Pregnancy in women with Sickle Cell Disease (SCD) is a high-risk situation, especially during the third trimester of gestation and in the post-partum period, due to chronic hypoxia and vaso-occlusive phenomena occurring in the maternal-fetal microcirculation: as a result, unfavorable outcomes, such as intra-uterine growth restriction, prematurity or fetal loss are more frequent in SCD pregnancies. Therefore, there is a consensus on the need for a strict and multidisciplinary follow-up within specialized structures. Transfusion support remains the mainstay of treatment of SCD pregnancies, although most appropriate modalities are still controversial: the benefit of prophylactic management, either by simple transfusions or by automated Red Blood Cell Exchange (aRBCX), is not unanimously recognized. We illustrate the cases of three SCD pregnant patients who underwent aRBCX procedures at our institution in different clinical scenarios. Moreover, we carried out a careful literature revision to investigate the management of pregnancy in SCD, particularly regarding the practice of aRBCX. Our experience and current literature support using aRBCX in pregnancy as a feasible and safe procedure provided that specialized equipment and an experienced apheresis team are available. However, further research in this high-risk population, with appropriately powered prospective trials, will be desirable to refine indications and timing of aRBCX and confirm this approach's advantages on other transfusion modalities.

This study assessed the associations between host genetic variants and subgingival microbiota in patients with metabolic syndrome (MetS); 103 patients with MetS underwent medical and periodontal examinations and had blood and subgingival plaque samples taken. DNA was extracted and processed (assessing a panel of selected single nucleotide polymorphisms (SNPs) first (hypothesis-testing), and then expanding to a discovery phase. The subgingival plaque microbiome from these patients was profiled. Analysis of associations between host genetic and microbial factors was performed, stratified for periodontal diagnosis. Specific SNPs within RUNX2, CAMTA1 and VDR genes were associated with diversity metrics, with no genome-wide associations detected for periodontitis severity or Mets components at p<10-7. Severe periodontitis was associated with pathogenetic genera and species. Some SNPs correlated with specific bacterial genera, as well as with microbial taxa, notably VDR (rs12717991) with Streptococcus mutans and RUNX2 (rs3749863) with Porphyromonas gingivalis. This is the first study exploring the role of host genotype variation in subgingival microbial dysbiosis in patients with MetS and periodontitis. In conclusion, variation in host genotypes may play a role in the dysregulated immune responses characterizing periodontitis and thus the oral microbiome, suggesting that systemic health-associated host traits further interact with oral health and microbiome.

Objectives: The aim of the study was to evaluate the effects of oral administration of clinical dose of beraprost for feline CKD in healthy cats, and also to examine whether NOS inhibition reversed them. Methods: A placebo-controlled pharmacological sequential design study was carried out to assess plasma aldosterone and renin concentrations, mean blood pressure, heart rate, renal plasma flow, and renal vascular resistance. Results: Beraprost reduced plasma aldosterone when compared to the placebo (P < 0.05); this was reversed when NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was added to beraprost treatment (P < 0.01). No differences in the plasma renin concentration or hemodynamic parameters were detected between beraprost and placebo. The correlation ratios (η2) showed opposite relationships between beraprost and added L-NAME effects on aldosterone concentration, mean blood pressure, heart rate, renal plasma flow, and renal vascular resistance (P < 0.001). Conclusions: In healthy cats, the clinical dose of beraprost suppresses plasma concentration of aldosterone, which can be reversed by inhibition of NOS.

Recent studies have discovered that functional connections are impaired in patients with Parkinson's disease (PD) accompanied by hallucinations(PD-H), even at the preclinical stage. The cerebellum has been implicated as playing a role in cognitive processes. However, the functional connectivity (FC) between cognitive sub-regions of the cerebellum of PD patients with hallucinations needs to be further clarified. Resting-state functional magnetic resonance imaging (rs-fMRI) data from three groups (17 PD-H, 13 no hallucinations accompanying the (PD-NH), and 26 healthy controls (HC) ) was collected in this study to explore the role of cerebellar FC changes in the cognitive performance. Additionally, we define cerebellar FC as a training feature for classifying all subjects using Support Vector Machine(SVM). We found that PD-H patients' cerebellum(Vermis_4_5 ) FC had increased within the left side of the precuneus(PCUN) compared to HC, cerebellum(Vermis_1_2) had increased within bilateral opercular part of the inferior frontal gyrus(IFGoprec) and triangular part of the inferior frontal gyrus(IFCtriang), left side of postcentral gyrus(PoCG), Inferior parietal lobe(IPL), and PCUNs compared to PD-NH. In the training results of machine learning, cerebellar FC has also been proven to be an effective biomarker feature, with a recognition rate of over 90% for PD-H. These findings indicate that cortico-cerebellar FC in PD-H and PD-NH patients were significantly disrupted with different distributions. The proposed pipeline offers a promising low-cost alternative for the diagnosis of preclinical PD-H and can be useful for other degenerative brain disorders.

Advances in cardiovascular therapies and cancer treatments result in longer patient survival. The coexistence of cancer and cardiovascular disease has been recognized as a complex clinical scenario. Beside cardiovascular disease, older people with cancer are at greater risk of experiencing multimorbidity and the geriatric syndromes such as frailty. In older people, the concurrent presence of cancer and cardiovascular disease increased the risk of mortality, and the presence of frailty can exacerbate their conditions and hinder the treatment effectiveness. Given the significant intersection among frailty, cardiovascular disease and cancer in older people, this paper aims to provide an overview of the current research in this field and identifies gaps in research to understand the burden and impact of frailty in these populations. While many studies have examined the prevalence and impact of frailty on adverse outcomes in patients with cancer or with cardiovascular disease, evidence of frailty in individuals with both conditions is lacking. There is no universally accepted definition of frailty, which leads to inconsistencies in identifying and measuring frailty in older adults with cardiovascular disease and cancer. The frailty index seems to be a preferred frailty definition in studies in patients with cancer, while the frailty phenotype seems to be more commonly used in cardiovascular research. However, differences in how the frailty index was categorised and in how patients were classified as ‘frail’ depending on the cut points may have negative effect on understanding the impact of frailty in the studied populations. This makes it challenging to compare findings across different studies and limits our understanding of the prevalence and impact of frailty in these populations. Addressing these research gaps will contribute to our understanding of the burden of frailty in older people with cardiovascular disease and cancer, and improved clinical care protocols in this vulnerable population.

The present study evaluates the response to betahistine in patients who presented vestibular drops attacks in the context of Ménière's disease (MD) and the factors that can predict an unfavorable response to it. A total of 43 patients were analyzed, out of which 33 were diagnosed with MD. It is a descriptive, cross-sectional study with retrospective data collection. Data as regards age, accompanying symptoms, etiological diagnosis and response to MD treatment were collected. A statistical analysis was carried out, and we found that the disease evolution time and specific alterations in the vestibulospinal and oculomotor physical examination present an unfavorable response to betahistine, as opposed to the use of intratympanic gentamicin, with which symptomatic control is achieved in 100% of the cases.

Real-time quaking-induced conversion (RT-QuIC) assays have become common in the detection of chronic wasting disease (CWD) and are very sensitive provided the assay duration is sufficient. However, a prolonged assay duration may lead to non-specific signal amplification. The wide range of pre-defined assay durations in current RT-QuIC applications presents a need for optimization of the RT-QuIC assay duration. In this study, receiver operating characteristic (ROC) analysis was applied to optimize assay duration for detection of CWD in obex and retropharyngeal lymph node (RLN) tissue specimens. Two different fluorescence thresholds were used: a fixed threshold based on background fluorescence (Tstdev) and a max-point ratio (maximum/background fluorescence) threshold (TMPR) to determine CWD positivity. The optimal assay duration was 27 h for both obex and RLN based on Tstdev, and 27 and 28 h for obex and RLN, respectively, based on TMPR. The optimized assay durations were then evaluated for screening CWD in white-tailed deer from an affected farm. Results by RT-QuIC using optimized duration based on Tstdev and TMPR were in 100% and 92.3 % or higher agreement with those by the widely used screening assay, ELISA. In comparison, when using a 40 h assay duration, the agreement between RT-QuIC and ELISA reduced to 89.2% or higher, and the RT-QuIC results were significantly (p < 0.05) different from those using optimum durations. These findings demonstrated that the application of ROC analysis for the optimization of assay duration could improve the RT-QuIC assay for screening CWD in white-tailed deer.

Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The impairment of the nervous system, in addition to the acroparesthesias, is characterized by hypohidrosis and cerebrovascular accidents. Gb3-accumulation supports the hypothesis that Gb3 is not solely responsible for disease manifestation. Overloading of lysosomes with Gb3 may simply lead to the rupture of cytoplasma and in consequence to cell death .Secondary effects of Gb3 accumulation which might be responsible for disease pathology include also inflammatory processes. Perturbed leukocyte function in Fabry disease compared to healthy controls and abnormal numbers of different immune cells, including lymphocytes, monocytes, CD8+ cells, B cells and dendritic cells . Noteworthy other studies reported no correlation between CRP-levels as a global inflammatory marker and the Mainz-Severity-Score-Index (MSSI) as a marker for disease severity . Other authors reported on auto-immunological reactions in α-galactosidase A deficiency. Others researchers found higher expressions of neuronal apoptosis inhibiting protein as a key anti-apoptotic mediator in children with Fabry disease compared to healthy controls. Noteworthy, this upregulation did not change after institution of ERT, whereas apoptosis inducing factor appears to be upregulated under ERT. The authors were not able to explain their observations, but further research has to be directed on this topic. Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. The authors hypothesized that ERT may enhance endothelial damage, allowing to understand continuously occurring strokes in patients on treatment. Furthermore, Gb3-accumulation has been reported to induce oxidative stress and/or the formation reactive oxygen species (ROS). Lipids and proteins may be oxidised and may be unable to function. Of note, ERT increased the generation of ROS in vitro, and up-regulated the intracellular adhesion molecule ICAM 1. Another gateway into alteration of endothelial function may be given by the Nitric-Oxide-Synthase-3-genotypes. Endothelium-derived nitric oxide is a key regulator of vessel wall function and cardiovascular homeostasis. Thus, neurological complications seem to be linked to different pathogenetic molecular mechanisms.Progressive accumulation of GB3 represent a possible pathogenetic event of peripheral nerve involvement, whereas central nervous involvement in the clinical setting of cerebrovascular ischemic events seem to be due to the endotheliopathy of Anderson-Fabry Disease with lacunar lesions and white matter hyperintensities ( WMHs) . In this review manuscript we revised molecular mechanisms of peripheral and central neurological complications of Anderson-Fabry Disease.

Cognitive impairment in patients with Parkinson’s disease (PD), which may occur in various severities, represents one of the commonest and most disabling non-motor manifestations during the course of the disease, causing a negative impact on patients’ quality of life. Eventually, it becomes a burden for the family members and/or the caregivers of patients, as it progresses to PD dementia. Current pharmacological treatments for cognitive impairment in PD exhibit partial efficacy, while novel effective therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline, and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, improvement of mitochondrial function, regulation of synaptic plasticity, impact on gut-brain axis, modulation of neuroinflammation, upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this overview, we aim to cover the clinical aspects of PD associated cognitive impairment, highlighting recent evidence on emerging treatment approaches that are currently under investigation at a preclinical and clinical level.

Cyclic neutropenia is a rare hematological condition characterized by periodic fluctuations in neutrophil counts, with a 21-day periodicity. Clinical presentation varies from mild to severe forms of the disease, with the onset of recurrent fever, painful oral ulcers, recurrent bacterial infections, peritonitis and septic shock. The availability of granulocyte colony-stimulating factor (G-CSF) has revolutionized the management and natural history of this disease, regulating the proliferation, differentiation and maturation of the progenitor cells, reducing the duration of neutropenia. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic pathologies with involvement of the gastrointestinal tract. Symptoms include diarrhea, abdominal pain, fever, weight loss and extraintestinal manifestations (EIMs). In recent years, the focus of IBD therapy, including conventional therapies and biological therapies, has moved from treatment of symptoms to "deep remission" of the disease. The association between cyclic neutropenia and CD is rarely reported in the literature. Here, we describe two case reports of patients who underwent surgery because of diagnosis of complicated CD. After surgery, because of persistent neutropenia, the hematologist consultant confirmed suspicions of cyclic neutropenia and therapy with G-CSF was started with benefits, underlining the crucial importance of proper differential diagnosis.

Crohn's disease is a non-specific inflammatory bowel disease, which is a chronic condition that affects the ileum and/or large intestine. At the same time, it can also involve any other part of the human body, that is, from the mouth to the anus. The symptoms are very bothersome and cause a significant reduction in quality of life and sometimes even crippling permanent damage to the gastrointestinal tract, which requires enteral or parenteral nutrition for life. The purpose of this study was to investigate tissue metalloproteinases as markers of recurrent Crohn's disease. The experimental groups included 31 patients and 10 patients with normal Crohn's disease, ranging in age from 23-70 years, with a mean age of 40.4. Collected tissues were frozen and then fragmented tissues were homogenized with Ripa Lysis buffer on ice. The supernatant was collared and four metalloproteinases - MMP 3, MMP 7, MMP 8 and MMP 9 - were an-alized by Enzyme-linked Immunosorbent Assay using SEA101HU, SEA102Hu, SEA103Hu and SEA553Hu kits (Cloud-Clone Corp., Kata, TX, USA). All chemical analyses were performed in triplicate. Metalloproteinase content was expressed as mean ± standard deviation. Metalloproteinase 3 and metalloproteinase 8) significantly influenced the possibility of Crohn recurrence

Crohn's disease (CD) is a chronic, relapsing disorder belonging to inflammatory bowel diseases (IBD). It is manifested by relapsing transmural inflammation found in any segment of the gastrointestinal tract. Chronic fatigue is a common and underrecognized symptom of CD, which prevalence is much higher in the population of CD patients as compared to healthy population. It stems from an intricate web of interactions between various risk factors, and its pathophysiology is still not fully understood. Implementation of routine screening and holistic, multidisciplinary approach involving psychological support may be crucial in management of CD patients with chronic fatigue. There is currently no single intervention aimed at decreasing fatigue alone, and its treatment is especially difficult in patients with fatigue persisting despite clinical and endoscopic remission. Extensive research is still needed in order to be able to predict, prevent, identify and ultimately treat fatigue associated with CD. The aim of this review is to summarize the knowledge on the etiology, diagnosis, and treatment of chronic fatigue in CD patients.

Charcot–Marie–Tooth disease (CMT) and associated neuropathies constitute the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments remain elusive. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and results in a lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are currently under clinical and preclinical investigation, and a broad array of therapeutic agents and their corresponding mechanisms have been discussed in this review. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, has been appraised. Each of these gene therapies has the potential for substantial advancements in future research.

Oral health involves physiological functions related to mouth, teeth and orofacial structures, but also includes psychological and social dimensions. In this sense, oral health is an integrated part of human general health and well-being. Our aim was to access and evaluate the general oral health status of a high- and elite-level sample of Portuguese athletes from different sports. One hundred and sixteen participants were examined regarding their dental relationships, teeth and periodontal health, the presence of parafunctional activities (bruxism), and current or past orthodontic treatment. Our sample were predominantly adolescents and young adults, including 54 high-level and 62 elite subjects (71 males and 45 males) from 11 different sports, but mainly from swimming and athletics. Most sport performers presented with normocclusion (77%), despite the presence of other sagittal, transverse and vertical malocclusions. Twenty-three participants were affected by dental caries and six had missing teeth. Gingivitis (~40%) and dental calculus (~30%) were presented in our sample. Bruxism signs (47%) and current or past orthodontic treatment (~22%) were also found. Oral health conditions are not under control among high- and elite-level athletes, supporting the importance of healthcare needs and oral health promotion strategies in sports.

Leukotrienes are proinflammatory mediators that participate in the process of atherogenesis and contribute to the development of symptomatic peripheral arterial disease. The aim was to evaluate the relationship between leukotriene E4 (LTE4) and B4 (LTB4) with parameters reflecting endothelial vascular function in patients with chronic lower limb ischemia. This prospective observational study enrolled 50 consecutive patients undergoing endovascular treatment due to chronic lower limb ischemia (Rutherford 3). All participants were followed-up for one year (after 1, 3, 6 and 12 months), with a sequential assessment of urinary LTE4 and LTB4, as well as measures of endothelial and vascular function: Flow-Mediated Dilatation (FMD), Intima-Media Thickness (IMT), corrected Augmentation Index (AI75), Shear Rate (SR), Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI). There was a significant relationship between LTE4 and measures of vascular function: FMD (R2 = 0.69, P&lt;0.001), IMT (R2=0.12, P&lt;0.01), AI75 (R2=0.43, P&lt;0.001), SR (R2=0.48, P&lt;0.001). Similar findings were noted for LTB4: FMD (R2=0.47, p&lt;0.001), IMT (R2=0.23, P&lt;0.001), AI75 (R2=0.61, P&lt;0.001) and SR (R2=0.33, P&lt;0.001). Alterations in parameters were significantly related: ΔLTE4 vs ΔFMD(R2=0.63, P&lt;0.001), ΔSR (R2=0.42, P&lt;0.001) and ΔLTB4 vs AI75(R2=0.40, P&lt;0.001), SR(R2=0. 29, P&lt;0.001). We conclude, that increasing concentrations of LTE4 and LTB4 are associated with impairment of vascular and endothelial function, which may lead to worse endovascular treatment clinical outcomes.

Repeated exposure to environmental ozone causes a chronic state of oxidative stress. This state is present in chronic degenerative diseases and induces a loss of control of the inflammatory response. The dysfunction of redox system and failures in control the inflammatory responses are involved in a vicious circle that maintains and increases the degenerative process. Intestine also responds to secondary reactive species formed by exposure to ozone doses, generating noxious stimuli that increase degenerative damage. This review aims to elucidate how environmental pollution, mainly by ozone, induces a state of chronic oxidative stress with the loss of regulation of the inflammatory response, both in the intestine and in the brain, where the functionality of both structures is altered and plays a determining role in some neurodegenerative and chronic degenerative diseases. For this purpose, we searched for information on sites like the Cochrane Library Database, PubMed, Scopus, and Medscape. Reviewing the data published, we can conclude that environmental pollutants are a severe health problem. Ozone pollution has different pathways of action, both molecular and systemic, and participates in neurodegenerative diseases such as Parkinson's and Alzheimer's disease as well in bowel diseases as Inflammatory Bowel Disease, Crohn's Disease and Irritable Bowel Syndrome.

Vibrio parahaemolyticus carrying a plasmid encoding toxins PirA and PirB is one of the causative agents leading to the severe disease of acute hepatopancreatic necrosis disease (AHPND) in shrimp aquaculture. However, there is a lack of deep understanding of the host resistant characteristics against V. parahaemolyticus infection. Here, we performed comparative transcriptome analysis on the expression profiles at the background level of hemocytes from shrimp with different resistant abilities against V. parahaemolyticus infection in two independent populations. Principal component analysis and sample clustering results showed that samples from the same population had a closer relationship than that from shrimp with similar disease-resistant abilities. Differentially expressed genes (DEGs) analysis revealed that the number of DEGs between two populations was much more than that between V. parahaemolyticus¬-resistant and susceptible shrimp. A total of 31 DEGs and 5 DEGs were identified from the comparison between V. parahaemolyticus¬-resistant and susceptible shrimp from population 1 and 2, respectively. There was no DEGs overlap between two comparisons. DEGs from population 1 were mainly cytoskeleton related genes, metabolic related genes, and immune related genes. DEGs from population 2 included tubulin alpha-3, dihydropyrimidinase-like gene, diacylglycerol kinase 1, prohibitin and iroquois-class homeodomain protein IRX-2-like. The data suggest that shrimp from different populations might adopt distinct disease-resistant mechanisms, which provided new insights into understanding disease-resistant mechanisms at population level against pathogen infection. A new strategy for screening disease resistant genes and disease resistant breeding was proposed based on the present study.

Background: Fabry disease cardiomyopathy (FDCM) has manifested some resistance to enzyme replacement therapy (ERT) particularly in its advanced phase. Recently myocardial inflammation of autoimmune origin has been demonstrated in FDCM. Aims: Aim of the study is the assessment of circulating anti-globotriaosylceramide (GB3) antibody as biomarker of myocardial inflammation in FDCM. Its sensitivity was based on the evidence of overlapping myocarditis at left ventricular endomyocardial biopsy. Methods and Results: From January 1996 to December 2021, 85 patients received in our Department the histological diagnosis of FDCM and 48 (56.5%) of them had an overlapping myocardial inflammation with negative PCR for the common cardiotropic viruses, positive anti-heart and anti-myosin abs. The presence of anti-GB3 antibodies was evaluated with an Elisa assay (BioGeM scarl Medical Investigational Research, MIR - Ariano Irpino, Italy) in the FDCM patients and compared with controls of healthy individuals. Circulating levels of anti-GB3 autoantibodies were compared with the presence or absence of myocardial inflammation at histology and with the severity of FDCM. The assay results showed that 42 out of 48 FDCM subjects with myocarditis were positive for anti-Gb3 antibodies while 30 out of 37 FDCM patients without myocarditis had negative anti-GB3 antibodies, with a sensitivity of 87.5 % and a specificity of 83.5%. Conclusions: The present study suggests a potential positive role of antiGB3 antibodies as marker of overlapping cardiac inflammation in patients with FDCM.

Background: Biomarker development, improvement, and clinical implementation in the context of kidney disease has been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well accepted biomarkers in kidney disease. With their known blind spot in early stages of kidney impairment and diagnostic limitations there is a need for better and more specific biomarkers. With the rise of large-scale analysis of thousands of peptides in serum or urine samples using mass spectrometry techniques hopes for biomarker development were high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. Methods: The Web of Science database (all databases) was searched on October 17th, 2020, using the search terms “marker*” OR biomarker* AND “renal disease” OR “kidney disease” AND “proteome*” OR “peptid*” AND “urin*”. English, full-text original articles on humans published within the last 5 years were included which were cited at least 5 times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA and studies on exosomal vesicles were excluded focusing on urinary peptide biomarkers. Results: The described search led to the identification of 3668 articles and application of inclusion and exclusion criteria as well as abstract and consecutive full-text analysis of 3 independent authors to a final number of 62 studies for this manuscript. The 62 manuscripts encompassed 8 established single peptide biomarkers and several proteomic classifiers including CKD273 and IgAN237. Discussion: This review provides a summary of recent evidence on single peptide urinary biomarkers in CKD while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies hopefully resulting in routine clinical applicability of new biomarkers.

Physical activity is well-established as an important protective factor against degenerative conditions and a promoter of tissue growth and renewal. The discovery of FNDC5 as the precursor of irisin in 2012 sparked significant interest in its potential as a diagnostic biomarker and a therapeutic agent for various diseases. Clinical studies have examined the correlation between plasma irisin levels and pathological conditions using a range of assays, but the lack of reliable measurements for endogenous irisin has led to uncertainty about its prognostic/diagnostic potential as an exercise surrogate. Animal and tissue-engineering models have shown the protective effects of irisin treatment in reversing functional impairment and potentially permanent damage, but dosage ambiguities remain unresolved. This review provides a comprehensive examination of the clinical and basic studies of irisin in the context of degenerative conditions and explores its potential as a therapeutic approach in the physiological processes involved in tissue repair/regeneration.

Background: Chronic kidney disease (CKD) is a common complication of non-kidney solid organ transplant (NKSOT). Identifying predisposing factors is crucial for an early approach and correct referral to nephrology. Methods: This is a single-center retrospective observational study of a cohort of CKD patients under follow-up in Nephrology Department between 2010 to 2020. Statistical analysis was performed between all the risk factors and four dependent variables: end-stage renal disease (ESKD), increased serum creatinine ≥50%, renal replacement therapy (RRT), and death in pre-transplant, peri-transplant and post-transplant period. Results: 74 patients were studied (7 heart transplant, 34 liver transplants, and 33 lung transplant). Patients who were not followed-up by nephrology in the pre-transplant (p&lt;0.027), peri-transplant (p&lt;0.046), and the longest time until outpatient clinic follow-up (HR 1,032) were associated with a higher risk of creatinine increase ≥50%. Receiving a lung transplant conferred higher risk than liver or hear transplant for developing a creatinine increase ≥50% and ESKD. Peri-transplant mechanical ventilation, peri-transplant and post-transplant anticalcineurin overdose, nephrotoxic and the number of hospital admissions were significantly associated to present a creatinine increase ≥50% and develop ESKD. Conclusion: An early follow-up by the nephrology department was associated with a decrease in the worsening of renal function.

The increasing number of people living with Long COVID requires the development of more personalized care, as for now limited treatment options and rehabilitation programs adapted to the variety of Long COVID presentations are available. Our objective was to design an easy-to-use Long COVID classification to help stratifying people with Long COVID. Individual characteristics and a detailed set of 62 self-reported persisting symptoms together with quality of life indexes 12 months after initial COVID-19 infection were collected in a cohort of SARS-CoV-2 infected people in Luxembourg. A hierarchical ascendant classification (HAC) was used to identify clusters of people. We identified 3 patterns of Long COVID symptoms with a gradient in disease severity. Cluster-Mild encompassed almost 50% of the study population and was composed of participants with less severe initial infection, fewer comorbidities, and fewer persisting symptoms (mean=2.9). Cluster-Moderate was characterized by a mean of 11 persisting symptoms and a poor sleep and respiratory quality of life. Cluster-Severe was characterized by a higher proportion of women and smokers as in the other clusters, with a higher number of Long COVID symptoms, in particular of vascular, urinary, and skin symptoms. Our study evidenced that Long COVID can be stratified in 3 sub-categories in terms of severity. If replicated in other populations, this simple classification will help clinicians to personalize the care of people with Long COVID.

This study aimed to evaluate the role of chest radiographs and electrocardiograms in predicting the hemodynamics of congenital heart disease (CHD). This retrospective study included 50 patients with a diagnosis of CHD who had undergone any form of cardiac intervention, either surgical or nonsurgical between September 2019 and September 2020. Chest radiographs and electrocardiograms were evaluated and compared with the diagnostic gold standard echocardiography. Chest radiographs had the highest sensitivity, specificity, and accuracy, with all being 100%, in detecting situs and cardiac position. There was a very good agreement between chest radiographs and echocardiography in the detection of both situs and cardiac position (κ = 1.00, p &lt; 0.001), while moderate agreement was observed for the detection of cardiomegaly, position of aortic knuckle, main pulmonary artery dilation, and right pulmonary artery dilation. Electrocardiograms had a high sensitivity (100.00%), but modest specificity and accuracy for the detection of left ventricle pressure overload. For the detection of left atrial enlargement and left ventricle volume overload, electrocardiograms had high specificity (94.12% and 94.29%, respectively) but low sensitivity and modest accuracy. There was a moderate agreement between electrocardiograms and echocardiography in the detection of right ventricle pressure overload (κ = 0.43, p = 0.002) and left ventricle volume overload (κ = 0.46, p &lt; 0.001). The study findings indicate that chest radiographs and electrocardiograms alone are not adequate for the assessment of hemodynamics of CHD and reinstates the recommendation that in addition to routine chest radiographs and electrocardiograms, echocardiography should be performed.

Background: Vaccinating children against COVID-19 is an essential public health strategy in order to reach herd immunity and prevent illness among children and adults. Parents are facing tremendous stress in relation to the COVID-19 pandemic and the effectiveness of the COVID-19 vaccination program for children. In this study, we aimed to investigate parents’ willingness to vaccinate their children against COVID-19 in North Kivu province (DRC). Methods: A cross-sectional survey between December 01, 2021 to January 20, 2022 in 6 health zones (Goma, Karisimbi, Butembo, Beni, Kamango and Katwa) was conducted in the province of North Kivu. In each health zone, we selected 5 clusters (Health area) using the method of probabilistic selection proportional to population size. In total, 522 parents participated in our study. Results: Overall, 32.8% of parents intended to vaccinate their children. In the multivariate analysis, younger age of parents (aOR : 2.40, CI : [1.50-3.83]), higher level of fear that “a member of my family” could contract COVID-19 (aOR : 2.35, CI : [1.38-4.02]), higher level of perceived vulnerability to COVID-19 within the family (aOR : 1.70, CI : [1.005-2.2881]), higher level of perceived susceptibility to COVID-19 within the family (aOR : 3.07, CI : [1.80-5.23]), and history of vaccination against COVID-19 among parents (aOR : 16.47, CI : [8.39-32.33]), were significantly associated with the intention to have their children or adolescents vaccinated. Conclusion: Willingness of parents to vaccinate their children against the COVID-19 vaccination was low in North Kivu. There is undeniably in this region a need to reinsure the populations about vaccine safety for both children and adults. Public health authorities should also address widespread misinformation about vaccines in a timely manner.

The number of people with neurodegenerative disease continues to increase every year. A new perspective is needed in overcoming this disease. In this review, researchers collected information about epigenetics and energy factors of neurodegenerative disease driven by mitochondria. Mitochondrial epigenetic dysregulation can cause damage to the neuron system. The increase in the amount and interaction of alpha-synuclein with SAMM50 in the mitochondria is one of the factors causing neurodegenerative disease. As an energy provider in the body, the existence of harmonization in the regulation of mitochondria specifically the mitochondrial outer membrane is important. Hydrogen peroxide (H₂O₂) has neuroprotective abilities to overcome the impairment function of mitochondria in neurodegenerative patients. Based on the computational simulation of this case, it can be used as the basic concept for the development of the role of H₂O₂ in neurodegenerative disease.

Objective: Several authors have analyzed the impact of the pandemic on the incidence rates of different conditions. Our aim was to analyze the impact of the COVID-19 pandemic on primary care new diagnoses of respiratory diseases. Methods: This was an observational retrospective study performed to describe the impact of COVID-19 pandemic on primary care new diagnosis of respiratory diseases other than lung cancer. Incidence rate ratio between pre-pandemic and pandemic period was calculated. Results: We found an decrease in the incidence of respiratory conditions (IRR 0.65) during the pandemic period. When we compared the different groups of diseases according to ICD-10, we found a significant decrease in the number of new cases during the pandemic period, except in the case of pulmonary tuberculosis, abscesses or necrosis of the lungs and other respiratory complications. Instead, we found increases in new diagnoses of flu and pneumonia (IRR 2.17) and respiratory interstitial diseases (IRR 1.41). Conclusion: There has been a decrease in new diagnosis of most respiratory diseases during the COVID-19 pandemic. The real clinical impact of this situation is still unknown. Large-scale real-life studies will make it possible to evaluate the long-term true impact of COVID-19 pandemic on the respiratory diseases management.

Uterine fibroid (UF) is a tumour in some parts of the uterus, which introduces health challenges or death due to failed surgery among women globally. This study was designed to ascertain the involvement of micro-nutrients, inflammation, and antioxidant enzymes in the UF development to gain further insights and provide a strategy for managing the disease. One hundred ninety reproductive-aged women were recruited and classified equally into case and control subjects. The supernatant obtained from excised tissues from the fibroid and the normal samples from the adjacent myometrium were assessed for the selected biochemical parameters with standard methods. The levels of vitamin A and sodium between 26-35 years; vitamins D, E, zinc, and selenium between 46-55 years; and vitamin E at 56 years and above significantly decreased (p&lt;0.05). Interleukin-2 (IL-2) level significantly increased (P &lt; 0.05) among the case between 36-45 years. An increase in the activity of glutathione-s-transferase and the reduction in glutathione peroxidase activity and vitamin A level in the uterus between 26-45 years were the most pronounced significant findings (p&lt;0.05) recorded. Prolonged vitamin A deficiency coupled with excess sodium salts facilitating inflammation induced by IL-2 are critical factors for UF development.

Epilepsy and Alzheimer's disease (AD) incidence increase with age. There are reciprocal relationships between epilepsy and AD. Epilepsy is a risk factor for AD and, in turn, AD is an independent risk factor for developing epilepsy in old age and abnormal AD biomarkers in PET and or CSF are frequently found in late onset epilepsies of unknown etiology. Accordingly, epilepsy and AD share pathophysiological processes including neuronal hyperexcitability and an early excitatory-inhibitory dysregulation leading to dysfunction in the inhibitory GABAergic and excitatory glutamatergic systems. Moreover, both β-amyloid and tau protein aggregates, the anatomopathological hallmarks of AD, have proepileptic effects. Finally, these aggregates have been found in the resection material of refractory temporal lobe epilepsies suggesting that epilepsy leads to amyloid and tau aggregates. Some epileptic syndromes, such as medial temporal lobe epilepsy share structural and functional neuroimaging findings with AD, leading to overlapping symptomatology such as episodic memory deficits and toxic synergistic effects. In this respect, the existence of epileptiform activity and electroclinical seizures in AD appears to accelerate progression of cognitive decline and the presence of cognitive decline is much more prevalent in epileptic patients than in elderly without epilepsy. Notwithstanding their clinical significance, the diagnosis of clinical seizures in AD is a challenge. Most are focal and manifest with altered level of consciousness without motor symptoms, and are often interpreted as cognitive fluctuations. Finally, despite the frequent association of epilepsy and AD dementia, there is a lack of clinical trials to guide the use of antiseizure medications (ASM). There is also a potential role for ASMs to be used as disease-modifying drugs in AD.

Autophagy is a cellular homeostatic process by which cells degrade and recycle their malfunctioned contents, and impairment in this process leads to Parkinson's disease (PD) pathogenesis. Dioscin, a steroidal saponin, has induced autophagy in several cell lines and animal models. The role of dioscin-mediated autophagy in PD remains to be investigated. Therefore, this study aims to investigate the hypothesis that dioscin-regulated autophagy and autophagy-related genes (ATG) could protect neuronal cells in PD via reducing apoptosis and enhancing neurogenesis. In this study, the 1-methyl-4-phenylpyridinium ion (MPP+) were used to induce neurotoxicity and impair autophagic flux in a human neuroblastoma cell line (SH-SY5Y). The result showed that dioscin pre-treatment counters MPP+-mediated autophagic flux impairment and alleviates MPP+-induced apoptosis by downregulating activated caspase-3 and Bax expression while increasing Bcl-2 expression. In addition, dioscin pre-treatment was found to increase neurotrophic factors and tyrosine hydroxylase expression, suggesting that dioscin could ameliorate MPP+-induced degeneration in dopaminergic neurons and benefit the PD model. Interestingly, the neuroprotective activities of dioscin were suppressed when co-treated with chloroquine (CQ), an autophagosome-lysosome inhibitor. In summary, we showed dioscin’s neuroprotective activity in neuronal SH-SY5Y cells might be partly related to its autophagy induction and suppression of the mitochondrial apoptosis pathway.

Background: Diabetes Mellitus is a metabolite disorder with parameters of high blood sugar levels. In the management of diabetes can be used the drug metformin is the gold of choice to achieve a therapeutic effect and rarely causes side effects of the drug, but it still has debate view. However, if used in excessive doses for patients with kidney disease, it will be contraindicated with side effects such as lactic acidosis. Objective: This study aims to evaluate the side effect of Metformin for diabetic kidney diseases (DKD) patients. Method: This study used the Narrative Review Method that was obtained from 2011 to 2021, in the English language from PubMed, Google Scholar, and Cochrane Library. Results: Metformin is at the forefront of the treatment of type 2 diabetes mellitus (DM2). Metformin is likely to have lactic acidosis-related adverse effects in chronic kidney disease (CKD) patients, such as increased arterial lactate. Lactic acidosis is defined as an increase in arterial lactate with an indicator of more than five mmol/L and an arterial blood pH of less than 7.35. Metformin-induced lactate levels are considered to be below the parameters. DKD risk factors can be conceptually classified as several susceptibility factors, initiation factors, and developmental factors. The two most prominent risk factors are hyperglycemia and hypertension. Conclusion: Metformin can increase lactate levels in CKD patients but is still below the parameters of lactic acidosis. This study may have some weaknesses and requires further prospective research to validate the results.

Background: A comparison of the amino acid (AA) plasma profile and markers of intestinal absorption-inflammation between healthy subjects aged 65-70 years and age-matched patients affected by stage 3b-4 chronic kidney disease (CKD3b-4) was performed. Methods: eleven healthy volunteers were compared with 12 CKD3b-4 patients at their first outpatient control (T0) and after 12-months (T12). Adherence to a low protein diet (LPD, 0.6±0.1 g/kg/day) was assessed by Urea Nitrogen Appearance. The following parameters were assessed: renal function, nutritional parameters, bioelectrical impedance analysis, plasma levels of 20 total aminoacids (TAAs), both essential (EAAs) including branched-chain amino acids (BCAAs) and non-essential (NEAAs). Zonulin and faecal Calprotectin markers were used to evaluate intestinal permeability/inflammation. Results: Four patients dropped out of the study; in the remaining 8 residual kidney function (RKF) remained stable, their LPD adherence had risen to 0.89g/kg/day, anaemia had worsened and extracellular body fluid had increased. In comparison to healthy subjects, TAA levels of histidine, arginine, asparagine, threonine, glycine, and glutamine had all increased. No variation in BCAAs was observed. A significant increase was detected in faecal calprotectin and zonulin levels in CKD patients as the disease progressed. Conclusions: This study confirms the finding in aged patients of an alteration in levels of several AAs secondary to uraemia. Intestinal markers provide confirmation of a relevant alteration to the intestinal function in CKD patients.

Background. Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches. Methods. This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson’s disease. In addition, we will focus on general treatment strategies and crucial challenges which need to be overcome. Results. Our current understanding of mitochondrial biology in parkinsonian disorders opens up the avenue for viable treatment strategies in Parkinsonian disorders. Insights can be obtained from primary mitochondrial diseases. However, substantial knowledge gaps and unique challenges of mitochondria-targeted gene therapies need to be addressed to provide innovative treatments in the future. Conclusions. Mitochondria-targeted gene therapies are a potential strategy to improve an important primary disease mechanism in Parkinsonian disorders. However, further studies are needed to address the unique design challenges for mitochondria-targeted gene therapies.

The poultry industry is affected by many epidemics and Newcastle Disease (ND) is a constant threat, known as a devastating disease for poultry farmers around the world. According to the average death time of chicken embryos, virus strains can be classified as lentogenic, mesogenic, or velogenic. The current research will clarify the vulnerable host range as well as the epidemiology and geographic distribution of ND in Pakistan. The introduction of the virus into poultry can have serious economic consequences, including the loss of production of sick and dying poultry, the cost of control measures (such as population reduction and disinfection measures), and possible trade restrictions in the event of an outbreak. The virus is transmitted by direct contact with sick poultry or carriers. Infected birds can also spread the virus in their feces. It can also be spread through respiratory secretions, contaminated feed, equipment, water, or feces. We will also discuss vaccines that which vaccines are available for NDV in Pakistan and vaccines can fight against this disease or not? In this study, a qualitative risk analysis was carried out to assess Pakistan's vulnerability to the introduction of virulent NDV strains

Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. Cardiac myocyte death is a fundamental process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review focuses primarily on induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also briefly summarize other stems- and progenitor-cell populations that have been used for regenerative myocardial therapy and attempt to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.

Neuroprotective strategies for stroke remain inadequate. Nanoliposomes comprised of phos-phatidylcholine, cholesterol and monosialogangliosides (NL) induced an antioxidant protective response in endothelial cells exposed to amyloid insults. We tested the hypotheses that NL will preserve SH-SY5Y neuroblastoma cell viability following hypoxic injury and will reduce injury in mice following middle cerebral artery occlusion (MCAO). Neuroblastoma were exposed to 20-hour physoxic (5% oxygen) or hypoxic (1% oxygen) condition without or with NL (100 or 300 µg/mL). Viability was measured using calcein-AM fluorescence and SH-SY5Y gene expression of antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1) and superoxide dismutase 1 (SOD1) were measured by quantitative polymerase chain reaction. C57BL/6J mice were treated with saline (N=8) or NL (10000 ug/mL, N=7) while undergoing 60-minute MCAO followed by reperfusion. Day 2 post-injury neurologic impairment score and infarction size were compared. Neuroblastoma showed reduced viability following hypoxia that was reversed by NL. NL increased gene expression of HO-1, NQO1 and SOD1 versus controls. NL-treated mice showed reduced neurologic impairment and brain infarct size (18.8±2% versus 27.3±2.3%, p=0.017) versus controls. NL reduced stroke injury in mice subjected to MCAO likely through induction of an antioxidant stress response. NL is a candidate novel agent for stroke.

Vaccination is widely regarded as a cornerstone in animal or herd health and infectious disease management. Nineteen vaccines against the major pathogens implicated in bovine respiratory disease are registered for use in the UK by the Veterinary Medicines Directorate (VMD). However, despite annual prophylactic vaccination, bovine respiratory disease is still conservatively estimated to cost the UK economy approximately £80 million per annum. This review examines the vaccine types available, discusses the surrounding literature and scientific rationale of the limitations and assesses the potential of novel vaccine technologies.

Uremic toxins are the compounds that emerge in the blood when kidney excretory function is impaired. The cumulative detrimental effect of uremic toxins results in numerous health problems and eventually death during acute or chronic uremia, especially in end-stage renal disease. More than 100 different solutes rise during uremia; however, the exact origin for most of them is still discussable. There are 3 main sources for such compounds: exogenous ones are consumed with food, whereas endogenous are produced by host metabolism or by symbiotic microbiota metabolism. In this article, we identified uremic toxins presumably of gut microbiota origin. We analyzed various databases to get information on enzymatic reactions in bacteria and human organism potentially yielded uremic toxins and to determine what toxins could be synthetized in bacteria residing in human gut. We selected biochemical pathways resulting in uremic toxins synthesis related to specific bacterial strains, and revealed links between toxin concentration in uremia and the proportion of different bacteria species, which can synthesize it. Moreover, we defined the relative abundance of human toxin-generating enzymes as well as the possibility of a particular toxin synthesis by the human metabolism. Finally, we analyzed which bacteria are potentially producing the biggest number of uremic toxins as well as which bacteria are decomposing them. Our study presents a bioinformatics-based approach for both elucidation of the origin of uremic toxins and search of the most likely human microbiome producers of toxins that can be targeted and used for the therapy of adverse consequences of uremia.

Biologists seek to identify a small number of significant features that are important, non-redundant, and relevant from diverse omics data. For example, statistical methods like LIMMA and DEseq distinguish differentially expressed genes between a case and control group from the transcript profile. Researchers also apply various column subset selection algorithms on genomics datasets for a similar purpose. Unfortunately, genes selected by such statistical or machine learning methods are often highly co-regulated, making their performance inconsistent. Here, we introduce a novel feature selection algorithm that selects highly disease-related and non-redundant features from a diverse set of omics datasets. We successfully applied this algorithm to three different biological problems: a) disease to normal sample classification, b) multiclass classification of different disease samples, and c) disease subtypes detection. Considering classification ROC-AUC, False-positive, and False-negative rates, our algorithm outperformed other gene selection and differential expression (DE) methods for all six types of cancer datasets from TCGA considered here for binary and multiclass classification problems. Moreover, genes picked by our algorithm improved the disease subtyping accuracy for four different cancer types over the state-of-the-art methods. Hence, we posit that our proposed feature reduction method can support the community to solve various problems, including the selection of disease-specific biomarkers, precision medicine design, and disease sub-type detection.

Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participated in the development of atherosclerosis. Previous studies indicated the therapeutic potential of anti-inflammatory therapy in anti-atherosclerosis. The present study examined the effect of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating endothelial dysfunction. IRAK1/4i showed little endothelial toxicity at concentrations from 1 to 10 μM. Inhibition of IRAK1/4 alleviated endothelial activation induced by LPS in vitro evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-κB. Taken together, our findings demonstrated that dual inhibition of IRAK1 and IRAK4 attenuates endothelial dysfunction, suggesting pharmaceutical inhibition of IRAK1/4 might be a potential strategy to combat endothelial dysfunction and atherosclerosis.

Abstract Introduction: COVID-19 has a relationship with patients’ demographic characteristics as well as their underlying diseases. This research has been conducted to evaluate factors' effect on Covid-19 patient's hospitalization rate and period in Hormozgan, Iran. Materials and Methods: The inclusion criteria of this retrospective study included all patients diagnosed as COVID-19 Patients after PCR who were referred to Covid-19 hospitals from February 2020 to June 2020 in Hormozgan province, Iran. After the completion of the consent form and observing ethical principles, 3480 patients' information was collected through the interview by Medical care monitoring center unit experts. The checklist was designed according to COVID-19 guidelines and approved by the World Health Organization and Iran Ministry of Health and Medical Education. The studied variables included gender, age, patients’ residence place, smoking history and medications use history, pregnancy, referral type to hospital, contact history with COVID-19 patients, early symptoms, gastrointestinal symptoms, intubation, Po2 level, history of cancer, chronic liver diseases, diabetes, chronic blood diseases, HIV/AIDS, acquired or congenital immunodeficiency, cardiovascular diseases, chronic kidney diseases, dialysis status, asthma and other chronic lung diseases, and chronic neurological disorders. These data were analyzed using descriptive (average-standard deviation-percentage) and analytical (including Chi-square, t-test, and regression tests) statistics with SPSS Ver.23 software. Results: In this study, 3480 COVID-19 patients including 1852 male patients (53.20%) with a median age of 43.11±21.72 and 1628 female patients (46/80%) with a median age of 44.86±22.40. The median age of men was significantly lower than the women's median age (P= 0.02). The duration of hospitalization of male and female patients was reported 2.64±4.14 and 2.76±4.297, respectively which was not statistically significant. The death rate of patients in our study was 6.6%. Conclusion: The results of this study also showed that the hospitalization period of HIV-positive patients and patients with cardiovascular and pulmonary diseases is much longer than other people, which imposes many human and financial costs on the country's health care system. Therefore, to maintain individual health and help improve the critical condition of the virus, it is better to develop and apply stricter protocols to prevent further outbreaks of the disease and check underlying diseases of people suspected to have Covid-19. These results can improve health care system planning and improving medical services presented to covid-19 patients.

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disorder complicated by left ventricle outflow tract (LVOT) obstruction, which can be treated with surgical myectomy. To date, no reliable biomarkers for LVOT obstruction exist. To determine whether metabolomic biomarkers for obstruction can be identified, we conducted metabolomic profiling on plasma samples of 18 HCM patients before and after undergoing surgical myectomy to measure changes in the plasma metabolome in the postoperative state. Plasma was collected approximately 4 weeks before surgery at the preoperative visit and approximately 3 months after the surgery at the postoperative visit. We found that 215 metabolites were altered in the postoperative state (p-value &lt; 0.05). Identified metabolites that were significantly reduced post-myectomy included metabolites of heme, such as bilirubin, and phenylacetylglutamine, a biomarker of urea cycle disorders, which suggests that liver and kidney function are improved in the postoperative state. Markers of arginine metabolism such as homoarginine and dimethylarginine are also decreased in the postoperative state, suggestive of reduction in nitric oxide production, inflammation and heart failure after surgery. 3-hydroxybutyrate (BHBA) was also decreased, suggesting possible increased fatty acid utilization and a return to normal heart function. 12 of these metabolites were notably significant after adjusting for multiple comparisons (q-value &lt; 0.05), including bilirubin, PFOS, PFOA, 3,5-dichloro-2,6-dihydroxybenzoic acid, 2-hydroxylaurate, trigonelline and 6 unidentified compounds, which support improved kidney and liver function and increased lean soft tissue mass. These findings suggest improved organ metabolic function after surgical relief of LVOT obstruction in HCM and further underscore the beneficial systemic effects of surgical myectomy.

Cardiovascular disease is the first leading cause of death in the world. Patients with cardiovascular disease may experience various problems, including physiological and psychological problems. Apart from pharmacological therapy, complementary therapy is necessary as a support to conventional medicine. This review aims to describe complementary and alternative therapies for pain and anxiety in patients with cardiovascular disease. This review utilized data from ProQuest, ScienceDirect, and PubMed with search keywords of "Complementary" AND "Nursing" AND "Pain" AND "Anxiety" AND "Coronary artery disease". Ten articles that met the inclusion criteria were analyzed. The results show that nursing actions increasingly develop along with the patient needs. One form of holistic nursing action is complementary and alternative therapy (CAT) that consists of three categories: body-based methods, mind therapies, and sensory therapies. CAT has positive impacts on patients with heart disease. It can reduce anxiety and pain, lower blood pressure, and improve the quality of life. This review also shows that CAT has a positive impact on the recovery of patients with heart disease. Proper therapeutic management should be implemented to reduce the risks of physiological and psychological problems in patients.

Health literacy is an indicator of a society’s ability to make better health judgement for themselves and the people around them. This study investigates the prevalence of health literacy among Malaysian adults and provides an overall picture of the current health literacy state of the society. The study also highlights socio-demographics markers of communities with limited health literacy which may warrant future intervention. A population based self-administered survey using the Health Literacy Survey Malaysian Questionnaire18 (HLS-M-Q18) instrument was conducted as part of the National Health Morbidity Survey 2019 in Malaysia. The nationwide survey utilized two-staged stratified random sampling method. A sample of 9478 individuals aged 18 and above participated in the study. The health literacy score was divided into three levels; limited, sufficient and excellent. Findings showed that majority Malaysian population has sufficient health literacy level, albeit leaning towards the lower end of the category with an average score of 35.5. The limited health literacy groups are associated with respondents with older age, lower education level and lower household income. Overall health literacy state for Malaysia is categorized at a lower sufficient level. Health literacy improvements should focus on communities with limited health literacy level.

Nanostructured carriers have been widely used in pharmaceutical formulations for dermatological treatment. They offer targeted drug delivery, sustained release, improved biostability, and low toxicity, usually presenting advantages over conventional formulations. Due to its large surface area, small size and photothermal properties, graphene oxide (GO) has the potential to be used for such applications. Nanographene oxide (GOn) presented average sizes of 197.6 ± 11.8 nm, and a surface charge of -39.4 ± 1.8 mV, being stable in water for over 6 months. 55.5 % of the mass of GOn dispersion (at a concentration of 1 mg mL-1) permeated the skin after 6 h of exposure. GOn dispersions have been shown to absorb near-infrared radiation, reaching temperatures up to 45.7 °C, within mild photothermal therapy temperature range. Furthermore, GOn in amounts superior to those which could permeate the skin were shown not to affect human skin fibroblasts (HFF-1) morphology or viability, after 24 h of incubation. Due to its large size, no skin permeation was observed for graphite particles in aqueous dispersions stabilized with Pluronic P-123 (Gt-P-123). Altogether, for the first time, GOn potential as a topic administration agent and for delivery of photothermal therapy has been demonstrated.

Smartwatches provide technology-based assessments in Parkinson’s disease (PD). We present results for sensor validation and disease classification via Machine Learning (ML). A comparison setup was designed with two different series of Apple smartwatches, one Nanometrics seismometer and a high-precision shaker to measure tremor-like amplitudes and frequencies. Clinical smartwatch measurements were acquired from a prospective study including 450 participants with PD, differential diagnoses (DD) and healthy participants. All participants wore two smartwatches and within a 15-min examination. Symptoms and medical history were captured on the paired smartphone. A broad range of different ML classifiers were cross-validated. Amplitude and frequency differences between smartwatches and the seismometer were under the level of clinical significance. The most advanced task of distinguishing PD vs DD was evaluated with 74,1% balanced accuracy, 86,5% precision and 90,5% recall by Multilayer Perceptrons. Deep Learning architectures significantly underperformed in all classification tasks. Smartwatches are capable of capturing subtle-tremor signs with low noise. This study provided the largest PD sample size of two-hand smartwatch measurements and our preliminary ML-evaluation shows that such a system provides powerful means for diagnosis classification and new digital biomarkers but it remains challenging for distinguishing similar disorders.

Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.

Keywords: lactic acid; ceramide; folate; nicotinamide; Alzheimer’s disease

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Hyperhomocysteinemia (HHcy) is typically defined as levels >15 micro mols/L. Elevated plasma levels of Hcy can be caused by the deficiency of either vitamin B12 or folate. The active role of homocysteine is quite ambivalent: many studies detected its potential impact on neurological events; others try to identify it as one of the possible risk factors of cardiovascular events, but with a complementary and secondary role. HHcy has been reported in many neurologic disorders, including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. Nowadays, homocysteine could be considered as a possible link between a common vascular risk factor and potential alterations in degenerative neuronal disorders. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum stress; all these aspects have been considered to play an essential role in the pathogenesis of several diseases, including atherosclerosis, major stroke, and vascular dementia. Specific models of astrocytes impairment in HHcy-mice, which mimic small vessel disease, have been developed with a three-step investigation (at 6, 10, 14 weeks of B6, B9, and B12 detrimental diet in wild type HHcy mouse). These studies found out that after ten weeks on a diet (at the most after 14 weeks), end-feet disruption occurs. This phenomenon is concomitant to reduced vascular labeling for aquaporin -4-water channels, lower protein/mRNA levels for Kir4.1, and BK potassium channels, associated with a higher expression of MMP-9. The most exciting finding is that microglial activation in this mice model was evident since the precocious time of observation (6-week time) and precedes astrocytic changes. Our research aims to review the possible role of HHcy in neurodegenerative disease and small-vessel disease and to understand its pathogenic impact.

Pulmonary arterial hypertension is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors, and likely gene x environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 36% of pediatric-onset idiopathic PAH (IPAH) compared to ~11% of adult-onset IPAH. De novo variants are frequently associated with PAH in children, and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, the increased etiologic heterogeneity, poorer prognosis and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

Background: To examine the association between income levels and mortality rates in patients with chronic kidney disease. Methods: We analyzed data obtained from 3,172 patients with chronic kidney disease obtained from the Korean National Health Insurance claims database (2003–2009). Each patient was monitored until December 2010 or until death, whichever came first. Individual income was estimated from the national health insurance premium. Information on mortality was obtained from the Korean National Statistical Office. Cox proportional hazard models were used to compare mortality rates between different income groups after adjusting for possible confounding risk factors. Results: A low income was significantly associated with a high mortality rate after adjusting for covariates (adjusted HR 1.298 [1.082–1.556]). In addition, dialysis patients who had low incomes were more likely to have higher mortality rates compared to those in dialysis patients who had high incomes (adjusted HR 1.528 [1.122–2.082]). Conclusion: The findings of this study indicate that chronic kidney disease patients with low incomes have the highest mortality risk. Promotion of targeted policies and priority health services for patients with low incomes may help reduce the mortality rate in this vulnerable group.

Frailty is an important age-associated risk-state. Despite this, many countries lack population estimates and large heterogeneity exists amongst studies. The Global Burden of Disease (GBD) study, provides comparable high-quality population-level data for 195 countries and territories. Frailty has never been measured in the GBD studies. This analysis applies the deficit accumulation model to construct a novel frailty index (FI) using the GBD 2017 dataset. Standard FI criteria were applied to all GBD categories such that selected items were health-related, age-correlated, sufficiently prevalent, did not saturate at an early age, had little redundancy/duplication, covered a range of systems, were plausible and were available serially for the same population. From all 554 GBD items, 36 were selected including 26 non-communicable diseases, 3 metabolic risks, 3 biological impairments, infectious diarrheal diseases, protein-energy malnutrition, injurious falls, and low physical activity. Variable face validity was displayed against a selection of established FIs. The mean GBD-FI score for the global population aged ≥70 years in 2017 was 0.16; scores were higher in females than males (0.16 vs 0.15, respectively). Deficits accumulated with age at an estimated rate of 0.026 per year. Adding the mean GBD-FI scores to a regression model including country-level variables for demographics (proportion ≥85 years, proportion female), healthcare quality (HAQ index), and development (SDI) increased the adjusted r2 value from 27.0% to 39.6% (p<0.001) for predicting country-level death rates from non-communicable diseases, suggesting that the GBD-FI is a useful predictor of mortality. Further analysis is required to compare the reliability and predictive validity of the GBD-FI with existing frailty tools

Coronavirus disease 2019 (COVID-19) since its declaration as a pandemic by world health organization (WHO) has spread across the various continent with little known about the most effective public health response for containing and mitigating the transmission of the epidemic. It is important to state that some authors have published on the lessons learned from transmission and management of COVID-19 infection but only a few considered it from the Africa perspective. Despite the late arrival of the pandemic in Africa and the notion that the virus may not thrive because of the high temperature in the continent; today the narrative has changed with the number of infected patients increasing daily. Herein, the authors have shared their perspectives and opinions on the dynamics and response to COVID-19 from Africa context to create more awareness and approach in mitigating the spread of the virus should the continent becomes the epicenter of COVID-19.

Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox, as the free acid (CPX) and its olamine salt (CPX-O) , are contained in number of commercially available topical antifungal agents. CPX is reported in the literature to possess anticancer activity in number of solid tumor cancers and hematological malignancy by several proposed mechanisms of action including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human cyst epithelial cells cultured in 3D collagen matrix. To determine if CPX-O inhibits PKD progression, we treated PKD mice with a low dose of 10 mg/kg CPX-O by daily intraperitoneal injections from day 21 to day 49 post- partum. CPX-O reduced the kidney to body weight ratio of the PKD mice. This was associated with decreased cell proliferation decrease cystic area and improved renal function. We found that ferritin levels were significantly elevated in cystic kidneys of PKD mice, and that CPX-O treatment reduced renal ferritin levels and increased ferritinophagy marker, NCOA4. Our data suggest that CPX-O dose dependently induces ferritin degradation via ferritinophagy which is associated with decreased cyst growth and disease progression in PKD mice. Most importantly these data indicate that CPX-O, a drug used to treat skin infections and currently in clinical trials for cancer, has the potential to treat ADPKD.

The Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, NfL and NG is the main alternation and connection to others. The neuro-inflammation, synaptic dysfunction and neuronal injury function is exhibited prior the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between the proteins that CSF SNAP-25, VILIP-1 and YKL-40 can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects are converted to AD, even with very high elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.

The nutritional habits regulate the gut microbiota and may provoke and/or prevent autoimmune disease. Western diet is rich in sugars, meat and poly-unsaturated fatty acids, which lead to dysbiosis of intestinal microbiota, disruption of gut epithelial barrier and chronic mucosal inflammation. On the other hand, Mediterranean Diet (MedDiet) is rich in ω3 fatty acids, fruits and vegetables and has anti-inflammatory properties, which can restore gut eubiosis. The effect of MedDiet and its components in health and disease states have been thoroughly analyzed in several studies. Moreover, several studies have specifically investigated the association between MedDiet, microbiota and risk for autoimmune diseases. Furthermore, the MedDiet has been associated with lower risk of cardiovascular diseases, which plays a critical role in reducing mortality in patients suffering from autoimmune diseases with comorbidities. The aim of the present review is to specifically highlight current knowledge regarding possible interactions of MedDiet with the patterns of intestinal microbiota focusing on autoimmunity and a blueprint through dietary modulations for the prevention and management of diseases’s activity and progression.

Parkinson’s disease (PD) is a slowly progressing neurodegenerative disorder that is coupled to both widespread protein aggregation and to loss of substantia nigra dopamine (DA) neurons, resulting in a wide variety of motor and non-motor signs and symptoms. Recent findings suggest that the PD process is triggered several years before there is sufficient degeneration of DA neurons to cause onset of overt motor symptoms. According to this concept, the number of DA neurons present in the substantia nigra at birth could influence the time from the molecular triggering event until the clinical diagnosis with lower number of neurons at birth increasing the risk to develop the disease. Conversely, the risk for diagnosis would be reduced if the number of DA neurons is high at birth. In this commentary, we discuss the genetic and epigenetic factors that might influence the number of nigral DA neurons that each individual is born with and how these may be linked to PD risk.

The aim of this study of patients with chronic kidney disease (CKD) is to assess the safety of daily consumption of walnuts on the physiological levels of phosphorous, potassium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), and to assess the short-term benefits of this intervention on risk factors associated with cardiovascular events. This led us to perform a prospective, randomized, cross-over, pilot clinical trial examined 13 patients with chronic kidney disease (CKD). Subjects were randomly assigned to a diet of 30 g of walnuts per day or the control diet. After 30 days, each group was given a 30-day washout period, and then switched to the alternate diet for 30 days. Urinary and serum levels of phosphorous and potassium, multiple vascular risk factors, and urinary inositol phosphates (InsPs) were measured at baseline and at the end of the intervention period. Our results showed that the walnut dietary supplement led to reduced blood pressure, LDL cholesterol, and serum albumin, but had no effect on the physiological levels of phosphorous, potassium, PTH, and FGF23. This is the first report to show that daily consumption of walnuts by patients with CKD does not alter their physiological levels of phosphorous, potassium, PTH, and FGF23. Consequently, this dietary supplement may prevent cardiovascular events in patients with CKD.

Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten and affects approximately 1% of the global population. Currently, the only treatment available is lifelong strict adherence to a gluten-free diet (GFD). Chronic diseases such as CD affect patients and their family members’ quality of life (QoL); particularly parents and caregivers who play an essential role in the child’s care and treatment. A higher level of psychological distress has been found in the parents of children with chronic ailments due to limited control over the child’s daily activities and the child’s illness. In this context, the validation of a specific questionnaire of QoL is a valuable tool to evaluate the difficulties faced by parents or caregivers of children with this chronic illness. A specific questionnaire for this population can elucidate the reasons for stress in their daily lives as well as the physical, mental, emotional, and social impact caused by CD. Therefore, this study aimed to develop and validate a specific questionnaire to evaluate the QoL of parents and caregivers of children and adolescents with CD. The study was developed in six steps: (i) development of the CD parent/caregiver QoL questionnaire (CDPC-QoL); (ii) subjective evaluation; (iii) validation of the questionnaire by the Delphi method; (iv) evaluation of the internal consistency and reproducibility of the CDPC-QoL; (v) application of the questionnaire to Brazilian CD parents or caregivers; and (vi) statistical analysis. Overall results showed that a higher family income resulted in a higher score of the worries domain. In addition, having another illness besides CD decreased the QoL (except in the worries domain). The other variables studied did not present a statistically significant impact on the QoL, which was shown to be low in all aspects. Knowledge of the QoL is important to help implement effective strategies to improve celiac patients’ quality of life and reduce their physical, emotional, and social burden.

Background and objective: Addressing the global morbidity associated with pulmonary disease is an important need for the respiratory community. However, there is also a growing momentum to show the efficacy of new tools of diagnosis. Despite this, there are few physiotherapeutic tools that help identify and categorize these conditions. The aim was to analyze the variables of physiotherapy index of the ventilatory workload (PIVW) in people with chronic obstructive pulmonary disease (COPD) during stability and exacerbation in an outpatient setting. Material and Methods: Analyzed retrospectively of 198 clinical records were reviewed. The PIVW was extracted in stability and exacerbation of these patients with COPD. After applying the exclusion and inclusion criteria; 54 patients were classified. Through the statistical analysis of chi-square, a significant association was reported for each of the variables and the total PIVW score. Results: when analyzing the baseline with the peak of PIVW, there was a significant increase in patients COPD exacerbation. Similarly, the variables that constitute the loads, translations and supports underwent a significant increase from baseline to exacerbation (p<0.0001), except for the additional oxygen contribution, where the frequency of patients was the same in basal and exacerbation as well. Conclusions: the PIVW, serves to determine ventilatory problemas in outpatients, characterizing the specific changes of loads, translators or assistance.

The basic pattern of MHC variation in fish, with MHC class I versus class II, and polymorphic classical versus nonpolymorphic nonclassical, is similar in fish and mammals. Nevertheless, in many or all teleost fishes, important differences with mammalian or human MHC were observed: (1) The allelic/haplotype diversification levels of classical MHC class I genes tend to be much higher than in mammals; (2) Teleost fish classical MHC class I and class II loci are not linked. The present article summarizes previous studies that performed quantitative trait loci (QTL) analysis for mapping differences in teleost fish disease resistance, and discusses them from MHC point of view. Overall, those studies suggest the possible importance of genomic regions including classical MHC class II and nonclassical MHC class I genes, whereas similar observations were not made for the genomic regions with the highly diversified classical MHC class I alleles. The present study is a review and discussion of the fish MHC situation.

Chronic kidney disease (CKD) is a major non-communicable disease associated with high rates of premature morbidity and mortality. The prevalence of hypovitaminosis D (deficiency of 25(OH)D or 25D) is greater in racial/ethnic minorities and in patients with CKD than the general population. Low 25D is associated with bone and mineral disorders as well as immune, cardiometabolic and cardiovascular (CV) diseases. Thus, it has been suggested low 25D contributes to the poor outcomes in patients with CKD. The prevalence of hypovitaminosis D rises progressively with advancing severity of kidney disease with over 30% of patients with CKD stage 3 and 70% patients with CKD stage 5 estimated to have low levels of 25D. This report describes several of the abnormal physiologic and counter-regulatory actions related to low 25D in CKD such as those in oxidative stress and inflammatory systems, and some of the preclinical and clinical evidence or lack of thereof of normalizing serum 25D levels to improve outcomes in patients with CKD, and especially for the high risk subset of racial/ethnic minorities who suffer from higher rates of advanced CKD and hypovitaminosis D.

The purpose of this study was to (a) compare macro- and micronutrient intakes between male and female CD patients (b) compare micronutrient intakes of CD patients to a representative population of healthy individuals, and; (c) describe Mediterranean diet scores (P-MDS) of male and female CD patients in remission recruited from an IBD clinic in Calgary, AB. Consecutive patients with ileal and/or colonic CD in endoscopic remission were recruited for participation in this cross-sectional study. Sixty-seven patients were enrolled, with a mean age of 45, and a BMI ≥ 25. Compared with the healthy population, patients with CD had similar energy, protein, carbohydrate and total fat intake. However, PUFA, omega-6 and 3 and MUFA were lower in CD patients and dietary fibre intake was higher. Vitamins C, D, thiamin, niacin, magnesium, phosphorus, zinc and potassium were all significantly lower in all CD patients compared to a healthy population. Few patients with CD met P-MDS criteria for olive oil, vegetable, legumes, and fish intake or consuming Sofrito sauce (mean 4.5, SD=1.1 in males and 4.7, SD=1.8 in females). Patients with CD in remission have suboptimal dietary intakes and patterns and targeted dietary interventions may be beneficial in this population to improve intake.

Air pollution has become a growing invisible killer in recent years and is major cause of morbidity and mortality globally. India stands 10th among the highly polluted countries with an average PM10 level of 134μg/m3 per year. It is also reported that 99% of India's population comes across air pollution level that exceed the World Health Organization Air Quality Guideline (AQG), PM2.5 permissible levels of 10 μg/m3. Maternal exposure to air pollution has a serious health outcome to the offspring because it can affect embryonic phases of development during the gestation period. Fetus is more prone to air pollution effect during embryonic developmental phases due to oxidative stress as antioxidant mechanisms are lacking at that stage. Any injury during this vulnerable period (embryonic phase) will have long-term impact on offspring health both in early and later in life. Epidemiological studies have revealed that maternal exposure to air pollution increases the risk of developing airways disease in offspring due to impaired lung development in utero. In this review, we discuss cellular mechanisms involved in maternal exposure to air pollution and how it can impact development of airways disease in offspring. Better understanding of these mechanisms in context of maternal exposure to air pollution can offer newer avenue to prevent development of airways disease in offspring.

Many insights into human disease have been built on experimental results in Drosophila, and research in fruit flies is often justified on the basis of its predictive value for questions related to human health. Additionally, there is now a growing recognition of the value of Drosophila for the study of rare human genetic diseases, either as a means of validating the causative nature of a candidate genetic variant found in patients, or as a means of obtaining functional information about a novel disease-linked gene when there is little known about it. For these reasons, funders in the US, Europe, and Canada have launched targeted programs to link human geneticists working on discovering new rare disease loci with researchers who work on the counterpart genes in Drosophila and other model organisms. Several of these initiatives are described here, as are a number of output publications that validate this new approach.

Irisin, a skeletal muscle-secreted myokine, produced in response to physical exercise, has protective functions in both the central and the peripheral nervous systems, including the regulation of brain-derived neurotrophic factors and modification of telomere length. Such beneficial effects may inhibit or delay the emergence of neurodegenerative diseases, including Alzheimer’s disease (AD). This review is based on the hypothesis that irisin produced by physical exercise helps control AD progression. Herein, we describe the physiology of irisin and its potential role in delaying or preventing AD. Although current and ongoing studies on irisin show promising results, further research is required to clarify its potential as a meaningful therapeutic target for treating human diseases.

The specific role of nicotinamide adenine dinucleotide (NAD) in hepatic triglyceride (TG) accumulation in alcoholic fatty liver disease (AFLD) were unclear. Poly ADP ribose polymerase (PARP) is a NAD-consuming enzyme and its specific role in the pathogenesis of AFLD is still elusive. In current investigation, we found that chronic alcohol exposure enhanced hepatic PARP expression and activity and lowered hepatic NAD⁺ level. PARP activity inhibitor PJ34 decreased the intracellular TG content in hepatocyte. Moreover, PJ34 suppressed the gene expression of DGAT1 and DGAT2 and elevated the intracellular NAD⁺ level in hepatocyte. These mechanistic observation was validated in alcohol-fed mice injected with PJ34 intraperitoneally. PJ34 injection attenuated hepatic TG accumulation in alcohol-fed mice. Further, the gene expression of hepatic SERBP-1c, DGAT1 and DGAT2 were lowered by PJ34 injection, while the hepatic NAD⁺ level was augmented by PJ34 injection in alcohol-fed mice. At last, the nicotinamide riboside supplementation alleviated hepatic TG accumulation in alcohol-fed mice. These data indicate that applying PARP specific inhibitor PJ34 by intraperitoneal injection attenuated hepatic NAD⁺ depletion and TG accumulation in alcohol-fed mice, which might be a potential candidate for AFLD therapy.

This review aims to show, by an analysis of the literature on the topic, that hyperinsulinemia associated with insulin resistance is a multiple risk factor for type 2 diabetes, cardiovascular diseases, cellular senescence and cancer, and neurodegenerative diseases. This condition is progressively increasing in developed and developing countries, and its prevalence has now exceeded 50% of the general population. Since it is asymptomatic or poorly symptomatic, it can last for many years before manifesting itself in the form of type 2 diabetes mellitus, cardiovascular disease, neoplasm, cognitive impairment or dementia, therefore determining enormous social and health care costs. For these reasons, we strongly believe that a screening plan for this pathology should be implemented, in order to identify affected subjects and promptly start them on preventive treatment.

In the past thirty years, childhood obesity rates have risen significantly worldwide, affecting over 340 million children in affluent nations. This surge is intricately tied to metabolic disorders, notably insulin resistance, type 2 diabetes mellitus (T2DM), and the continually evolving spectrum of metabolic-associated (dysfunction) steatotic liver disease (MASLD). This review underscores the alarming escalation of childhood obesity and delves comprehensively into the evolving and dynamic changes of nomenclature surrounding diverse conditions of hepatic steatosis, from the initial recognition of non-alcoholic fatty liver disease (NAFLD) to the progressive evolution into MASLD. Moreover, it emphasizes the crucial role of pediatric endocrinologists in thoroughly and accurately investigating MASLD onset in children with T2DM where each condition influences and exacerbates the progression of the other. The review critically highlights the inadequacies of current screening strategies and diagnosis, stressing the need for a paradigm shift. A proposed solution involves the integration of hepatic magnetic resonance imaging assessment in the diagnostic arsenal for children showing insufficient glycaemic control and weight loss post-T2DM diagnosis, thereby complementing conventional liver enzyme testing. This holistic approach aims to significantly enhance diagnostic precision, fostering improved outcomes in this vulnerable high-risk pediatric population.

Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity. As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was done in four patients, and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by disruptions in memory, cognition, and personality, significantly impacting morbidity and mortality rates among older adults. However, the exact pathophysiological mechanism of AD remains unknown, and effective treatment options for AD are still lacking. Human induced pluripotent stem cells (iPSC) are emerging as promising platforms for disease research, offering the ability to model genetic mutations associated with various conditions. Patient-derived iPSCs are useful for modeling neurodegenerative and neurodevelopmental disorders. In this study, we generated AD iPSCs from peripheral blood mononuclear cells obtained from a 65-year-old patient with AD carrying the E682K mutation in the amyloid precursor protein (APP) gene. Cerebral organoids derived from AD iPSCs recapitulated the AD phenotype, exhibiting significantly increased levels of tau protein. Our analysis revealed that an iPSC disease model of AD is a valuable assessment tool for pathophysiological research and drug screening.

Many neurodegenerative diseases are directly related to the formation of toxic protein aggregates, such as Parkinson’s and Alzheimer’s diseases, which are associated with the aggregation of alpha-synuclein (α-syn) and beta-amyloid (Aβ ), respectively. In this context, protein fibrils are the hallmark of these neurodegenerative diseases. In this sense, planning or designing compounds that are capable of preventing or reducing the formation of protein aggregation in the brain can be of fundamental importance for the curative treatment of these diseases. This work presents an in silico and experimental study to investigate the inhibitory potential of the ligands Octovespin (bioinspired by the wasp venom Polybia Occidentalis) and Fraternine-10 (bioinspired by the wasp venom Parachartergus fraternus wasp) against the aggregation of fibrils of the peptides Aβ(17-42) and α-syn, respectively. Using molecular docking and molecular dynamics simulations with 100 ns, the disaggregation capacity of these ligands was studied. The results obtained indicate that Octovespin and Fraternine-10 interact with the Aβ and α-syn protein fibrils throughout the simulation time. The RMSD values and the interactions with amino acids responsible for fibril aggregation demonstrate that both Octovespin and Fraternine-10 have a significant disaggregation potential, which corroborates the observations in vitro and in vivo. Furthermore, experimental results of Fraternine-10 demonstrate an anti-aggregation effect, indicating that it can promote the disaggregation of fibrils and prevent them from aggregating again to form oligomers. These discoveries qualify these molecules as potential candidates to become medicines against Parkinson’s and Alzheimer’s diseases.

Abstract The relationship between cancer and neurodegeneration has spurred extensive scientific discourse, challenging their historical classification as distinct disorders. While cancer signifies uncontrolled cellular proliferation and neurodegeneration marks progressive neuronal loss, recent insights highlight intriguing interconnections between these seemingly disparate conditions. Cancer entails perpetual signaling for growth, evasion of growth inhibitors, resistance to cell death, acquisition of replicative immortality, stimulation of blood vessel growth (angiogenesis), and initiation of invasion and metastasis. Conversely, investigations emphasize disrupted cellular energy regulation and evasion of immune surveillance as key traits arising from genome instability, mutations, and inflammation driving tumorigenesis. Neurodegeneration involves neuronal malfunction and depletion, synaptic impairment, and protein abnormalities aggregations contributing to muscle atrophy and cognitive deficits. Varied clinical studies underscore contrasting correlations between cancer and neurodegeneration, hinting at mirrored molecular pathways that foster cell resilience or vulnerability. Research explores cellular signaling in tumorigenesis, shared with neurodegenerative disorders. Aberrant expression or mutations in crucial genes implicated in neurodegeneration also surface in cancer contexts. Debates persist on the nature of the relationship between cancer and neurodegeneration, contemplating inverse associations or shared pathways. Understanding their complex interplay, encompassing genetics, cellular mechanisms, and environmental influences, remains pivotal in unraveling their connections. This review explores the intriguing perspective that neurodegeneration and cancer might share fundamental genetic links, delving into potential implications for their onset and progression.

ABSTRACTBackground: Crohn's disease (CD) is a chronic inflammatory bowel disorder with limited treatment options. Mitochondrial dysfunction has been implicated in CD pathogenesis, and mitochondrial-based interventions have emerged as a potential therapeutic avenue. This systematic review aimed to assess the efficacy of mitochondrial-based interventions in the management of CD.Methods: A systematic search of multiple databases was conducted to identify relevant studies in accordance with the PRISMA protocol. Inclusion criteria encompassed studies investigating mitochondrial-targeted interventions in CD patients. Methodological quality and risk of bias assessments were performed. Data synthesis involved both quantitative meta-analysis and qualitative narrative synthesis.Results: A total of 23 studies were included in this review, comprising randomized controlled trials, observational studies, and case reports. Mitochondrial-based interventions encompassed nutraceuticals, probiotics, exercise, and dietary modifications. However, the overall quality of evidence was moderate, primarily due to methodological limitations in some studies.Conclusion: This systematic review suggests that mitochondrial-based interventions hold promise as adjunctive therapies for CD management. They appear to contribute to clinical remission and amelioration of disease activity. Nevertheless, the moderate quality of evidence underscores the need for further well-designed clinical trials to substantiate these findings and delineate optimal intervention strategies.

Non-pharmacologic options like the ketogenic diet (KD) and intermittent fasting (IF) are practical nutritional interventions with minor reported side effects like gastrointestinal symptoms, dyslipidemia, and hypomagnesemia for various medical ailments. In conjunction with IF, KD shows promise in weight loss, diabetes management, cardiovascular disorders, polycystic ovarian syndrome, cancer, and chronic neurological disorders. Based on prior research, we have examined the mechanism of action of KD and IF and their effect on neurological diseases, cancer, and obesity. We have also suggested evidence-based recommendations for the safer practice of KD and IF. Despite potential benefits, long-term adherence to KD poses challenges. Periodic KD implementation may thus benefit newly diagnosed overweight or obese patients with type 2 diabetes mellitus, aiding blood glucose and lipid management while promoting weight loss. KD is a high-fat and low-carbohydrate diet with a ratio of fat to carbohydrates and protein being 4:1 or 3:1, and thus, for peripheral tissues and the brain, fatty acids become the mandatory source of cellular energy. Ketone bodies have been used as the primary energy source during fasting. KD has been utilized as an effective treatment for refractory epilepsy since the 1920s. Evidence of the neuroprotective role of KD in diseases like epilepsy, stroke, traumatic brain injury, Alzheimer’s disease, and other neurological diseases has been noted. Since the 1960s, KD has become a popular method for obesity treatment. In addition, KD has been suggested as a potent anticancer therapy when used alone or as an adjuvant. KD may increase tumor cell sensitivity when combined with classic chemotherapy and radiotherapy. Thus, the probability that modifying the diet can help manage obesity, cancer, and chronic neurological disease without depending on pharmacological treatment and their serious side effects for a lifetime is promising and requires further investigation. KD holds promise as a potential adjunctive therapy in various neurological disorders, offering new avenues for treatment and neuroprotection. IF has shown potential in slowing the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's by promoting antioxidant defense and suppressing inflammation. KD and IF show promise in cancer therapy by targeting altered cancer cell metabolism. Additionally, KD may enhance the effects of standard treatments like chemotherapy and radiotherapy. Some of the most robust reports of keto's possible benefits have come from glioblastoma, a very aggressive brain cancer. KD has also shown strong evidence for its effectiveness in weight loss, mainly attributed to its appetite-suppressing action in ketosis. However, long-term adherence to KD can be challenging, and periodic KDs may help manage blood glucose and lipid levels in overweight or obese patients with type 2 diabetes mellitus. Likewise, IF may be more effective than regular calorie restriction for achieving weight loss goals when combined with exercise programs. More prospective human studies are warranted to evaluate both KD and IF's potential therapeutic effectiveness and safety.

Work from the last years indicate that the extracellular matrix (ECM) plays a direct role in vari-ous cellular processes including proliferation, migration and differentiation. Besides homeostat-ic processes, its regulatory function in inflammation becomes more and more evident. In in-flammation like inflammatory bowel disease, the ECM composition is constantly remodeled which can result in a structuring of fistulizing disease course. Thus, tracking early ECM changes might bear the potential to predict the disease course. In this review, we will provide an over-view of relevant diagnostic methods focusing on ECM changes.

The brain reciprocally communicates with the rest of the body via neural, endocrine, immune, and other systems. This is crucial for coordinating the complex behavioral and physiological responses needed to cope with the many challenges of life. The Anterior Cingulate Cortex (ACC) is a key brain structure involved in assessing rewards and threats, as well as activating appropriate responses. This is a dynamic process that depends on evolving needs and challenges. Important challenges include illness or injury. These typically involve inflammation and pain, which evoke neuroinflammatory processes in the brain to drive sickness behaviours. In the short term, sickness behaviours are considered adaptive, as they promote convalescence (e.g. low mood; lethargy, fatigue, social withdrawal), and enhanced threat appraisal (e.g. anxiety) to combat increased risk/vulnerability associated with sickness. Chronic inflammation, however, appears to remodel the system to inappropriately activate threat-coping responses, resulting in depressive and/or anxious phenotypes. These mood disorders are particularly pronounced in diseases and disorders associated with gut dysfunction, which feature chronic inflammation and altered ACC function. We propose that chronic inflammation remodels ACC physiology such that it errantly predicts heightened danger based on a mental model (a.k.a ‘schema’) of the world. This evokes chronic activation of threat-coping systems, including endocrine signaling (e.g. adrenaline), and anxiety. Inflammation can be driven by brain systems involving ACC, leading to a feedback-cycle that self-reinforces pathological states. This theory accounts for a wealth of clinical and preclinical data that implicate the ACC in disorders of mood and gastrointestinal function, and reveals a key player in the gut-brain axis that may represent a novel therapeutic target.

Background CDK4/6 inhibitors are the standard of care for HR+/HER2-negative metastatic breast cancer in combination with endocrine therapy. However, the real-world efficacy and safety of standard versus reduced doses in elderly patients remain unclear. This study aims to compare the clinical outcomes of standard versus reduced doses of CDK4/6 inhibitors in elderly patients with metastatic breast cancer. Methods This multicenter retrospective cohort study included 158 patients aged ≥70 years diagnosed with HR+/HER2-negative metastatic breast cancer who received either standard or reduced doses of CDK4/6 inhibitors (Ademaciclib, Ribociclib, Palbociclib) as first-line therapy. Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. PFS and OS were estimated using the Kaplan-Meier method, and comparisons between groups were performed using the log-rank test. Results Of the total population, 108 patients (68.4%) received the standard dose, and 50 patients (31.6%) received a reduced dose. The standard dose group had significantly longer median PFS compared to the reduced dose group (21.3 vs. 15.2 months, p = 0.014), while median OS did not differ significantly (37.2 vs. 37.2 months, p = 0.103). Subgroup analyses revealed no significant differences in PFS or OS between standard and reduced doses for Ademaciclib and Ribociclib, while Palbociclib at standard dose showed superior PFS (21.9 vs. 12.7 months, p = 0.029) and OS (50.5 vs. 28.6 months, p = 0.026). The incidence of Grade 2-4 AEs was higher in the standard dose group (74.2% vs. 56.8%, p = 0.044). Conclusions Dose reduction of CDK4/6 inhibitors, particularly Ademaciclib and Ribociclib, is a viable option in elderly patients, maintaining comparable OS outcomes to standard dosing while reducing the risk of adverse events. Palbociclib at standard dose may offer superior outcomes. These findings support personalized dosing strategies to optimize efficacy and tolerability in frail or elderly patients.

There is a strong global demand for sulfate- free personal cleansing products. The objective of sulfate-free personal cleansing technology should not be aimed at the absence of “sulfate” wording in the ingredient listing, but on the true benefits to both people and the planet, including but not limited to safety, mildness, and sensory for the people perspective and renewability, low carbon footprint, low water footprint, biodegradability &amp; sustainability for the planet perspective. In addition, some surfactants or their precursors contain 1,4-dioxane as a by-product in their manufacturing, which is a major safety concern. In this paper, several commonly used sulfate-free surfactants are compared based on a variety of desirable criteria from both the people and the planet perspective. There is also an important trend promoting green manufacturing processes using natural, renewable, safe, biodegradable &amp; sustainable feedstocks to mitigate the challenges presented by climate change. It is concluded that the best options for the sulfate-free personal cleansing products of the future are glutamates for skin cleansing and alaninates for hair cleansing.

Patients with heart failure (HF) with improved LVEF (HFimpEF) demonstrate better clinical outcomes when compared with individuals without restoration of cardiac function. Identification of predictors for HFimpEF may play a crucial role in individual management of HF with reduced EF (HFrEF). Cell-free nuclear (cf-nDNA) DNA are released from damaged cells and contribute to adverse cardiac remodeling, cardiac dysfunction and inflammation. The purpose of the study was to elucidate whether cf-nDNAs are associated with HFimpEF. It has been prescreened 1416 patients with HF using local database. Between October 2021 and August 2022 we included 452 patients chronic HFrEF after prescription of optimal guideline-based therapy and identified HFimpEF in 177 individuals from them according to the criteria of European Society of Cardiology. Measurements of circulating biomarkers were performed at baseline and in 6 months. Detection of cf-nDNA was executed with real time quantitative PCR (qPCR) using NADH dehydrogenase, ND2 and beta-2-microglobulin. We found that HFimpEF was associated with a significant decrease in the levels of cf-nDNA when compared with the patients from persistent HFrEF cohort. Presence of ischemia-induced cardiomyopathy (odds ration [OR] = 0.75; confidence interval [CI] = 0.62 – 0.88; p = 0.044), type 2 diabetes mellitus (OR = 0.77; CI = 0.71 – 0.82; p = 0.042) and digoxin administration (OR = 0.85; CI = 0.72-0.97; p = 0.042) were negative factors for HFimpEF, whereas NT-proBNP ≤1940 pmol/mL (OR = 1.42; 95% CI = 1.19-1.98, p = 0.001), relative decrease in NT-proBNP levels (&gt;35% vs. ≤35%) from baseline (OR = 1.52; 95% CI = 1.38-0.69, p = 0.001) and cf-nDNA ≤7.5 μmol/L (OR = 1.56; 95% CI = 1.07-2.94, p = 0.001) were positive predictors for HFimpEF. Multivariate logistic regression adjusted to ischemia-induced cardiomyopathy, IV HF NYHA class, and digoxin use yielded that NT-proBNP ≤1940 pmol/mL (OR = 1.43; 95% CI = 1.21-1.88, p = 0.001) and cf-nDNA ≤7.5 μmol/L (OR = 1.64; 95% CI = 1.19-2.15, p = 0.001) independently predicted HFimpEF. In conclusions: we established that the levels of cf-nDNA≤7.5 μmol/L independently predicted HFimpEF and improved discriminative ability of as single measured NT-proBNP as well as relative decrease in NT-proBNP levels ≤35% from baseline.

Smart Transformer (ST)-based Meshed Hybrid AC/DC Microgrids (MHM) are a feasible alternative to increase the performance of conventional microgrids (MG) and to increase the penetration of Distributed Energy Resource (DER) at the same time, active and reactive power dispatch on the system. Despite this, MHMs present challenges in managing resources under uncertainties and controlling electronic converters associated with the ST and DER, making it complex to achieve optimal system performance. In this paper, a Data-Driven Distributionally Robust Optimization (DDDRO) for Day-Ahead Operation Planning of an ST-based MHM considering the reactive power dispatch of the DER that minimizes network losses, voltage deviations, and operation cost simultaneously, considering uncertainties of Photovoltaic Generators (PVG) and demand, is proposed. The Column and Constraint Generation (C&amp;CG) algorithm and Duality-Free Decomposition (DFD) method are adopted. Besides, the original mixed-integer non-linear planning problem is converted into a Mixed-Integer (MI) Second-Order Cone Programming (SOCP) problem through second-order cone relaxation and positive octagonal constraint method. Simulation experiments and results with a connected MHM system demonstrate the effectiveness and performance of the proposed model. Finally, we observe the effect of the meshed structure of MG and the positive impact of integrating the ST to form MHM, taking advantage of the degrees of freedom of this multi-stage converter for optimal energy management under uncertain conditions.

Rapidly digestible starch can be obtained by gelatinization (cooking), cooking extrusion, use of small granule starch, breaking down starch granules, or by hydrolysis to maltodextrins. Resistant starch includes five groups: the first group is physically encapsulated starch within a food/polymer matrix, the second one is some native starch, the third one is recrystallized starch, the fourth one is chemically modified starch, and the fifth one is starch-lipid complexes. Starch digestion in the human body is also influenced by the degree of chewing, activity of α-amylase in the intestine, and transit time through the stomach and small intestine. Resistant starch or dietary fiber (DF) enriches specific bacterial groups located in the large intes-tine. They produce short chain fatty acids (SCFAs) and gases, causes the lowering of the pH, and inhibits pathogens. SCFAs are considered endogenous signaling molecules, acting through their free fatty-acid receptors 2 and 3 which can trigger the secretion of glucagon-like peptide-1 and peptide PYY, being released together following a meal to mediate postprandial satiety. A sufficient intake of DF reduces the risk of cardiovascular disease, coronary heart disease, stroke, hyperten-sion, colorectal cancer, and type 2 diabetes. Gluten matrix or phenolic compounds can lead to a low digestion rate of starch.

To date, various chimeric lysins have been developed as efficacious antibiotics against multidrug-resistant bacteria, but direct comparisons of their antibacterial activities have been difficult due to the preparation of multiple recombinant chimeric lysins. Previously, we reported an E. coli cell-free expression method to screen better chimeric lysins against Staphylococcus aureus, but we still needed to increase the amounts of expressed proteins enough to be able to detect them non-isotopically for quantity comparisons. In this study, we improved the previous cell-free expression system by adding a previously reported artificial T7 terminator and reversing the different nucleotides between the T7 promoter and start codon to those of the T7 phage. The new method increased the expressed amount of chimeric lysins enough for us to detect them using Western blotting. Therefore, the qualitative comparison of activity between different chimeric lysins has become possible via the adjustment of the amount variables between samples without protein purification. We applied it to select more active chimeric lysins derived from our previously reported chimeric lysin (ALS2). Finally, we compared the antibacterial activities of our selected chimeric lysins with reported chimeric lysins (ClyC and ClyO) and lysostaphin, and determined the rank orders of antibacterial activities on different S. aureus strains in our experimental conditions.

Space–air–ground integrated network (SAGIN) is considered as an enabler for the sixth-generation (6G) networks. By integrating terrestrial and non-terrestrial (satellite, aerial) networks, SAGIN seem to be a quite promising solution to provide reliable connectivity everywhere and all the time. Their availability can be further enhanced if hybrid free space optical (FSO)/radio frequency (RF) links are adopted. In this paper, the performance of a hybrid FSO/RF communication system operating in SAGIN has been analytically evaluated. In the considered system, a high altitude platform station (HAPS) is used to forward the satellite signal to the ground station. Moreover, the FSO channel model assumed takes into account the turbulence, pointing errors and path losses, while for the RF links, a relatively new composite fading model has been considered. In this context, a new link selection scheme has been proposed that is designed to reduced the signaling overhead required for the switching operations between the RF and FSO links. The analytical framework that has been developed is based on the Markov chain theory. Capitalizing on this framework, the performance of the system has been investigated using the criteria of outage probability and the average number of link estimations. The numerical results presented reveal that the new selection scheme offers a good compromise between performance and complexity.

Resveratrol is currently considered an option for chemoprevention and treatment of oral cancer, but the instability and unfavorable pharmacokinetics hinder its use in clinical practice. The present study deals with the preparation of resveratrol liposomes by a method that preserves stability and provides payload high enough for chemoprevention and/or treatment of oral cancer. Different temperatures, RSV concentrations and molar fractions, as well as the presence or absence of vitamin C in the hydration media were assayed. Liposome hydrodynamic diameter, polydispersity and zeta potential were evaluated by dynamic light scattering. In vitro biocompatibility, antioxidant activity and permeability were evaluated using TR146 cells and PermeaPad® membranes. Liposomes were included in hydrogels and films, and their suitability for buccal application was evaluated. According to the results, a temperature of 37ºC was optima to efficiently produce the resveratrol liposomes. Vitamin C was found to influence the liposome size, while resveratrol concentration significantly influenced the entrapment efficiency. High cell biocompatibility and potent intracellular antioxidant activity were observed and the inclusion of vitamin C reinforced the antioxidant effects. High permeation across PermeaPad® membranes and efficient uptake by TR146 cells was proved for resveratrol loaded liposomes. Liposomal hydrogels and films appropriated for buccal application were obtained and the payload of the formulations was high enough to produce mucosa concentrations above resveratrol IC50 values reported for cancer cells.

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lym-phoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analysed patient records (1984–2016) from 27 clinical sites in Eurpe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS), and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. Median (range) times from start of first-line therapy to first R/R MF and from first to second R/R MF were 11.2 (0.3–166.5) and 13.5 (0.0–174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radio-therapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). Median (95% confidence interval [CI]) OS from the diagnosis of first R/R MF was 11.5 (6.5–not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); es-timated median PFS (95% CI) from the time of first R/R MF was 1.3 (1.0–2.1) years. (4) Conclu-sion: High rates of R/R disease were observed after second- and third-line treatments in this re-al-world cohort, with longer median OS in patients receiving non-chemotherapy versus chemo-therapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

In the framework of mean field approximation, we consider a spin system consisting of two interacting sub-ensembles: spins interactions with in each sub-ensemble are ferromagnetic, while the inter-ensemble interactions are antiferromagnetic. We define the effective number of the nearest neighbors, and show that if the two sub-ensembles have the same effective number of the nearest neighbors, the classical form of critical exponents (, , , ) gives way to the non-classical form (, , , ), and the scaling function changes simultaneously. We demonstrate that this system allows for two second-order phase transitions and two first-order phase transitions. We observe that an external magnetic field does not destroy the phase transitions, but only shifts their critical points, allowing for control of the system’s parameters. We discuss the regime when the magnetization as a function of the magnetic field develops a low-magnetization plateau, and show that the height of this plateau abruptly rises to the value of one when the magnetic field reaches a critical value. Our analytical results are supported by a Monte Carlo simulation of a three-dimensional layered model.

A topical challenge for algorithms in general and for automatic image categorization and generation in particular is presented with the aim of highlighting strengths and deficiencies of current Artificial Intelligence approaches while sketching a way forward. A general lack of encompassing symbol-embedding and (not only) -grounding in some bodily basis is made responsible for current deficiencies. A concomitant dearth of hierarchical organization of concepts follows suite. As a remedy for these shortcomings, it is proposed to take a wide step back and to newly incorporate aspects of cybernetics and analog control processes. It is claimed that a promising overarching perspective is provided by the Ouroboros Model with a valid and versatile algorithmic backbone for general cognition at all accessible levels of abstraction and capabilities.

Keywords: head-and-neck cancer; chemoradiation; cisplatin; carboplatin; loco-regional control; metastases-free survival; overall survival; toxicity.

Variable Angle Tow (VAT) laminates offer a promising alternative to classical straight fiber composites in terms of design and performance. However, analyzing these structures can be more complex due to the introduction of new design variables. Carrera's Unified Formulation (CUF) has been successful in previous works for buckling, vibrational, and stress analysis of VAT plates. Typically, one-dimensional (1D) and two-dimensional (2D) CUF models are used, with a linear law describing the fiber orientation variation in the main plane of the structure. The objective of this article is to expand the CUF 2D plate finite elements family to perform free vibration analysis of composite laminated plate structures with curvilinear fibers. The primary contribution is the application of Reissner's Mixed Variational Theorem (RMVT) to a CUF finite element model. The Principle of Virtual Displacements (PVD) and RMVT are both used as variational statements for the study of monolayer and multilayer VAT plates dynamic behavior. The proposed approach is compared to Abaqus three-dimensional (3D) reference solutions, classical theories and literature results to investigate the effectiveness of the developed models. Results demonstrate that mixed theories provide the best approximation of the reference solution in all cases.

The objective of parsing is to transform a natural language sentence it in to a standard order. and in a same way a sentence is tokenized with an appropriate format. There are certain English grammar evaluation rules and the parsing approach which is to be followed for the proper formation of a particular sentence syntactically and semantically using the parsing approach. A sentence in English language is the main element in the semantic parser, which creates a parse tree with the help of applying semantic dating technique to a number of phrases. A parser divides a token into smaller components by applying sets of guidelines that characterize and a series of the tokens to determine its structure of the language, which specified by grammar. The illustration provides easy records on grammatical connections, which can simply know and put into practice with those who have no prior knowledge of the language, such as those who need to obtain textual family members. The semantic family members represent the relationships of a number of the words in the sentence. We advocate utilizing our parser to acquire the tagged sets as well as a context-free layout grammatical representation for the source form. All pronouns, adverbs, singular, plural, nouns, verbs, people, adjectives, tenses and other words are kept in a database.

The synergic features and enhancing strategies for various photopolymerization systems are reviewed by kinetic schemes and the associated measurements. The important topics include: (i) photo crosslinking of corneas for the treatmnet of corneal deseases using UVA-light (365 nm) light and riboflavin as the photosensitizer; (ii) synergic effects by a dual-function enhancer in a 3-initiator system; (iii) synergic effects by a 3-initiator C/B/A system, having an electron-transfer and oxygen-mediated energy-transfer pathways; (iv) copper-complex (G1) photoredox catalyst in G1/Iod/NVK systems for free radiical (FRP) and cationic photopolymeriation (CP); (v) radical-mediated thiol-ene (TE) photopolymerizations; (vi) superbase photogenerator based-catalyzed thiol−acrylate Michael (TM) addition reaction; and the combined system of TE and TM usinghual wavelength; (vii) dual-wavelength (UV and blue) controlled photopolymerization confinement (PC); (viii) dual-wavelength (UV and red) selectively controlled 3D printing; and (ix) 3-wavelength selectively controlled in 3D printing and additive manufacturing (AM). With minimum mathematics, we present ( for the first time), the synergic features and enhancing strategies for various systems of multi-commponents, initiators, monomers, and under one- two- and there-wavelength light. Therefore, this Review provides not only the bridging between modeling and measurements, but also guidances for further experimantal stuides and new applications in 3D printings and additive manufacturing (AM), based on the innovative concepts (kinetics/schemes).

The development of platinum group metal-free (PGM-free) electrocatalysts derived from cheap and environmentally friendly biomasses for oxygen reduction reaction (ORR) is a topic of relevant interest, particularly from the point of view of sustainability. Fe-nitrogen-doped carbon materials (Fe-N-C) have attracted particular interest as alternative to Pt-based materials, due to the high activity and selectivity of Fe-Nx active sites, the high availability and good tolerance to poisoning. Recently, many studies focused on developing synthetic strategies, which could transform N-containing biomasses into N-doped carbons. In this paper chitosan was employed as a suitable N-containing biomass for preparing Fe-N-C catalyst in virtue of its high N content (7.1%) and unique chemical structure. Moreover, the major application of chitosan is based on its ability to strongly coordinate metal ions, a precondition for the formation of Fe-Nx active sites. The synthesis of Fe-N-C consists in a double step thermochemical conversion of a dried chitosan hydrogel. In acidic aqueous solution, the preparation of physical cross-linked hydrogel allows to obtain sophisticated organization, which assure an optimal mesoporosity before and after the pyrolysis. After the second thermal treatment at 900 °C, a highly graphitized material was obtained, which has been fully characterized in term of textural, morphological and chemical properties. RRDE technique was used for understanding the activity and the selectivity of the material versus the ORR in 0.5 M H2SO4 electrolyte. Special attention was put in the determination of the active site density according to nitrite electrochemical reduction measurements. It was clearly established that the catalytic activity expressed as half wave potential linearly scales with the number of Fe-Nx sites. It was also established that the addition of the iron precursor after the first pyrolysis step leads to an increased activity because of both an increased number of active sites and of a hierarchical structure, which improves the access to active sites. At the same time, the increased graphitization degree, and a reduced density of pyrrolic nitrogen groups are helpful to increase the selectivity toward the 4e- ORR pathway.

As reported by us and others previously (1, 2), the D614G mutation appeared in the spike glycoprotein (SPG) of the SARS-CoV-2 (the pathogen behind COVID-19) at the early stages of the pandemic and then G614 containing variant of SARS-CoV-2 became the predominant strain in most human populations across the world. However, one of the most recent reports from India (3) stated the incidence of G614 to be only 26% in the Indian population. This report is contradictory to the information available through the GenBank (4) SARS-CoV-2 sequence deposits made by various laboratories from India. The above stated report currently circulating in the Indian media is likely to create a public perception that the Indian strain is less contagious and such a notion could be harmful to people’s welfare. In view of this concern we have re-evaluated, updated and recalculated the incidence of the G614 variant in the Indian population by analyzing 395 Indian SARS-CoV-2 genomic sequences available in the GenBank as of June 26, 2020. In our analysis we have categorized the samples by the month in which the samples were collected. We have used an alignment-free software tool named Compare (5, 6), and the Basic Local Alignment Search Tool (BLAST) (7) in the present analysis. We finally inspected each of the 395 sequences physically for the presence of aspartic acid (D) or glycine (G) at the 614^th position of the spike glycoprotein. We analyzed an Australian cohort in parallel for comparison. We have found that the prevalence of G614 variant in the Indian samples for the month of June 2020 is 90.6%. The trends are similar with the Australian samples.

Reduced nutrient mineralization rates under minimum tillage are usually compensated by mineral fertilizer application. These cannot be applied in organic farming systems, however. We hypothesized that organic minimum tillage based on frequent cover cropping and application of dead mulch will improve soil fertility and can compensate for the potential negative effects of minimum tillage. Two long-term field experiments were set up in 2010 and 2011 comparing plough versus minimum tillage including application of transferred mulch. As second factor, the application of compost versus mineral potassium and phosphorus was compared. In 2019, soils were analyzed for soil pH, organic carbon, macro-, micronutrients, microbial biomass, microbial activity and total nematode abundance. In addition, performance of pea in the same soils was determined under greenhouse conditions. Across both experiments, macronutrients (+52%), micronutrients (+11%), microbial biomass (+51%), microbial activity (+86%), and bacterivorous nematodes (+112%) increased in minimum tillage compared with the plough-based system. In the greenhouse, pea biomass was 45% higher in the soil that had been subjected to minimum tillage compared to the plough. In conclusion, soil fertility can be improved in organic minimum tillage systems by intensive cover cropping and application of dead mulch to levels higher than in a plough-based system.

In this paper, we study a generalised CIR process with externally-exciting and self-exciting jumps, and focus on the distributional properties and applications of this process and its aggregated process. The first and second moments of this jump-diffusion process are used to calculate the insurance premium based on mean-variance principle. The Laplace transform of the aggregated process is derived, and this leads to an application for pricing default-free bonds which could capture the impacts of both exogenous and endogenous shocks. Illustrative numerical examples and comparisons with other models are also provided.

Background: Video assisted thoracoscopic surgery (VATS) has become the recommended approach for treatment of resectable lung cancer. However, no large randomized clinical trial has been conducted formally comparing surgical resections completed by VATS to those done by open thoracotomy (OT) in low volume centers. The current study sought to assess differences in recurrence-free survival (RFS), overall survival (OS), positive margins and postoperative length of stay (LOS) between VATS and OT lobectomies in our center. Method: A single institution retrospective chart review from May 2005 through May 2015 was conducted. All patients diagnosed with stage I through III lung cancer who underwent surgical resection were selected. Patient and tumor characteristics recorded included age at diagnosis, sex, tobacco use, tumor location (side and lobe), stage, size and receipt of chemotherapy or radiotherapy. Chis-square and Wilcoxon-Mann-Whitney tests were used to compare demographics, tumor characteristics and LOS. Multiple logistic and Cox regression analyses were used to compute relative risk (RR) for positive margins and mortality hazard ratios along with 95 percent confidence intervals (95%CI), respectively. Results: Of the 235 patients, 101 subjects had VATS while OT was performed in 134 patients. Age at diagnosis, sex, tobacco use, tumor location, and size were comparable for VATS and OT. No significant difference was observed in the relative risk of positive margins for VATS versus OT, RR = 0.56 (95%CI = 0.26, 1.05). However, VATS had shorter median LOS compared to OT (4 vs. 6 days, respectively), p = 0.002. A comparison of VATS versus OT showed no significant difference in the risk of recurrence, HR = 1.21 (95%CI = 0.74, 2.00), or death, HR = 1.34 (95%CI = 0.88, 2.06), in the intent-to-treat population. Similarly, no significant differences in recurrence or mortality risk were observed between VATS versus OT for analyses conducted separately for each cancer stage group or those limited to patients with negative margins. Conclusion: Our study indicates that compared to OT, VATS leads to shorter LOS while achieving comparable margins status, recurrence-free and overall survival regardless of tumor stage at diagnosis.

Bodybuilders utilize peaking strategies in a bid to fine-tune their aesthetics for competition day. The most prevalent peaking strategies utilized by natural bodybuilders are unreported in the current literature. Eighty-one (M - 59, F - 22) natural bodybuilders were recruited from competitions during the 2016 and 2017 British Natural Bodybuilder Federation seasons. Competitors completed a 34-item questionnaire designed to investigate peaking and contest day strategies. The questionnaire listed commonly utilized peaking strategies and provided additional space for qualitative information. Analysis of the data indicated that carbohydrate (CHO), water and sodium manipulation were the most commonly utilized peak week strategies. The consumption of high glycemic index CHO was the most common competition day strategy. Only 6.2 % of competitors reported following their regular diet the week prior to competition. The CHO manipulation strategies were similar to classical CHO loading, whereby bodybuilders attempt to maximize muscle glycogen concentrations. Furthermore, bodybuilders attempted to remove superfluous water by exploiting the diuretic/polyuria effect associated with water loading/restriction. The potentially deleterious effects of peaking on bodybuilders' health is considered and the efficacy of these strategies to enhance appearance is discussed. The findings of the present investigation are likely to be of interest to bodybuilders and their coaches.

A new optical steganography scheme is proposed that transmits a stealth optical code-division multiple-access (OCDMA) signal through a public binary phase-shift keying (BPSK) channel. Polarization beam splitters and arrayed waveguide gratings are used to implement a spectral-polarization coding (SPC) system with an incoherent optical source. We employ a Walsh–Hadamard code as the signature code of the user who wants to transmit stealth information using the system. A free space optical link applied to this system maintains the polarization states of light during propagation. The secret data is extracted using correlation detection and balanced subtraction in the OCDMA decoder of the intended receiver, and the other signal from the public channel is reduced by the OCDMA decoder. At the demodulator of the public channel, BPSK demodulation eliminates the stealth signal so that the public channel is not affected by the stealth signal. The two signals cannot interfere with each other. The results of this study show that our proposed optical steganography system is highly secure. The stealth signal can be favorably hidden in the public channel when the average source power of the stealth signal, public noise, and public signal are −5, −3, and 0 dBm, respectively.

The activity and cyclability of Cu-MOF-74 as catalyst was studied for the ligand-free C-O cross-coupling reaction of 4-nitrobenzaldehyde (NB) with phenol (Ph) to form 4-formyldiphenyl ether (FDE). Cu-MOF-74 is characterized by unsaturated copper sites in a highly porous metal-organic framework. The influence of solvent, reaction temperature, NB/Ph ratio, catalyst concentration and basic agent (type and concentration) were evaluated. High conversions were achieved at 120°C, 5 mol% of catalyst, NB/Ph ratio of 1:2, DMF as solvent and 1 equivalent of K2CO3 base. The activity of Cu-MOF-74 material was higher than other ligand-free copper catalytic systems tested in this study. This catalyst was easily separated and reused in five successive runs, achieving a remarkable performance without significant porous framework degradation. The leaching of copper species in the reaction medium was negligible. The O-arylation between NB and Ph took place only in the presence of Cu-MOF-74 material, being negligible without the solid catalyst.

The microvessel neurovascular unit with its brain endothelial cell (BEC) and blood-brain barrier remodeling is important in the development of impaired cognition in sporadic or late-onset Alzheimer’s disease (LOAD) and vascular dementia or vascular cognitive impairment and dementia including cerebral amyloid angiopathy in neurodegeneration. LOAD is considered to be the number one cause of dementia globally; however, when one considers the role of mixed dementia (MD) (the combination of both the amyloid cascade hypothesis and the vascular hypothesis of LOAD), it becomes apparent that MD is the number one cause. The microvessel BECs are the first cells in the brain to be exposed to the peripheral neurotoxins of the systemic circulation and are therefore the brain cells at the highest risk for early and chronic injury. Therefore, it is not surprising that microvessel BECs are the first cells to undergo injury and the response to injury wound healing mechanism and remodeling that is excessive and recurrent in the aging process plus other age-related diseases such as cerebro-cardiovascular disease, hypertension, type 2 diabetes mellitus, Parkinson’s disease, plus others. This narrative review explores the intricate relationship between microvessel remodeling, cerebral small vessel disease (SVD), and neurodegeneration as occurs in LOAD. Further, it discusses the current understanding of how microvessel dysfunction, disruption, and pathology contribute to the pathogenesis of LOAD and thus, highlights potential avenues for therapeutic interventions.