Background: The modified Duke index derived from coronary computed tomography angiography (CCTA) was designed to predict cardiovascular outcomes based on the severity of coronary ste-nosis. However, it does not take into consideration the presence or severity of peri-coronary in-flammation. The peri-coronary fat attenuation index (FAI) is a novel imaging marker determined by CCTA which reflects the degree of inflammation in the coronary tree in patients with coronary artery disease. Purpose: To assess the association between the modified Duke index assessed by CCTA, cardiovascular risk factors and peri-coronary inflammation in the coronary arteries of pa-tients with coronary artery disease. Methods: One hundred seventy-two patients who underwent CCTA for typical angina were assigned into two groups based on the modified Duke index: group 1 – patients with low index ≤ 3 (n=107) and group 2 – patients with high index > 3 (n=65). Demo-graphic, clinical and CCTA data were collected for all patients, and FAI analysis of coronary in-flammation was performed. Results: Patients with increased values of the modified Duke index were significantly older compared to those with a low index (61.83 ± 9.89 vs. 64.78 ± 8.9; p = 0.002). No differences were found between the two groups in terms of gender distribution, hypertension, hypercholesterolemia or smoking history (all p > 0.5). The FAI score was significantly higher in patients from group 2, who presented a significantly higher score of inflammation compared to the patients in group 1, especially at the level of the right coronary artery (FAI score 20.85 ± 15.80 vs. 14.61 ± 16.66; p = 0.01 for the right coronary artery, 13.85 ± 8.04 vs. 10.91 ± 6.5; p = 0.01 for the circumflex artery, and 13.26 ±10.18 vs. 11.37 ± 8.84; p = 0.2 for the left anterior descending artery). CaRi-Heart® analysis identified a significantly higher risk of future events among patients with a high modified Duke index (34.84 % ± 25.86 % versus 16.87 % ± 15.80 %; p

Monkeypox (mpox) caused by the monkeypox virus (MPXV) is currently the most common orthopoxvirus (OPXV) zoonotic disease. Since 2022, a multi-country outbreak of mpox has been reported with atypically rapid human-to-human transmission. The present work aimed to investigate the frequency of MPXV and OPXV DNA detection in different clinical materials taken at acute and convalescent phases of the infection in Bulgarian patients. A total of 181 clinical samples from 42 Bulgarian patients with possible mpox infections were tested. Screening for MPXV DNA (F3L gene) and OPXV DNA (rpo18 gene) were performed by real-time PCR assays. Of all tested patients six (14%) were confirmed with mpox infection. MPXV DNA was detected in 23/181 (12,71%) and OPXV DNA in 20/181 (11,05%) clinical samples. All confirmed patients were men who have sex with men, aged 23 to 44 (at an average age of 35,17±7,91 years) and two of them were HIV positive. The commonest clinical features of patients were fever (5/6), vesicular-pustular rash: perianal (6/6), penile (4/6), and limbs (4/6). MPXV DNA was found with the greatest frequency in specimens of vesicle contents and nasal/oropharyngeal swabs in 6/6 and 5/6. OPXV DNA mainly was detected in vesicle contents (6/6), nasal/oropharyngeal swabs (4/6), and urine (4/6). In the collected follow-up samples, MPXV DNA was detected in the highest percentage in the specimen's vesicle contents (6/6) and urine (6/6) and not demonstrated in samples of feces and saliva. The laboratory surveillance of MPXV is critical to contain the outbreak and to elucidate the new fast transmission of the virus.

This review examines the effects of lingonberry (Vaccinium vitis-idaea L.) on general and oral health. The effects of lingonberry are based on the vitamins, minerals, fibers and polyphenolic compounds it contains. Lingonberry's bioactive substances have a diverse range of antimicrobial, anti-inflammatory, antiproteolytic, anticarcinogenic and antioxidant properties. Research results suggest that lingonberries can have a positive effect on human health. Berries, lingonberry juice/lingonberry nectar/fermented lingonberry juice and polyphenol fractions have been used in clinical studies. Lingonberries balance post-meal blood sugar, free fatty acids and insulin levels. Fermented lingonberry juice reduces Streptococcus mutans, Candida and periodontal pathogen counts, but is probiotic because it favors growth of Lactobacilli. In addition, it increases saliva secretion and thus lowers the risk of oral infections. It lowers the clinical parameters of periodontitis and the active matrix metalloprotease-8, reducing the low-grade inflammation associated with periodontal diseases. More studies on humans are needed.

Mammarenavirus Wenzhouense (WENV) is broadly distributed in Asia, while the he dynamics process of WENV infection remains unclear. A field derived strain of WENV was used to inoculate Sprague-Dawley (SD) rats by intramuscular injection, the process of virus infection was de-tected by controlling time for 28 days. Viral RNA became detectable in the blood at 3 d pi, and remained detectable for about 12 d. In most organ tissues, viral RNA peaked at 7 d pi, then began to decline by 14 d, however remained detectable in intestine and brain tissues at 21 and 28 d pi. Virus shedding had been detected from fecal samples for 5 days from 6 to 11 d pi using qRT-PCR, and was recovered from feces collected at 8 d pi. Horizontal contact infection occurred among cage-mates at 14 and 21 d pi. Antibodies against the nucleocapsid were detected at 5 dpi, next increased and persisted until the end of experiment. The results enabled to discriminate the kinetic of viremic response, virus shedding in feces and horizontal transmission, as well as the potential sites for WENV replication or maintenance of the virus in nature.

A prospective clinical-epidemiological study was conducted to evaluate the dynamics of biomarkers in hospitalized patients with moderate to severe COVID-19 (according to the National Institute of Health severity scale) treated with Anakinra, compared to those receiving standard treatment. The study included 65 patients with a mean age of 75.51±9.54 years, ranging from 44 to 99 years. Among the study participants, 38 (58.5%) were male and 27 (41.5%) were female. The patients were divided into two groups: control group (standard treatment): 24 patients (36.9%) and target group (Anakinra treatment): 41 patients (63.1%). The results showed a significant relationship between the dynamics of leukocytes, ASAT, LDH, D-dimer, ferritin, and IL-6 and the administration of Anakinra. In the control group, no significant dynamics were observed in leukocyte count, D-dimer, ferritin, or IL-6. A statistically significant decrease in ASAT and LDH values in the control group was noted only on Day 7. In the Anakinra group, significantly (or with borderline statistical significance, p<0.1) lower mean values were observed for leukocytes, NLR, D-dimer, ferritin, and IL-6 on Days 3 and 7 compared to the control group. Additionally, significantly lower CRP values were detected in the Anakinra group on Day 7 compared to the control group.

Fractional flow reserve (FFR) is well recognized as a gold standard measure for the estimation of functional coronary stenosis. Technological progressions in image processing have empowered the reconstruction of three-dimensional models of the coronary arteries via both non-invasive imaging modalities, such as Coronary Computed Tomography Angiography (CCTA), and invasive coronary angiography or intravascular imaging. The application of computational fluid dynamics (CFD) techniques to coronary 3D anatomical models allows the virtual evaluation of the hemodynamic significance of a coronary lesion with high diagnostic accuracy in comparison to the invasive FFR using pressure wires. These opportunities providing hemodynamic information based on anatomy have given rise to a new era of functional angiography and coronary imaging. However, further validations are needed to overcome several scientific and computational challenges before these methods are applied in everyday clinical practice. This review aims to present all the data on the studies and methodologies that have been presented for the virtual estimation of FFR, and the diagnostic execution of the virtual tools for the hemodynamic assessment of coronary lesions compared to the invasive FFR.

The purpose of the present study was to determine the relationship between healthy lifestyle behaviors, physical fitness and coronary risk factors in university students. 320 male and female (n_m:171; n_f:149) students from a university participated in this study voluntarily. For the determination of body composition and Body Mass Indexes (BMI), subjects’ height, body weight, and skinfold thickness were taken and body fat percentage (%Fat) was determined. Healthy lifestyle behaviors were determined using the healthy lifestyle behaviors questionnaire. Indicators of physical fitness included flexibility (sit-up) (F), muscle strength and endurance (isometric knee (KS), back strength (BS) and a total of shuttle (TS), sprint performance, BMI, and body fat percentage (%fat). Coronary heart disease risk factors included mean arterial blood pressure (systolic (SBP) and diastolic (DBP)), fasting blood levels of triglycerides (TG), total cholesterol (TC), hematocrit (HT), and hemoglobin (HM). Results indicated subjects have normal body mass index, body fat percentage, SBP, DBP, TG, TCF, BS, KS. The results of the Pearson Product Moment Correlation Analysis, indicated that SBP, DBP, TG, TCF, BS, KS for male and female was significantly correlated with flexibility (sit-up) (F), muscle strength and endurance (isometric knee (KS), back strength (BS) and total of shuttle (TS)), sprint performance. (p<0.01; p<0.05), In conclusion, the findings of the present study indicated that physical fitness and healthy lifestyle behaviors play a determinant role in coronary heart disease risk factors for male and female students from a university.

Malaria parasites increase their host erythrocyte’s permeability to obtain essential nutrients from plasma and facilitate intracellular growth. In the human P. falciparum pathogen, this increase is mediated by the plasmodial surface anion channel (PSAC) and has been linked to CLAG3, as encoded by one member of the conserved clag multigene family. Whether paralogs encoded by other clag genes also contribute to PSAC formation or serve unrelated roles remains unknown. Here, we generated transfectant lines carrying epitope-tagged versions of each CLAG. Each paralog colocalized with CLAG3, with concordant trafficking via merozoite rhoptries to the host erythrocyte membrane of newly-invaded erythrocytes. Each also exists within infected cells in at least two forms: an alkaline-extractable soluble form and a form integral to the host membrane. Like CLAG3, CLAG2 has a variant region cleaved by extracellular protease but CLAG8 and CLAG9 are protease-resistant. Paralog knockout lines, generated through CRISPR/Cas9 transfection, exhibited uncompromised growth in PGIM, a modified medium with more physiological nutrient levels; this finding is in marked contrast to a recently reported CLAG3 knockout parasite. CLAG2 and CLAG8 knockout lines exhibited compensatory increases in transcription of remaining clags and associated rhoph genes, yielding increased PSAC-mediated uptake to specific solutes. We also report distinct transport properties of these knockout lines, suggesting partially overlapping roles of CLAG paralogs in PSAC activity. We propose that the nutrient channel pore is formed by a higher order assembly of CLAG proteins at the host membrane.

The risk of a fatal outcome was 41% in unvaccinated patients (p = 0.713), which increased by 2.66% with co-infection with two pathogens (p = 0.342) and by 26% with three pathogens (p = 0.005). Additionally, 50% of ICU patients had a triple infection, compared with only 1.3% in the inpatient unit (p = 0.0029). The risk of death and/or ICU admission was 12 times higher (p = 0.042) with an additional pathogen and increased by 95% (p = 0.003) with a third concomitant pathogen. Regular multiplex testing is important for prompt treatment and targeted antibiotic use.

Apis mellifera, especially weak ones, are highly vulnerable to Carpoglyphus lactis mites, which can rapidly infest and consume stored pollen, leading to weakened colonies and potentially colony collapse. This study aimed to ascertain and investigate the prevalence of this mite in honeybee colonies across 9 provinces in the Republic of Korea (ROK). A total of 615 honeybee colonies were collected, from 66 apiaries during the spring and 58 apiaries during the summer of 2023. A 1,242 bp segment of the the Cytochrome c oxidase subunit 1 (COI) gene was amplified using the polymerase chain reaction method. The detection levels of C. lactis in the honeybees were compared between winter and summer. Based on the COI sequence analysis, the nucleotide sequence similarity of C. lactis mites isolated in the ROK with those from China (NC048990.1) was found to be 99.5%, and with those from the United Kingdom (KY922482.1) was 99.3%. This study is the first report of C. lactis in Korean apiaries. The findings in this study demonstrate a significantly higher detection rate in winter, which is 4.1 times greater than that in summer (p &lt; 0.001). Furthermore, the results underscore the usefulness of molecular diagnostic techniques for detecting C. lactis mites.

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

Severe inherited alpha-1 antitrypsin deficiency (AATD) is an autosomal genetic condition linked to chronic obstructive pulmonary disease (COPD). The significance of heterozygous, milder deficiency variants (Pi*M, Pi*S, Pi*Z) is less clear. We studied AATD genotypes in 145 children (up to 72 months old) with assessed wheezing severity using the Pediatric Respiratory Assessment Measure (BCCH PRAM score). A control group of 74 children without airway obstruction was included. AAT concentration and Pi phenotype were determined from dry blood spot samples using nephelometry and real-time PCR; PiS and PiZ alleles were identified by isoelectrofocusing. Among the wheezers, the Pi*S allele incidence was 2.07% (3 cases) and Pi*Z allele was 6.9% (10 cases). The Pi*Z allele frequency was higher in wheezers compared to controls (44.8% vs. 20.27%) and the general Lithuanian population (44.8% vs. 13.6%) and was similar to adult COPD patients in Lithuania: Pi*S 10.3% vs. 15.8% and Pi*Z 44.8% vs. 46.1%. No association was found between AAT genotypes and wheezing severity. Finding that wheezer children exhibit a frequency of Z* and S* alleles like that found in adults with COPD suggests a potential genetic predisposition that links early wheezing in children to the development of COPD in adulthood. Larger cohort studies are needed to confirm this finding.

Background: The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation. Methods: We performed a prospective study in 5 referral centers for HIV care in Italy. PLHIV who consented to participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI that started chemoprophylaxis were followed until the ending of therapy. Results: A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, 6 were lost to follow-up before discriminating between latent and active TB. Among PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6-9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.

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.

Vascular inflammation is recognized as the primary trigger of acute coronary syndrome (ACS). However, current noninvasive methods are not capable of accurately detecting coronary inflammation. Epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT), in addition to their role as an energy reserve system, have been found to contribute to the development and progression of coronary artery calcifica-tion, inflammation, and plaque vulnerability. They also participate in the vascular re-sponse during ischemia, sympathetic stimuli, and arrhythmia. As a result, the evalua-tion of EAT and PCAT using imaging techniques such as computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear imaging has gained significant atten-tion. PCAT-CT attenuation, which measures the average CT attenuation in Hounsfield units (HU) of the adipose tissue, reflects adipocyte differentiation/size and leukocyte infiltration. It is emerging as a marker of tissue inflammation and has shown prognos-tic value in coronary artery disease (CAD), being associated with plaque development, vulnerability, and rupture. In patients with acute myocardial infarction (AMI), an in-flammatory pericoronary microenvironment promoted by dysfunctional EAT/PCAT has been demonstrated, and more recently, it has been associated with plaque rupture in non-ST-segment elevation myocardial infarction (NSTEMI). Endothelial dysfunc-tion, known for its detrimental effects on coronary vessels and its association with plaque progression, is bidirectionally linked to PCAT. PCAT modulates the secretory profile of endothelial cells in response to inflammation and also plays a crucial role in regulating vascular tone in the coronary district. Consequently, dysregulated PCAT has been hypothesized to contribute to type 2 myocardial infarction with non-obstructive coronary arteries (MINOCA) and coronary vasculitis. Recently, quan-titative measures of EAT derived from coronary CT angiography (CCTA) have been included in artificial intelligence (AI) models for cardiovascular risk stratification. These models have shown incremental utility in predicting major adverse cardiovas-cular events (MACE) compared to plaque characteristics alone. Therefore, the analysis of PCAT and EAT, particularly through PCAT-CT attenuation, appears to be a safe, valuable, and sufficiently specific noninvasive method for accurately identifying cor-onary inflammation and subsequent high-risk plaque. These findings have been sup-ported by biopsy and in vivo evidence. Although speculative, these pieces of evidence open the door to a fascinating new strategy in cardiovascular risk stratification. The incorporation of PCAT and EAT analysis, mainly through PCAT-CT attenuation, could potentially lead to improved risk stratification and guide early targeted primary pre-vention and intensive secondary prevention in patients at higher risk of cardiac events.

This study delves into the dynamic field of medical education research, emphasizing the integration of research training within medical curricula. It seeks to understand the impact of such integration on the competencies of future medical professionals. The primary aim is to systematically categorize and analyze the current trends and future directions in medical education research. This involves assessing the influence of research training on medical students' skills and the methodologies used in such research. Methods: The research employs an extensive bibliographic literature review across multiple databases. It classifies studies into categories like experiential or case studies, editorials, and original research articles. This classification is based on criteria such as geographical location, research objectives, theoretical frameworks, and methodologies. Results: Findings reveal a diverse landscape in medical education research, with a significant emphasis on research training. The research showcases varying methodologies and approaches used globally, highlighting the thematic focus and geographical distribution of these studies. Conclusion: Medical education research is a globally expansive and evolving field. It underscores the importance of continuous investigation, particularly focusing on integrating research elements at curricular levels and exploring innovative educational strategies. The study also points out potential gaps in research, especially in underrepresented regions, indicating directions for future research efforts.

Background: Osteoporosis and bone fractures affect health and quality of life. Since bone disease is multifactorial, identifying risk factors is key in prevention. There are multiple reports on how viral hepatitis especially chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are affecting bone disease, but results vary. Here, we analyzed the potential association between CHB/CHC and osteoporosis or bone fractures in a large outpatient cohort in Germany. Methods: We included 3,136 outpatients with CHB and 15,608 matched non-hepatitis individuals as well as 2,867 outpatients with CHC and 14,335 matched non-hepatitis individuals from the Disease Analyzer Database between 2005 and 2022. The main outcome was the 5-year cumulative incidence of osteoporosis and bone fractures as a function of either CHB or CHC. Results: Within 5 years of the index date, 2.9% vs. 1.6% of patients with and without CHB were diagnosed with osteoporosis (p=0.001) and 1.0% vs. 0.4% were diagnosed with bone fractures (p<0.001). Moreover, 3.3% of CHC patients and 2.2% of individuals without hepatitis were diagnosed with osteoporosis (p=0.002). In Cox-regression analyses, CHB was significantly associated with an increased risk for osteoporosis (HR: 1.76) and fractures (HR:2.43) and CHC with osteoporosis (HR: 1.54). For both CHB and CHC, the association with osteoporosis was restricted to the female subgroup. Conclusion: CHB and CHC are associated with osteoporosis in women. CHB in male patients is associated with a higher risk of fractures. More research is are needed to understand the underlying pathophysiological mechanisms.

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

Hemophagocytic lymphohistiocytosis (HLH) is a serious haematologic condition that can be re-lated to various diseases, including tuberculosis (TB). The patient is a previously healthy 26-years-old man, originally from Western Africa, admitted to hospital for fever and weight loss. Given the results of computed tomography (CT) scan, ocular examination and microbiologic tests, a miliary TB with pulmonary, lymph nodal and ocular involvement was diagnosed. Following introduction of antitubercular treatment (ATT) an increase in inflammation indexes and severe pancytopenia were observed; at this point the patient presented six of eight diagnostic criteria for HLH and the diagnosis of HLH secondary to TB was raised. Therefore, HLH treatment with high dose of dexamethasone was started with a good clinical response. We performed a literature re-view of TB-related HLH, which shows a high mortality rate; ATT is necessary to ensure patient survival to remove the antigenic driver. Our patients developed HLH after initiation of ATT as a paradoxical reaction, that may be linked to the release of antigens due to the bactericidal effect of ATT.

Mouthparts are the main feeding organs of insects, which play vital roles in the feeding process. The morphology of insect mouthparts has greatly evolved according to different foods and feeding habits. Therefore, studying the structure of the mouthparts is the key to understanding their feeding mechanisms. Vibidia duodecimguttata is an important biological control agent for powdery fungus. In this study, the fine morphology of the mouthpart of V. duodecimguttata was studied by scanning electron microscopy. The basic components of mouthpart of V. duodecimguttata are similar to those of other ladybeetles, while the specific morphology of each part is different. In total, six kinds of sensilla were identified on mouthpart, and twelve types of sensilla were divided according to their morphology, length and distribution. In addition, two kinds of glandular structures were also found, perforated plates and cuticular pores. Finally, the morphological differences between mycetophagous and other feeding habits ladybeetles were compared, and the function of each kind of sensilla were discussed, which may lay a solid foundation for further understanding of the feeding mechanism of ladybirds.

Introduction: Although aging is a natural phenomenon, in recent years it has accelerated. One key factor implicated in the aging process is oxidative stress. Oxidative stress play also role in frailty (frail) and metabolic syndrome (MetS). Methods: 66 elderly persons (65 years old and older) with no acute or severe chronic disorders were assessed: waist circumference (WC), arterial blood pressure, glycemia, glycated hemoglobin (HbA1c), plasma lipids and activity of erythrocyte superoxide dismutase (SOD-1). Patients were classified as NonMetS-Nonfrail (n=19), NonMetS-frail (n=20), MetS-Nonfrail (n=17), and MetS-frail (n=10). Results: There were no significant differences in superoxide dismutase activity among investigated elderly groups. However, the data suggests that MetS individuals, both frail and nonfrail, have higher risk factors for cardiovascular disease compared to NonMetS individuals. The correlations analyses of SOD-1 and other metabolic indices suggest that SOD-1 levels may be influenced by age, total cholesterol, HDL cholesterol, and fasting glucose levels in certain groups of seniors. Conclusions: Aging is associated with decreased antioxidant enzyme SOD-1 activity with glucose alteration in frailty syndrome as well as with lipids disturbances in metabolic syndrome.

Interferon-gamma (IFN-γ) is an important cytokine in host defense against tuberculosis infection. In some cases, administration of IFN-γ during tuberculosis infection can promote faster cure. In the present work, we have shown that in a mouse model, human interferon-gamma, exhibits some anti-tuberculosis activity, especially in combination with isoniazid.

Fractional flow reserve (FFR) is regarded as the gold standard for assessing the functional significance of coronary artery lesions, yet it remains underutilized in clinical practice. Our objective was to investigate whether FFR results have the potential to alter treatment decisions for coronary lesions compared to visual assessments of angiographic images made by three operators at a high-volume interventional center. In this retrospective study, we aimed to reassess the angiographic images of 63 patients presenting with chronic coronary syndrome (n=39, 61.9%) and acute coronary syndrome (n=24, 38.1%) who underwent FFR. Three experienced interventional cardiologists (with >300 PCI procedures per year) reevaluated, blinded to FFR results, 105 ambiguous lesions in 63 patients to determine angiographic significance and treatment strategy. The observers reached a concordant agreement (≥2 operators made the same decision) to perform PCI in 60 (57.1%) of the lesions based on angiographic evaluation. Interestingly, 9 (15%) of these lesions were functionally non-significant (FFR &gt;0.80). The observers agreed to defer PCI in 45 (42.9%) of the lesions; however, 4 (8.9%) of these were functionally significant (FFR ≤0.80) and required PCI. Thus, inter-observer concordance in visual-guided therapeutic decision-making is variable and not always confirmed by the functional significance of coronary lesions.

This study is aimed to assess the prevalence of Coxiella burnetii infection among veterinary medicine students from two Bulgarian Universities, located in Sofia and Stara Zagora. A total of 185 veterinary students blood samples were collected and tested for the detection of C. burnetii phase II antibodies and presence of DNA using an enzyme-linked immunosorbent assay (ELISA) and end-point PCR test, respectively. Out of all samples, 29.7% were positive for at least one C. burnetii phase II antibody marker or by PCR test. Veterinary students from Stara Zagora showed significantly seropositive status of Q fever (33.6%), then those who studied in Sofia (23%). The evidence for recent exposition with detection of anti-C. burnetii IgM (+) antibodies had 14.6%. Seroprevalence among students in Stara Zagora was higher (15.3%). Anti-C. burnetii phase II IgG antibodies were detected in 21.6% examined samples. Our study revealed a higher seropositivity among male students (32.8%) as compared to the female ones (16.0%). End-point PCR assay detected as positive 5.9% blood samples. The relative risk (RR) of Q fever exposure for male students was 40.7%, whereas for female (24.6%). Findings from this study indicated that the C. burnetii infection is widely distributed amongst veterinary students from Bulgaria. The study emphasizes the need for improved safety protocols and infection control measures in veterinary training programs.

The Rose grain aphid, a notable agricultural pest, releases saliva while feeding. Yet, there is a need for a comprehensive understanding of the specific identity and role of secretory proteins released during probing and feeding. Therefore, a combined transcriptomic and proteomic approach was employed to identify putative secretory proteins. The transcriptomic sequencing result led to the assembly of 18030 unigenes out of 31344 transcripts. Among these, 705 potential secretory proteins were predicted and functionally annotated against publicly accessible protein databases. Notably, a substantial proportion of secretory genes (71.5%, 69.08%, and 60.85%) were predicted to encode known proteins in Nr, Pfam, and Swiss-Prot databases, respectively. Conversely, 27.37% and 0.99% of gene transcripts were predicted to encode known proteins with unspecified functions in the Nr and Swiss-Prot databases, respectively. Meanwhile, the proteomic analysis result discovered, 30 salivary proteins. Interestingly, most salivary proteins (53.3% proteins) showed close similarity to A. craccivora, while 36.67% to A. pisum and A. glycines. However, to verify the expression of these secretory genes and characterize the biological function of salivary proteins further intervention should be geared towards gene expression and functional analysis.

Chronic pancreatitis is a progressive fibroinflammatory disorder with no currently satisfactory treatment. Emerging evidence suggests an association between gut microbial dysbiosis and chronic pancreatitis. Although direct causative evidence is lacking, it is hypothesized that the gut microbiota may play a pivotal role in modulating pancreatic function via the gut-pancreas axis. Thus, modulating the gut microbiota through the administration of probiotics or prebiotics may alleviate pancreatic disorders. In this review, we first propose the potential mechanisms by which specific probiotics or prebiotics may ameliorate chronic pancreatitis, including the alleviation of small intestinal bacterial overgrowth (SIBO), facilitation of short-chain fatty acids (SCFAs) production, activation of the glucagon-like peptide 1 receptors (GLP-1Rs) in the pancreas. Since there are currently no probiotics or prebiotics used for the treatment of chronic pancreatitis, we have discussed research in other disease models that use probiotics or prebiotics to modulate pancreatic endocrine and exocrine functions and prevent pancreatic fibrosis. This provides indirect evidence for their potential application in the treatment of chronic pancreatitis. We anticipate that this research will stimulate further investigation into the gut-pancreas axis and the potential therapeutic value of probiotics and prebiotics in chronic pancreatitis.

Extracellular vesicles (EVs) hold enormous potential in the diagnosis and treatment of diseases, benefit from their roles in intercellular signaling, as well as their plentiful presence and stability in body fluids. However, conventional EV isolation methods are labor-intensive, and harvest EVs with low purity and compromised recovery. In addition, the drawbacks, such as limited sensitivity and specificity of traditional EV analysis methods hinder the application of EVs in clinical use. Therefore, it is urgent to develop effective and standardized methods for isolating and detecting EVs. Microfluidics technology is a powerful and rapidly developing technology that has been introduced as a potential solution for the above bottlenecks. It holds the advantages of high integration, short analysis time, low consumption of samples and reagents. In this review, we summarize the traditional techniques alongside microfluidic-based methodologies for the isolation and detection of EVs. We emphasize the separation advantages of microfluidic technology in enhancing EV capture efficiency and precise targeting, while summarizing its analytical role in targeted detection and discussing the significance of EV detection in the tumor microenvironment, providing a direction for achieving automated and high-throughput EV detection in clinical samples.

M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of M184V mutation on the treatment outcomes in people with HIV (PWH). Since lamivudine remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure. ART guidelines do not recommend the use of drugs impacted by resistance-associated mutations as they have been confirmed to comprise a risk factor for virological failure. However, previous authors suggest that 3TC/FTC can remain active even in the presence of M184V. Obtaining the viral resistance profile for each individual both treated or ART-naïve is a key challenge for lifelong treatment management.Given the potential benefits of lamivudine in the ART combinations, the investigation of M184V remains of high interest for clinicians and researchers. This is a review of literature for the challenges in treating both naïve and experienced individuals carrying the M184V resistance mutation, including virological failure, virological suppression, and resistance to ART.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track response to therapy, and parse causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

Cardiac autonomic neuropathy (CAN) is a severe complication of diabetes mellitus (DM) strongly linked to a nearly five-fold higher risk of cardiovascular mortality. Patients with Type 2 Diabetes Mellitus (T2DM) are a significant cohort in which these assessments have particular relevance to the increased cardiovascular risk inherent in the condition. This study aimed to explore the subtle correlation between the Ewing test, Sudoscan-cardiovascular autonomic neuropathy score, and cardiovascular risk calculated using SCORE 2 Diabetes in individuals with T2DM. The cohort consisted of 211 patients diagnosed with T2DM with overweight or obesity without established ASCVD, aged between 40 to 69 years. The prevalence of CAN in our group was 67.2%. In the study group, according SCORE2-Diabetes, four patients (1.9%) were classified with moderate cardiovascular risk, thirty-five (16.6%) with high risk, and one hundred seventy-two (81.5%) with very high cardiovascular risk. On multiple linear regression, the SCORE2-Diabetes algorithm remained significantly associated with Sudoscan CAN-score and Sudoscan Nephro-score and Ewing test score. Testing for the diagnosis of CAN in very high-risk patients should be performed because approximately 70% of them associate CAN. Increased cardiovascular risk is associated with sudomotor damage and that Sudoscan is an effective and non-invasive measure of identifying such risk.

This study aimed to evaluate the impact of Candida albicans on subgingival biofilm formation on dental implant surfaces. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were used to compare biofilm structure and microbial biomass in the presence and absence of the fungus after periods of 24, 48, and 72 h. Quantitative polymerase chain reaction (qPCR) was used to quantify the number of viable and total micro-organisms for each of the biofilm-forming strains. A general linear model was applied to compare CLSM and qPCR results between control and test conditions. The biofilm developed with C. albicans at 72 h had a higher bacterial biomass, with a significantly higher cell viability (p &lt; 0.05). After both 48 and 72 h of incubation, in the presence of C. albicans, there was a significant increase in counts of Fusobacterium nucleatum and Porphyromonas gingivalis and in the cell viability of Streptococcus oralis, Aggregatibacter actinomycetemcomitans, F. nucleatum, and P. gingivalis. Using a dynamic in vitro multispecies biofilm model, C. albicans exacerbated the development of the biofilm grown on dental implant surfaces, significantly increasing the number and cell viability of periodontal bacteria.

Background: Large-cell neuroendocrine carcinoma presents significant treatment challenges owing to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. Methods: In this non-randomized study, patients with metastatic LCNEC were treated with ei-ther standard chemotherapy plus atezolizumab or standard chemotherapy alone. The primary outcomes measured were progression-free survival (PFS) and overall survival (OS), with an ex-ploratory analysis of miR375 in plasma as a potential biomarker. Results: Of the 22 screened patients, 17 met the inclusion criteria and were stratified into the atezolizumab and chemotherapy (n=10) or chemotherapy alone(n=7) groups. After a median follow-up of 23.3 months, the 12-month survival rate for the atezolizumab group was 57.1% (95% CI: 32.6%-100%) and 45.7% at 24 months (95% CI: 22.4%-93.2%). In contrast, the chemotherapy group had a 14.3% survival rate at both 12 and 24 months (95% CI: 2.33%-87.7%). The log-rank test for survival showed a statistically significant difference in the atezolizumab-treated group (chi-squared = 4, df = 1, p = 0.04). A non-significant correlation was found between disease pro-gression and elevated levels of miR375. Conclusions: This pilot study suggests that atezolizumab combined with chemotherapy may be effective in treating metastatic LCNEC. The non-significant correlation between plasma miR375 levels and disease progression suggests its biomarker potential, warranting further validation research.

Introduction Atherosclerotic disease is a major contributor to heart failure, stroke, and myocardial infarction, significantly lowering the quality of life and life expectancy, with a significant burden on healthcare. Not all lesions deemed non-significant are benign, and conversely, not all significant lesions are causative of ischemia. Fractional flow reserve (FFR) provides a functional assessment of coronary lesions, while optical coherence tomography (OCT) offers detailed imaging of plaque morphology, aiding in therapeutic decision-making. The objective of this study was to evaluate the utility of OCT and FFR as adjunctive tools in the catheterization laboratory for guiding therapeutic decisions in patients with multivessel disease for non-culprit vessels. Specifically, we aimed to assess how OCT and FFR influence therapeutic decision-making in patients with multi-vessel coronary artery disease. Methods 36 patients with acute coronary syndrome (ACS) and multivessel disease were randomized 1:1 into two groups: one guided by FFR alone, and the other by a combination of FFR and OCT. For the FFR group, revascularization decisions for non culprit lesions were based solely on FFR measurements. If the FFR was >0.8, the procedure concluded, and the patient received maximal medical treatment. If the FFR was ≤0.8, a stent was placed. For the FFR + OCT group, if the FFR was >0.8, the revascularization decision was based on OCT findings. If there were no vulnerable plaques (VP), the procedure concluded, and the patient received maximal medical treatment. If OCT imaging indicated VP, then the patient underwent revascularization. If the FFR was ≤0.8, the patient underwent revascularization regardless of OCT findings. Results OCT imaging altered the therapeutic decision in 11 cases where FFR measurements were above 0.8, but the lesions were characterized as VP. Analyzing the total change in the decision to stent, 4 cases in the FFR group and 15 cases in the FFR and OCT group (4 based on FFR and 11 on OCT) revealed a statistically significant difference (p = 0.0006; Relative Risk = 0.2556; 95% CI: 0.1013 to 0.5603). When analyzing the change in the total decision both to stent and not to stent, we observed a statistically significant difference, with Group 1 having 7 cases and Group 2 having 15 cases (p = 0.0153; Relative Risk = 0.4050; 95% CI: 0.2004 to 0.7698) Conclusion Based on the findings of this study, OCT significantly increases the percentage of stenting procedures by identifying vulnerable lesions. The use of intracoronary imaging facilitates the timely identification and treatment of these vulnerable lesions. This underscores the crucial role of OCT in enhancing the precision of coronary interventions by ensuring timely intervention for vulnerable lesions, thereby potentially improving patient outcomes Acknowledgment funding „This work was supported by the University of Medicine, Pharmacy, Science and Technology ,, George Emil Palade’’ of Targu Mures Research Grant number 510/14/17.01.2022”

Dried blood spot (DBS) testing on confetti is one of the most common methods used to collect and extract DNA from field samples for molecular epidemiology of malaria studies. Here, we investigated whether ethanol or other solutions used to clean scissors are a source of sample contamination. DBS were prepared from 3 drops of blood from two Plasmodium falciparum cultures spotted on confetti, and 3 solutions (water, ethanol and DNase) were used to clean scissors between spots during DNA extraction. For each cleaning solution, two blank confetti were used as negative controls. Samples were analyzed by PCR-based genotyping of merozoite surface proteins 1 & 2 (msp-1 and msp-2), and P. falciparum chloroquine resistance transporter (Pfcrt). A total of 15 samples were analyzed. Based on msp-1 and msp-2 amplification, P. falciparum was detected on blank confetti when scissors were washed with ethanol. Based on Pfcrt amplification, DNA of P. falciparum was detected on blank confetti when scissors were cleaned with ethanol or water. No P. falciparum genes were detected on blank confetti when scissors were cleaned with DNase. Scissors cleaned with DNase prevented cross-contamination between samples during processing of dried blood spots, whereas ethanol (which is commonly used) fails to avert cross-contamination.

In the majority of children with growth hormone (GH) deficiency (GHD), normal GH secretion may occur before the attainment of final height. The aim of the study was to assess the incidence of persistent and transient GHD and the effectiveness of recombined human GH (rhGH) therapy in children with isolated idiopathic GHD, with respect to the moment of therapy withdrawal and according to different diagnostic criteria of GHD. Analysis included 260 patients (173 boys, 87 girls) with isolated idiopathic GHD who completed rhGH therapy and have reassessed GH and IGF-1 secretion. The incidence of transient GHD with respect to different pre- and post-treatment criteria was compared together with assessment of GH therapy effectiveness. Incidence of transient GHD, even with respect to pediatric criteria was very high. Normal GH secretion occurred before the attainment of near-final height. Application of more restricted criteria decreased the number of children diagnosed with GHD but not the incidence of transient GHD among them. Poor response to GH therapy was observed mainly in patients with normal IGF-1 before treatment, suggesting that diagnosis of GHD may be false positive. Further efforts should be made to avoid overdiagnosis GHD and overtreatment of the patients.

Background Sarcopenia is a state with progressive and generalized loss of skeletal muscle mass and strength. It is a serious complication occurring in chronic kidney disease (CKD) patients which increases morbidity and mortality rate. Sarcopenia is diagnosed when loss of both compartments - muscle strength and skeletal muscle quality or quantity are present. However, there are still numerous patients, also with CKD, diagnosed as pre-sarcopenic individuals with low muscle strength and normal skeletal muscle quality or quantity and conversely, with correct muscle strength and decreased skeletal muscle mass, who are prone to develop sarcopenia in future life. It is crucial to examine numerous variables possibly associated with changes of skeletal muscle mass and muscle strength in terms of preventing the development of sarcopenia. The aim of the study was to investigate anthropometric and clinical correlates and sources of variation in both skeletal muscle mass and muscle strength in advanced stages of CKD. Methods The study sample consisted of 84 non-dialysis dependent patients of both sexes (including 45.2% of women) with eGFR < 45 ml/min/1.73m²: 26.2% with eGFR 30-44 mL/min/1.73 m², 65.5% with eGFR 15-29 mL/min/1.73 m² and 8.3% with eGFR < 15 mL/min/1.73 m². Muscle strength was estimated by measuring hand grip strength (HGS) with the use of handheld hydraulic dynamometer. Muscle quantity was measured by bioimpedance spectroscopy using Body Composition Monitor. Appendicular skeletal muscle mass (ASM) was calculated according to Lin’s formula. Serum creatinine, urea, uric acid and albumin were measured. Results In bivariate analysis we found that ASM significantly and positively correlated with anthropometric variables such as body mass (r=0.903, p<0.001), NH weight (r=0.882, p<0.001), height (r=0.694, p<0.001), body mass index (BMI) (r=0.701, p<0.001), lean tissue mass (LTM) (r=0.664, p<0.001), lean tissue index (LTI) (r=0.433, p<0.001), fat mass (r=0.614, p<0.001) and fat tissue index (FTI) (r=0.449, p<0.001), and was negatively associated with clinical variable such as hydration status (p<0.001). HGS significantly and positively correlated with anthropometric parameters such as body mass (r=0.319, p=0.003), NH weight (r=0.315, p=0.004), height (r=0.666, p<0.001), LTM (r=0.490, p<0.001), LTI (r=0.238, p=0.029), and ASM (r=0.501, p<0.001), and was negatively associated with clinical variables like uric acid (p=0.039) and urea (p<0.001). After adjustment for age, sex and height, HGS remained significantly and negatively related with uric acid (β=-1.078, p=0.041) and hydration status (β=-0.805, p=0.042). Conclusions In CKD patients, ASM is determined mainly by anthropometric parameters but HGS - both by anthropometric and clinical variables specific for CKD.

The global antibiotic resistance crisis, driven by antibiotic overuse and misuse, is multifaceted. This study aimed to assess the microbiological and genetic characteristics of raw retail pork meat, including the isolation, antibiotic susceptibility testing (AST), whole genome sequencing (WGS) of selected indicator bacteria, antibiotic residue testing, and metagenomic sequencing. Samples were purchased from 10 randomly selected retail stores in Gauteng, South Africa. Samples were aseptically separated, with a portion sent to an external laboratory for isolating indicator bacteria and antibiotic residue testing. Identification of the isolated bacteria was reconfirmed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). AST was performed using the Microscan Walkaway system. WGS and metagenomic sequencing were performed using the Illumina NextSeq 550 instrument. The isolated E. coli and enterococci exhibited little phenotypic resistance, with WGS revealing tetracycline resistance genes. Isolated bacteria and meat samples all harboured tetracycline resistance genes, and the antibiotic residue concentrations were within acceptable limits for human consumption. In the metagenomic context, most identified bacteria were of food/meat spoilage and environmental origin, with the resistome analysis primarily indicating beta-lactam, tetracycline and multidrug resistance genes. Further research is needed to understand the broader implications of these findings on environmental health and antibiotic resistance.

Carbapenemase-producing Enterobacter spp. Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (CP-ESCPM) are increasingly identified as causative agents of nosocomial infections but are still not under systematic genomic surveillance. In this study, using a combination of whole genome sequencing and conjugation experiments, we sought to elucidate the genomic characteristics and transferability of resistance genes in clinical CP-ESCPM isolates from Bulgaria. Among the 36 sequenced isolates, NDM-1 (12/36), VIM-4 (11/36), VIM-86 (8/36) and OXA-48 (7/36) carbapenemases were identified; two isolates carried both NDM-1 and VIM-86. The majority of carbapenemase genes were found on self-conjugative plasmids. IncL plasmids were responsible for the spread of OXA-48 among E. hormaechei, C. freundii and S. marcescens. IncM2 plasmids were generally associated with the spread of NDM-1 in C. freundii and S. marcescens, and also of VIM-4 in C. freundii. IncC plasmids were involved in the spread of the recently described VIM-86 in P. stuartii isolates. IncC plasmids carrying blaNDM-1 and blaVIM-86 have been observed too. blaNDM-1 was also detected on IncX3 in S. marcescens and on IncT plasmid in M. morganii. The significant resistance transfer rates highlight the role of the ESCPM group as a reservoir of resistance determinants and stress the need for strengthening the infection control measures.

Background: Coronary tortuosity is a common angiographic finding. Scarce data is available on clinical profile of patients with coronary tortuosity (CT) and its relation with coronary artery disease (CAD). Method: A total 224 patients undergoing angiography for suspected CAD were included in the study. CT was defined by the presence of ≥3 consecutive bends of > 45 degree measured at end-diastole in an epicardial artery ≥2 mm in diameter. CT was present in 45(20.08%) patients in the study and another 45 patients without CT was randomly selected as control (NCT group). Clinical profile of CT and NCT group was compared. Results: Incidence of CT was significantly higher in females (p=0.000) and hypertensives (p=0.001) patients. CT was most commonly seen in Left circumflex coronary artery. Incidence of CAD was significantly lower in CT group as compare to NCT group (0.02). Risk factors for CAD was associated with reduced incidence of CT. Majority (88.46%) patient with CT without CAD presented with chronic stable angina out of which (65.21%) had an objective evidence of myocardial ischemia. Conclusion: CT is more commonly seen females and hypertensive patients. It has negative correlation with CAD. Risk factors of CAD do not predict CT. CT itself can lead to myocardial ischemia.

Background: Two explored EDA1 variants regulate the biological behaviors of human dental pulp stem cells (hDPSCs), such as proliferation and migration, as well as their effects on odontogenic differentiation, providing a theoretical basis for further exploration of the mechanisms underlying EDA1-induced tooth development. Methods: The experimental groups included a wild-type EDA1 group (Wt), non-syndromic tooth agenesis variants EDA1 group (NSTA-A259E, NSTA-S374R), syndrome type variant EDA1 group (STA-H252L), and an empty vector control group (PCR3/NC). CCK-8 method was used to investigate the proliferative activity of hDPSCs. The cell cycle distribution of hDPSCs was detected by flow cytometry; The cell migration ability was assessed using the cell scratch and Transwell tests; Odontogenic differentiation medium was used to induce mineralization of hDPSCs, followed by statistical analysis. RNA-Seq revealed that FOS, JUN and other genes were found to be enriched in MAPK signaling pathway and osteoclast differentiation pathway. qPCR was used to detect mRNA expression of hub genes (FOS and JUN). Results: Compared with the NSTA-EDA1 and STA-EDA1, Wt-EDA1 promotes the proliferation and transformation of hDPSCs from the G0/G1 phase to S phase (p<0.01), with no significant difference between NSTA-EDA1 and STA-EDA1 (p>0.05). Wt-EDA1 also upregulated hDPSCs cell migration compared to NSTA-EDA1 and STA-EDA variants, as demonstrated by migration assays (p<0.01). NSTA-EDA1 and STA-EDA1 variants inhibited the odontogenic differentiation of hDPSCs compared to the Wt group, as shown by Alizarin red staining and ALP staining (p<0.01). RNA sequencing revealed that the differentially expressed genes FOS and JUN were enriched in the MAPK signaling pathway and osteoclast differentiation. Compared with Wt-EDA1, EDA1 variants lost the ability to promote c-FOS mRNA expression, as confirmed by qPCR. Conclusions: EDA1 variants fail to the promote c-FOS mRNA expression in hDPSCs, thereby inhibiting odontogenic differentiation and losing the ability to enhance the proliferation of hDPSCs.

Water samples for bacterial microbiome studies undergo a biomass concentration, DNA extraction and taxonomic identification steps. Through benchmarking, we studied the applicability of Skimmed milk flocculation (SMF) for bacterial enrichment, an adapted in-house DNA extraction protocol, and six 16S rRNA databases (16S-DBs). Surface water samples from two rivers were treated with SMF and Vacuum filtration (VF) and subjected to amplicon or shotgun metagenomics. A mock community standard underwent five DNA extraction protocols, taxonomical identification with six different 16S-DBs and evaluated by the Measurement Integrity Quotient (MIQ) score. In SMF samples, the skimmed milk was metabolized by members of lactic acid bacteria or genera such as Polaromonas, Macrococcus, and Agitococcus, resulting in increased relative abundance (p &lt; 0.5) up to 5.0 log fold change compared to VF, rendering SMF inapplicable for bacterial microbiome studies. The best performing DNA extraction protocols were FastSpin Soil, the in-house method and EurX. All 16S-DBs yielded comparable MIQ scores within each DNA extraction kit, ranging from 61-66 (ZymoBIOMICs) up to 80-82 (FastSpin). DNA extraction kits exert more bias to the composition than the 16S-DBs. This benchmarking study presented valuable insights to inform future water metagenomic study designs.

The article presents the case of a 27-year-old female patient with idiopathic congenital complete heart block who was referred by her primary care physician for cardiological evaluation. The conduction disturbance was recognized at the age of 6 years and was asymptomatic. The disqualification from pacemaker implantation included detailed history of a patient’s symptoms, echocardiographic assessment of the heart, exercise testing and ECG Holter monitoring. The aid of salbutamol administered orally was also useful.

In July 2017, a family of three members; a 46-year-old male, a 45-year-old female and their 8-year-old daughter, returned to South Africa from Thailand. They presented symptoms consistent with mosquito-borne diseases, including fever, headaches, severe body aches and nausea. Mosquito bites in all family members suggested recent exposure to arthropod-borne viruses. Dengue virus 1 (Genus Orthoflavivirus) was isolated (isolate no. SA397) from the serum of the 45-year-old female via intracerebral injection in neonatal mice and subsequent passage in VeroE6 cells. Phylogenetic analysis of this strain indicated close genetic identity with cosmopolitan genotype 1 DENV1 strains from Southeast Asia, assigned to major lineage K, minor lineage 1 (DENV1I_K.1), such as GZ8H (99.92%) collected in November 2018 from China and DV1I-TM19-74 isolate (99.72%) identified in Bangkok, Thailand, in 2019. Serum samples from the 46-year-old male yielded a virus isolate that could not be confirmed as DENV1, prompting unbiased metagenomic sequencing for virus identification and characterization. Illumina sequencing identified multiple segments of a Mammalian orthoreovirus (MRV), designated Human/SA395/SA/2017. Genomic and phylogenetic analysis classified Human/SA395/SA/2017 as MRV-3 and assigned a tentative genotype MRV-3d based on the S1 segment. Genomic analyses suggested Human/SA395/SA/2017 may have originated from reassortments of segments among swine, bat, and human MRVs. The closest identity of the viral attachment protein σ1 (S1) was related to a human isolate identified from Tahiti, French Polynesia, in 1960. This indicates ongoing circulation and cocirculation of Southeast Asian and Polynesian strains, but detailed knowledge is hampered by limited availability of genomic surveillance. This case represents a rare concurrent importation of two distinct viruses with different transmission routes in the same family with similar clinical presentations. It highlights the complexities of diagnosing diseases with similar sequelae in travellers returning from tropical areas.

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.

Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained through an extensive review of the literature, and additionally included target genes identified by the COVID-19 Host Genetic Initiative, as well as the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with severe COVID-19 outcome.

A number of studies suggested that influenza vaccination can provide protection against COVID-19 but the underlying mechanisms that could explain this association is still unclear. In this study, the effect of the 2021/2022 seasonal influenza vaccination on the immune response to the booster dose of anti-SARS-CoV-2 vaccination was evaluated in a cohort of healthy individuals. One hundred and thirteen participants were enrolled, and 74 of them with no prior COVID-19 diagnosis or significant co-morbidities were considered for the analysis. Participants received the anti-influenza tetravalent vaccine and the booster dose of the anti-SARS-CoV-2 vaccine or the anti-SARS-CoV-2 vaccine alone. Blood was collected before and 4 weeks after each vaccination and 12 weeks after SARSCoV2 vaccination and analyzed for anti-flu and anti-spike-specific antibody titers and for in vitro influenza and SARS-CoV-2 neutralization capacity. Results indicated an increased reactivity in subjects who received both influenza and SARSCoV2 vaccinations, as compared to those who received only the SARS-CoV-2 vaccine, with sustained anti-spike antibody titers up to 12 weeks post-vaccination. Immune response to influenza vaccine was evaluated and individuals were stratified as high or low responders. High responders showed increased antibody titers against SARSCoV2 vaccine both after 4- and 12-weeks post-vaccination. On the contrary, the individuals classified as low responders were less responsive to the SARS-CoV-2 vaccine. These data indicate that both external stimuli, such as influenza vaccination, and the host's intrinsic ability to respond to stimuli play a role in the response to vaccine.

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.

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring the underlying pathophysiological mechanisms and implications for clinical management. NOCAD and AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. NOCAD, characterized by the presence of atherosclerotic plaques without significant luminal stenosis, can lead to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, in this way sustaining the focal ectopic activity in atrial myocardium. Atrial fibrillation, on the other hand, is the most common sustained cardiac arrhythmia, associated with an increased risk of stroke and heart failure, which may accelerate atherosclerosis and may increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, thus promoting the development or worsening of coronary ischemia. Therefore, NOCAD and AF seems to be a complex Interplay with one begets another.

The domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 hr, 48 hr and 5 days post infection condition. Total 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides corresponding to 129 proteins were identified. Functional annotation of proteome data analysis reveals activation of RIG-I-like receptor and Jak-STAT signaling pathways, that lead to induction of interferon stimulated genes (ISGs) expression. The pathway analysis of phosphoproteome datasets also confirms the activation of RIG I, Jak-STAT signaling, NF-kappa B signaling and MAPK signaling pathways in the lung tissues. The induction of ISGs proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5 and PKR) establishes protective antiviral immune response in duck lung tissue. Further, the protein-protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1 and MAPK1 as main hub proteins that might play important roles in disease progression in ducks. Together, functional annotation of proteome and phosphoproteome datasets reveals the molecular basis of the disease progression and disease resistance mechanism in ducks infected with HPAI H5N1 virus.

In Brazil, Brazilian borreliosis (BB), characterized molecularly, exhibits symptoms akin to Lyme disease (LD) but presents unique epidemiological, clinical, and morphological features. This study explores the incidence, diagnostic challenges, and awareness initiatives regarding this disease in Brazil. Employing a narrative review methodology, data were sourced from Pubmed, Ebsco, Google Scholar, and Web of Science without temporal constraints. Results reveal diagnostic complexities in Brazil due to the low sensitivity of conventional tests and the use of North American B. burgdorferi antigens. Despite challenges, epidemiological studies indicate an upswing in cases in humans and animals. Therefore, there is an urgent need to define new biomarkers, molecular strategies, or new antigenic targets to advance the development of vaccines and diagnostics. Early and accurate pathogen identification is crucial for active surveillance to comprehend and manage this zoonosis.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and elderly. Infections caused by this species are exceptionally challenging to treat due to its multiresistance to antimicrobials. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on paediatric infections caused by E. anophelis. Accurate identification with MALDI-TOF, or using molecular techniques, is crucial because of varying susceptibilities among species. Early, accurate diagnosis and prompt effective treatment optimize outcomes.

1) Background- Coronary artery bypass grafting (CABG) is a common surgical intervention for patients with severe coronary artery disease. The Model for End-Stage Liver Disease (MELD) score has been widely used to predict mortality risk in patients with end-stage liver disease, but its utility in predicting postoperative outcomes in cardiac surgery patients is less well-established. 2) Methods-This retrospective study aims to investigate the association between preoperative MELD score and post-operative complications, length of hospital stay, and mortality in patients under-going coronary artery bypass grafting. This is a single-center, retrospective cohort study conducted at a tertiary care academic medical center. The study includes all adult patients who underwent elective coronary artery bypass grafting between January 2011 and December 2020. Preoperative MELD scores were calculated for each patient, and postoperative outcomes including major ad-verse cardiac events, length of hospital stay, and 30-day mortality was assessed. To ensure a homogeneous study cohort, we excluded patients who underwent emergent cardiac procedures or had incomplete data necessary for the calculation of MELD scores and assessment of postoperative outcomes. Data was extracted from the electronic medical records, including patient de-mographics, comorbidities, preoperative laboratory values, operative details, and postoperative outcomes. The study protocol was approved by the Institutional Review Board, and the require-ment for informed consent was waived due to the retrospective nature of the study.3) Results- This study reveals a statistical association between the MELD score calculated at admission and the length of hospital stay, duration in the ICU, patient age, and the duration of aortic clamping and extracorporeal circulation. Specifically, there is an exponential increase in the MELD score corre-lating with the rise in these factors, both collectively and individually, highlighting a significant relationship between the duration of extracorporeal circulation and aortic clamping time. 4) Conclusion-Patients with a high MELD score had an increased risk of postoperative complications and mortality compared to those with a low MELD score. Careful preoperative patient selection and optimization of the patient's clinical condition may improve outcomes in patients with advanced liver disease undergoing cardiac surgery.

Background: Pharmacists need up-to-date knowledge and decision-making support in HIV care. We aim to develop MARVIN-Pharma, an adapted artificial intelligence-based chatbot initially for people with HIV, to assist pharmacists, considering evidence-based needs. Methods: From Dec 2022 to Dec 2023, an online needs-assessment survey evaluated Québec pharmacists' knowledge, attitudes, involvement, and barriers relative to HIV care, alongside perceptions relevant to the usability of MARVIN-Pharma. Recruitment involved convenience and snowball sampling, targeting National HIV and Hepatitis Mentoring Program affiliates. Results: Forty-one pharmacists (28 community, 13 hospital-based) across 15 Québec municipalities participated. Participants perceived their HIV knowledge as moderate (M=3.74/6). They held largely favorable attitudes towards providing HIV care (M=4.02/6). They reported a “little” involvement in the delivery of HIV care services (M=2.08/5), most often ART adherence counseling, refilling, and monitoring. The most common barriers reported to HIV care delivery were a lack of time, staff resources, clinical tools, and HIV information/training, with pharmacists at least somewhat agreeing that they experienced each (M≥4.00/6). On average, MARVIN-Pharma's acceptability and compatibility were in the ‘undecided’ range (M=4.34, M=4.13/7, respectively), while pharmacists agreed to their self-efficacy to use online health services (M=5.6/7). Conclusion: MARVIN-Pharma might help address pharmacists' knowledge gaps and barriers to HIV treatment and care, but pharmacist engagement in the chatbot’s development seems vital for its future uptake and usability.

Coronary angiography, long considered the gold standard for coronary imaging, faces limitations in assessing coronary vessel wall anatomy and guiding percutaneous coronary intervention (PCI). Despite its prevalence, studies have demonstrated that it is suboptimal in estimating the severity of coronary disease and physiologic significance of stenosis. Intracoronary imaging techniques, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT), offer promising alternatives to overcome these limitations. This review delves into the nuances of IVUS and OCT, highlighting their strengths and limitations as adjuncts to PCI. IVUS, utilizing ultrasound technology, and OCT, based on near-infrared light, each provide unique insights into coronary pathology. They differ in terms of temporal and spatial resolution, influencing their capabilities in plaque characterization and vessel assessment. The discussion navigates their historical evolution, technical specifications, and clinical utility. Meta-analyses and adjusted observational studies suggest that both IVUS and OCT-guided PCI correlate with reduced cardiovascular risks compared to angiographic guidance alone. While IVUS has demonstrated consistent benefits in terms of clinical outcomes, the evidence supporting OCT is less robust. However, the utilization of these imaging modalities remains variable across regions, with increasing adoption in recent years, particularly in IVUS-guided PCIs. Intravascular ultrasound's journey from early motion detection to current high-resolution mechanical systems is traced, including improvements in catheter size and compatibility. On the other hand, optical coherence tomography has advanced significantly, utilizing near infrared light to achieve unparalleled resolutions, albeit requiring temporary blood clearance for optimal imaging. In conclusion, IVUS and OCT offer valuable insights into coronary pathophysiology and guide interventions with improved precision compared to traditional angiography. While IVUS remains more extensively utilized, OCT's growing potential is underscored by advancements in technology, culminating in enhanced imaging capabilities. Both modalities demonstrate comparable clinical outcomes, emphasizing the need for tailored imaging choices based on individual clinical scenarios. The continued refinement and broader integration of intravascular imaging are expected to play a pivotal role in optimizing coronary interventions and patient outcomes.

This retrospective study aimed to assess coronary artery calcium (CAC) progression in serial computed tomography measurements according to risk factor changes. In 448 asymptomatic adults who underwent CAC measurements with more than one-year intervals, CAC progression was assessed according to age, sex, variable traditional risk factors (diabetes mellitus, hypertension, hyperlipidemia, and smoking), and initial CAC score (0, 0.1–100, and &gt;100). Univariate and multivariate logistic regression analyses were assessed for independent predictors of rapid CAC progression (△CAC/year&gt;20). During the 3.5-year follow-up, coronary artery calcifications occurred in 43 (12.8%) of 336 individuals with an initial CAC score of zero. Of 112 individuals with initial CAC presence, 60 (53.6%) had △CAC/year&gt;20. Age, male sex, body mass index, and all risk factors were significantly associated with △CAC/year&gt;20, but recently diagnosed hypertension (odds ratio [OR], 11.3) and initial CAC score (OR, 1.05) were significant independent predictors in multivariate regression analyses. CAC progression was affected by demographic and traditional risk factors, but adjusting for these factors, recently diagnosed hypertension and initial CAC score were the most influential factors for rapid CAC progression. These findings suggest that patients with higher initial CAC scores may benefit from more frequent follow-up scans and checks regarding risk factor changes.

To elucidate the cellular immune response to coronavirus disease (COVID-19) among children, we assessed cellular immunity in 8 children post-vaccination for COVID-19 and 11 children after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, using the T-SPOT®.COVID assay for both the spike (S) and nucleocapsid (N) proteins. In the vaccinated group, the T-SPOT®.COVID assay for the S protein yielded positive results in all eight children. In contrast, in the post-infection group, the assay for the N protein was positive in 5 of 11 children, with 3 of these 5 children requiring hospital admission, including 2 who needed mechanical ventilation. Therefore, the T-SPOT®.COVID assay is valuable for assessing cellular immunity against COVID-19, and most children infected with COVID-19 may not develop such immunity unless the disease severity is significant.

Nurses continue to experience intense psychological repercussions despite the official conclusion of the COVID-19 pandemic. In this cross-sectional study conducted after the end of the pandemic crisis, in nurses, we evaluated the levels and explored the associations between anger, insomnia and resilience. A total of 442 nurses participated in an online survey and were invited to state their work experience, gender and age and complete the self-report measures of the Dimensions of Anger Reactions-5 (DAR-5), the Athens Insomnia Scale (AIS) and the Brief Resilience Scale (BRS). 62.1% of participants presented with positive scores on the AIS, 41.5% displayed positive values on the DAR-5 scale, whereas 24.9% of nurses demonstrated scores indicative of low resilience on the BRS scale. Regression analysis revealed that 23.5% of the variance in the AIS scores can be attributed to the DAR-5 scores and 3% to the BRS scores. Mediation analysis confirmed the protective role of resilience contributing as a negative mediator in the DAR-5 and the AIS relationship. Screening for insomnia symptoms and anger issues among nurses after the end of the pandemic and implementing appropriate interventions is considered imperative to avoid long-term health consequences.

Aortic stenosis (AS) is a prevalent valvular disorder that often requires surgical aortic valve replacement (SAVR) to alleviate symptoms and improve survival. However, the selection of an appropriate prosthetic valve size is crucial to avoid patient-prosthesis mismatch (PPM), which can lead to suboptimal hemodynamic outcomes. Von Willebrand factor (VWF), a key component of hemostasis, has been shown to be altered in AS patients and may contribute to the hemostatic imbalance observed following valve replacement. This prospective study aimed to investigate the impact of PPM on postprocedural VWF levels in patients undergoing SAVR for severe AS. The study included 31 consecutive patients diagnosed with severe AS who underwent SAVR. By focusing on the relationship between PPM and VWF dynamics, this study sought to provide valuable insights into the potential role of VWF as a marker for hemostatic changes associated with PPM, ultimately informing strategies for optimal valve selection and perioperative management to minimize complications.

Since the discovery of transposable elements (TEs) in Maize in the 1940s by Barbara McClintock [1] transposable elements have been described as junk, as selfish elements with no benefit to the host, and more recently as major determinants of genome structure and genome evolution. TEs are DNA sequences that are capable of moving to new sites in the genome and make additional copies while doing so. To limit the propagation of TEs, host silencing mechanisms are directed at transposon-encoded genes that are required for mobilization. The mutagenic properties of TEs, the potential of TEs to form new genes and affect gene expression, together with the host silencing mechanisms shape eukaryotic genomes and drive genome evolution. While TEs constitute more than half of the genome in many higher eukaryotes, transposable elements in the nematode C. ele-gans form a relatively small proportion of genome, about 15% [2]. Genetic studies of transposon silencing and the discovery of RNAi in C. elegans, propelled C. elegans to the forefront of studies of RNA-based mechanisms that silence TEs. Here, I will review the transposable elements that are present and active in the C. elegans genome, and the host defense mechanisms that silence these elements.

Background/aims: Prior research identified a significant association between heart disease and metabolic dysfunction-associated liver steatohepatitis (MASLD), but the mechanisms are unclear. This study aims to search predictive biomarkers for grade I left ventricular diastolic dysfunction (LVDD), an early stage of heart failure (HF), in type 2 diabetes mellitus (T2DM) patients. Methods: This single-center, prospective observational study screened 73 T2DM patients for grade 1 LVDD and MASLD using 2D echocardiography, tissue analysis, spectral color Doppler, and Fibromax. Results: The study analyzed 50 patients (mean age 58±11.3 years) with a median diabetes duration of 7 years, abdominal obesity (mean BMI 34.4±5.9 kg/m2), and a mean HbA1c of 7.9±1.5%. The prevalence of grade I LVDD, fibrosis, mild steatosis, moderate to severe liver steatosis, mild MASLD, and moderate MASLD was 54%, 44%, 14%, 80%, 43%, and 34%, respectively. Regression analysis revealed that grade 1 LVDD was positively associated with age, Fibrotest, ɑ2-macroglobulin, epicardiac adipose tissue (EAT), and negatively associated with lateral s`, E wave, E/e`, E/A, medium E`, and septal e` (p&lt; 0.05 for all). ɑ2-macroglobulin &gt; 1.92 g/L (AUROC= 0.782, sensitivity 70.4%, specificity 81.2%) and fibrotest score &gt; 0.11 (AUROC 0.766, sensitivity 92.6%, specificity 56.2%) were significant predictors of grade I LVDD. Conclusion: HF is a multifaceted disorder associated with multisystem organ damage, including nonalcoholic MASLD. Although the underlying mechanisms remain unclear, innovative non-invasive biomarkers, such as ɑ2-macroglobulin or fibrotest, could concurrently indicate liver stiffness and the likelihood of grade I LVDD, an early, asymptomatic HF stage in T2DM patients.

Background. During the COVID-19 pandemic, there was an increased number of the hospitalized COVID-19 positive patients suffering from type 2 diabetes mellitus (T2DM). The objective of this research was to explore factors associated with the length of hospitalization of patients with T2DM and mild form of COVID-19. Material and Methods. This retrospective cohort study involved all patients who tested positive for COVID-19 and were treated in the dedicated COVID department of the University Clinical Center (UCC) in Nis between September 10, 2021, and December 31, 2021. Upon admission, patients underwent blood tests for biochemical analysis, including blood count, kidney and liver function parameters (C-reactive protein-CRP, creatinine kinase, D-dimer), as well as glycemia and HbA1c assessments. Additionally, all patients underwent lung radiography. Univariate and multivariate regression analyses were employed to assess the impact of specific factors on the length of hospitalization among patients with T2DM. Results. Out of the total 549 COVID-19 positive patients treated, 124 (21.0%) had T2DM, while 470 (79.0%) did not have diabetes. Among patients with T2DM, men were significantly younger than women (60.6±16.8 vs. 64.2±15.3, p

Neurodegenerative diseases (NDDs) are a class of cognitive and motor disorders that include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and others. They are caused by lesions in cells and tissues of the central nervous system, resulting in corresponding dysfunctions and consequent decline in cognitive and motor functions. Neural tissues are extremely vulnerable to oxidative stress, which plays critical biological roles in NDDs. Aromatic compounds are found extensively in natural plants and have substantial effects of anti-oxidative stress damage, which not only have a wide range of research applications in cosmetics, foods, etc., but are also frequently utilized in the treatment of various central nervous system diseases. This review summarizes the relevant oxidative stress mechanisms in NDDs (AD, PD, HD, and ALS) and reviews aromatic compounds such as polyphenols, terpenoids, and flavonoids that can be used in the management of neurodegenerative diseases, as well as their specific mechanisms of antioxidant action. This review will serve as a reference for future experimental studies on neurodegenerative illnesses while also offering fresh insights into clinical therapy.

Introduction: The association between epilepsy and myasthenia gravis has rarely been reported, and only in small case series. Objective: To report the frequency of epilepsy and myasthenia gravis and to describe a case series of patients with myasthenia gravis and epilepsy, focusing on their clinical characteristics and searching for a possible physiopathological mechanism. Methods: A retrospective, observational, adult center study was conducted in 2022. Patients were recruited from the database of the outpatient clinic of the Myasthenia Gravis unit and Epilepsy unit. Results: Five patients were included. Frequency of epilepsy in the myasthenia gravis cohort was 5/469 (1.1%), and of myasthenia gravis in the epilepsy cohort was 5/1432 (0.35%). All patients suffered focal epilepsy, mainly fronto-central, and drug-resistant in half of them. Myasthenia gravis was generalized and with exacerbations in half of them. Three patients were thymectomized. Other autoimmune diseases were found in 2 (40%). Epilepsy onset preceded myasthenia gravis onset in all patients. Both diseases were considered autoimmune-related in 3/5 (60%). Conclusion: Epilepsy and myasthenia gravis are only infrequently associated. In adult patients, epilepsy onset precedes myasthenia onset in most cases. In some cases, epilepsy has an autoimmune aetiology and coexists with other autoimmune conditions.

Coronary no-reflow (CNR) is a frequent phenomenon that develops in patients with ST-segment elevation myocardial infarction (STEMI) following reperfusion therapy. CNR is highly dynamic and develops gradually (over hours) and persists for days to weeks after reperfusion. Microvascular obstruction (MVO) developing as a consequence of myocardial ischemia, distal embolization and reperfusion-related injury is the main pathophysiological mechanism of CNR. The frequency of CNR or MVO after primary PCI differs widely depending on the sensitivity of the tools used for diagnosis and timing of examination. Coronary angiography is readily available and most convenient to diagnose CNR but it is highly conservative and underestimates the true frequency of CNR. Cardiac magnetic resonance (CMR) imaging is the most sensitive method to diagnose MVO and CNR that provides information on the presence, localization and extent of MVO. CMR imaging detects intramyocardial hemorrhage and accurately estimates the infract size. MVO and CNR markedly negate the benefits of reperfusion therapy and contribute to poor clinical outcomes including adverse remodeling of left ventricle, worsening or new congestive heart failure and reduced survival. Despite extensive research and the use of therapies that target almost all known pathophysiological mechanisms of CNR, no therapy has been found that prevents or reverses CNR and provides consistent clinical benefit in patients with STEMI undergoing reperfusion. Currently the prevention or alleviation of MVO and CNR remain unmet goals in the therapy of STEMI that continue to be under intense research.

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

Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) serve an essential role in tumor angiogenesis and have emerged as potential therapeutic targets in lung cancer. This review explores the significance of serum VEGF levels as a predictive biomarker in non-small cell lung cancer (NSCLC). The VEGF family, consisting of VEGFA, VEGFB, VEGFC, VEGFD, and placenta growth factor (PlGF), engages with specific receptors, including tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3) and neuropilin receptors (NRP-1 and NRP-2), to promote angiogenesis and lymphangiogenesis. VEGF-A, the primary component of the VEGF family, binds to VEGFR-2 to stimulate endothelial cell proliferation and migration, while VEGF-B, VEGF-C, and VEGF-D interact with VEGFR-1 and VEGFR-3 to regulate tumor angiogenesis, lymphangiogenesis, and metastasis. The VEGF/VEGFR signaling pathway activates various downstream effectors, including phospholipase Cγ1, MAPK, and PI3K/Akt, which are essential for maintaining vascular homeostasis and promoting angiogenesis. In NSCLC, elevated serum VEGF levels have been observed, and the VEGF/VEGFR axis is frequently impaired, leading to irregular blood vessel formation and metastatic spread. Despite the development of anti-VEGF therapies, their impact on lung cancer outcomes has been limited. Further research is needed to optimize the effectiveness of these treatments and elucidate the potential of serum VEGF as a predictive biomarker in NSCLC.

Immunosuppressed individuals, such as people living with HIV (PLWH), remain vulnerable to severe COVID-19. We analyzed the persistence of specific SARS-CoV-2 humoral and cellular immune responses in a retrospective, cross-sectional study in PLWH on antiretroviral therapy. Among 104 participants, 70.2% had anti-S IgG antibodies and 55.8% had significant neutralizing activity against the Omicron variant in a surrogate virus neutralization test. Only 38.5% were vaccinated (8.76 ± 4.1 months prior), all displaying anti-S IgG, 75% with neutralizing antibodies and anti-S IgA. 29.8% had no SARS-CoV-2 serologic markers and displayed significantly lower CD4 counts and HIV viral load. Severe immunosuppression (present in 12.5% of participants) was linked to lower levels of detectable anti-S IgG (0.0003), anti-S IgA (p &lt; 0.0001) and lack of neutralizing activity against Omicron variant (p &lt; 0.0001). T-cell responses were present in 86.7% of tested participants, even in those lacking serological markers. In PLWH without severe immunosuppression, neutralizing antibodies and T-cell responses persisted for up to 9 months post-infection or vaccination. Advanced immunosuppression led to diminished humoral immunity, but retained cellular immune.

Mpox, formerly known as Monkeypox, is a rare viral disease initially discovered in Africa in 1958. Since its first identification, several outbreaks have occurred in various African nations. Recently, the global community has witnessed a resurgence in the number of Mpox cases reported worldwide, prompting the World Health Organization (WHO) to declare the ongoing multi-country outbreak a public health emergency in July 2022. This study reports on the first cases of Mpox detected in Khartoum State, Sudan, outlining the epidemiology, preparedness, and public health response to this new challenge. A total of 55 suspected cases were identified, with two confirmed cases. The clinical manifestations observed in these cases align with the classic skin rash typical of Mpox, presenting alongside symptoms like fever, headache, and joint pain. The findings underscore the need for heightened surveillance, early detection, and timely intervention to prevent the domestic spread of Mpox and its potential impact on public health. Continued global efforts are needed to support effective screening, diagnostic, and control measures, ultimately enhancing preparedness and response in the face of this emerging disease.

Escherichia coli is an indicator microorganism in One Health antibiotic resistance surveillance programmes. The purpose of the study was to describe and compare E. coli isolates obtained from pigs and human contacts from a commercial farm in South Africa using conventional methods and whole genome sequencing (WGS). Porcine E. coli isolates were proportionally more resistant phenotypically and harboured a richer diversity of antibiotic resistance genes, as compared to human E. coli isolates. Different pathovars, namely ExPEC (12.43%, 21/169), ETEC (4.14%; 7/169), EPEC (2.96%, 5/169), EAEC (2.96%, 5/169) and STEC (1.18%, 2/169) were detected at low frequencies. Sequence type complex (STc) 10 were the most prevalent (85.51%, 59/169) among human and porcine isolates. Six STcs (STc10, STc86, STc168, STc206, STc278 and STc469) were shared at the human-livestock interface according to multilocus sequence typing (MLST). Core genome MLST and hierarchical clustering (HC) showed that human and porcine isolates were overall genetically diverse, but some clustering at HC2 to HC200 were observed. In conclusion, even though the isolates shared a spatio-temporal relationship, there were still differences in the virulence potential, antibiotic resistance profiles, and cgMLST and HC according to the source of isolation.

Major cardiovascular events (MACE) are a cause of major mortality worldwide. The narrowing and blockage of coronary arteries with atherosclerotic plaques is diagnosed and treated with percutaneous coronary intervention (PCI). During this procedure, coronary angiography (CAG) remains the most widely used guidance modality for the evaluation the affected blood vessel diameter in order to decide if intervention with stent colocation is suitable, where small blood vessels (&lt; 2.75 mm) are majorly left untreated; however, small vessel coronary artery disease (SvCAD) is a significant risk factor for recurrence of MACE, and there are some limitations to the use of CAG that could be improved with the use of newer techniques such as intravascular ultrasound (IVUS), although at higher costs, which might explain their underuse. To address this discrepancy and identify specific cases for its use, we conducted a retrospective study in patients who underwent PCI for MACE with at least one small blood vessel affected. The affected small blood vessels’ diameter was obtained with both CAG and IVUS, additionally we underwent a multivariate analysis to identify risk factors associated with a change in diameter. We included information from 48 patients with mean + SD age of 69.1 + 11.9 years and 34% were masculine gender. We found a significant positive low correlation in diameter measurements of small blood vessels (r=0.1242 p=0.014). Mean diameter with CAG and IVUS was 2.1 mm (95% CI 1.9-2.2), and 2.8 (2.8-3.0) the estimated difference was of 0.8 mm (95 % CI 0.7-0.9). In total 37 (77%) of patients had a reclassification of their blood vessels from a small to medium (2.75-3.00 mm) in 21 cases, or even large (&lt;3.00 mm) in 15 cases, after IVUS; this was important for the decision of intervention and stent collocation. The only variable associated with reclassification of blood vessels after adjusted in a multivariate analysis was DT2 (p=0 0.035). Our findings corroborate that blood vessels might appear smaller with CAG, especially in the diabetes population, therefore at least in these cases the use of IVUS is recommended over CAG.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

(1) Background: Heart rate variability (HRV) has emerged as a potential prognostic tool in cardiovascular diseases, offering individualized insights into autonomic nervous system activity. However, real-time HRV data during the acute phase of STEMI, particularly during percutaneous coronary intervention (PCI), was not previously explored. (2) Methods: This single-center, observational cohort study included 104 STEMI patients undergoing primary percutaneous coronary intervention (PCI). HRV parameters were measured using a wearable device (CE marked) during PCI, capturing dynamic responses. The association between HRV parameters and adverse outcomes, including in-hospital mortality and major adverse cardiovascular events (MACE), were assessed. (3) Results: HRV parameters significantly decreased after myocardial revascularization, particularly SDNN, RMSSD, pNN50, HF, SD1, and SD2/SD1 ratio. Significant associations were found between reduced SD2/SD1 ratio, approximate entropy, and adverse outcomes, including increased in-hospital mortality and MACE. The SD2/SD1 ratio was significantly lower in patients who died during the hospital stay (p = 0.008) compared to survivors. Approximate entropy was also significantly lower in deceased patients (p = 0.019). (4) Conclusions: Real-time HRV monitoring using wearable technology offers valuable data regarding dynamic physiological changes during primary PCI. The integration of HRV into routine clinical practice, facilitated by wearable devices, could improve the risk stratification and event prediction in STEMI patients.

After decades of studies, the pathogenesis of Autism Spectrum Disorder (ASD) remains unclear and there still lackseffective treatment strategies for core symptoms. Our recent work, combined with others’ research in a diversity ofmodels and clinical trials, suggested a concise, but potentially rational theory that can illustrate the key of the pathogenesis and treatment of ASD from the aspect of damage control.

Background/Objectives: Multisystem Inflammatory Syndrome in children (MIS-C) is a rare but severe post-infectious complication of COVID-19, that often requires admission to the Pediatric Intensive Care Unit (PICU). The present study aimed to compare the demographic, clinical and laboratory characteristics between children diagnosed with MIS-C who were admitted to the PICU or did not require PICU admission. Methods: Children diagnosed with MIS-C from September 2020 to April 2023 were included in this case-control study. Patient’s demographic, clinical and laboratory data, were collected from medical records. Results: Fifty children with MIS-C were included in the study [median (IQR) age: 7.5 (4.3, 11.4) years, 28/50 (56%) males]. Twenty-two (22/50, 44%) children required admission to the PICU. In the multivariate regression analysis, hepatic (OR:12.89, 95%CI: 1.35-123.41, p-value=0.03) and cardiological involvement (OR:34.55, 95%CI: 2.2-541.91, p-value=0.01) were significantly associated with hospitalization at the PICU. Regarding the laboratory and imaging parameters during the first 48 hours from admission, D-dimer levels higher than 4μg/mL and decreased Left Ventricular Ejection Fraction were associated with an increased risk of PICU admission (OR:7.95, 95%CI:1.48-42.78, p-value=0.02 and OR=1.28, 95%CI:1.07-1.53, p-value=0.01). Children who were admitted to the PICU were more likely to develop complications during their hospitalization (10/22, 45.5% vs. 3/28, 10.7%, p-value=0.005) and were hospitalized for more days, than children in the pediatric wards (median length of stay (IQR): 20 (15,28) days vs. 8.5 (6, 14) days, p-value&lt;0.001). Conclusions: In the present study, cardiovascular, hepatic involvement and increased D-dimer levels in children with MIS-C were associated with admission to the PICU.

Mulberry leaves, when infected by pathogens, can suffer significant yield loss or even death if early disease detection and timely spraying are not performed. To enhance the detection performance of mulberry leaf diseases in natural environments and to precisely locate early small lesions, we propose a high-precision, high-efficiency disease detection algorithm named YOLOv8-RFMD. Based on improvements to You Only Look Once version 8 (YOLOv8), we first proposed the Multi Dimension Feature Attention (MDFA) module, which integrates important features at the pixel-level, spatial and channel dimensions. Building on this, we designed the RFMD Module, which consists of the Conv-BatchNomalization-SiLU (CBS) module, Receptive-Field Coordinated Attention (RFCA) Conv, and MDFA, replacing the Bottleneck in the model’s Residual block. We then employed Adown down sampling structure to reduce the model size and computational complexity. Finally, to improve the detection precision of small lesion features, we replaced the complete intersection over union (CIOU) loss function with the Normalized Wasserstein Distance (NWD) loss function. Results show that the YOLOv8-RFMD model achieves an mAP50 of 94.3% and an mAP50:95 of 67.8% on experimental data, representing increases of 2.9% and 4.3% respectively compared to the original model. The model size is reduced by 0.53 MB to just 5.45 MB, and the number of floating-point operations is reduced by 0.3 G to only 7.8 G. The improved model meets the deployment requirements of mobile embedded devices and can provide a theoretical reference for the automated spraying operations of mulberry leaves.

This study describes KPC-204, a novel variant of Klebsiella Pneumoniae carbapenemase, characterized by a KDD amino acid insertion at Ambler position 269 deviates from KPC-2. This variant was identified in an ST11-type clinical isolate of carbapenem-resistant Klebsiella Pneumoniae from China. Notably, KPC-204 exhibits resistance to both ceftazidime-avibactam and carbapenems. Genetic analysis revealed that blaKPC-204 was located on a highly mobile IncFII/IncR plasmid within a complex genetic structure that facilitates its spread. Functional analysis, achieved through cloning into E. coli DH5α, validates KPC-204's contribution to increased resistance to ceftazidime-avibactam. The kinetic parameters showed that KPC-204 exhibited similar affinity to KPC-2 toward ceftazidime and reduced sensitivity to avibactam. Mating experiments demonstrated the resistance's transmissibility. This investigation underscores the evolving diversity of KPC variants affecting ceftazidime-avibactam resistance, highlighting the necessity for continuous monitoring.

Equine herpesvirus type 1 (EHV-1) causes rhinopneumonitis, abortion and neurological outbreaks (equine herpesvirus myeloencephalopathy, EHM) in horses. EHV-1 also causes lethal encephalitis in laboratory small animals such as mice and hamsters experimentally. EHV-1 ORF76 is a homologue of HSV-1 US9, which is a herpesvirus kinase. Starting with an EHV-1 bacterial artificial chromosome clone of neuropathogenic strain Ab4p (pAb4p BAC), we constructed an ORF76 deletion mutant (Ab4p∆ORF76) by replacing ORF76 with the rpsLneo gene. Deletion of ORF76 had no influence on replication, cell-to-cell spread in cultured cells or replication in primary neuronal cells. In western blots of EHV-1-infected cell lysates, an EHV-1 Us9-specific polyclonal antibody detected multiple bands ranging from 35 to 42-kDa. In a CBA/N1 mouse infection model following intranasal inoculation, the parent and Ab4p∆ORF76 revertant caused the same histopathology in the brain and olfactory bulbs. The parent, Ab4p∆ORF76 and revertant mutant replicated similarly in the olfactory mucosa, although Ab4p∆ORF76 was not transported to the olfactory bulbs and was unable to infect the CNS. These results indicated that the ORF76 (US9) plays an essential role in the anterograde spread EHV-1.

Background: Resistant hypertension (HTN) is associated with high risk of cardiovascular complications. Our study aimed to assess prevalence, characteristics and treatment of patients with resistant HTN; Methods: We screened 4340 consecutive cardiovascular patients and identified 3762 with HTN. Of them 128 fulfilled criteria for resistant HTN and were included in our study. We matched these patients to 128 hypertensive patients with controlled HTN; Results: Resistant HTN patients were 3.4% of all hypertensives. Most of these patients (67.2%) were at high or very high cardiovascular risk compared to controlled HTN patients (40.6%), p&lt;0001. Resistant HTN patients had more frequently concomitant chronic kidney disease (CKD) (60.9%), overweight/obesity (52.3%), dyslipidemias (35.2%), smoking (27.3%) and diabetes (21.9%) compared to controlled HTN patients (37.5%, 29.7%, 28.1%, 14.1% and 7.8% respectively), p&lt;0.001. Regression analysis showed strongest association of resistant HTN with CKD (OR 6.64), stage III HTN (OR 3.07) and obesity/overweight (OR 2.60). In contrast, single-pill combinations (SPCs) were associated with lower likelihood of uncontrolled HTN (OR 0.58); Conclusions: Resistant HTN represented a small proportion of all hypertensives in our study, but it was characterized by high/very high cardiovascular risk. Optimized therapy including increased usage of SPCs could improve blood pressure control and long-term prognosis of these patients.

The detection of Fasciola eggs in ruminant fecal samples typically occurs around 15 weeks post-infection during patent infections. The recent introduction of coproantigen ELISA (cELISA) diagnostics, which capture antigenic enzymes in fecal material, holds promise for monitoring Fasciola fecal egg count (FFEC) to implement control programs, particularly targeted treatments. This study compared two study groups, those with positive FFEC (FFEC+ve) and negative FFEC (FFEC-ve), to assess the sensitivity of Flukefinder sedimentation and a cELISA kit. This study reports that the coproantigen ELISA detection limit was 4.5 eggs per gram (epg) for a 100% positivity rate. Additionally, a moderate, statistically significant positive correlation (r²=0.716, p-value < 0.01) and an odds ratio of 1.96 (p-value < 0.01) were observed between FFEC and Fasciola coproantigen from cELISA. This implies that for every single unit increase in FFEC, there is a 96% likelihood of obtaining a higher optical density (OD) reading from the cELISA test. The results suggest that cELISA can complement fecal sedimentation tests, serving as a valuable tool for detecting cattle with high FFEC. This capability facilitates targeted treatment strategies, thereby aiding in the control and prevention of the spread of fasciolosis within the studied area.

Minimal access cardiac surgery appears to be the future. It is increasingly desired by cardiologists and demanded by patients who perceive superiority. Minimal access coronary artery revascularisation has been increasingly adopted throughout the world. Here we review the history of minimal access coronary revascularization and see that it is almost as old as the history of cardiac surgery. Modern minimal access coronary revascularization takes a variety of forms – namely minimal access direct coronary artery bypass grafting (MIDCAB), hybrid coronary revascularisation (HCR) and totally Endoscopic Coronary Artery Bypass Grafting (TECAB). It is noteworthy that there is significant variation in nomenclature and approaches for minimal access coronary surgery and this truly presents a challenge to comparing the different methods. However, these approaches are increasing in frequency and proponents demonstrate clear advantages for their patients. The challenge that remains, as for all areas of surgery, is demonstrating superiority of these techniques over tried and tested open techniques which is very difficult. There is a paucity of randomized controlled trials to help answer this question, and the future of minimal access coronary revascularisation to some extent is dependent on such trials. Thankfully some are underway and the results eagerly anticipated.

The mechanistic Target of Rapamycin Complex 1 (mTORC1) regulates ribosome biogenesis and the transcription of ribosomal genes. Its inactivation impacts protein synthesis necessary for transport of cell adhesion molecule. In Dictyostelium discoideum, the activity of mechanistic Target of Rapamycin Complex 2 (mTORC2) is crucial for cAMP synthesis and relay, processes that depend on heterotrimeric G-proteins and Ras GTPases. Mutants lacking rip3 or lst-8 genes exhibit impaired adenyl cyclase activation and cAMP signaling, resulting in deficient expression of the cell adhesion protein CsaA. Despite this, rip3^- cells, which have impaired mTORC2, upregulate Cad-1 expression, a cell adhesion protein regulated by Ras-GTPases, to compensate for the loss of CsaA. lst-8^- cells, which have both mTORC1 and mTORC2 inactivated, show reduced nutrient sensing, premature CsaA expression and solitary cell behavior. These cells also show defective transport of adhesion proteins to the cell surface, impeding aggregation. Similar defects are observed with caffeine treatment, suggesting both mTORC1 and mTORC2 inhibition. This study highlights the interplay between mTORC1 and mTORC2 in regulating cell adhesion and aggregation through cAMP signaling and protein synthesis pathways in Dictyostelium.

ABSTRACTCaffeine is known to impair both growth and development in the model social amoeba Dictyostelium discoideum. However, little is known about the transcriptional regulation in response to caffeine treatment in Dictyostelium. In yeast cells, caffeine mimics the effect of rapamycin in inhibiting mTORC1 activity. Here, we investigated whether changes in growth and development of Dictyostelium in the presence of caffeine or rapamycin are mediated by mTORC1 and/or mTORC2. Results: Treatment of wild type cells with caffeine or rapamycin resulted in severely impaired growth and in the formation of small aggregates in comparison to untreated cells. rip3‾ cells (lacking a mTORC2 component) and lst8‾cells (lacking a component of both mTOR complexes) showed higher and slower growth rates, respectively, in comparison to parental AX3 cells. Parental AX3 and rip3‾ cells displayed similar sensitivity to rapamycin and caffeine, while lst8‾ cells were more sensitive to these compounds. When developed in the presence of caffeine or rapamycin, AX3 cells formed aggregates after a long delay. Caffeine did not alter the morphology of small rip3‾ mounds and lst8‾ cells continued to remain solitary. However, in the presence of 1µM rapamycin rip3‾cells failed to form mounds while AX3 cells streamed and formed aggregates. Complementation of lst8‾ cells with the wild type lst8 gene rescued the aggregation phenotype. cDNA microarray analysis to uncover the spectrum of differentially regulated genes in response to caffeine treatment revealed 104 and 193 differentially expressed genes at 3-and 6-hours of development, respectively, in comparison to control cells. After 6 hours of starvation in the presence of caffeine, 25 genes encoding ribosomal proteins and 4 encoding elongation factors were up regulated. Furthermore, we identified that upon caffeine treatment at the 3- and 6-hours’ time points, 12 (10 up and 2 down) and 21 (13 up and 8 down) genes, respectively, encoding proteins involved in early development. Conclusion: We conclude that caffeine and rapamycin have similar effects in decreasing the growth rate and in reducing the aggregate size of D. discoideum. Studies with lst8‾ and rip3‾ cells suggest that these compounds affect cell growth and aggregation by acting on both mTOR complexes, mTORC1 and mTORC2. Analysis of the differentially expressed genes after caffeine treatment suggests a key role of these genes in growth and aggregation.

Following the detection of highly pathogenic avian influenza (HPAI) virus in countries bordering Kenya to the west, we conducted surveillance among domestic and wild birds along the shores of Lake Victoria. In addition, between 2018 and 2020, we conducted surveillance among poultry and poultry workers in live bird markets and among wild migratory birds in various lakes that are resting sites during migration to assess introduction and circulation of avian influenza viruses in these populations. We tested 7,464 specimens (oropharyngeal and cloacal swabs) from poultry and 6,531 fresh fecal specimens from wild birds for influenza A viruses by real-time RT-PCR. Influenza was detected in 3.9% (n=292) of specimens collected from poultry and 0.2% (n=10) of fecal specimens from wild birds. On hemagglutinin subtyping, most of the influenza A positives from poultry (274/292, 93.8%) were H9. Of 34 H9 specimens randomly selected for further subtyping, all were H9N2. On phylogenetic analysis, these viruses were genetically similar to other H9 viruses detected in East Africa. Only two of the ten influenza A positive specimens from the wild bird fecal specimens were successfully subtyped; sequencing analysis of one specimen collected in 2018 was identified as low pathogenicity avian influenza H5N2 virus of the Eurasian lineage and the second specimen, collected in 2020, was subtyped as H11. A total of 18 OP/NS swabs from poultry workers with ARI (12%) were collected; none were positive for influenza A virus. We observed significant circulation of H9N2 influenza viruses in poultry in live bird markets in Kenya. During the same period, low pathogenic H5N2 virus was detected in a fecal specimen collected in a site hosting a variety of migratory and resident birds. Although HPAI H5N8 was not detected in this survey, these results highlight the potential for introduction and establishment of highly pathogenic avian influenza viruses in poultry populations and the associated risk of spillover to human populations.

Enterococcus faecalis is a growing cause of nosocomial and antibiotic-resistant infections. Treating drug-resistant E. faecalis requires novel approaches. The use of bacteriophages (phages) against multidrug-resistant (MDR) bacteria has recently garnered global attention. Biofilms play a vital role in E. faecalis pathogenesis as they enhance antibiotic resistance. Phages eliminate biofilms by producing lytic enzymes, including depolymerases. In this study, Enterococcus phage vB_Efs8_KEN04 (ФKEN04), isolated from a sewage treatment plant in Nairobi, Kenya, was tested against clinical strains of MDR Enterococcus faecalis. This phage had a broad host range against 100% (26/26) of MDR E. faecalis clinical isolates and cross-species activity against Enterococcus faecium. It was able to withstand acidic and alkaline conditions, from pH 3 to 11, as well as temperatures between -80ᵒC and 37ᵒC. It could inhibit and disrupt the biofilms of MDR E. faecalis. Its linear double-stranded DNA genome of 142,402 bp contains 238 coding sequences with a G+C content and coding gene density of 36.01% and 91.46%, respectively. Genomic analyses showed that ФKEN04 belongs to the genus Kochikohdavirus in the family Herelleviridae. It lacked antimicrobial resistance, virulence, and lysogeny genes, and its stability, broad host range, and cross-species lysis indicate strong potential for the treatment of Enterococcus infections.

Background: Telemonitoring systems in cardiology have shown potential in improving chronic cardiovascular disease (CVD) management. This study aims to evaluate the impact of telemonitoring, mainly through mobile applications, on patient outcomes such as self-care, blood pressure control, quality of life, and hospitalization. Methods: We systematically reviewed studies assessing telemonitoring methods for patients with chronic CVD. The analysis included studies from various geographic regions and healthcare settings, focusing on qualitative outcomes without performing a meta-analysis. Results: Telemonitoring was found to aid in maintaining blood pressure and significantly enhance self-care abilities. Improvements in quality of life were observed in some studies, though results varied. Most studies indicated telemonitoring could effectively manage blood pressure and reduce hypertension-related complications. However, the heterogeneity of interventions and outcomes measured across trials posed challenges for a comprehensive meta-analysis. Conclusions: Integrating telemonitoring systems into routine care can significantly improve disease management and patient outcomes for chronic CVD patients. Future research should standardize telemonitoring interventions and outcome measures, conduct long-term studies, and evaluate the cost-effectiveness of these systems. Greater blindness in future randomized controlled trials and more studies on atrial fibrillation are also necessary. Significant potential exists for telemonitoring to improve patient outcomes and assist in managing chronic illnesses.

Background: Atrial fibrillation (AF) is increasingly recognized in pediatric patients, presenting unique challenges in management due to its association with various underlying heart conditions. This study aimed to evaluate the prevalence, management strategies, and outcomes of AF in this population. Methods: A retrospective analysis was conducted at a tertiary pediatric cardiology center, including patients aged ≤18 years diagnosed with AF between January 2015 and December 2023. The study focused on demographic details, clinical presentations, treatments, and outcomes. Descriptive statistics were employed to assess treatment efficacy, recurrence rates, and complications. Results: The study included 36 pediatric patients (median age: 15 years, IQR: 13-17; 58% male). Of these, 52.8% had acquired heart disease, 16.7% had congenital heart anomalies, and 16.7% presented with lone AF. The initial management strategies involved electrical cardioversion in 53.3% of patients and pharmacological conversion with amiodarone in 46.7%. Rhythm control therapy was administered to over 80% of the cohort, and 63.9% were placed on oral anticoagulation, predominantly for rheumatic and congenital heart diseases. The overall success rate of rhythm control was 96.2%, with an AF recurrence rate of 3.8%. Ischemic stroke was the most common complication, occurring in three patients, all with underlying rheumatic heart disease. Conclusion: AF in pediatric patients is predominantly associated with rheumatic and congenital heart diseases, though a significant proportion of patients present with lone AF. Despite effective rhythm control in most cases, neurological complications, particularly ischemic strokes in patients with underlying heart disease, remain a critical concern. These findings underscore the need for more comprehensive studies to better understand the etiology, risk factors, and optimal management strategies for pediatric AF.

Lipoprotein (a) is a highly atherogenic, lipid particle whose concentration is genetically determined, and represents an independent risk factor for cardiovascular disease. On the other hand, metabolic syndrome represents a cluster of interconnected cardiovascular risk factors (obesity, insulin resistance, arterial hypertension, dyslipidemia) that are a direct consequence of an unhealthy lifestyle. Some evidence suggests a connection between each component of metabolic syndrome and high levels of lipoprotein (a). Still, the exact mechanisms are not fully understood and may involve complex interactions between various metabolic pathways. High levels of lp(a) are associated with insulin resistance, a key feature of type 2 diabetes mellitus and obesity. Although there is no significant association between lp(a) and other lipid levels (LDL-C, HDL-C, triglycerides), studies have shown a strong synergistic effect of genetically elevated LDL-C and Lp (a) on the development of cardiovascular events. Also, there is supporting evidence that hypertensive patients with high levels of lp(a) have higher cardiovascular risk, there is no direct association between hypertension and lp (a). Treatment of metabolic syndrome is often long-term and challenging but very important to reduce the overall cardiovascular risk, especially in individuals with higher levels of Lp (a), in whom the risk of developing cardiovascular disease is much higher.

A single coronary artery is a very rare condition, commonly associated with other congenital anomalies. It could be generally classified as neither benign nor malignant form of congenital coronary artery anomalies since its pathophysiological and clinical implications grossly depend on different anatomical patterns defined by the site of origin and distribution of the branches. By presenting the patient with an isolated single coronary artery, who underwent successful combined aortic valve replacement and coronary artery bypass grafting surgery, we intend to distinguish casual from causal in this extremely rare clinical and surgical scenario. This is the first-ever case published, combining such underlying pathology, clinical presentation, and surgical treatment.

Background Coronary artery disease (CAD) is a widely recognized cardiovascular disease that is considered the leading cause of death worldwide, affecting people on a global scale. Percutaneous coronary intervention (PCI), which involves procedures such as balloon angioplasty or stenting, plays an important role in opening blocked arteries and minimizing damage to the cardiac muscle. While the use of drug-eluting stents (DESs) has significantly reduced the occurrence of coronary restenosis, the problem of in-stent restenosis (ISR) continues to pose a significant clinical challenge. Gaining a deeper understanding of the clinical predictors associated with ISR is vital for early detection and appropriate treatment. Hence, this study aimed to evaluate the clinical predictors of ISR specifically in Taiwanese patients. Methods We conducted a single-center, retrospective case-control study, enrolling 517 CAD patients undergoing previous coronary stenting and stable angina with positive stress test or acute coronary syndrome (ACS) during follow-up between January 2019 and December 2022 at National Taiwan University Hospital. The patients were categorized into two groups: the ISR group, consisting of individuals who received drug-coated balloon (DCB) treatment (n=177), and the non-ISR group, comprising patients who did not receive DCB treatment (n=340). To gather relevant data, we meticulously reviewed the medical records and analyzed the findings from coronary angiography to assess the clinical characteristics of the patients. Results Patients with three-vessel disease (3VD) exhibited a higher prevalence of underlying diseases and were more likely to be taking aspirin and clopidogrel. Moreover, our analysis revealed that age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00 - 1.04, p = 0.037) and the presence of 3VD (adjusted odds ratio [aOR] 2.15, 95% confidence interval [CI] 1.03 - 4.46, p = 0.039) were significantly associated with an increased risk of coronary ISR. Conclusions Older age and 3VD were the independent predictors of coronary ISR in CAD patients receiving coronary stent implantation.

Autoimmune blistering diseases represent a group of chronic severe, disabling, potentially fatal disorders of the skin and/or mucous membranes primarily mediated by pathogenic auto-antibodies. Despite their rarity, these diseases are associated with significant morbidity and mortality, a profound negative impact on the patient’s quality of life and impose a considerable economic burden. Rituximab, an anti CD-20 monoclonal antibody represents the first line of therapy for pemphigus, regardless of its severity as it ensures high rates of rapid, long-lasting complete remission. Nevertheless, disease recurrence is the rule, all patients requiring maintenance therapy with rituximab sooner or later. While innate resistance to rituximab in pemphigus patients is exceptional, acquired resistance is frequent and may develop even in patients with initial complete response to rituximab, representing a real challenge for physicians. We discuss the various resistance mechanisms and their complex interplay, as well as the numerous therapeutic alternatives that may be used to circumvent rituximab resistance. As no therapeutic measure is universally efficient, individualization of rituximab treatment regimen and tailored adjuvant therapies in refractory pemphigus cases are mandatory.

Porcine parvovirus 8 (PPV8), a novel virus in the Parvoviridae family, was first identified in 2022 in lung samples of domestic pigs from China. Retrospective analyses showed that it had been circulating in China since 1998, but no other countries had reported its presence so far. A recent study conducted in South America did not detect any PPV8-positive samples in that region. Here we report the detection of PPV8 in Hungarian and Slovakian pig farms and the estimated prevalence of the virus in Hungary. Altogether 2230 serum, 233 oral fluid, and 115 processing fluid samples were systematically collected from 23 Hungarian and 2 Slovakian pig farms between 2020 and 2023. A real-time quantitative PCR method was developed to detect the viral genome. Our results revealed the presence of PPV8 on 65% of the Hungarian farms and on both Slovakian farms included in our study, marking its first detection in Europe. Oral fluid samples showed the highest positivity rates, reaching up to 100% in some herds. The viral genome was successfully detected in serum and processing fluid samples too, but with significantly lower prevalence rates of 4% and 5%, respectively. Genetic analysis of 11 partial VP2 sequences demonstrated high similarity to the original Chinese strain but with unique amino acid mutations, suggesting possible local evolution of the virus. Our study presents the first scientific evidence of PPV8 infection outside of China and offers a comprehensive assessment of its prevalence in the Hungarian pig population. Further research is required to understand its potential impact on swine health.

High-flow oscillatory ventilation (HFOV) is a common rescue treatment in infants and children with respiratory failure. This type of ventilation is an effective technique in numerous diseases that affect a child in the postnatal period, such as ARDS, meconium aspiration syndrome (MIS), postnatal pulmonary bleeding and idiopathic pulmonary hypertension (IPH). Although this ventilation technique is commonly recognized as a valuable therapeutic option in the general pediatric population, this is not the same for children with congenital cardiovascular diseases. The key mechanism of oscillatory ventilation is continuous positive pressure administered within the airways via a small tidal volume at high frequency. Tidal volumes are between 1 and 3 ml/kg delivered at 5 – 15 Hz equivalent to 300 – 900 breaths per minute. Few older studies conducted on humans and animals highlight that HFOV may be dangerous for congenital heart patients. According to these evidences, hemodynamic parameters such as blood pressure, wedge pressure, central venous pressure, heart rate and inotrope level can be dangerously changed for patients with congenital heart disease, therefore oscillatory ventilation should be avoided. Numerous retrospective studies have pointed out how oscillatory ventilation constitutes a valid therapeutic option in children with congenital heart disease. Recently, new evidences have highlighted how hemodynamic parameters are modified in a non-significant way by this type of ventilation, remaining beneficial as in the normal pediatric population. This narrative review aims to describe the mechanisms of oscillatory ventilation and collect all the available evidences to support its use in pediatric patients with congenital heart problems.

The high transmissibility, rapid evolution, and immune escape of SARS-CoV-2 variants can influence the course of infection and, in turn, morbidity and mortality in COVID-19, posing a challenge in controlling transmission rates and contributing to the emergence and spread of new variants. The factors that shape viral genetic variation are consequently essential for understanding the evolution and transmission of SARS-CoV-2, especially in vaccinated individuals where immune response plays a role in the progression and spread of this disease. This study assessed. In this context, we evaluated the impact of immunity induced by the CoronaVac vaccine (Butantan/Sinovac) on intra-host genetic diversity, analyzing 118 whole-genome sequences of SARS-CoV-2 from unvaccinated and vaccinated patients infected with the Gamma variant. Vaccination with CoronaVac favors negative selection at the intra-host level in different genomic regions and prevent greater genetic diversity of SARS-CoV-2, which may help reduce the emergence of new mutations, reinforcing the importance of vaccination in reducing virus transmission.

Rationale:First discovered in 1990, the endocannabinoid system (ECS) was initially shown to have an intimate relationship with central areas of the nervous system associated with pain, reward, and motivation. Recently, however, the ECS has been extensively implicated in the cardiovascular system with contractility, heart rate, blood pressure, and vasodilation. Emerging data demonstrates modulation of the ECS plays an essential role in cardio metabolic risk, atherosclerosis, and can even limit damage to cardiomyocytes during ischemic events.Patient Concerns:This case describes a 63-year-old male who presented to a primary care physician for a medical cannabis (MC) consult due to unstable angina (UA) not relieved by morphine or cardiac medications; having failed all first- and second-line poly-pharmaceutical therapies. The patient reported frequent, unprovoked, angina and exertional dyspnea.Diagnosis:Having a complex cardiac history, the patient first presented 22 years ago after a suspected myocardial infarction (MI). He re-presented in 2010 and underwent stent placement at that time for inoperable triple-vessel coronary artery disease (CAD) which was identified via percutaneous transluminal coronary angioplasty. UA developed on follow up and, despite medical management over the past 6 years, his UA became progressively debilitating.Interventions and Outcomes:In conjunction with his standard cardiac care, patient had a gradual lessening of UA related pain, including frequency and character, after using an edible form of medical cannabis (MC) (1:1 CBD:THC). Following continued treatment, he ceased long term morphine treatment and describes the pain as no longer crippling. As demonstrated by his exercise tolerance tests, the patient experienced an improved functional capacity and reported an increase in his daily functioning, and overall activity.Lessons:This case uniquely highlights MC in possibly reducing the character, quality, and frequency of UA; while concordantly improving functional cardiac capacity in a patient with CAD. Additional case reports are necessary to verify this.

Aims: Clinical evidence indicates that innate immune cells may contribute to the onset and outcome of acute coronary syndrome (ACS). Our prospective study aimed at analysing neutrophil phenotypes in ACS and their role in predicting 1-year major cardiovascular events. Methods: Blood neutrophil phenotypes were analysed by flow cytometry. Differential blood cell count and plasma levels of soluble markers were recorded at admission and at 6-month follow-up. Results: 108 patients categorized in chronic stable coronary artery disease (n=37), unstable angina (UA) (n=19), Non-ST-Elevation Myocardial Infarction (NSTEMI) (n=25), and ST-Elevation Myocardial Infarction (STEMI) (n=27) were included. STEMI and NSTEMI patients displayed higher neutrophil count and neutrophil-to-lymphocyte ratio (NLR) than stable and UA patients (P<0.0001), which normalized at 6-month after MI. STEMI patients were characterized by elevated percentages of band cells in low-density neutrophils (P=0.007) and in high-density neutrophils (P=0.019) compared to the other patients. Multivariable logistic regression analysis revealed that plasma levels of total MPO was associated with STEMI when compared to stable (OR: 1.434; 95% CI: 1.119-1.837; P<0.0001), UA (1.47; 1.146-1.886; P=0.002), and NSTEMI (1.213; 1.1-1.134; P=0.0001) patients, while increased neutrophil SSC signal intensity was associated with NSTEMI compared to stable patients (3.828; 1.033-14.184; P=0.045). Based on multivariable Cox regression analysis, elevated plasma levels of PCSK9 and low-density neutrophil percentage predicted 1-year outcome independently of cardiovascular risk factors (c-index: 0.915; IQR: 0.908-0.929). Conclusions: Changes in neutrophil phenotype are concomitant to ACS. These changes may differ between STEMI and NSTEMI. They may also contribute to ACS risk and patient outcome.

Coronary revascularization is one of the most studied treatment modalities in cardiology, however, there is no consensus among experts about its indications in patients with stable coronary artery disease (SCAD). Contemporary data regarding the role of revascularization in SCAD are in clear conflict with the current European guidelines. This article discusses the main statements of the most significant American and European Guidelines on myocardial revascularization of the last decade, and also analyzes the appropriateness of revascularization to improve the prognosis and symptoms in CCS in the light of new research data, primarily the ISCHEMIA study (NCT01471522) and ACC/AHA 2021 Revascularization Guidelines based on them. Data on the revascularization in CCS obtained after the completion of ISCHEMIA (including the interim analysis of ISCHEMIA-EXTEND) and their potential significance are discussed. The results of ISCHEMIA sub-analyses in the most important ‘controversial’ subgroups (3-vessel disease, proximal left anterior descending artery (LAD) disease, strongly positive stress test, etc.) are reviewed, as well as the results of the ISCHEMIA-CKD substudy in patients with severe chronic kidney disease (CKD).

Clostridial infections in cattle are a significant concern for Brazilian livestock. These diseases are caused by various species of Clostridium, which are known for their ability to produce potent toxins. Botulism in cattle is a serious and often fatal condition caused by the ingestion of neurotoxins produced by C. botulinum. This bacterium thrives in decomposing organic matter, such as spoiled feed, carcasses, and contaminated water. Tetanus while less common, tetanus is a serious disease following contamination of wounds with Clostridium tetani spores. It results in muscle stiffness, spasms, and often death due to respiratory failure. Blackleg (C. chauvoei) is this disease primarily affects young cattle, leading to acute lameness, swelling, and high fever. Malignant edema (C. septicum and others) is characterized by rapid onset of swelling at wound sites, malignant edema can occur after injuries or surgical procedures. Enterotoxemia is triggered by the rapid growth of C. perfringens in the gut following excessive carbohydrate intake. This leads to toxin production that causing sudden death. In conclusion, clostridial bovine infections remain a persistent challenge for Brazilian cattle farmers. With continued focus on vaccination, good management practices, and research, the impact of these diseases can be minimized, safeguarding the livestock industry's economic viability.

The emergence of drug-resistant mycobacteria has rendered many clinical drugs and regimens ineffective, imposing significant economic and healthcare burden on individuals and society. Repurposing drugs intended for treating other diseases is a time-saving, cost-effective, and efficient approach for identifying excellent anti-mycobacterial candidates or lead compounds. This study is the first to demonstrate that rupatadine (RTD), a drug used to treat allergic rhinitis, possesses excellent activity against mycobacteria without detectable resistance, particularly Mycobacterium tuberculosis and Mycobacterium marinum, with a minimal inhibitory concentration as low as 3.13 µg/mL. Furthermore, RTD exhibited moderate activity against nonreplicating M. tuberculosis with the minimal inhibitory concentrations lower than drugs targeting the cell wall, suggesting that RTD has the great potential to be modified and used for the treatment of nonreplicating M. tuberculosis. Additionally, RTD exhibits partial synergistic effects when combined with clofazimine, pretomanid, and TB47 against M. tuberculosis, providing the theoretical foundation for the development of treatment regimens. Transcriptomic profiling leads us to speculate that eight essential genes may be the targets of RTD or may be closely associated with the mycobacterial resistance to RTD. In summary, RTD may be a promising hit for further anti-mycobacterial drug or regimen optimization, especially in case of nonreplicating mycobacteria.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins and decrease levels of toxic proteins. ASOs are being developed for the treatment of several diseases, including motor neuron diseases (MNDs), a group of neurodegenerative disorders characterised by the loss of motor neurons, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MND, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Weight-bearing computed tomography (WBCT) enables acquisition of three dimensional bony structure images in a physiological weight-bearing position, which is fundamental in under-standing the pathologic lesions and deformities of the ankle joint. Over the past decade, re-searchers focused on validating and developing WBCT measurements, which has significantly enhanced our knowledge of common foot and ankle disease. Consequently, understanding the application of WBCT in clinical practice is becoming more important to produce improved out-comes in the treatment of disease around the ankle joint. This review will describe an overview of what is currently being evaluated in the foot and ankle surgery using WBCT and where the course of research will be heading in the future.