ICU in Mayotte, a French island with a high incidence rate of leptospirosis but with original strain specificities. Despite very severe clinical pictures, mortality remains rather low.

The pathology of idiopathic intracranial hypertension (IIH), a disease characterized by papillary edema and increased intracranial pressure (IICP), is not yet understood; this disease significantly affects quality of life due to symptoms, including vision loss, headache, and pulsatile tinnitus. By contrast, superficial siderosis (SS), a disorder in which hemosiderin is deposited on the surface of the cerebral cortex and cerebellum, potentially causes cerebellar ataxia or hearing loss. So far, no cases of IIH with infratentorial and supratentorial cortical SS have been reported. Herein, we report a case of a 31-year-old woman with obesity who developed this condition. The patient suddenly developed headache and dizziness, had difficulty walking, and subsequently became aware of diplopia. Fundus examination revealed bilateral optic nerve congestive papillae and right eye abducens disturbance. Head magnetic resonance imaging (MRI) showed prominent SS on the cerebellar surface and cerebral cortex. Lumbar puncture revealed IICP of 32 cmH2O, consistent with the diagnostic criteria for IIH, and treatment with oral acetazolamide was started; subsequently, the intracranial pressure decreased to 20 cmH2O. Her abduction disorder disappeared, and the swelling of the optic papilla improved. She was now able return to her life as a teacher without any sequelae. SS is caused by persistent slight hemorrhage into the subarachnoid space. In this case, both infratentorial and supratentorial cortical superficial SS was observed. Although cases of IIH complicated by SS are rare, it should be kept in mind that a causal relationship between IIH and SS was inferred from our case. Our findings also suggest that cerebrospinal fluid dynamic analysis using MRI is effective in diagnosing IIH and in determining the efficacy of treatment.

Colorectal cancer is one of the most common causes of cancer mortality worldwide, and innovative drugs for the treatment of colorectal cancer are continually being revealed. 5-Fluorouracil (5-FU) is a common clinical chemotherapeutic drug. Acquired resistance to 5-FU is a clinical challenge in colorectal cancer. Parecoxib is a selective COX-2-specific inhibitor, which has been demonstrated to inhibit metastasis in colorectal cancers in our previous study. This study aimed to investigate the synergistic antimetastatic activities of parecoxib to 5-FU in human colorectal cancer cells and determine the underlying mechanism. parecoxib and 5-FU synergistically suppressed metastasis in colorectal cancer cells. Treatment with the parecoxib /5-FU combination induced an increase in E-cadherin and decrease in β-catenin. The parecoxib/5-FU combination could inhibit MMP-9 and MMP-2 expression and MMP-9 activity, and the NF-κB pathway might be suppressed as well. Mechanistic analysis denoted that the parecoxib/5-FU combination hindered the essential molecules of the PI3K/Akt route to obstruct metastatic colorectal cancer. Furthermore, the parecoxib/5-FU combination could inhibit reactive oxygen species. Our work showed the antimetastatic capacity of the parecoxib/5-FU combination for colorectal cancers via targeting the PI3K/Akt /NF-κB pathway.

To investigate switching from brimonidine and ripasudil, and brimonidine or ripasudil to a fixed combination of brimonidine and ripasudil and evaluate the associated efficacy and safety in glaucoma patients. Glaucoma patients undergoing treatment with at least brimonidine and ripasudil (n = 25) or treatment with at least brimonidine or ripasudil (n = 45) were evaluated in this retrospective study. After switching patients taking brimonidine and ripasudil, or brimonidine or ripasudil to a ripasudil/brimonidine fixed-combination ophthalmic suspension (RBFC), intraocular pressure (IOP), superficial punctate keratopathy (SPK) and conjunctival hyperemia were evaluated at baseline and at 4, 12 and 24 weeks. No significant differences in the IOPs were observed at any of the time points after switching from brimonidine and ripasudil to RBFC. However, at 4, 12 and 24 weeks, a significant decrease was observed in the mean baseline IOP from 17.0 ± 4.4 mmHg to 15.7 ± 3.2 mmHg (P < 0.01), 14.3 ± 3.4 mmHg (P < 0.01) and 14.4 ± 4.1 mmHg (P < 0.01), respectively, after switching from brimonidine or ripasudil to RBFC. No significant changes were noted for the SPK score or conjunctival hyperemia at any time points after switching to RBFC. Throughout the 24-week evaluation period, the IOP was maintained after switching from brimonidine and ripasudil to RBFC. However, there was a significant IOP decrease after switching from brimonidine or ripasudil to RBFC. These results demonstrate that RBFC is safe for use in the treatment of glaucoma patients.

Background: Bariatric surgery (BS) has a significant impact on body composition (BC) and con-sequently may affect established sarcopenic obesity (SO) in candidate patients. The aim of this study is to assess the utility of muscle ultrasound (MUS) of rectus femoris thickness (RFT) for the evalua-tion of BC and skeletal muscle function in patients undergoing BS compared to bioimpedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA) and dynamometry. On the other hand, we aim to demonstrate how MUS of RFT correlates better with the quality of life (Qol) in this population, likely because it enables the detection of regional quadriceps muscle sarcopenia, in comparison to the other mentioned methods. Methods: This is a prospective pilot study including 77 subjects (64.9% female, mean age: 53.2 ± 8.67 years) who underwent BS. Handgrip strength was measured using a dynamometer, fat-free mass index (iFFM) was assessed by BIA, appendicular muscle index (AMI) was calculated using DEXA and RFT was measured by MUS. Moreover, Homeostasis Model Assessment of Insulin Resintance (HOMA-IR) was calculated. All these measurements were conducted 1 month prior to BS and at the 12-month follow-up. QoL was as-sessed using the Moorehead-Ardelt questionnaire. Results: The mean BMI decreased by 12.95 ± 3.56 kg/m2 (p=0.001). Firstly, we observed positive correlation pre-surgery between HOMA and: RFT (r=0.27, p=0.02), iFFM (r=0.36, p=0.001), AMI (r=0.31, p=0.01) and dynamometer (r=0.26, p=0.02). In addition, we found correlation between RFT and iFFM (pre-surgical: r=0.31, p=0.01; post-surgical: r=0.25, p=0.05) and between RFT and lower extremities AMI post-surgical (r=0.27, p=0.04). Secondly, we observed significant reductions in iFFM, AMI and RFT (p=0.001), but not with dynamometer (p=0.94). Finally, a tendency to a positive correlation between QoL question-naire and RFT post-surgery (r=0.23, p=0.079) was observed. Conclusions: Our results suggest that RFT measured by MUS for the evaluation of SO and the follow-up after BS of these patients. Moreover, RFT can provide relevant information about regional sarcopenia and probably has an accurate correlation with QoL in comparison with the other methods.

Background: This study aimed to examine the effect of 7-Ketositosterol (7-KSS), on sphingomyelin/ceramide metabolites and apoptosis in human breast MCF-7 and human liver HepG2 cancer cells. Methods: Anti-proliferative effects of 7-KSS treatment were assessed at different concentrations and periods. Cell viability was assessed through MTT analysis, whereas the levels of sphingosine-1-phosphate (S1P), sphingomyelins (SMs), and ceramides (CERs) were measured using LC-MS/MS. Phosphorylated 44/42 ERK1/2 and NF-kB p65 (Ser536) protein levels were measured by western blot analysis and immunofluorescence staining. Apoptosis was evaluated by TUNEL staining and flow cytometric assessment of annexin-V and propidium iodide (PI) labeling. Results: Treatment with 7-KSS significantly decreased cell survival, S1P, p-44/42 ERK1/2, and p-NF-κBp65 protein levels in cancer cells compared to controls. A substantial rise was detected in intracellular amounts of C16-C24 CERs and apoptosis in cancer cells incubated with 7-KSS. Conclusions: 7-KSS stimulated ceramide accumulation and apoptosis while decreasing cell proliferation via downregulating S1P, p-44/42 ERK1/2 and p-NF-κBp65 protein levels.

Regardless of the SARS-CoV-2 pandemic containment, it remains paramount to comprehensively understand its underlying mechanisms to mitigate potential future health and economic impacts, comparable to those experienced throughout the course of the pandemic. The angiotensin-converting enzyme 2 (ACE2) provide anchorage for SARS-CoV-2 binding, thus implicating that ACE and ACE2 might contribute to the variability in infection severity. This study aimed to elucidate predisposing factors influencing the disease course among people infected by SARS-CoV-2, focusing on angiotensin-converting enzyme (ACE) and ACE2 polymorphisms. Notably, despite similar demographics and comorbidities, COVID-19 patients exhibit substantial differences in prognosis. Genetic polymorphisms in ACE and ACE2 have been implicated in disease progression, prompting our investigation into their role in COVID-19 evolution. Using next-generation sequencing (NGS), we analyzed ACE and ACE2 genes in a sample group comprising six subjects infected by SARS-CoV-2. Our findings revealed a correlation between specific polymorphisms and COVID-19 outcomes. Specifically, ACE and ACE2 intronic deletions were observed in all deceased patients, suggesting a potential association with mortality. These results highlight the significance of genetic factors in shaping the clinical course of COVID-19, emphasizing the importance of further research into the impact of genetic variations on COVID-19 severity.

The burden of hypertension remains unacceptably high globally, particularly in low- and middle-income countries (LMICs). Workplace offer enormous potential as an idea setting for early detection and treatment of hypertension among the working class. Analysis of such a Workplace Screening Programme can reveal information about its potential impact. Machine learning techniques such as k-Means Clustering are untapped tools for such analyses. We set out to deploy this tool for the analysis of our university annual medical screening of workforce for hypertension. An anonymized dataset containing the demography and blood pressure measurements values obtained from staffs of different departments/units in an academic institution was obtained. The total number of samples or data points are 1, 723 in which the input dataset contains six features, including year category (2018, 2019, 2021,2022), Department/Unit (academic and non-academic), gender (male and female), while the target output is the blood pressure status (low, normal and high) respectively. Analysis of the dataset was carried out using machine learning techniques. In this retrospective analysis, it was observed that the mean age for this working class is 42 years old. Similarly, it was discovered that hypertension was prevalent among members of staff above the age of 40 irrespective of their gender or professional category (academic or non-academic). The analysis also revealed that there was a steady decline in the prevalence of hypertension from 2018 to 2022. From the research, it is evident that the adoption of machine learning techniques for periodic analyses of workplace health status screening initiative (especially for hypertension) is effective, feasible, and sustainable to diagnose and control hypertension among the working class.

Background: An aberrant cellular microenvironment characterized by pathological cells or inflammation represents an added risk factor across various cancer types. While the significance of chronic inflammation in the development of most diffuse tumors has been extensively studied, an exception to this analysis exists in the context of Chondrosarcomas. Chondrosarcomas represent 20–30% of all skeletal sarcomas and have an estimated incidence of 1 in 100,000 worldwide. The mean age of presentation is 50, with over 70% of patients over the age of 40 at the time of diagnosis. The aim of this retrospective study was to analyze the role of C-reactive protein (CRP) as a prognostic factor in relation to the histopathological findings for Chondrosarcoma. Methods: This retrospective study included 73 patients with confirmed Chondrosarcoma diagnosis treated between 2004 and 2019. Preoperative CRP determination was assessed in mg/dL with a non-pathological value below 0.5 mg/dL. Disease-free survival time was calculated as the time between the initial diagnosis and an event like local recurrence or metastasis. Follow-up status was described in death of disease, no evidence of disease and alive with disease. The exclusion criteria of this study included insufficient laboratory values, lack of information regarding the follow-up status and incomplete histopathological report. Results: The calculate risk estimation of a reduced follow-up time was 2,25 time higher in the patients with an CRP level &gt;0.5 mg/dL (HR 2,25 and 95% CI 1,13-4,45) and 3 times higher in patients with a tumour size &gt;pT2 (HR 3 and 95% CI 1,59-5,92). We can easily confirm that the most elevated risk for a reduce follow-up time relies in chondrosarcomas high grading, preoperative pathological CRP- level and a size &gt;8 cm. Conclusions: In Chondrosarcoma cases, we can consider CRP pretreatment value &gt;0.5 mg/dL a sensitive prognostic and sensitive risk factor for distant metastasis.