The presence of antibiotic residues in honey has recently become a growing public health concern due to the overuse of these products in beekeeping and their transfer to the food industry. The aim of this study was to develop and validate a simple, selective and sensitive method for the simultaneous identification and quantification of residues of twenty-two sulfonamides, trimethoprim and dapsone in honey using a rapid and reliable liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. The developed method showed good linearity, specificity, precision (repeatability and intra-laboratory reproducibility) and recovery. The decision limit (CCalpha) ranged between 2.16-22.12 µg/kg for CCα, while the detection capability (CCbeta) was between 2.16- 2.67-27.36 µg/kg. The method proved to be rapid, reliable and effective for the determination of sulfonamides, trimethoprim and dapsone from honey samples. The average recoveries were estimated to be between 70 and 106%. The relative standard deviations (RSDs) were between 6-18%. In practice, the method is essential to check the honey sold on the market and ensure its safety before it reaches the consumer.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

Dirofilariosis is an infectious disease caused by species of the Dirofilaria genus. It is manifested by the appearance of a subcutaneous swelling, especially in the eye region. We present the case of a 29-year-old patient that accused facial asymmetry in the right genian region. Following clinical and paraclinical evaluations, the diagnosis of parasitic cyst was established in the context of dirofilariosis with Dirofilaria repens (D. repens). Treatment consisted of surgical excision of the formation associated with prophylactic antibiotic medication. Macroscopic analysis of the excision piece revealed a structure that contains a cystic cavity and a filamentous form with a length of approximately 10 mM and a diameter of 1 mM. This is the first case of dirofilariosis located in the genian region reported in Romania. The overview of this pathology is important to raise awareness among physicians about its presence and its clinical variations.

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI are introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating benefits of TH. Some studies have shown benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal should be advocated on an individual basis.

Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that has significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.

Acute and chronic graft versus host disease (a/cGVHD) are major complications of allogeneic stem cell transplantation and a frequent cause of non relapse-mortality. The treatment of a/cGVHD consists of steroid administration at full dose. In the case of aGVHD, around 60 % of patients with grade III/IV fails to respond (steroid-resistant, SR), requiring a second line therapy. Extracorporeal photopheresis (ECP) represents a good option for second line treatment, leading to multiorgan response in several patients. Here, we have evaluated the performances of a cytofluorimetric quality control of the first ECP procedure in 29 patients with severe SR aGVHD who underwent ECP. The quality control represents a check control of in vitro cell apoptosis/death induction in collected and irradiated CD3+ cells by ECP. Our analysis shows that in more than 70 % quality controls a relevant apoptotosis/death of CD3+ cells was observed after cell irradiation, as compared to non-irradiated controls. Albeit observed in a small patients’ series, the occurrence of relevant in vitro effect after ECP relates to less procedures and/or to a better survival on ECP. Age, disease, gender, aGVHD grade and time from transplant to the first ECP had not impact on ECP efficacy in this patients’ series.

Hepatitis C virus (HCV) is a major public health threat associated with serious clinical consequences worldwide. The WHO reports an estimated 58 million people globally living with chronic hepatitis C virus (HCV) infection, with 1.5 million new cases and over 350,000 deaths annually due to HCV-related diseases. Despite the existence of multiple diagnostic methods, the accessibility of diagnosis and treatment is often hindered across the continent by limited resources, insufficient healthcare infrastructure, and low public awareness of Hepatitis C virus Hepatitis C virus infection is a major public health concern in African countries, which have the highest prevalence rates of HCV in the world (1–26%). Egypt, African country which had the highest prevalence of Hepatitis C virus infection in the world. Its national hepatitis C elimination initiative emerges as an exemplary case of success an having screened over 60 million individuals, and treated more than 4 million, thereby markedly diminishing both the prevalence and incidence of the disease. The strategies employed by Egypt offer critical insights and adaptable frameworks for other African Countries facing analogous challenges. The Aim of this Review is to highlight the triumphs and hurdles of Egypt's approach, while also providing strategic guidance for African Countries to accelerate the journey towards the eradication of hepatitis C.

Giant unilamellar vesicles (GUVs) are membrane model used to study membrane properties. Electroformation is one of the methods used to produce GUVs. During electroformation protocol dry lipid film is formed. Drying of the lipid film induce Cholesterol (Chol) demixing artifact, in which Chol forms anhydrous crystals, where these crystals does not participate in formation of vesicles. This leads to a lower Chol concentration in the vesicle bilayers compared to the Chol concentration in the initial lipid solution. To address this problem, we propose novel electroformation protocol that includes rapid solvent exchange, plasma cleaning and spin-coating methods to produce GUVs. We tested the protocol focusing on vesicles with high Chol content using different spin-coating durations and vesicle types deposition. Additionally, we compared the novel protocol using completely dry lipid film. The optimal spin-coating duration for vesicles made out of phosphatidylcholine/Chol mixture was 30 s. Mulitlamellar vesicles (MLVs), large unilamellar vesicles (LUVs) obtained by extrusion of MLVs through 100 nm membrane pores and LUVs obtained by extrusion of previously obtained LUVs through 50 nm membrane pores were deposited on electrode for 1.5/1 Chol/phosphatidylcholine lipid mixture and the results were compared. Electroformation using all three deposited vesicle types gave a high GUVs yield, but deposition of LUVs obtained by extrusion of MLVs through 100 nm membrane pores gave the most reproducible results. Using deposition of these LUVs, we produced GUVs with high yield for 6 different Chol concentrations (from 0 % to 71.4%). Using protocol that includes dry lipid film GUVs yield was lower and Chol demixing artifact was induced, proving that the lipid film should never undergo drying when Chol content is high.

Melioidosis is an endemic infectious disease caused by Burkholderia pseudomallei bacteria, which contaminates soil and water. To better understand the environmental changes that have contributed to melioidosis outbreaks, this study used spatiotemporal analyses to clarify the distribution pattern of melioidosis and the relationship between melioidosis morbidity rate and local environmental indicators (land surface temperature, normalised difference vegetation index, normalised difference water index) and rainfall. A retrospective study was conducted from January 2013 to December 2022, covering data from 219 sub-districts, with each exhibiting varying morbidity rate of melioidosis on a monthly basis. Spatial autocorrelation was determined using local Moran’s I, and the relationship between melioidosis morbidity rate and the environmental indicators was evaluated using geographically weighted Poisson regression. The results revealed clustered spatiotemporal patterns of melioidosis morbidity rate across sub-districts, with hotspots predominantly observed in the northern region. Furthermore, we observed a range of coefficients for the environmental indicators, varying from negative to positive, which provided insights into their relative contributions to melioidosis in each local area and month. These findings highlight the presence of spatial heterogeneity driven by environmental indicators and underscore the importance of public health offices implementing targeted monitoring and surveillance strategies for melioidosis in different locations.

Daridorexant, as the first Dual Orexin Receptor Antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, the aim of this study was to assess its safety profile using a large-scale pharma-covigilance database. Daridorexant-related Adverse Drug Reaction (ADR) reports from the FDA Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to daridorexant were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-dorexant-related reports were selected; nightmares (n = 146; Dari vs. RG1: ROR = 113.74; 95%CI[95.13, 136]; Dari vs. RG2: ROR = 2.35; 95CI%[1.93, 2.85]), depression (n = 22; Dari vs. RG1: 2.13; [1.39, 3.25]; Dari vs. RG2: ROR = 2.31; 95CI%[1.45, 3.67]), and hangover (n = 20; Dari vs. RG1: ROR = 127.92; 95CI%[81.98, 199.62]; Dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of dari-dorexant, supporting the existence of safety signals related to nightmares, depression, and hang-over.

Background: The pandemic caused by the SARS-CoV-2 virus demonstrated the importance of prevention through a healthy diet and lifestyle, the most vulnerable people being those with severe chronic conditions, those who are overweight, and those with an unbalanced immune system. Methods: The evaluation of the eating habits and lifestyle of the Romanian population in the post-pandemic period was carried out based on a cross-sectional observational study with the help of a questionnaire. Results: 4704 valid answers were registered (3136 female and 1568 male respondents). Among the respondents, most of them belong to the young population, 2892 between the ages of 18 and 40, i.e., 61.5%. Most male respondents are overweight (1400) and obese (780). Most respondents indicated a tendency to consume 1-2 meals per day irregularly (p=0.6167). Only 974 respondents adopted a healthy diet, and 578 a healthy lifestyle. Conclusion: The present study reports low adherence to a healthy diet (20.7%) and healthy lifestyle (12.28%), especially among the young population (&lt; 30 years). In the current context, it reports a reduced tendency to consume vegetables and fruits among the population, below the daily average recommended by the nutrition guidelines, a tendency towards sedentary behavior, and even deficient hydration of some of the respondents; these negative aspects can create a long term a series of nutritional and psycho-emotional imbalances. Our results evidence that complex surveys among the population are regularly required to investigate nutritional or lifestyle deficiencies; moreover, it could be helpful in further educational measures in nutrition, food, and environmental safety.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography–tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that CAs in these organs primarily consist of common proteins (β2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked β2-microglobulin and lysozyme, and exhibited evident destruction of surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

Coccidioidomycosis (Valley Fever) is a disease caused by inhalation of Coccidioides spp. This neglected tropical disease of the Americas has substantial public health impact despite its geographic restriction to desert areas of the southwestern U.S., Mexico, Central and South America. The incidence of this infection in California and Arizona has been increasing over the past fifteen years. The burden of disease in outside the U.S. remains poorly understood. Several large cities are within the endemic region in the U.S. Coccidioidomycosis accounts for 25,000 hospital admissions per year in California. While most cases of coccidioidomycosis resolve spontaneously, up to 40% are severe enough to require anti-fungal treatment, and a significant number disseminate beyond the lungs. Disseminated infection, especially involving the meninges, is fatal without appropriate treatment. Infection with Coccidioides spp. is protective against a second infection, so vaccination seems biologically plausible. This review of efforts to develop a vaccine against coccidioidomycosis focuses on vaccine approaches and the difficulties in identifying protein antigen/adjuvant combinations that protect in experimental mouse models. Although the quest for a vaccine has not yet resulted in a clinically useful product, scientific efforts of vaccine development pave the way for future success.

Wilms tumor (WT), the most prevalent type of renal cancer in children, exhibits overall survival rates exceeding 90%. However, chemotherapy resistance, which occurs in approximately 10% of WT cases, is a major challenge for the treatment of WT, particularly for advanced-stage patients. In this study, we aimed to discover potential mutation markers and drug targets associated with chemotherapy resistance in advanced stage WT. We performed exome sequencing to detect somatic mutations and molecular targets in 43 WT samples, comprising 26 advanced stage WTs, of which 7 cases are chemotherapy-resistant. Our analysis revealed four genes (ALPK2, C16orf96, PRKDC, and SVIL) that correlated with chemotherapy resistance and reduced disease-free survival in ad-vanced-stage WT. Additionally, we identified driver mutations in 55 genes within the chemo-therapy-resistant group, including 14 druggable cancer driver genes. Based on the mutation profile of the resistant WT samples, we propose potential therapeutic strategies involving platinum-based agents, PARP inhibitors, and antibiotic/antineoplastic agents. Our findings provide insights into the genetic landscape of WT and offer potential avenues for targeted treatment, particularly for patients with chemotherapy resistance.

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

The aim of the present trial was to evaluate the growth performance of buffalo calves fed diets characterized by different forage/concentrate ratio with or without the Saccharomyces Cerevisiae supplementation (CBS 493.94, Yea-Sacc®). Twenty-four male buffalo calves (mean age 145.1 ± 16.1 days; mean weight 108.0 ± 18.7) were assigned randomly to 4 groups, homogeneous for age, fed four different diets: diet 1 F:C ratio 50:50; diet 2 F:C ratio 30:70; diet 3 F:C ratio 50:50 + Yea-Sacc® and diet 4 F:C ratio 30:70 + Yea-Sacc®. Buffalo calves were individually weighted before the start of the experiment and the data were used as a covariate, monthly until the end of the trial. Dry matter intake (DMI), daily weight gain (DWG) and feed conversion ratio (FCR) were calculated. The differences in diets’ composition significantly (p

Herein, we examined the effects of weather parameters and individual clinicodemographic risk factors on hemorrhagic stroke (HS) incidence, severity on admission, and disability at discharge in a harsh desert climate. In a retrospective design we studied patients admitted to a stroke unit in Arab Emirates in 2016-2019. With a distributed lag nonlinear model we explored immediate and delayed effects of weather on stroke incidence. Supervised machine learning was used to build models predictive of scores in NIHSS and mRS scales. We assessed model performance by calculating ROC AUC, F1 scores, specificity, and sensitivity. HS risk increased after a significant change in any weather parameter. The risk was reduced below baseline after 1-week adjustment to environmental changes. Climate input from the previous 3 days yielded reliable classification models. Humidex was a better predictor of severity than air temperature, whereas body mass index, age, and time of day at stroke onset were the strongest clinical predictors. Weather parameters before admission were stronger predictors of disease severity than individual clinical factors. We addressed limitations of previous studies by analyzing a full set of climate parameters: ambient temperature, relative humidity, humidex, atmospheric pressure, and wind speed. Predictive models may help to optimize patient management and develop preventative strategies.

Annually, more than 1.5 million preventable new hepatitis B (HBV) infections continue to occur, with an estimated global burden of 296 million individuals living with chronic hepatitis B infection. This substantial health challenge results in over 820,000 annual deaths attributed to complications such as liver cirrhosis and hepatocellular carcinoma (HCC). HBV vaccination remains the cornerstone of public health policy to prevent chronic hepatitis B and its related complications. It serves as a crucial element in the global effort to eliminate HBV, as established by the World Health Organization (WHO), with an ambitious 90% vaccination target by 2030. However, reports on global birth dose coverage reveal substantial variability, with an overall coverage rate of only 46%. This comprehensive review thoroughly examines global trends in HBV vaccination coverage, investigating the profound impact of vaccination on HBV prevalence and its consequences across diverse populations, including both high-risk and general demographics. Additionally, the review addresses the formidable challenges and facilitating factors essential for achieving WHO's HBV vaccination coverage objectives and elimination strategies in the coming decade and beyond.

The growing demand for nutritious foods has spurred investigations into alternative sources of nutrition beyond traditional options. For this reason, the present study approaches the amaranth, which is a plant with high potential, highlighting the morphological growth, grain biomass pro-duction, and quantitative traits of seven varieties of amaranth cultivated in the pedoclimatic con-ditions of Somes meadow in Transylvania. A bifactorial trial was implemented with factors ama-ranth species and amaranth varieties. Two amaranth species and seven varieties were studied. Differences are reported between morpho-productive and quantitative traits of the seven amaranth varieties studied in this research. The interrelationships between amaranth morphological traits quantified by using Pearson simple correlations show that morphological traits moderately con-tribute to grain fresh biomass yield, while morphological traits and fresh biomass strongly con-tributed to grains dry biomass yield. Our study shows that morpho-productive, and nutritional characteristics of the seven amaranth varieties comprised by our study recommend the plans to be used in various nutritional aims, being a valuable replacer of traditional raw materials in specific food and feed industry sectors.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding its applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.

Neonatal mortality remains a public health concern and timely identification and prompt intervention in the delivery room could improve the outcome in neonatal morbidity and mortality. We performed a retrospective study to help us finding the profile of the high-risk newborn regarding the need for NICU admission, necessary to establish a protocol regarding the mobilization of human and material resources for the urgent management of these situations. All deliveries and neonates born in Maternity of Bihor County Emergency Clinical Hospital from Romania were reviewed, including relevant maternal, foetal and perinatal data to identify risk factors that result in birth of newborns needing resuscitation at birth between 2012-2019. The number of births showed a downward trend but around 90% of the births were on term. The incidence of neonatal emergencies is increasing, the most frequently were respiratory, sepsis and other infections, cardiovascular emergencies, and extreme prematurity. It is noted that in 2021 the incidence of these neurological emergencies increased by three times compared to previous years. The neonatal and maternal risk factors associated with admission to the NICU were mother's age over 35 years, low level of education, second/more gestation, weight under 2500 g, Apgar score under 7, premature rupture of membranes, macrosomia and mother's infectious pathology. Accurate identification of risk factors and anticipation at the birth of a high-risk neonate would result in adequate preparation and prompt resuscitation of neonates who need some level of intervention and thus, reducing neonatal morbidity and mortality.

Peri-implant diseases are defined as pathological inflammatory reactions in the tissue surrounding the osseointegrated implants. They are classified into two categories: mucositis - defined as peri-implant soft tissue inflammation and peri-implantitis - bone loss in the peri-implant region. A clinical case of a 61-years-old woman with an implant in the 46 anatomical position and a 5-year follow-up is presented. A probe depth of 5mm and a bone defect length of 35% was observed. The Implacure® Protocol was applied, with the main objective of eliminating the biofilm present on the exposed implant surface. There are multiple approaches to treat peri-implant diseases. While non-surgical treatment is essential for mucositis control, the treatment of peri-implantitis surgical treatment should be considered. Regenerative bone reconstruction promotes bone repair in the defect area and reduces bleeding during probing. To achieve that, autologous fibrin combined with Cerasorb M® was used. The proposed approach in the exposed clinical case involves the application of Implacure® Protocol, whose combination of the physical decontamination technique, together with the use of chlorhexidine and orthophosphoric acid, added with the combination Piperacillin + Tazobactam together with hyaluronic acid, provide a base that allows to regenerate bone using platelet-rich fibrin with Cerasorb M® and increase the survival time of the implant.

Neuronal cells are believed to rely on autophagy to maintain cellular homeostasis. Nevertheless, autophagy may be a therapeutic target for neurodegenerative diseases because of the role it plays in neuronal cell death. Despite Beclin 1 association with autophagy and apoptosis, the molecular mechanisms that underlie Tau-induced vesicular pathology and Tau protein aggregates in humans remain poorly understood. Here, we set out to examine the role of three genes-ATG14L, Beclin 1 and VPS34- in autophagy nucleation failure-associated Tau disorders in fruit fly models. We found that either reduced ATG14L levels improve neuronal outcomes, or transgenic expression of ATG6/Beclin 1 greatly reduced age-dependent neurodegeneration and Tau pathology; whereas, the loss of Beclin 1 exacerbated these effects. Prior to p-Tau accumulation, the neuronal Beclin 1 network is critical for reducing p-Tau accumulation, indicating that the loss of Beclin 1 causes Tau pathology and neurodegeneration. As neurodegeneration progressed, glial cells showed an upregulation of vesicular Beclin 1 immunoreactivities. The reduced VPS34 also resulted in p-Tau accumulation, suggesting that neurons require both Beclin 1 and VPS34 to reduce p-Tau accumulation. Our results provide mechanistic insight into the molecular pathways that cause age-dependent Tau pathology and neurodegeneration due to an excess of autophagy nucleation processes and autophagy activity, and we derive novel inferences on the therapeutic possibilities of rebalanced Beclin 1 network by reducing autophagic specific nucleation component of ATG14L.

Kinesiophobia (fear of movement) has been recognized as a significant barrier to recovery and rehabilitation in patients after total knee arthroplasty (TKA). Our goal was to identify predictors of kinesiophobia and examine its correlation with early functional outcomes in TKA recipients. On the first and fifth postoperative days (POD1 and POD5), we evaluated pain using the International Pain Outcomes Questionnaire (IPO-Q) and created multidimensional pain composite scores (PCS). Pain Composite Score-total (PCStotal) assesses the overall impact of pain, taking into account outcomes of pain intensity, pain-related interference with function, and emotions and side effects. Functional status on POD 5 was determined by the Barthel index, 6-minute walking test, and knee range of motion. Kinesiophobia was measured on POD5 using the Tampa Scale for Kinesiophobia (TSK) and multivariable logistic regression was used to assess factors associated with kinesiophobia. Among 75 TKA patients, 27% exhibited kinesiophobia. The final regression model highlighted PCStotal on POD5 (OR=6.2, CI=1.9-19.9), PCStotal (OR=2.1, CI=1.2-3.8) on POD1, and the intensity of chronic pain before surgery (OR=1.4, CI=1.1-2.1) as significant kinesiophobia predictors. On POD5, those with kinesiophobia showed increased dependency, slower gait, and poorer knee extension recovery. This study highlights the importance of identifying and addressing kinesiophobia in TKA patients to optimize functional outcomes and improve recovery. Also, it is important to assess not only pain intensity but also the physical and emotional interference caused by pain, which can contribute to the development of kinesiophobia.

The paper presents the findings of research on companies in the early stage of development based on the concept of ensuring their sustainability. The starting point is attributes shaping a sustainable model of start-ups. A solution has been proposed and examined that identifies the factors dynamising a business model, which give the company the ability to make fast changes in the configuration of the business model, and that applies stabilizing factors based on the concept of the Triple Bottom Line. The research problem is a response to the phenomena of the bankruptcy of many start-ups that cannot find a way to survive in the long term. The business models of companies in the early stage of development should be designed taking into account the possibility of their dynamic and iterative changes when the earlier assumptions do not work when implemented in practice. A cognitive gap has been observed as the relevant literature does not propose a systemic solution to the problem of instability of the startups viewed from the perspective of the business model concept. The research problem, therefore, is to identify potential new methods to ensure the sustainability of young companies trying to combine aspects dynamising changes in business models, taking into account economic, environmental and social aspects. The findings of research on companies in the early stage of development show that when the methods of increasing the flexibility of the business model are applied and attention is drawn to environmental and social activities and a strong emphasis is put on financial performance, reflecting the expectations of shareholders, the concept of ensuring the sustainability of young companies from the point of view of sustainable business model attributes emerges.

Introduction: Carcinoid heart disease is a rare cause of right-sided valvular dysfunction, an important complication in patients with carcinoid syndrome. Objectives: We aim to present our own experience regarding early myocardial dysfunction in patients with carcinoid syndrome. Methods: 64 patients (35-90 year old, 62,5% female, 37,5% male patients) with carcinoid syndrome were evaluated be-tween October 2017 and June 2021. All patients underwent two-dimensional echocardiography with additional tissue Doppler and speckle-tracking techniques. For all patients there were measured urinary level of 5- hydroxyindolacetic acid, serotonin and NT-proBNP values. Results: The following echocardiographic features: global longitudinal strain of both ventricles, mean systolic velocity of the left ventricle, systolic velocity of the free wall of right ventricle, correlated with high values of specific biomarkers: serotonin, and urinary 5-hydroxyindolacetic acid, and also with the presence of hepatic metastases and poorly differentiated tumors. Discussion: In this study we identified several patients with early myocardial dysfunction due to carcinoid syndrome, representing a predictive model of poor prognosis, requiring further investigations. Conclusion: Echocardiographic assessment based on the measurement of systolic velocities, as well as the global longitudinal strain of both ventricles, together with specific biomarkers may contribute to better recognition of carcinoid heart disease in clinical practice, but this needs validation through further studies enrolling larger number of patients.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

The BET family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises Brd2, Brd3, Brd4, and Brdt, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-Myc. These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models.

More than 20 years after the discovery of the first anelloviruses (AVs), they still remain a mysterious group of viruses. To date, there is no clear understanding of their impact on the host organism, although information is emerging about their participation in various pathologies. However, it is well known that AVs are an important component of the human virome. In the current study we assessed the abundance of AVs in viromes from four nasal and pharyngeal samples from children with respiratory symptoms using a metagenomic approach. It is worth noting that three patients had known respiratory viruses and one did not have any. Regarding AVs, they were detected in all samples, namely Torque teno mini virus (TTMV). The greatest abundance and diversity of AVs (Torque teno virus (TTV), TTMV and Torque teno midi virus (TTMDV)) were shown in a diseased patient with an absence of respiratory viruses, which may indicate the potential involvement of AVs in the maintenance of respiratory symptoms. An activated immune system to combat the main pathogens, against the background of which the number of AVs decreases, is discussed as a possible reason for the reduced diversity of anellome in other patients. We also compared the results of the metagenomic approach and qPCR for major respiratory viruses, which were in agreement. In addition, metagenomic sequencing made it possible to obtain additional data on viral genomes in order to establish their taxonomic identification and characterize individual viral profiles in patients from the Siberian part of Russia.

Safe water is a global public health concern amid increasing scarcity and pollution. Bottled water production and consumption contribute to these problems. This study examines tap water consumption in Italy, assessing associated sociodemographic factors and related health outcomes such as obesity and self-perceived health status. Data from the Italian National Statistics Institute's "Aspects of daily life" survey (N=45,597) were analyzed. Covariates included education, age, gender, economic status, region, concerns about waste and climate change, consumption of carbonated drinks excluding water, alcohol consumption, consumption of vegetables, consumption of snacks, body mass index, and self-perceived health status. Bivariate analyses and mixed-effect logistic regression models explored the associations. People who drink tap water were 19,674 with a higher prevalence in people aged 45 to 59 old, people with a graduate/post-graduate degree diploma, with optimal economic resources, and concerned about waste production and climate change, coming from the North-East regions of Italy. Underweight people showed a higher prevalence of TW assumption as well as those who drink less than occasionally carbonated drinks, drink alcohol, consume vegetables more than once a day, and snacks less than once a week with a satisfying level perceived health status. Regressions showed that all age classes are less likely to drink tap water than people younger than 20 years old. The category with “inadequate” economic resources is more likely to consume tap water. Low educational classes show a low likelihood of consuming tap water as well as Islands. A concern about waste production and climate change is associated with an increased likelihood of assuming tap water. Tap water consumption was negatively associate with obesity but not with a satisfactory Self-perceived health status. Insights from this study can inform public health strategies.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematology parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h nor at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, temporary clamping of the aorta in aortic surgery, and acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress. Cerium oxide (CeO2) nanoparticles mimic the antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n=6), diabetes group (group D, n=8), diabetes-CeO2 (group DCO, n=8), diabetes-ischemia/reperfusion (group DIR, n=8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n=8). DCO and DIRCO groups were given doses of CeO2 0.5mg/kg intraperitoneally 30 minutes before the IR procedure. A 120-minute ischemia-120-minute reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p=0.047 and p=0.022, respectively). In group DIRCO and total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p

Synchronous electrical cardioversion is a relatively common procedure in the emergency department (ED), often performed for unstable supraventricular tachycardia (SVT) or unstable ventricular tachycardia (VT). However, it is also used for stable cases resistant to drug therapy, which carry a risk of deterioration. In addition to the inherent risks linked with procedural sedation, there is a possibility of malignant arrhythmias or bradycardia, which could potentially result in cardiac arrest following this procedure. Here, we present a case of complete heart block unresponsive to transcutaneous pacing and positive inotropic and chronotropic drugs for 90 minutes, resulting in multiple cardiac arrests. The repositioning of the transcutaneous cardio-stimulation electrodes, one of them placed in the left latero-sternal position and the other at the level of the apex, led to immediate stabilization of the patient. Extubation of the patient was performed the following day, while full recovery and discharge within 7 days, after insertion of a permanent pacemaker.

Background: The bacterium Capnocytophaga spp. is a part of the oral microbiome of dogs, which has zoonotic potential. This study aimed to assess factors that influence the prevalence of Capnocytophaga cynodegmi and Capnocytophaga canimorsus in Wrocaw’s dog population. Methods: Molecular detection (PCR) involved 105 swabs, examining parameters such as oral cavity condition, underlying health issues, recent antibiotics, age, medications, material collection, and dog chews. Results: The study highlighted significant associations between the presence of Capnocytophaga cynodegmi and oral cavity condition, material collection method, and use of dog’s chews. Conclusions: Correlations obtained in this study between the oral health of Wroclaw's dog population and the presence of Capnocytophaga cynodegmi suggest its significance in the oral microbiome of dogs. Limitations, including the small sample size, highlight the need for more research to comprehensively understand additional factors that affect the prevalence of Capnocytophaga spp. in dogs

Acoustic Radiation Forced Impulse (ARFI) is an ultrasound integrated method, measuring stiff-ness by point shear wave elastography. To evaluate the diagnostic performance of ARFI of the liver and of the spleen, combined with spleen dimension and platelet count, in predicting clinical events in cirrhosis, a prospective and cross-sectional study was conducted between February 2017 and February 2021. The following ratio scores with ARFI measurements were performed: ALSDP (ARFI Liver-Spleen Diameter-to-Platelets ratio score), ASSDP (ARFI Spleen-Spleen Diam-eter-to-Platelets ratio score), ASSAP (ARFI Spleen-Spleen Area-to-Platelets ratio score), ALSAP (ARFI Liver-Spleen Area-to-Platelets ratio score). In 100 enrolled subjects, spleen ARFI, ASSDP, ASSAP, were significantly associated with high-risk oesophageal varices (HRVs) in the prospec-tive short- and long-term follow-up and in the cross-sectional study (p 0.7). ARFI-ratio scores can predict, in cirrhotic patients, the risk of developing HVRs in short and long-term period.

Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of adverse events and an efficiency frequently comparable with that of conventional drugs. Nevertheless, their mechanism of action is in many cases elusive and/or uncertain. Even many of them have been proved effective in studies done in vitro or on animal models, there is a scarcity of human clinical evidence. The purpose of this review is to summarise the available scientific information on these joint-friendly medicinal plants, which have been already tested in human studies: Arnica montana, Boswelliaspp., Curcuma spp., Equisetum arvense, Harpagophytumprocumbens, Salix spp., Sesamumindicum, Symphytumofficinalis, Zingiberofficinalis, Panaxnotoginseng, Whitaniasomnifera.

Objective: Mechanical bowel preparation is essential for the visualisation of the colon during colonoscopy, and previous studies have identified changes in gut microbiota composition after bowel preparation and colonoscopy. Considering the gut microbiota is increasingly implicated in mood, we aimed to explore the potential impact of this intervention on mood and the microbiota-gut-brain axis. Methods: We conducted a pre-post intervention study, with timepoints of one week before and one month after bowel preparation and colonoscopy, in community-dwelling adults referred for colonoscopy. Our primary outcome was change in average Hospital Anxiety and Depression Scale depression sub-scores using generalised estimating equations. We also examined changes in average anxiety, stress, and quality of life scores, and faecal microbiota composition and potential function using 16S rRNA sequencing. We further explored associations between changes in depressive symptoms and the gut microbiota and conducted post-hoc analyses to explore potential effect modifiers. Key Results: 59 participants were included in the analyses. Depressive symptoms decreased one-month post-procedure compared to baseline (adjusted β=−0.64; 95%CI: −1.18, −0.11). Irritable bowel syndrome (IBS) appeared to moderate this relationship (1.78; 0.292, 3.26); depressive symptoms increased in those with, and decreased in those without, IBS. Changes in gut microbiome composition included reduced alpha diversity, modest effects on beta-diversity, and increases in genera associated with potential health benefits, one-month post-procedure compared to baseline. Increases in the CLR-transformed abundance of Ruminococcaceae UCG-009 were associated with improvements in depressive symptoms. Conclusions: There is preliminary evidence of a potential mental health effect of bowel preparation and colonoscopy, which may be associated with changes to the gut microbiota. There may also be a differential mental health impact of this procedure for those with and without IBS. Considering the limitations of our study, further research is required to confirm these findings and their clinical relevance.

Objective: This study aimed to demonstrate the availability of portable devices for nasal FeNO measurement, which could replace exhaled NO measurement based on the continuous aspiration of multiple flow measurement systems. Methods: A descriptive cross-sectional study. The healthy subjects without rhinosinusis disorders (control group) and those with diagnosed allergic rhinitis (AR group) were enrolled in the study. They underwent nasal and bronchial FeNO measurements by both fixed flow NObreath® connected to nasal mask and multiple flows HypAir FeNO®. Results: A total of 153 people were recruited including 63 healthy subjects and 90 subjects with AR. There were no statistically significant differences in anthropometric characteristics between the two groups (P > 0.05). There were a significant increase in FeNO values in the AR group compared to the control group; concentrations of nasal and bronchial FeNO mearsured by NObreath® were 76.0 ± 50.7 ppb (vs 36.0 ± 28.1 ppb, P < 0.01) and 32.3 ± 15.4 ppb (vs 9.2 ± 5.6 ppb, P < 0.001), and those mearsured by NObreath® Hypair FeNO® were 1796.9 ± 523.3 ppb (vs 400.2 ± 123.1 ppb, P < 0.001) and 37.3 ± 23.0 ppb (vs 17.4 ± 18.3 ppb, P < 0.01). A weak correlation between the values measured by NObreath® and Hypair FeNO® devices was observed (r = 0.023 and r = 0.089, respectively; p < 0.05). Conclusions: The handheld NObreath® device is effective in measuring FeNO concentrations in both normal subjects and AR patients. The advantages in price and size, creating a compact, low-cost device that is convenient for use and research.

Background: Health insurance (HI) run by government is providing health care service to large population. Due to poor accountability, participation and sustainability, cooperative health insurance is becoming more popular and effective in low and middle income and some high-income countries too. In Nepal, there are public and cooperative HI is in practice. The aim of this study is to compare the effectiveness of public (government) and cooperative HI in relation to benefit packages, population coverage, inclusiveness, health care utilization, and promptness for treatment in these two health insurance models in Nepal. Method: This is an institution based concurrent mixed study consists of qualitative and quantitative variables from public and cooperative groups. We included all public HI operated by government hospitals and cooperatives groups those purchased hospital service in contract. Two separate study tools were applied to access the effectiveness of insurance models. The key questions were asked for the representatives of government and private health insurance. The numeric information consisted of in quantitative data and subjective response was included in qualitative approach. Descriptive statistics and Mean Whitney U test was applied in numeric data and qualitative information were analyzed by inductive approach Results: The study revealed that new enrolment was not increased, health care utilization rate was increased and the benefit package was almost same in both groups. The overall inclusiveness was higher for the government HI, but enrolment from the religious minority, proportion of negotiated amount during treatment were significantly higher (p<0.05). During illness, the response time to reach hospital was significantly faster in cooperative health insurance than government health insurance. Qualitative findings showed that level of participation, accountability, transparency and recording system was better in cooperative health insurance than public. Conclusion: Cooperative HI could be more sustainable and accountable to the community for all; low, middle and high-income countries.

Global coverage and scale up of interventions to reduce newborn mortality remains low, though progress has been achieved in improving newborn survival in many low-income settings. An important factor in the success of newborn health interventions, and moving to scale, is appropriate design of community-based programs and strategies for local implementation. We report the results of formative research undertaken to inform the design of a newborn health intervention in Cambodia. Information was gathered on newborn care practices over a period of three months using multiple qualitative methods of data collection in the primary health facility and home setting. Analysis of the data indicated important gaps, both at home and facility level, between recommended newborn care practices and those typical in the study area. The results of this formative research have informed strategies for behavior change and improving referral of sick infants in the subsequent implementation study. Collection and dissemination of data on newborn care practices from settings such as these can contribute to efforts to advance survival, growth and development of newborns for intervention research, and for future newborn health programming.

Tumor to stroma ratio is a highly debated prognostic factor in the management of several solid tumors and there is no universal agreement on its practicality. In our study we proposed to confirm or dismiss the hypothesis that a simple measurement of stroma quantity is an easy-to-use and strong prognostic tool. We have included 74 consecutive patients with colorectal cancer who underwent primary curative abdominal surgery. The tumors have been grouped into stroma-poor (stroma &lt;10%), medium-stroma (between 10 and 50%) and stroma-rich (over 50%). The proportion of tumor stroma ranged from 5% to 70% with a median of 25%. Very few, only 6.8% of patients had stroma-rich tumors, 4% stroma-poor tumors and 89.2%tumors with a medium quantity of stroma. The proportion of stroma, at any cut-off, had no statistically significant influence on the disease specific survival. This can be explained by the low proportion of stroma-rich tumors in our patient group and the inverse correlation of stroma proportion with tumor grade. The real-life proportion of stroma-rich tumors and the complex nature of the stroma-tumor interaction has to be further elucidated.

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS &gt; 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (&lt; 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS &gt; 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.

Introduction: The association of gene variants for interleukin 6(IL-6) (rs1800796), interleukin 10 (IL-10) (rs1800896) and tumor necrosis factorα (TNFα (rs1800629) with the occurrence of spontaneous preterm birth (PTB) was investigated to determine whether these genetic variants are a risk factor. Materials and methods: 199 blood samples from pregnant women who had given birth prematurely and 200 control blood samples were analyzed to determine single nucleotide polymor-phisms (SNPs) of genes for IL-6 (rs1800796), IL-10 (rs1800896) and TNFα (rs1800629). The control samples were samples from pregnant women with term delivery. Isolation of DNA was per-formed on mini-spin columns according to the manufacturer's protocol. The quality and purity of the isolated DNA were tested using a Qubit 3 fluorometer. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. The genotypes obtained were an-alyzed using the 7500 Software v2.3 package. Results: Carriers of the A/A genotype for the rs1800629 of the TNFα gene have 4.81 times greater chance of late-onset PTB compared to carriers of the G/G and A/G genotypes in the recessive inheritance model. The presence of the G/G genotype in the recessive inheritance model compared with the G/A and A/A genotypes for the rs1800896 of the IL-10 gene represents a potentially protective factor, with mothers in the term-birth group having an almost 2-fold lower odds of PTB in general and an almost 10-fold lower odds of early PTB. On the other hand, carriers of the A/G genotype of rs1800896 have a 1.54-fold higher chance of preterm birth in general and a 1.6-fold higher chance of late preterm birth in the super dominant inheritance model compared to the A/A and G/G genotypes in the group of mothers with PTB. In this study, no association was found between PTB and rs1800796 of the IL-6 gene. Conclusion: rs1800629 in mothers was associated with PTB. rs1800896 shows a potentially protective effect for the occurrence of PTB in this study. No association was found between PTB and rs1800796.

Agroforestry is increasingly being recognized as a holistic food production system that can have numerous significant environmental, economic, and social benefits. This growing recognition is paralleled in the U.S. by the budding interest in regenerative agriculture and motivation to certify regenerative practices. Current efforts to develop a regenerative agriculture certification offer an opportunity to consider agroforestry’s role in furthering regenerative goals. To understand this opportunity, we first examine how agroforestry practices can advance regenerative agriculture’s five core environmental concerns: soil fertility and health, water quality, biodiversity, ecosystem health, and carbon sequestration. Next, we review a subset of certification programs, standards, guidelines, and associated scientific literature to understand existing efforts to standardize agroforestry. We determine that development of an agroforestry standard alongside current efforts to certify regenerative agriculture offers an opportunity to leverage common goals and strengths of each. Additionally, we determine that there is a lack of standards with measurable criteria available for agroforestry, particularly in temperate locations. Lastly, we propose a framework and general, measurable criteria for an agroforestry standard that could potentially be implemented as a standalone standard or built into existing agriculture, forestry, or resource conservation certification programs.

Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: small duct type and large duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes–inflammation and proliferation–have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches.

Coronavirus disease 2019 (COVID-19) has affected medical practice. More than 7,000,000 patients died worldwide after being infected with COVID-19; however, no specific laboratory markers have yet been established to predict death related to this disease. In contrast, electrocardiographic changes owing to COVID-19 include QT prolongation and ST-T changes; however, there have been no studies on ambulatory electrocardiographic markers of COVID-19. We encountered three patients diagnosed as having COVID-19 who did not have a prior history of significant structural heart diseases. All had abnormalities in ambulatory echocardiogram parameters detected by high-resolution 24-h electrocardiogram monitoring: positive late potentials (LPs) and T-wave alternans (TWA), abnormal heart rate variability (HRV), and heart rate turbulence (HRT). Case 1 involved a 78-year-old woman with a history of chronic kidney disease, Case 2 a 76-year-old man with hypertension and diabetes, and Case 3 a 67-year-old man with renal cancer, lung cancer, and diabetes. None of them had a prior history of significant structural heart disease. Although no significant consistent increases in clinical markers were observed, all three patients died, mainly because of respiratory failure with mild heart failure. LP, TWA, HRV, and HRT were all positive in three cases with no significant structural cardiac disease at the initial phase of admission. There is a possibility that LP, TWA, HRV, and HRT have the potential to be risk stratifiers of COVID-19 pneumonia in the early phase of admission. Further accumulation of data regarding ambulatory electrocardiographic markers in patients with COVID-19 is needed.

(1) Background: Among the chronic complications of type 2 diabetes mellitus, cancer became the leading cause of death in several countries. Our objective was the determination of whether prevalent type 2 diabetes mellitus is associated with a higher incidence of cancer. (2) Methods: This study is a nationwide analysis performed in Hungary. Study population was divided into a group with type 2 diabetes mellitus and into a non-diabetic group. The primary outcome was the risk related to overall cancer incidence. A key secondary outcome was the overall incidence of cancer in distinct study years. Further outcomes were the annual percent changes. (3) Results: The odds ratio related to the overall incidence of cancer was 2.50 (95% confidence interval: 2.46-2.55, P&lt;0.0001) in patients with diabetes as related to controls. The odds ratio was higher in males than in females. The highest risk was found in the 18-39-year-old subgroup. The annual cancer incidence rate declined in controls, but not in patients with diabetes. Several types of cancer showed a decreasing tendency in non-diabetic controls.; (4) Conclusions: type 2 diabetes is associated with a higher risk of cancer. High risk in young patients with type 2 diabetes suggests that these young individuals should be considered as a risk group.

(1) Background: Patients with type 2 diabetes mellitus (T2DM) are at higher risk of cancer but how these two diseases associate is still debated. The goal was the assessment of the overall incidence of cancer among patients with newly diagnosed T2DM in Hungary. Summarizing, incident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months. (2) Methods: A nationwide, retrospective, longitudinal study was performed using a Hungarian database. The incident T2DM and diabetes free Hungarian population were included in the study. The primary endpoints were the overall and site-specific incidence and annual percentage change of the incidence of cancer in both populations. (3) Results: The overall incidence of cancer in patients amounted to 29.4/1000 and 6.6/1000 with or without T2DM, respectively, and the OR (95%CI) of cancer of the T2DM group was 4.32 (4.14-4.53), p&lt;0.0001. The risk of having cancer was age-dependent, having the highest odd in the age group 18-39. The incidence of cancer was declining in the non-diabetic but was unchanged in T2DM population. The average lag time of diagnosing a cancer after the detection of T2DM was 3.86 months.; (4) Conclusions: Iincident T2DM is associated with a significantly higher overall risk of incident cancer, with a reverse correlation of age. Newly registered T2DM patients were suggested to be screened for cancer within 6 months.

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

A facilitative transport system exists on the blood brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to brain. But glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter brain in material quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exist only on the luminal membranes whereas Na+-dependent transport systems for glutamate, glutamine and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple the energy of the Na+-gradient to move glutamate and glutamine into the ECF whereupon glutamate can exit to blood on the luminal facilitative glutamate transporter. Glutamine may also exit brain on a separate facilitative transport system that exists on the luminal membranes or glutamine can be hydrolyzed to glutamate within the BBB thereby releasing ammonia that is freely diffusible. The γ-glutamyl participate cycle participates indirectly by producing oxoproline (pyroglutamate) that stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.

Congenital heart disease (CHD) is a prevalent congenital disorder diagnosed with high frequency, affecting approximately 0.8% to 1.2% of all live births. Research has demonstrated that the use of pulse oximetry and clinical examination as a screening tool for CHD diagnosis has proven extremely valuable. We conducted a retrospective longitudinal study over a 3-year period that involved screening 1188 newborns admitted to the NICU during the first 72 hours of life within this timeframe. 201 newborns were diagnosed with CHD. Almost all (n=198) had a positive screening test during the 72-hour period, while 3 had a negative screening test, but were later diagnosed using echocardiography. The prevalence rate was 16.67%. A confusion matrix was constructed with 198 true positives (TP), 3 false negatives (FN), no false positives (FP), and 987 true negatives (TN). The sensitivity of the screening test was 98.51%, while the specificity 100%, with no false positives. In our study, a total of 9 deaths occurred. Using the Kaplan-Meier method, the survival probability appeared to be slightly above 0.9 (95.5%), indicating that almost all patients survived past 72 hours after being diagnosed with CHD. Pulse oximetry is an effective, low cost and easy-to-use method and a useful tool to assess and lead to the diagnosis of CHD.

Conventional cancer clinical trials can be time-consuming and expensive, often yielding results with limited applicability to real-world scenarios and presenting challenges for patient participation. Real-world data (RWD) studies offer a promising solution to address evidence gaps and provide essential information about the effects of cancer treatments in real-world settings. Defining RWD based on its original intent, which is the collection of data at the point of care for clinical purposes, can distinguish it from conventional clinical trial data. RWD can be generated using experimental designs that resemble those used in conventional clinical trials, but with several advantages, such as improved efficiency and a better balance between internal and external validity. RWD can support pharmacovigilance, insights into disease progression, and the development of external control groups. Prospective RWD collection enables evidence generation based on pragmatic clinical trials (PCTs) that support randomized study designs and expand clinical research to the point of care. To ensure the quality of real-world studies, it is crucial to implement auditable data abstraction methods and develop new incentives to capture clinically relevant data electronically at the point of care. The treatment landscape is constantly evolving, with the integration of front-line immune checkpoint inhibitors (ICIs), either alone or in combination with chemotherapy, affecting subsequent treatment lines. Real-world effectiveness and safety in underrepresented populations, such as the elderly, patients with poor performance status (PS), hepatitis, or human immunodeficiency virus-infected patients, are still largely unexplored. Similarly, the cost-effectiveness and sustainability of these innovative agents are important considerations in the real world.

Background: Disparity in adult mortality (AM) with reference to social dynamics and health care has not been sufficiently examined. This study aimed to identify the gap in the understanding of AM in relation to religion, political stability, economic level, and universal health coverage (UHC). Methods: A cross-national study was performed with different sources of data, using the administrative record linkage theory. We created a new data set using data from the 2013 World Bank data catalogue by region, The Economist (Political instability index 2013), Stuckler David et al. (Universal health coverage, 2010), and religious categories of all UN country members. Descriptive statistics, a t-test, an ANOVA followed by a post hoc test, and a linear regression were used where applicable. Result: The average AM rate for males and females was 0.20 ± 0.10 and 0.14 ± 0.10, respectively. AM was significantly higher in economically weak countries, countries with political instability, countries with traditional religion, without achievement of UHC, and Sub-Saharan Africa (p<0.01). There was high disparity of AM between countries with and without UHC (F = male: 61.89, female: 51.85, p<0.001) and between groups with low and high income (F = male: 36.33, female: 42.39, p<0.001). UHC and political stability would significantly reduce AMR by > 0.41 in both sexes and high economic status would reduce male AMR by 0.44, and female AMR by 0.70, in relation to countries without UHC, with political instability, and low economic status. Conclusions: Disparities in AM can be reduced after the achievement of UHC and economically productive activities for those adults affected by conflict and political unrest.

Stallion mules have been used as working equids in several countries. Aggressiveness, under the influence of testosterone, resulted in the necessity for surgical castration before work training. The gonadotropin-releasing hormone (GnRH) vaccine may be an alternative method for immunocastration in mules. The objectives were to evaluate the effect of GnRH vaccine on anti-GnRH antibody production, serum testosterone level, clinical adverse effects, and behavior toward human manipulation. Twenty-five mules were separated into 3 groups: Control-intact, Control-castrated, and Treatment. Treatment was further divided into subgroups according to condition (intact or unilateral cryptorchid) and age. Treatment received 195 µg GnRH vaccine intramuscularly at week 0, 4, and 8. Anti-GnRH antibody increased at week 6 and 10, then gradually decreased to baseline at week 22. Treatment-intact-young had the highest anti-GnRH antibody, resulting in lower serum testosterone levels during week 2-6 and 12-16 compared to Control-intact. Subcutaneous edema adjacent to the injection site was detected only in Treatment-intact after booster vaccination. During week 6-22, the behavioral scores of Treatment significantly changed toward at ease with human contact compared to a score before vaccination. In conclusion, mules responded to GnRH vaccine, which could temporarily suppress testosterone for up to 16 weeks.

This study aimed to determine shifts in microbial populations regarding richness and diversity from daily use of a popular over-the-counter nasal spray. In addition, the finding of nasal commensal bacterial species that overlap with the oral microbiome may prove to be potential probiotics for the “gateway microbiomes.” Nasal swab samples were obtained before and after using the most popular over-the-counter (OTC) nasal spray in 10 participants aged 18–48 years. All participants were healthy volunteers with no significant medical histories. The participants were randomly assigned a number by randomizing software and consisted of five men and five women. The sampling consisted of placing a nasal swab atraumatically into the nasal cavity, which is similar to the sampling performed for COVID-19 testing, with only very slight discomfort, if any. The samples were preserved and sent to Northwestern University Sequencing Center for whole-genome deep sequencing. After 21 days of OTC nasal spray use twice daily, the participants returned for further nasal microbiome sampling. The microbial analysis included all bacteria, archaea, viruses, molds, and yeasts via deep sequencing for species analysis. The Northwestern University Sequencing Center utilized artificial intelligence analysis to determine shifts in species and strains following nasal spray use that resulted in changes in diversity and richness.

To better understand anogenital warts (AGW) natural history and dynamic of HPV6/11 infection in regional hairs, 32 newly diagnosed AGW male patients and 32 age-matched healthy controls were closely followed. During enrollment and six follow-up visits (every 2.6 months) 43 AGW tissue and 1,232 anogenital and eyebrow hair samples were collected. This represents the closest longitudinal monitoring of AGW patients to date. Patients were treated according to standard-of-care. HPV6/11 prevalence was 19.9% in patients’ hair samples (HPV6 B1 in 87.5%) and 0% in controls. The highest HPV6/11 prevalence was found in pubic hairs (29.0%) and lowest in eyebrows (7.1%). Odds for HPV6/11-positive hairs increased with smoking, shaving anogenital region and age. A close association between HPV6/11 presence in hairs and clinically visible AGW was observed. The proportion of patients with visible AGW and HPV6/11-positive hairs declined during follow-up with similar trends. No particular HPV6/11 variant was linked with increased AGW recurrence, but sublineage HPV6 B1 showed significantly higher clearance from hairs. Despite treatment, 78.1% and 62.5% of AGW patients experienced one and two/more post-initial AGW episodes, respectively. Patients having HPV6/11-positive hairs or visible AGW at preceding visit demonstrated substantially higher odds for presenting with visible AGW in subsequent visit.

Analysing the human body by direct observation can lead to misinterpretation of underlying trends, whereas in vitro organ models facilitate their understanding. Likewise, in vitro organ models serve as valuable tools for assessing the toxicity of compounds. However, none of the existing models had the features we considered critical for toxicity assessment, so we developed an in vitro liver model for toxicity assessment. We used four different types of primary liver cells: Hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volume of cell medium, hepatocyte proportion of total cells, and addition of extracellular matrix. We added rifampicin, ibuprofen and 5-fluorouracil to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured by the clinical instruments used in clinical diagnostics. When we exposed the selected model configuration to rifampicin, ibuprofen and 5-fluorouracil, the viability of Kupffer cells and liver sinusoidal endothelial cells was significantly lower than in the untreated samples. In contrast, we observed negligible viability of hepatocytes compared to the untreated samples. We have built an in vitro liver model that resembles the liver microenvironment and we have analysed it with clinical instrumentation to facilitate the data translation. In this sense, we have established that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.

Background and Objectives: Wilson disease (WD) is a disorder of copper metabolism caused by genetic muta-tions in the ATP7B gene which lead to the accumulation of copper in the body. The aim of the present study is to investigate the severity of WD in patients in Romania. Materials and Methods: This study was conducted us-ing an online questionnaire consisting of 32 questions in a group of patients suffering from Wilson disease. Results: The study included 67 people aged 7 to 56 with WD. The most common symptoms of the participants were hepatic and neurological in 22 cases (32.8%). The most common neurological symptom in the assessed cases was muscle stiffness (49.5%), followed by tremor (45%), and speech disorders (40.5%). The Kay-ser-Fleischer ring was present in 50.7% of the participants. The most commonly used drug treatment in the participants was D-penicillamine (77.61%). Conclusions: The severity of WD is based on many aspects, the most important being early diagnosis and access to treatment throughout the year. The prognosis is favorable with early diagnosis and treatment, but it is crucial to diagnose individuals before they develop major symp-toms. Therefore, advances in WD screening can lead to an earlier diagnosis and better results.

Cortex Periplocae, as a traditional Chinese herbal medicine, has been widely used for autoimmune diseases, especially rheumatoid arthritis. Due to its potential pharmaceutical values, more studies about the biological activities of Cortex Periplocae have been conducted recently. Meanwhile, the adverse reaction of Cortex Periplocae is not a negligible problem in clinic. In this article, we reviewed a series of articles and summarized the recent studies of Cortex Periplocae in the areas of phytochemistry and pharmacology. More than 100 constituents have been isolated and identified from Cortex Periplocae, including steroids, cardiac glycosides, terpenoids, and fatty acid compounds. The crude extracts of Cortex Periplocae and its active compounds exhibit various biological activities, such as cardiotonic effect, anticancer action, and anti-inflammatory effect. This paper aims to provide an overall review on the bioactive ingredients, pharmacological effect, and toxicity of this plant. Furthermore, this review suggests investigating and developing new clinical usages according to the above pharmacological effects.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

Candida spondylodiscitis (CS) is a rare disease, for which therapeutic option are limited to fluconazole or echinocandins and the treatment should be administered up to 12 months. In case of reduced azole susceptibility, there is a scarcity of therapeutic options with adequate bone penetration and limited toxicity. We report the first case of successful use of rezafungin for a spondylodiscitis due to Candida parapsilosis with reduced susceptibility to azoles. The patient, affected by paraplegia and short bowel syndrome, was diagnosed with CS with culture on vertebral biopsy guided by a 18-FDG-PET/CT scan. He received rezafungin 200 mg weekly for 26 weeks, after 10 weeks of previous antifungal treatment. He had a full clinical, radiologic and biochemical response to the therapy with rezafungin, with no adverse effects. Rezafungin is a promising therapy for Candida osteomyelitis, especially when first line therapies are ineffective or contraindicated.

Heart failure is a global major healthcare problem with millions of hospitalizations annually and with a very high mortality. There is an increased interest in finding new and reliable biomarkers for the diagnostication, prognostication and therapeutical guidance of patients hospitalized for acute heart failure. There is data to sustain the role of CA 125, a worldwide used marker of ovarian cancer, in patients with heart failure. Several studies have shown links between CA 125 levels and congestion seen in acute heart failure, high mortality and readmission rates at 6 months follow up after discharge from acute heart failure and also a role of CA 125 in the guidance of heart failure therapy. There are also clinical trials that showed that several particularities of CA 125 make it even better than NTpro BNP ( a classical and more utilised marker of heart failure) in several scenarios of acute heart failure.

A large diversity of epigenetic factors, such as microRNAs and histones modifications, are known to be capable of regulating gene expression without altering DNA sequence itself. In particular, miR-1 is considered the first essential microRNA in cardiac development. In this study, miR-1 potential role in early cardiac chamber differentiation is analyzed through specific signaling pathways. For this, we performed in chick embryos functional experiments by means of miR-1 microinjections into the posterior cardiac precursors -of both primitive endocardial tubes- committed to sinoatrial region fates. Subsequently, embryos were subjected to whole mount in situ hybridization, immunohistochemistry and RT-qPCR analysis. As a relevant nov-elty, our results revealed that miR-1 increases Tbx5, Gata4 and AMHC1, while this microRNA diminishes Mef2c expression, during early differentiation of cardiac sinoatrial region. Further-more, we observed in this developmental context that miR-1 upregulates CRABPII and RARß, and downregulates CRABPI, which are three crucial factors in retinoic acid signaling pathway. Interestingly, we also noticed that miR-1 directly interacts with HDAC4 and Calmodulin, as well as with Erk2/MAPK1, which are three key factors actively involved in Mef2c regulation. Our study shows, for the first time, a key role of miR-1 as an epigenetic regulator in early differenti-ation of cardiac sinoatrial region through orchestrating opposite actions between retinoic acid and Mef2c, fundamental to properly assign cardiac cells to their respective heart chambers. A better understanding of those molecular mechanisms modulated by miR-1 will definitely help in fields applied to therapy and cardiac regeneration and repair.

Probiotic feed additives have attracted considerable research interest in recent years because the effectiveness of probiotics can differ across microbial strains and the supplemented macroorganisms. The present study was conducted on 16 lambs divided into two groups (C - control and E - experimental). The examined lambs were aged 11 days at the beginning of the experiment and 40 days at the end of the experiment. The diet of group E lambs was supplemented with a multi-strain probiotic formulation (Lactobacillus plantarum AMT14, Lactobacillus plantarum AMT4, Lactobacillus rhamnosus AMT15, and Bifidobacterium animalis AMT30), whereas group C lambs did not receive the probiotic additive. At the beginning of the experiment (day 0) and on experimental days 15 and 30, blood was sampled from the jugular vein to determine and compare: phagocytic activity (PHAGOTEST) and oxidative metabolism (PHAGOBURST) of peripheral blood granulocytes and monocytes by flow cytometry. An analysis of the phagocytic activity of granulocytes and monocytes revealed significantly higher levels of phagocytic activity (expressed as the percentage of phagocytic cells and mean fluorescence intensity) in lambs administered the multi-strain probiotic formulation than in the control group. The probiotic feed additive also exerted a positive effect on the oxidative metabolism of both granulocytes and monocytes (expressed as the percentage of oxidative metabolism and mean fluorescence intensity) after stimulation with Escherichia coli bacteria and with PMA (4-phorbol-12-β-myristate-13-acetate).

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age representing the primary cause of anovulatory infertility. The nonapeptide oxytocin (OT) plays an important role in cognitive, emotional, and reproductive functions in human beings. Oxytocin receptors are expressed in several body parts including the ovaries. Despite this, the possible role played by oxytocin in symptoms of PCOS is not clear. The present systematic review aimed at understanding, the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. After a systematic search in the principal databases, seven studies, five human and two animal, were included. Most of the studies highlighted the role played by oxytocin in fertility issues related to PCOS. Studies that analyzed oxytocin basal levels in PCOS women agreed that PCOS is associated with a reduction in the serum level of oxytocin. Two studies found that in PCOS the serum levels of oxytocin were lower than healthy controls. One human and one animal study agreed about lower levels of PCOS, confirming a possible implication of a dysfunction of OT, in the pathogenesis of PCOS.

The study aimed to determine the effect of heat stress (HS) on reproductive parameters [calving to first service (CTFS) and first service conception rate (FSCR)] and general physiological responses [rectal temperature (RT) and respiratory rate (RR)] in tropical Holstein Friesian dairy cows raised in Ratchaburi province, Thailand. Cows were divided into a moderate HS (n = 22) and a mild HS (n = 22) group. Cycling cows were detected and injected with PGF2α at the beginning of the experimental period. Reproductive and physiological parameters were recorded. The average temperature humidity indices experienced by the cows were 80.67 ± 0.79 and 77.81 ± 1.09 for the moderate and mild HS groups, respectively. Cows showed significantly lower RT and RR in the mild (38.47 ± 0.21°C and 41.04 ± 4.55 bpm, respectively) than in the moderate HS group (38.87 ± 0.15°C and 51.17 ± 10.52 bpm). Under mild HS, cows showed a better response to injection of PGF2α than those under moderate HS. The percentage of cows that ovulated after being induced by PGF2α and showed estrus signs was higher in the mild than the moderate HS groups (54.55% versus 18.18%). Furthermore, the FSCR of cows under mild HS tended to be higher than in the moderate HS group (54.55 % and 42.11%, respectively), while the average CTFS interval was significantly shorter under mild than moderate HS (69.47 ± 18.18 and 84.60 ± 27.68, respectively). These results indicate that HS impairs reproductive performance in cross-bred Holstein cows, especially in moderate HS conditions.

One mechanism by which fructose could exert deleterious effect in metabolism and inflammation is via its potency vis-à-vis de Maillard reaction. We employed simulated stomach and duodenum digestion of ovalbumin to test the hypothesis that indeed AGEs are formed by fructose during simulated digestion of an ubiquitous food protein with intrinsic allergenic potential and under model physiological conditions. Methods: OVA was subjected to simulated gastric and intestinal digestion using standard models, in presence of fructose or glucose (0-100 mM). Peptide fractions were analyzed by fluorescence spectroscopy and intensity at Excitation: λ370 nm, Emission: λ 440nm. Results: AGE adducts form between fructose and OVA which can be found in peptide fractions (< 5 kDa) at times (30 min) and concentration ranges (10 mM) plausibly found in the intestines, whereas no reaction occurs with glucose. The reaction is inhibited by chlorogenic acid at concentrations compatible with those found in the gut. The reaction is inhibited by AG, a specific antiglycation agent. Conclusion: Our proof of principle study shows that fructose-AGE formation on an ubiquitous allergenic protein indeed occurs in one hour and thereby may pave the way for the study of yet another mechanism by which the excess fructose in our Western diets is contributing to disease: intestinal AGE formation, absorption and RAGE engagement.

Background: Cardiovascular (CV) morbidity and mortality are many times higher in chronic kidney disease (CKD), as well as IgA nephropathy (IgAN), than in the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The study aimed to determine the prognostic role of metabolic profiles in a homogenous group of CKD patients. Methods: One hundred and forty-five IgA nephropathy patients (92 male, 53 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for a median of 190 months. The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal). Results: Patients with MetS had significantly more endpoint events (16/27 patients vs. 15/98 patients, p = 0.001) compared to the nonMetS group. Of the secondary endpoints (CV or renal separately), the rate of the renal and CV endpoints was significantly higher in the MetS group (p = 0.001 and p = 0.029). The primary endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus, as determined by Cox regression analysis. Independent predictors of secondary renal endpoint were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. Kaplan-Meier curves showed significant differences in MetS and non-MetS when examined at the combined endpoints (CV and renal) or at each endpoint separately. The primary endpoint rate increased significantly with the increased number of MetS components (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). Conclusion: Our results showed that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy.

Keywords: Oral health, diabetes, periodontal disease, caries, periodontitis.

The implementation of sentinel lymph node (SLN) biopsy is changing the scenario in the surgical treatment of early-stage cervical cancer and the oncologic safety of replacing bilateral pelvic lymphadenectomy with SLN biopsy is currently under investigation. One of the undisputed values of SLN biopsy is its diagnostic accuracy in detecting low-volume metastases (LVM) via pathologic ultrastaging. In early-stage cervical cancer, the reported incidence of LVM ranges from 4 to 20%. The prognostic impact and the role of adjuvant treatment in patients with LVM is still unclear. Some non-prespecified analyses in prospective studies showed no impact on the oncologic outcomes compared to node-negative disease. However, the heterogeneity of the studies, the differences in the disease stage and the use of adjuvant treatment, and the concomitant pelvic lymphadenectomy (PLND) make any conclusion on this topic hard. Current guidelines suggest considering micrometastasis (MIC) as a node-positive disease, while isolated tumor cells (ITC) as a node-negative disease, with a low level of evidence. This review aims to highlight the unanswered questions about the definition, identification, prognostic and therapeutic role of LVM and underline the present and future challenges we are facing. We hope this review will guide further research, giving robust evidence on LVM and their impact on clinical practice.

The objective of this study is to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the equivalence ratio distributions and the injected fuel droplet behavior in the cylinder of the RCCI engine. The spray simulation was conducted by dividing two-part. First, the spray validation simulations progressed to find the spray-influenced factor of the test injector. Next, the engine simulations were performed with the spray-influenced factor obtained from spray validation simulations to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the injected fuel atomization and the equivalence ratio distributions. The introduced total heating value was fixed at 595J based on the lower heating value of diesel 14mg. The heating value of the premixed ethanol ratio varied from 0% to 40% based on the same total heating value in-cylinder in steps of 10%. It was revealed that when the premixed ethanol ratio based on the same total heating value in-cylinder was increased, the spray tip penetration value was reduced from the time after 4deg of diesel injection start because of the short injection duration by the small amount of diesel fuel. The SMD value was also more enormous up to 32.58% with increasing the premixed ethanol ratio because of the low kinetic energy of the injected fuel by the short injection duration and the slow evaporation of the injected fuel by the low cylinder temperature.

Cryptococcus neoformans is a facultative intracellular fungal pathogen. Ten-generation-old (10GEN) C. neoformans cells are more resistant to phagocytosis and killing by macrophages than younger daughter cells. However, mechanisms that mediate this resistance and intracellular parasitism are poorly understood. Here, we identified factors important for the intracellular survival of 10GEN C. neoformans, such as urease activity, capsule synthesis, and DNA content using flow cytometry and fluorescent microscopy techniques. Real-time visualization of time-lapse imaging was applied to determine the phagosomal acidity, membrane permeability, and vomocytosis (non-lytic exocytosis) rate in J774 macrophages that phagocytosed C. neoformans of different generational ages. Our results showed that old C. neoformans exhibited higher urease activity, and enhanced capsule formation, which was supported by an increased Golgi complex. In addition, old C. neoformans were more likely to be arrested in the G2 phase, resulting in the occasional formation of aberrant trimera-like cells. To finish, the advanced generational age of the yeast cells slightly reduced vomocytosis events within host cells, which might be associated with increased phagolysosomal pH and membrane permeability. Altogether our results contribute to a better understanding of the strategies used by old C. neoformans to resist phagosomal killing and suggest that old generation C. neoformans intracellular behavior may be driving cryptococcosis pathogenesis.

Background: Bacteria can survive antibiotic exposure by mechanisms like tolerance without a shift in antimicrobial susceptibility. In this study, we investigated the presence of tolerance to three antimicrobials, ceftriaxone (CRO), azithromycin (AZM), and ciprofloxacin (CIP), in clinical isolates and WHO reference panel of N. gonorrhoeae and explored the prevalence between urogenital and anorectal infection sites. Methods: We examined 66 N. gonorrhoeae clinical isolates, evenly divided between anorectal and urogenital infection sites, using a modified tolerance disk (TD test) for three antibiotics. The isolates underwent a three-step incubation process wherein the isolates were exposed to an antibiotic disc for 20 hours of incubation (Step I), followed by the replacement of the antibiotic disc with a nutrient disc for overnight incubation (Step II) and additional overnight incubation with extra nutrients (Step III). Results: Four isolates were lost due to contamination. Of 62 clinical isolates, 7 exhibited tolerance to AZM, with 6 from anorectal and 1 from urogenital sites (p = 0.0496). Tolerance to CRO was observed in 11 isolates, which was significantly associated with the infection site, with 9 from the anorectum, and 2 from the urogenital site being tolerant (p = 0.02). Tolerance to CIP was found in 11 isolates, but was not significantly associated with the infection site. Tolerance was also detected in 8 (K, M, N, O, P, U, V, W) out of the 14 WHO (World Health Organization) reference strains, with varying patterns of tolerance to CRO (n=8), CIP (n=2) and AZM (n=1). Conclusion: This study identified CRO, AZM, and CIP tolerance in clinical Neisseria gonorrhoeae isolates. Significant variations in tolerance proportions between anorectal and urogenital infection sites, particularly for CRO, were observed. Additionally, tolerance was detected in WHO reference strains.

This study proposes an innovative pharmacovigilance approach, VIGI-4, leveraging ChatGPT Teams Pro version. Our method involves aggregating data from all phase 4 studies published in February 2024 to identify adverse reactions. These results are categorized by disease state alphabetically, demonstrating the method's capacity to generate structured and easily navigable outputs. The results section is tailored to exemplify the valuable, actionable insights attainable through our workflow. This research emphasizes the game-changing potential of integrating advanced technologies such as ChatGPT into pharmacovigilance, signaling a new era in safeguarding drug safety.

Artificial Intelligence (AI) is rapidly transforming the field of medicine, announcing a new era of innovation and efficiency. Among AI programs designed for general use ChatGPT holds a prom-inent position using an innovative language model developed by OpenAI. Thanks to the use of deep learning techniques, ChatGPT stands out as an exceptionally viable tool, renowned for gen-erating human-like responses to queries. Various medical specialties, including rheumatology, oncology, psychiatry, internal medicine, and ophthalmology, have been explored for ChatGPT in-tegration, with pilot studies and trials revealing each field's potential benefits and challenges. However, the field of genetics and genetic counseling, as well as that of rare disorders, represents an area suitable for exploration, with its complex data sets and the need for personalized patient care. In this review, we synthesize the wide range of potential applications for ChatGPT in the medical field, highlighting its benefits and limitations. We pay special attention to rare and genetic disorders, aiming to shed light on the future roles of AI-driven chatbots in healthcare. Our goal is to pave the way for a healthcare system that is more knowledgeable, efficient, and centered around patient needs.

Peritoneal dialysis (PD) is a home-based efficacious modality for replacement of renal function in end-stage kidney failure patients but is still under-prescribed. A major limitation is the durability of the dialytic technique. Continuous exposure of the peritoneum to bioincompatible conventional glucose-based solutions is thought to be the main cause of long-term morpho-functional peritoneal changes eventually resulting in ultrafiltration failure. Poor PD solution biocompatibility is primarily related to the high glucose content, which is not only detrimental to the peritoneal membrane but has many potential metabolic side effects. To improve the clinical outcome and prolong the survival of the treatment, PD-related bioincompatibility urgently needs to be overcome. However, combining dialytic and osmotic efficacy with a satisfactory biocompatible profile proves quite difficult. New approaches targeting the composition of the PD solution include replacement of glucose with other osmotic agents and the addition of cytoprotective or osmo-metabolic compounds. Other strategies include infusion of mesenchymal cells or the administration of orally active agents. In the present article we review the current evidence on efforts to improve the biocompatible and functional performance of PD, focusing on studies performed in vivo (animal models of PD, human subjects on PD).

Gene regulation is vital for cellular function and homeostasis, involving diverse mechanisms controlling specific gene products and contributing to tissue-specific gene expression. Dysregulation leads to diseases, emphasizing the need for understanding these mechanisms. Non-coding regions, notably enhancers and super-enhancers (SEs), act as crucial gene regulators, orchestrating transcriptional activity via transcription factors (TFs). SEs, with high activity, are pivotal in cell identity and disease progression. Current computational approaches focus on individual regulators like TFs and miRNAs, neglecting SE interactions. We emphasize incorporating SEs into models to enhance understanding. Experimental studies have recently linked miRNAs and TFs to SEs. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides valuable SE information. In this review, we categorize computational methods leveraging TF and miRNA data into three areas and explore challenges integrating enhancers/SEs. These include unraveling indirect regulatory networks, identifying network motifs, and enriching pathway identification by dissecting gene regulators, including SEs. We hypothesize that addressing these challenges will enhance our understanding of gene regulation, aiding in identifying therapeutic targets and disease biomarkers. We believe that understanding the role of ChIP-Seq data in predicting the effect of miRNA on gene regulation is crucial to construct statistical/computational model that would tackle these challenges.

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

Global public health systems have continuously faced challenges from the advent of novel infectious illnesses, necessitating quick and efficient actions to stop their spread.First discovered in Saudi Arabia in 2012, Middle East respiratory syndrome (MERS) is a viral respiratory disorder caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). Since then, the nation has reported most cases and fatalities related to this sickness, with occasional outbreaks happening in other nations and regions. Severe sickness and high mortality are caused by MERS-CoV, especially in older persons and those with underlying chronic conditions. Through intimate contact, the virus can spread from people to dromedary camels and vice versa. It has sparked multiple epidemics both domestically and abroad in the Middle East, raising the possibility of fatalities and widespread transmission, especially in susceptible groups. The Riyadh region was the main target of the most current MERS-CoV outbreak in Saudi Arabia, which began in 2023 and ended on September 1, 2023, with 312 confirmed cases and ninety-seven fatalities. With the use of published studies and their contributions to the field, we hope to present a thorough overview of the MERS-CoV outbreak in Saudi Arabia in this review of the literature, including its epidemiological investigation, public health response, impact, and lessons learned. In addition to highlighting the importance and continued relevance of this problem, our work suggests ways to lower the risk of MERS-CoV transmission and avert further outbreaks.

Childhood obesity has become a global epidemic, with significant increases in prevalence over recent decades. While excessive calorie consumption and physical inactivity are known factors, emerging research highlights the role of Endocrine-Disrupting Chemicals (EDCs), particularly obesogens, in obesity's pathogenesis. This review explores the historical context of the environmental obesogens hypothesis, their sources, mechanism of action, impact on prenatal and postnatal development and epigenetics. Additionally, it discusses the long-term consequences of childhood obesity and proposes prevention strategies that will mitigate the negative health effects. Obesogens were found to disrupt hormonal balance and metabolic processes through various mechanisms such as altering gene expression, hormonal interference, and inflammation. Especially significant, was exposure during critical windows of development which correlates with increased risk of obesity in childhood or adolescence. Long-term effects of childhood obesity include chronic health conditions and psychosocial issues. A comprehensive approach is necessary to address childhood obesity, encompassing genetic, environmental, and lifestyle factors. Prevention strategies should focus on reducing obesogens exposure, promoting healthy lifestyles, and implementing regulatory policies. Future research should investigate obesogens-diet interactions, microbiome impacts, and combined obesogens effects. Long-term human studies are also crucial for validating findings from animal models and allow for inform decision-making to combat the obesity pandemic.

Immune checkpoint inhibitors (ICI’s) are in the forefront of advanced Non Small Cell Lung Cancer (NSCLC) treatment. Still, only 27- 46% of patients respond to initial therapy with ICI’s and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4%-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post-hoc analyses of several clinical trials. Future research of ICI rechallenge for NSCLC should focus on better patient stratification, to reflect the underlying biology of immunotherapy resistance more accurately.

In the context of sustainable development, integrating the work aspect into health promotion systems is essential, ensuring that employees maintain a healthy balance between their professional and personal lives, which respects and amplifies the potential of every individual. Lately, there has been a noticeable shift of medical professionals from the public to the private sector. This trend paints a bleak picture, highlighting the vulnerabilities of a system teetering on the brink of failure, with significant impacts on patient care. Among the myriad reasons behind this shift, burnout stands out prominently. Medical professionals face increasing pressures due to understaffing, limited organizational support, and insufficient resources, leading to feelings of cynicism, exhaustion, and detachment from their roles. Utilizing the Maslach et al. questionnaire, we assessed the risk of burnout among physicians in public hospitals to identify and underscore preventive measures and improvements, correlating our findings with key aspects of organizational empowerment. Our research indicates that enhancing interpersonal relationships and resources—both within teams and between the organization and its physicians—is crucial for the revival of the healthcare system. This approach aims at improving the delivery of healthcare services and offering appropriate recognition to healthcare professionals, aligning with the principles of sustainable employment.

Objectives: To assess the short-term impact of a single global stretching session on plantar pressures and lumbar range of motion (RoM) over one week in sedentary university students. Design: A randomised controlled trial with two parallel groups. Participants: Sixty-four university students were randomly assigned to a stretching group or control group. The stretching group received a single session of global stretching and the control group remained seated for the same length of time as the stretching session. Main outcome measures: Lumbar RoM and plantar pressures were assessed before, immediately after, 48 hours after, and 7 days after intervention. Results: Group-by-time interaction was significant for lumbar lateral flexion (p = 0.044), right maximal pressure (p = 0.003), left maximal pressure (p = 0.008), right mean pressure (p = 0.025), left mean pressure (p = 0.002), and maximal pressure minus mean pressure in right foot (p = 0.007). The model with plantar pressures showed a significant difference for group-by-time interaction (p = 0.010).Conclusion: Global stretching seems to counteract the ill-effects of prolonged sitting up to seven days with respect to plantar pressure in standing without improving lumbar ROM

Background: Schistosome egg deposition in pregnant women may affect the placenta of infected mothers and cause Placental Schistosomiasis (PS). Histopathological examination of placental tissue is an inadequate detection method due to low sensitivity. So far, there has not been any sys-tematic review on PS. Methods: We conducted a systematic literature search on PubMed and in-cluded relevant secondary literature found in the citations of the primarily included publications. Results: We found a total of 8 publications describing PS with a total of 92 cases, describing egg deposition of dead and/or viable eggs and worms of S. haematobium and S. mansoni in placental tissue. One cross-sectional study investigating the prevalence of PS and its association to adverse birth outcomes, found 22% of placentas to be infested using a maceration technique but only < 1% using histologic examination. Additionally, no direct link to deleterious pregnancy outcomes could be shown. Conclusions: PS is a highly unattended and underdiagnosed condition in en-demic populations, due to a lack of awareness as well as low sensitivity of histopathological examinations. However, PS may play an important role in mediating or reinforcing adverse birth outcomes (ABO) such as fetal growth restriction (FGR) in maternal schistosomiasis, possibly by placental inflammation.

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-aminofluorene (2-AAF). HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.

Previously, we described a 19-base pair double-stranded RNA with 3'-trinucleotide overhangs, acting as immunostimulatory RNA (isRNA). This molecule demonstrated notable antiproliferative effects on cancer cells, inhibited tumor growth, and elicited immunostimulatory and antiviral responses by inducing cytokine and interferon production. Within this study, we compared the efficiency of lung fibrosis development, initiated in mice by BLM or LPS using different schemes of induction. Then we compared the effect of isRNA used in a preventive or therapeutic regimen on the development of fibrosis in selected BLM- and LPS-induced mouse models and showed that isRNA can be used in pathological conditions accompanied by the development of inflammation and the risk of fibrosis formation, without adverse side effects. Prophylactic regimen of isRNA application is beneficial for prevention of the development of pulmonary fibrosis.

Sterol homeostasis in mammalian cells and tissues involves balancing three fundamental processes: de novo sterol biosynthesis; sterol import (e.g., from blood-borne lipoproteins); and sterol export. In complex tissues, composed of multiple different cell types (such as the retina), import and export also may involve intra-tissue, inter-cellular sterol exchange. Disruption of any of these processes can result in pathologies that impact the normal structure and function of the retina. Here, we provide a brief overview of what is known currently about sterol homeostasis in the vertebrate retina and offer a proposed path for future experimental work to further our understanding of these processes, with relevance to the development of novel therapeutic interventions for human diseases involving defective sterol homeostasis.

The importance of personalized medicine is growing, since there is an urged need to avoid unnecessary and expensive treatments. In nuclear medicine, the theranostic approach is an established tool for a specific molecular targeting in means of diagnostics and therapy. The visualisation of potential targets can help to predict if a patient would benefit from a particular treatment or not. Thanks to the quick development of radiopharmaceuticals and diagnostic techniques, the use of theranostic agents is constantly rising. In this article important milestones of nuclear therapies and diagnostics in the context of theranostics are highlighted. It begins with the well-known radioiodine therapy in patients with thyroid cancer and then guides through different approaches for the treatment of advanced cancer with targeted therapies. The aim of this review is to provide a summary of background knowledge, current applications and advantages of targeted therapies and imaging in nuclear medicine practice.

Background: Despite their generally favorable prognosis, hepatic fibrosis remains a possible complication for hepatitis B virus (HBV) inactive carriers. This study aimed to estimate the prevalence of significant fibrosis and associated risk factors among Omani HBV inactive carriers. Methods: A retrospective study was conducted of 200 Omani HBV inactive carriers visiting a tertiary hospital in Muscat, Oman, between January 2017 and December 2018. Significant fibrosis (stage F2 or higher) was identified using two-dimensional shear-wave elastography. Baseline clinical, laboratory, and radiological data were analyzed to determine associations. Results: Of the total sample, 106 patients (53%) were male, and the mean age was 44.6 ± 9.3 years. The prevalence of significant fibrosis was 20% (n = 40). Male gender (p = 0.007), age ≥60 years (p = 0.024), and fatty changes in liver ultrasound (p = 0.044) were found to be independent factors for significant fibrosis. Conclusion: the prevalence of significant fibrosis was relatively high among a sample of Omani HBV inactive carriers, with several sociodemographic and clinical risk factors identified. Periodic assessment of liver function is needed for patients with these risk factors; moreover, routine biochemical parameters could be useful predictors of disease prognosis. Further research is recommended to substantiate these findings.

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously [1]. In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

Patients with predominantly antibody deficiencies (PAD) display hypogammaglobulinemia with a high prevalence of infections, along with autoimmune manifestations, benign and malignant lymphoproliferation and granulomatous disease. It is noteworthy that PAD patients, even those with defects in the same causative genes display a variable clinical phenotype, suggesting that additional genetic polymorphisms, located in either immune-related or non-immune-related genes, may affect their clinical and laboratory phenotype. In this context, we analyzed 80 PAD patients, including 70 with common variable immunodeficiency (CVID) for SERPINA1 defects, in order to investigate their possible contribution to PAD clinical phenotype. Eight CVID patients carried heterozygous pathogenic SERPINA1 defects with normal alpha-1 antitrypsin levels. Interestingly, the presence of the Z allele (rs28929474) which was found in three patients, was significantly associated with liver disease; hepatic complications were also observed in patients carrying the p.Leu23Gln (rs1379209512) and the p.Phe76del (rs775982338) alleles. Conversely, no correlation of SERPINA1 defective variants with respiratory complications was observed, although patients with pathogenic variants exhibit a reduced probability of developing autoimmune diseases. Therefore, we recommend SERPINA1 genetic analysis in PAD, in order to identify patients with a higher risk for liver disease.

New antiviral agents are essential to improving treatment and control of SARS-CoV-2 infections that can lead to the disease COVID-19. Antimicrobial peptoids are sequence-specific oligo-N-substituted glycine peptidomimetics that emulate the structure and function of natural antimicrobial peptides but are resistant to proteases. We demonstrate antiviral activity of a new peptoid (TM9) against the coronavirus, murine hepatitis virus (MHV), as a closely related model for the structure and antiviral susceptibility profile of SARS-CoV-2. This peptoid mimics the human cathelicidin LL-37, which has also been shown to have antimicrobial and antiviral activity. In this study TM9 was effective against three murine coronavirus strains, demonstrating the therapeutic window is large enough to allow use of TM9 for treatment. All three isolates of MHV generated infection in mice after 15 min of exposure by aerosol using the Madison aerosol chamber and all three viral strains could be isolated from the lungs throughout the 5-day observation period post-infection, with the peak titers on day 2. MHV-A59 and MHV-A59-GFP were also isolated from liver, heart, spleen, olfactory bulbs, and brain. These data demonstrate that MHV serves as a valuable natural murine model of coronavirus pathogenesis in multiple organs, including the brain.

We aimed to evaluate the association between daily dietary calcium intake and the risk of cardiovascular disease (CVD) in postmenopausal women using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included 12,348 women aged 45–70 years who had reached natural menopause. They were classified into three groups according to daily dietary calcium intake: &lt; 400 mg, 400–800 mg, and &gt;800 mg. The risks of CVD, stroke, angina, and myocardial infarction were assessed in each group. Further, we performed subgroup analysis according to the post-menopause duration (≤10 vs. &gt;10 postmenopausal years). We performed logistic regression analysis with adjustment for age, menopausal age, income, urban area, education, insulin use, body mass index, hypertension, diabetes mellitus, dyslipidemia, high alcohol intake, smoking, exercise, oral contraceptive use, and hormonal therapy use. Calcium intake level was not significantly associated with the risk of CVD in the total population and the ≤10 postmenopausal years subgroup. However, in the &gt;10 postmenopausal years subgroup, daily calcium intake &gt;800 mg was associated with significantly decreased risks of all CVD (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11–0.64), stroke (OR, 0.06; 95% CI, 0.01–0.42), and myocardial infarction (OR, 0.27; 95% CI, 0.11–0.64). Our findings suggest that a dietary calcium intake of &gt;800 mg/day decreases the risk of CVD events in women who have been menopausal for &gt;10 years.

ABSTRACT Background: To date, the COVID-19 pandemic has been the foremost health concern for humankind in the new millennia. This paper aims to describe the related hospitalizations in Italy during the first two years of the health emergency. Design and methods: This is a retrospective, population-based study of Italian hospitalizations for patients diagnosed with COVID-19 during the 2020-2021 period, extracted from the National Hospital Discharge Registry. The outcome variables considered include hospital admissions, costs, and length of stay, among other hospitalization-level variables. Costs were estimated through the charges associated with the Diagnosis-Related Group and Major Diagnostic Categories coding system, plus an additional cost attributed to COVID-19 admissions. To these charges was added an extra cost defined by the ministry of health. Results: In Italy, there were 357,354 hospitalizations for COVID-19 attributed to 298,856 patients in 2020 and 399,043 hospitalizations for COVID-19 attributed to 333,447 patients in 2021. COVID-19 patients faced a transfer rate thrice that of other patients. Hospitalizations were concentrated predominantly in the northern regions, particularly in the first year. Hospitalization rates varied by age in a sine wave pattern, peaking in the youngest and oldest age groups, with mortality rates escalating with age— tending to remain below 3% for those under 44 but surging to 40% in individuals over 75. The financial impact of COVID-19 hospitalizations was substantial, with total costs reaching €3.97 billion in 2020 and €4.99 billion in 2021. Costs per admission and per day also rose, from €11,112 and €807 in 2020 to €12,503 and €844 in 2021, respectively. Excluding the added financial burden of COVID-19, costs would have been notably lower. Hospitalizations involving continuous invasive mechanical ventilation were particularly costly (about 24.000 euros x admission), reflecting the significant resources required for these treatments. Conclusion: Implementing a protective pad around the entire health system that leverages networks of family doctors and nurses, connected in real time to the entire health system, can be crucial. Such a network, tasked with monitoring the local epidemiological situation, protecting vulnerable individuals also through telehealth visits, and establishing a triage system for infections in the initial phase, may effectively help in managing virus spread and protecting hospitals from unpredictable waves of admission demand. Strengthening primary health care could be a decisive factor for the future and enhance the system's resilience in facing new challenges.

This review article focuses on the role of Artificial Intelligence (AI) in transforming healthcare in Africa, specifically in combatting infectious diseases, neglected tropical diseases (NTDs), and antimicrobial resistance. We provide a comprehensive overview of the significance of AI in the healthcare industry, highlighting its urgency and importance in addressing these specific health challenges in Africa. We begin by discussing the role of AI in infectious disease surveillance and outbreak detection. We explore how AI technology can be employed for real-time tracking and prediction of outbreaks, providing examples of successful AI applications in infectious disease surveillance within the African context.Next, we examine the potential of AI-enabled diagnosis and treatment for faster and more accurate diagnoses of infectious diseases and NTDs. We highlight specific examples of AI applications in diagnosing and treating these diseases in Africa, showcasing the potential of AI to improve clinical outcomes and save lives.Furthermore, we focus on how AI-driven drug discovery and development can expedite the search for new treatments for infectious diseases and combat antimicrobial resistance. We present examples of AI applications in drug discovery within the African context, illustrating the potential for AI to revolutionize the development of effective therapeutics.In addition, we delve into how AI-powered public health interventions can enhance the design and implementation of targeted interventions. We explore how AI can optimize resource allocation and facilitate data-driven decision-making processes, providing examples of AI applications in public health in Africa.Finally, we address the challenges and limitations of implementing AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. We discuss potential barriers and ethical concerns surrounding AI applications in healthcare, aiming to encourage informed and responsible utilization of AI technologies.Overall, this review emphasizes the importance and potential of AI in combatting infectious diseases, NTDs, and antimicrobial resistance in Africa. It positions AI as a catalyst for revolutionizing healthcare in the region, leading to more effective disease surveillance, diagnosis, treatment, drug discovery, and public health interventions.

The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly in gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5,397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

Despite the recent availability of immune checkpoint inhibitors, not all patients affected by Non-Small Cell Lung Cancer (NSCLC) benefit from immunotherapy. The reason for this variability relies to a variety of factors which may allow the identification of novel biomarkers. Presently, a variety of biomarkers are under investigation, including the PD1/PDL1 axis, the tumor mutational burden, and the Microbiota. This latter is made by all bacteria and other microorganisms hosted in our body. The gut microbiota is the most represented and has been involved in different physiological and pathological events, including cancer. In this light, it appears that all conditions modifying gut microbiota can influence cancer, its treatment, and its treatment-related toxicities. The aim of this review is to analyze all conditions influencing the gut microbiota and, therefore, affecting response to immunotherapy, iRAEs and their management in NSCLC patients. The investigation of the landscape of these biological events can allow novel insights for optimal management of NSCLC immunotherapy.

There is increasing evidence that some adult mitral valve pathologies may have developmental origins involving errors in cell signaling and protein deposition during valvulogenesis. While early and late gestational stages are well-documented in zebrafish and small mammalian models, longitudinal studies in large mammals with a similar gestational period to humans are lacking. Further, the mechanism of chordae tendineae formation and multiplication remains unclear. This current study presents a comprehensive examination of mitral anterior leaflet and chordae tendineae development in a bovine model (with a gestational period of 9 months). Remarkably distinct from small mammals, bovine development displayed early branched chordae, with increasing attachments only until birth, while the anterior leaflet grew both during gestation and postnatally. Chordae also exhibited accelerated collagen deposition, maturation, and crimp development during gestation. These findings suggest that the bovine anterior leaflet and chordae tendineae possess unique compartmentalized processes of development despite being a continuous collagenous structure.