Objective: A previous study showed that schizophrenia is accompanied by lowered levels of trace/metal elements including cesium. There are no data whether changes in cesium, rubidium and rhenium are associated with activated immune-inflammatory pathways, cognitive impairments, and the symptomatology of schizophrenia. Methods: This study measured cesium, rubidium, and rhenium, cognitive impairments (using the Brief Assessment of Cognition in Schizophrenia) and the cytokines/chemokines interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and CCL11 (eotaxin) in 120 schizophrenia patients and 54 healthy controls. Severity of illness was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale and the Hamilton Depression Rating Scale (HAM-D). Results: Serum cesium was significantly lower in schizophrenia patients as compared with controls. Serum cesium was significantly and inversely associated with CCL11 and TNF-α, but not IL-1β. Moreover, there were significant inverse associations between serum cesium levels and the BPRS, FF, HAM-D and SANS scores and positive correlations between cesium and neurocognitive probe results including the Tower of London, Symbol Coding, Controlled Word Association, Category Instances, Digit Sequencing Task, and List Learning tests. Conclusion: The results suggest that lowered serum cesium levels may play a role in the pathophysiology of SCZ, specific symptom domains including negative, depressive and fatigue symptoms, neurocognitive impairments (spatial working, episodic and semantic memory and executive functions) and neuro-immune pathways as well.

Nutrition is crucial for the management of patients affected by chronic kidney disease (CKD) to slow down disease progression and to correct symptoms. The mainstay of the nutritional approach to renal patients is protein restriction coupled with adequate energy supply to prevent malnutrition. However, other aspects of renal diets, including fiber content, can be beneficial. This paper summarizes the latest literature on the role of different types of dietary fiber in CKD, with special attention to intestinal microbiota and the potential protective role of renal diets. Fibers have been identified based on aqueous solubility, but other features, such as viscosity, fermentability, and bulking effect in the colon should be considered. A proper amount of fiber should be recommended not only in the general population but also in CKD patients, to achieve an adequate composition and metabolism of intestinal microbiota and to reduce the risks connected with obesity, diabetes, and dyslipidemia.

The association between the choice of general anesthetic agents and the risk of acute kidney injury (AKI) and long-term renal function after nephrectomy has not yet been evaluated. We reviewed 1087 cases of partial or radical nephrectomy. The incidence of postoperative AKI, new-onset chronic kidney disease (CKD) stage 3a and CKD upstaging were compared between different general anesthetic agent groups: propofol, sevoflurane, and desflurane. Four different propensity score analyses were performed to minimize confounding for each pair of comparison (propofol vs sevoflurane; propofol vs desflurane; sevoflurane vs desflurane; propofol vs volatile agents). Study outcomes were compared before and after matching. Kaplan-Meier survival curve analysis was performed to compare renal survival determined by the development of CKD stage 3a between groups up to 36 months after nephrectomy before and after matching. Propofol was associated with a lower incidence of AKI, CKD upstaging and a higher three-year renal survival after nephrectomy compared to sevoflurane or desflurane group after matching (AKI: propofol 23.2% vs. sevoflurane 39.5%, P=0.004, vs. desflurane 34.3%, P=0.031; CKD upstaging: propofol 27.2% vs. sevoflurane 58.4%, P<0.001, vs. desflurane 48.6%, P=0.017; Log-rank test propofol vs. sevoflurane P<0.001, vs. desflurane P=0.015). Propofol was also associated with a lower incidence of new-onset CKD after nephrectomy compared to sevoflurane after matching (P<0.001). However, there were no significant differences between sevoflurane and desflurane. In conclusion, propofol, compared to volatile agents, may be the reasonable choice of general anesthetic agent for nephrectomy to attenuate postoperative renal dysfunction. Randomized prospective trials are warranted to test this hypothesis.

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

Background. A rat model of chronic tympanic membrane perforation was developed to be used in the search of new materials for the sealing of these perforations. Methods. A longitudinal study was carried out in rats subjected to incisional myringotomy followed by the application of mitomycin C alone or with dexamethasone. Rats were checked at days 3, 7, 10, 14 and weekly thereafter until perforation closure, for up to 6 months. Results. The addition of dexamethasone is a key component in order to obtain a chronic opening. Myringotomies treated with saline had a mean healing time of 8.5 days. At 8 weeks, 70.5% of these remained perforated and at 6 months this number fell to 21.4%. Conclusion. This technique is able to maintain more than 70% of tympanic membrane perforations patent for at least 8 weeks. This rat model is adequate for its use in preclinical or translational research.

Introduction: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, in patients who have been treated with recommended doses of antibiotics yet remain symptomatic. Persistent spirochetal infection despite antibiotic therapy has recently been demonstrated in non-human primates. We present evidence of persistent Borrelia infection despite antibiotic therapy in patients with ongoing Lyme disease symptoms. Materials & Methods: In this pilot study, culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of 10 control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. Results: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR) methods. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. Conclusions: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined.

Chronic obstructive pulmonary disease (COPD) patients are particularly susceptible to respiratory infections like influenza, which exacerbate symptoms and increase healthcare utilization. While smoking cessation and influenza vaccination are recommended preventive measures, their combined impact on healthcare resource utilization is underexplored. The Charlson Comorbidity Index (CCI) assesses comorbidity burden in COPD patients and may influence healthcare outcomes. We conducted a retrospective analysis of 357 COPD patients, evaluating smoking cessation success over one year and influenza vaccination receipt, stratifying patients by CCI scores. Healthcare utilization outcomes included emergency room visits, hospitalizations, and medical expenses. Results showed that 51.82% of patients quit smoking and 59.66% received influenza vaccination, with higher comorbidity prevalence in advanced COPD stages (p=0.002). Both smoking cessation and influenza vaccination independently correlated with decreased emergency room visits, hospital admissions, days, and costs. Patients who both quit smoking and received influenza vaccination exhibited the lowest healthcare utilization rates. In conclusion, smoking cessation and influenza vaccination significantly reduce healthcare resource utilization in COPD patients, with the combination yielding synergistic benefits, particularly in those with lower CCI scores. Integrating these interventions and comorbidity management in COPD strategies is essential for optimizing patient outcomes and healthcare efficiency.

Evolutionary Machine Learning (EML) has demonstrated its effectiveness in modeling various real-world application domains, including the dynamics of diseases and the creation of predictive models across diverse fields. However, the challenge of data imbalance adversely impacts the performance of EML models. While strategies involving misclassification costs or cost-sensitive learning exist to address this issue, their integration into EML has yet to be thoroughly explored. This paper aims to fill this gap by investigating the application of cost-sensitive EML for intelligent health risk prediction. More specifically, this paper delves into the utilization of cost-sensitive genetic programming (CSGP) and cost-sensitive genetic algorithms (CSGA), which are among the most widely used algorithms in the EML category. The study entails training CSGP and CSGA to predict the early onset of three chronic conditions (hypertension, diabetes, and fatty acid-related disorders) through the development of an EML model. Subsequently, the model's performance is evaluated through standard fitness functions such as sensitivity, specificity, and F1-score. From the experimental results, EML models demonstrate promising results in identifying the occurrence of chronic diseases. Further optimization of the cost-sensitive EML model holds the potential for enhanced outcomes in modeling medical problems.

Introduction. This retrospective study aimed to compare the risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Methods. Baseline data from 30 pre-HD and 85 HD patients were analyzed, including iPTH, vitamin D, FGF23, fetuinA, sclerostin, and VC scores (Adragao method). Multivariable linear regression identified VC predictors. Results: The prevalence of VC was similar in both groups, but HD patients had more pronounced VC scores ≥6. Pre-HD patients were older, with higher prevalence of Balkan endemic nephropathy, hypertension, and less frequent use of calcium phosphate binders. Both groups exhibited similar patterns of hyperphosphatemia, low vitamin D, and iPTH levels. In HD group normal phosphate was significantly common in patients with VC, whereas hyperphosphatemia was significantly common in patients without VC. Fetuin-A levels were higher in pre-HD patients, while FGF23 was elevated in HD patients. In pre-HD patients, male gender was associated with reduced VC risk, while in HD patients, malignancies and serum phosphate levels were negative VC predictors. Conclusion: Effective monitoring and tailored treatment of VC in CKD are still focused on phosphate regulation. Besides, mineral disturbances, hormones and biomarkers regulation, and patient-specific variables need to be considered.

Functional neurological disorders (FND) are relatively frequent disabling conditions. Given their complexity, multidisciplinary rehabilitation is envisaged. Whole-body cryostimulation (WBC) represents a promising adjuvant treatment, mainly because of its anti-inflammatory and exercise-mimicking effects. Here, we propose a novel use of WBC in a wheelchair-ridden 61-year-old woman diagnosed with FND and other comorbidities, who, after several therapeutic and rehabilitation failures, underwent a multidisciplinary rehabilitation program including WBC. The 4-week program included physiotherapy, nutritional intervention, psychological support, and WBC. Questionnaires to assess disease impact, pain level, perceived fatigue and sleep quality were administered. At discharge, improvements in body composition, haematological biomarkers, physical performance, and questionnaire scores were observed. The patient was able to walk with a walker for medium distances, even outdoors. We observed unprecedented improvements, particularly in functional parameters and questionnaire scores. Although we cannot ascertain to which extent WBC per se contributed to the improvements measured, subjective reporting and our clinical observation were that WBC, the only intervention not previously experienced by the patient, acted as a booster for the rehabilitation interventions. Further research will be necessary to rule out any possible placebo effect and to assess the effects of WBC on FND.

Background: Recommended CKD first-line diagnostics is based on GFR-determination by Creatinine. Cystatin C-use may provide better assessment. Methods: We compared creatinine- and cystatin C-derived eGFR determination in first-line di-agnostic of 112 hospital patients aged >60 years (median=76 years). Patients were judged kid-ney-sane according to first-line diagnostic recommendations (N=61, eGFR (CKD-EPI) ≥60ml/min/m2, total urine protein <150mg/g creatinine, urinary red and white blood cells not increased) or classified at-risk for kidney insufficiency due to aortic valve dysfunction (N=51). Plausibility of eGFR-values was evaluated retrospectively by final case diagnoses. Results: eGFR (CAPA) was found linearly correlated to eGFR (CKD-EPI) (R2=0.5, slope=0.69, p<0.0001). In 93/112 (>80%) cases, eGFR (CAPA) yielded lower values (on average ≈20%). In 55/112 (49%) cases CKD-stage decreased. CKD-reclassification from kidney-sane to kid-ney-insufficient state (i.e. CKD1/2 to CKD3a/b or 4) or reclassification to more severe kidney in-sufficiency (i.e. CKD3a3b/4 or 3b4) was found in 41/112 (37%) cases. Worsening of CKD-classification (kidney-sanekidney-insufficient) based on eGFR (CAPA) was in 30% of cases plausible in the light of final case-diagnoses. Conclusion: In elderly patients (>60 years), renal function appears systematically overestimated by creatinine-based eGFR (CKD-EPI) heralding for this group employment of cystatin C-based eGFR (CAPA) as first-line diagnostic.

Contrary to popular belief, we have known for many years that the endometrium is not a sterile environment and is considered to be a low-biomass milieu compared to the vagina. Numerous trials and studies have attempted to establish a valid sampling method and assess its physiological composition, but no consensus has been reached. Many factors such as ethnicity, age and inflammation, can influence the microbiome. Moreover, it possesses a higher alpha-diversity and therefore contains more diverse bacteria than the vagina. For instance, Lactobacillus has been shown to be a predominant genus in the vaginal microbiome of healthy women. Consequently, even if a majority of scientists postulate that a predominance of Lactobacillus inside the uterus improves reproductive outcomes, vaginal contamination by these bacteria during sampling cannot be ruled out. Certain pathologies, such as chronic endometritis, have been identified as inflammation perpetrators that hinder the embryo implantation process. This pro-inflammatory climate created by dysbiosis of the endometrial microbiota could induce secondary inflammatory mediators via Toll-like receptors, creating an environment conducive to the development of endometriosis and even promoting carcinogenesis. However, studies to this day have focused on small populations. In addition, there is no clearly defined healthy uterine composition yet. At most, only a few taxa have been identified as pathogenic. As sampling and analysis methods become increasingly precise, we can expect the endometrial microbiota to be incorporated into future diagnostic tools and treatments for women’s health.

Chronic kidney disease (CKD) is actually considered a public health priority according to the increasing number of patients affected by this condition: this casuistry is not only related to specific glomerular, tubular or autoimmune diseases or a consequence of acute kidney injury (AKI) episodes leading to organ failure, but it is tied to the progression of life expectancy and the impact of comorbidities such as cardiovascular disease, diabetes and cancer. CKD and its comorbidities promote low grade inflammatory status with an impact on patients’ clinical conditions, reducing their possibility for kidney transplantation or graft survival and their survival when receiving renal replacement therapies such as hemodialysis (HD) or peritoneal dialysis (PD). CKD is often referred to as an ageing accelerator: innate immune system dysregulation, in the uraemic proinflammatory milieu, is involved in this accelerated senescence phenomena and pentraxins, particularly Pentraxin-3 (PTX-3), are of particular interest in the development of kidney disease. A complete understanding of the mechanism of CKD progression, innate immune system involvement and a proper definition of PTX-3 role in kidney disease, could redefine the approach for diagnosis and a more centered patients’ management to slow down CKD progression over time and reduce its clinical and social impact.

The kidney and the heart work together in balancing the body circulation and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidney physiology is primarily designed to maintain a stable metabolic rate and has limited capacity to cope with any steep increase in renal metabolism. In the kidneys the glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of renal glucose transport in disease states is providing better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over-exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.

Biomarkers have become an important tool in the diagnosis and management of cardio renal syndromes (CRS), a complex condition characterized by dysfunction in both the cardiovascular and renal systems. These biomarkers can help identify the presence and severity of CRS, predict its progression and outcomes, and facilitate personalized treatment options. Several biomarkers, including natriuretic peptides, troponins, and inflammatory markers, have been extensively studied in CRS and have shown promising results in improving diagnosis and prognosis. In addition, emerging biomarkers such as kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin offer potential for early detection and intervention of CRS. However, the use of biomarkers in CRS is still in its infancy, and further research is needed to establish their utility in routine clinical practice. This review highlights the role of biomarkers in the diagnosis, prognosis, and management of CRS and discusses their potential as valuable clinical tools for personalized medicine in the future.

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

Chronic noncommunicable diseases (CNCDs) have been a major public health concern worldwide, especially diabetes, cardiovascular disease, chronic obstructive pulmonary disease, hypertension, in addition to obesity, which is even more worrying when the subject involves the covid-19 pandemic, because such incidences correlate with the need for intensive care units, including the possibility of death of the patient. Therefore, for countries with the highest numbers of critical cases, it is important to assess the incidence of these diseases to guide the public that most needs guidance on public policies for social isolation.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolising patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signalling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

RNA epigenetics is perhaps the most recent aspect of interest for translational epigeneticists. RNA modifications create such an extensive network of epigenetically driven combination whose role in physiology and pathophysiology is still far from being elucidated. Not surprisingly, some of the players determining changes into RNA structure are in common with those involved in DNA and chromatin structure regulation, while other molecules seem very specific to RNA. It is envisaged, then, that new small molecules, acting selectively on RNA epigenetic changes, will be reported soon, opening new therapeutic interventions based on the correction of the RNA epigenetic landscape. In this review, we shall summarize some aspects of RNA epigenetics limited to those in which the potential clinical translatability to cardiovascular disease is emerging.

COPD is currently the fourth leading cause of death in the world. Globally, due to continued exposure to COPD risk factors and an aging population, the burden of COPD is expected to increase in the coming decades. The BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index is a practical and multidimensional predictor for prognosis of COPD, and better than FEV1.We used the database of Kaohsiung Chang Gung Memorial Hospital medical center, Taiwan to analyze the correlation between BODE index, healthcare resource utilization, and Charlson comorbidity index (CCI). This retrospective study to collect COPD patients with complete BODE index data who had undergone a 6-minute walk examination in our hospital from January 2015 to December 2016. The medical cost and comorbidities database were analyzed from January 1, 2015, to August 31, 2017. Of 396 patients, 382 (96.5%) were male, with an average age of 71.3 ± 8.4 years. There was a significant association between the BODE index and the CCI of COPD patients (p < 0.001). Healthcare resource utilization was positively correlated with the BODE index during the 32 months of retrospective clinical outcomes: positively correlated with the number of hospitalizations (p<0.001), hospitalization days (p<0.001), hospitalization expenses (p=0.005), and total medical expenses (p=0.024), respectively. Our findings provide the crucial information for clinician to predict medical burden and comorbidities in patients with COPD by using BODE index.

The standard of care measures for kidney function, proteinuria, and serum creatinine (SCr) are poor predictors of early stage kidney disease. Measures that can detect chronic kidney disease in its earlier stages are needed to enable therapeutic intervention and reduce adverse outcomes of chronic kidney disease. We have developed the Kidney Injury Test (KIT) and a novel KIT Score based on the composite measurement and validation of multiple biomarkers across a unique set of 397 urine samples. The test is performed on urine samples that require no processing at the site of collection and without target sequencing or amplification. We sought to verify that the pre-defined KIT test, KIT Score, and clinical thresholds correlate with established chronic kidney disease (CKD) and may provide predictive information of early kidney injury status above and beyond proteinuria and renal function measurements alone. Statistical analyses across six DNA, protein, and metabolite markers were performed on a subset of residual spot urine samples with CKD that met assay performance quality controls from patients attending the clinical labs at the University of California, San Francisco (UCSF) as part of an ongoing IRB approved prospective study. Inclusion criteria included selection of patients with confirmed CKD and normal healthy controls; exclusion criteria included incomplete or missing information for sample classification, logistical delays in transport/processing of urine samples or low sample volume, and acute kidney injury. Multivariate logistic regression of kidney injury status and likelihood ratio statistics were used to assess the contribution of the KIT Score for prediction of kidney injury status and stage of CKD as well as assess the potential contribution of the KIT Score for detection of early stage CKD above and beyond traditional measures of renal function. Urine samples were processed by a proprietary immunoprobe for measuring cfDNA, methylated cfDNA, clusterin, CXCL10, total protein, and creatinine. The KIT Score and stratified KIT Score Risk Group (High versus Low) had a sensitivity and specificity for detection of kidney injury status (healthy or CKD) of 97.3% (95% CI: 94.6%–99.3%) and 94.1% (95% CI: 82.3%–100%). In addition, in patients with normal renal function [eGFR ≥ 90], the KIT Score clearly identifies those with predisposing risk factors for CKD, which could not be picked up by eGFR or proteinuria (p < 0.001). The KIT Score uncovers a burden of kidney injury that may yet be incompletely recognized, opening the door for earlier detection, intervention and preservation of renal function.

In 2011, it was reviewed that there is a strong co-occurrence between major depression and chronic fatigue syndrome (CFS), with fatigue and physio-somatic symptoms being key symptoms of depression, and depressive symptoms appearing during the course of CFS. Moreover, the comorbidity between both conditions may in part be explained by activated immune-inflammatory pathways, including increased translocation of Gram-negative bacteria and increased levels of pro-inflammatory cytokines, such as interleukin (IL)-1. Nevertheless, the possible involvement of activated microglia in this comorbidity has remained unclear. This paper aims to review microglial disturbances in major depression, CFS and their comorbidity. A comprehensive literature search was conducted using the PubMed / MEDLINE database to identify studies that are relevant to this current review. Depressed patients present neuroinflammatory alterations, probably related to microglial activation, while animal models show that a microglial response to immune challenges including lipopolysaccharides is accompanied by depressive-like behaviors. Recent evidence from preclinical studies indicate that activated microglia have a key role in the onset of fatigue. In chronic inflammatory conditions, such as infections and senescence, microglia orchestrate an inflammatory microenvironment thereby causing fatigue. In conclusion, based on our review we may posit that shared immune-inflammatory pathways and activated microglia underpin comorbid depression and CFS and that activated microglia are the main orchestrators of this comorbidity. As such, microglial activation and neuro-inflammation may be promising targets to treat the overlapping manifestations of both depression and CFS.

BACKGROUND: Chronic hepatitis B infected with Hepatitis B virus remains a major health concern worldwide. Despite standard interferon-α and nucleotide analogues have been shown to reduce the deterioration of liver disease among chronic hepatitis B patients, covalently closed circular DNA was still difficult to eradicate. METHODS: A literature search of Pubmed and Web of science was performed with the following key words: ‘CRISPR’, ‘CRISPR/Cas9’, ‘hepatitis B’, ‘HBV’, ‘chronic hepatitis B’ and ‘HBV cccDNA’. The information about CRISPR/Cas9 for the treatment of HBV cccDNA or hepatitis B was reviewed. RESULTS: CRISPR/Cas9 could treat hepatitis B through suppressing or clearing HBV cccDNA with different gRNAs. CONCLUSION: With the emergence of CRISPR/Cas9 (the RNA-guided clustered regulatory interspaced short palindromic repeats, CRISPR) editing technology, clearance of hepatitis B virus and better prevention of liver carcinoma seemed to be possible.

Fermented foods and ingredients, including fermentates derived from lactic acid bacteria (LAB) in dairy products, can modulate the immune system. Here we describe the use of reconstituted skimmed milk powder to generate novel fermentates from Lactobacillus helveticus strains SC232, SC234, SC212, and SC210, and from Lacticaseibacillus casei strains SC209 and SC229, and demonstrate using in vitro assays that these fermentates can differentially modulate cytokine secretion by bone marrow derived dendritic cells (BMDCs) when activated with either the viral ligand, loxoribine, or an inflammatory stimulus, lipopolysaccharide. Specifically, we demonstrate that SC232 and SC234 increase cytokines IL-6, TNF-α, IL-12p40, IL-23, IL-27 and IL-10, and decreased IL-1β in primary bone marrow derived dendritic cell (BMDCs) stimulated with a viral ligand. In contrast exposure of these cells to SC212 and SC210 resulted in increased IL-10, IL-1β, IL-23, and decreased IL-12p40 following activation of the cells with the inflammatory stimulus LPS. Interestingly SC209 and SC229 had little or no effect on cytokine secretion by BMDCs. Overall, our data demonstrates that these novel fermentates have specific effects and can differentially enhance key immune mechanisms that are critical to viral immune responses, or can suppress responses involved in chronic inflammatory conditions, such as Ulcerative Colitis (UC), and Crohn’s disease (CD).

Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation, and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors, or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDM) in vitro. Human BMDM were exposed to NE or control vehicle and the abundance of HDACs and Sirtuins was determined by western blotting of total cell lysates or nuclear extracts, or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE-treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1 which shifted BMDM to a pro-inflammatory phenotype.

BACKGROUND: Patients with diabetic foot ulcers (DFU) and chronic limb-threatening ischemia (CLTI are at higher risk for major amputations and mortality. The aim of this study was to assess the safety and cost-efficacy of intramuscular injection of autologous monocyte-rich PRP platelet-rich plasma Tropocells® PRP (Estar Medical, Holon, Israel) in diabetic patients with chronic limb-threatening ischemia (CLTI) in which revascularization was not feasible. METHODS: a retrospective study was carried out on a series of patients with type 2 diabetes, grade Texas 3C or D DFU, and CLTI. All patients had undergone at least a previous revascularization and were allocated to a surgery waiting list for major amputation. According to the data provided by the manufacturer (https://www.zuccatobiotech.it/index.php/prodotti/tropocells), the monocyte-rich PRP kit obtained a platelet-rich plasma with a high concentration of peripheral blood mononuclear cells (with a proportionately lower amount of lymphocytes), a low concentration of neutrophils and an almost complete depletion of red blood cells. All patients underwent a procedure of local infiltration of autologous mononuclear cells through multiple perilesional and intramuscular injections of 10 mL PBMNC suspensions (0.2–0.3 mL in boluses) performed below the knee along the relevant vascular axis (anterior tibial artery and posterior tibial artery) at intervals of 1–2 cm and to a mean depth of 1.5–2 cm, using a 21 G needle. The procedures were performed according to the instructions of the manufacturer and were repeated at least two times (maximum 3 times) at intervals of 30 days. The principal endpoint was a composite of TcPO2 values at the first toe ≥30 mmHg and/or TcPO2 increase of at least 50% from baseline and/or ulcer healing. Secondary endpoints were individual components of the primary endpoint, quality of life, any adverse events, and direct costs. All the endpoints were evaluated at 26 weeks. RESULTS: Out of 21 enrolled patients, 13 (61.9%) reached the primary endpoint, whereas three patients underwent a major amputation, and two patients died. The median TpCO2 was significantly increased, and pain was significantly reduced. The overall mean and median cost per patient were 9,255±7,328€ and 4,001 [2,991;7,565]€, respectively. CONCLUSIONS: the use of PBMNCs implants in patients with DFU and no-option CLTI seems to be efficacious in reducing the risk of major amputation and improve ulcer healing.

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection by HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms have generated the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFN-, then IFN-α plus ribavirin (IFN-RBV); then, pegylated-IFN--RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing the patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced SVR (&gt; 90%); the compounds were able to inhibit HCV replication without significant side effects, even in pediatric populations. The management of coinfected patients HBV-HCV and HCV-HIV has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research focuses on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection to different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is an acquired disease with significant morbidity that affects both children and adults. Effective tools to assess functional capacity (FC) are severely lacking which has significant consequences for timely diagnosis, assessments for patient disability benefits and assessing the impact and effectiveness of interventions. In interventional research the inability to assess FC can result in an incomplete assessment of the potential effect of the intervention. Specifically of concern is that if an intervention is effective in reducing symptom load, patients may increase their activity level to reach a pre-intervention symptom load. Thus, if FC is not accurately assessed, beneficial treatment outcomes may be missed. To address this issue, using extensive, repeated patient feedback we have developed a new questionnaire, FUNCAP, to achieve optimal FC assessment in ME/CFS patients. The questionnaire covers eight domains and activity types: A. Personal hygiene / basic functions, B. Walking / movement, C. Being upright, D. Activities in the home, E. Communication, F. Activities outside the home, G. Reactions to light and sound, and H. Concentration. Through five rounds of anonymous web-based surveys and a further test - retest validation round, two versions of the questionnaire were developed; a longer version comprising 55 questions (FUNCAP55) to improve diagnostic and disability benefit/ insurance FC assessments and a shorter version (FUNCAP27) for interventional research and less extensive FC assessments. FUNCAP may also be useful in other conditions where fatigue and PEM is present, such as Long Covid.

Rationale: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency. Although most mutations are linked to the X chromosome, therefore affecting males, there are autosomal recessive forms that therefore affect both sexes. Clinically it is characterized by recurrent and severe bacterial and fungal infections, with formation of granulomas, due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytosed microorganisms. Patient concerns: We reported a 12-year-old boy with pneumonia with pneumatocele of possible staphylococcal etiology at one year of age, bilateral orchitis secondary to Salmonella with hematogenous spread, osteomyelitis due to Salmonella, gastroenteritis due to Salmonella enteritidis, liver abscesses due to Staphycococcus aureus and lymphomatoid papulosis and pyodermititis. Diagnoses: In the biochemical diagnosis, the presence of yellow dye (NBT) and absence of dark bluish black dye (formazan) was evidenced. Regarding the genetic diagnosis, the presence of the mutation in exon 10 of CYBB (OMIM 306400) (Xp21.1) that encodes the gp91phox protein was demonstrated. Interventions and outcomes: Treatment was started with trimethoprim/sulfamethoxazole 400/80 mg every 24 hours via oral, and antifungal prophylaxis with itraconazole 200 mg every 24 hours orally is added, after which he does not present serious bacterial or fungal infections, not being able to administer immunomodulatory treatment with recombinant human Interferon gamma-1b. Lessons: The clinical finding of frequent severe infections associated with granulomas, CGD should be suspected. Treatment of this primary immunodeficiency is trimethoprim/sulfamethoxazole and itraconazole. Importantly, it indicated that the mutation in exon 10 of CYBB (Xp21.1) that encodes the gp91phox might influence the pathogenesis of CGD.

Although the frequency of myocarditis in the general population is very difficult to accurately determine due to the large number of asymptomatic cases, the incidence of this disease is increasing significantly due to better defined criteria for diagnosis and the development of modern diagnostic method. The multitude of different etiological factors, the diversity of the clinical picture and the variability of the diagnostic findings make this disease often demanding both for the selection of the diagnostic modality and for the proper therapeutic approach. The previously known most common viral etiology of this disease is today overshadowed by new findings based on immune-mediated processes, associated diseases that in their natural course can lead to myocardial involvement, but also the iatrogenic cause of myocarditis due to use of immune checkpoint inhibitors in the treatment of cancer patients. Suspecting that a patient with polymorphic and non-specific clinical signs and symptoms, changes in ECG and echocardiography has myocarditis is the starting point in the diagnostic algorithm. Cardio magnetic resonance imaging is non-invasive diagnostic gold standard for diagnosis and clinical follow-up of thses patients. Endomyocardial biopsy as an invasive method is the diagnostic choice in life-threatening patients with suspicion of fulminant myocarditis where the diagnosis has not yet established or there is no adequate response to the applied therapeutic regimen. The treatment of myocarditis is increasingly demanding and includes conservative methods of treating heart failure, immunomodulatory and immunospressive therapy, methods of mechanical circulatory support and heart transplantation. The goal of developing new diagnostic and therapeutic methods is to reduce mortality from this complex disease, which is still high.

Prevention of infections is crucial in solid organ transplant (SOT) candidates and recipients. These pa-tients are exposed to an increased infectious risk due to previous organ insufficiency and to pharmaco-logic immunosuppression. Besides infectious-related morbidity and mortality, this vulnerable group of patients is also exposed to the risk of acute decompensation and organ rejection or failure in the pre- and post-transplant period respectively, since antimicrobial treatments are less effective than in the immunocompetent patients. Vaccination represents a major preventive measure against specific infec-tious risks in this population but as responses to vaccines are reduced, especially in the early post-transplant period or after treatment for rejection, an optimal vaccination status should be obtained prior to transplantation whenever possible. This review reports the currently available data on the indications and modalities of vaccination in SOT adult candidates and recipients.

Initially, renal resistive index (RRI) was investigated to improve diagnosis in kidney diseases, but failed to meet this goal. Recently many papers highlighted the prognostic significance of RRI in chronic kidney disease, in the estimation of revascularization success of renal artery stenoses or the evolution of the graft and recipients in renal transplantation. Moreover, RRI gained importance in prediction of acute kidney injury in critically ill patients. Along with RRI study in renal pathology have been revealed correlations of this index with parameters of systemic circulation. The theoretical and experimental premises of this connection were reconsidered, and studies for analyzing the link between RRI and arterial stiffness, central and peripheral pressure or left ventricular flow were conducted with this purpose. A high amount of data is currently indicating that RRI is influenced more by pulse pressure and vascular compliance than by renal vascular resistance – assuming that RRI reflects the complex interplay between systemic circulation and renal microcirculation and should be considered as a marker of systemic cardiovascular risk beyond its prognostic relevance for kidney disease. In this review we will go through clinical research that revealed the implications of RRI in renal and cardiovascular disease.

The covid-19 pandemic has generated substantial changes in the lives of the population, such as increased physical inactivity, which can lead to overweight and, consequently, repercussions on glucose homeostasis. A population-based household epidemiological survey was conducted by stratified, multistage probability cluster sampling (October and December 2020) in Brazil. Participants were classified as physically active or inactive during leisure time according to the recommendations of the World Health Organization. HbA1c levels were categorized as normal (≤6.4%) or with glycemic changes (≥ 6.5%). The mediating variable was excess weight (overweight and obese). Multivariate logistic regression analyzes were performed to examine the association between physical inactivity and glycemic changes. Mediation was analyzed using the Karlson–Holm–Breen method to verify the influence of excess weight on the association. We interviewed 1,685 individuals, mostly women (52.4%), 35–59 years old (45.8%), race/ethnicity brown (48.1%), and excess weight (56.5%). The mean HbA1c was 5.68% (95% CI: 5.58-5.77). Individuals physically inactive were 2.62 times more likely to have glycemic alterations (OR:2.62.95% CI:1.29-5.33), and 26.87% of this association was mediated by excess weight (OR:1.30:95% CI:1.06-1.57). Physical inactivity in leisure time increases the chances of glycemic alterations, and part of this association can be explained by excess weight.

Commonly the periodontitis has been linked to periodontopathogens categorized in Socransky's microbial complexes, however, there is a lack of knowledge regarding “other microorganisms” or "cryptic microorganisms", which are rarely thought of as significant oral pathogens and are neither previously categorized nor connected to illnesses in the oral cavity. This study hypothesized that these cryptic microorganisms could contribute to the modulation of oral microbiota present in health or disease (periodontitis and/or OSA patients). For this purpose, the presence and the correlation among these cultivable cryptic oral microorganisms were identified and their possible role in both conditions was determined. Data from oral samples of individuals with or without periodontitis and with or without OSA were obtained from a previous study. Demographic data, clinical oral characteristics, and genera and species of cultivable cryptic oral microorganisms identified by MALDI-TOF were recorded. The data of 75 participants were analyzed to determine the relative frequencies of cultivable cryptic microorganisms’ genus and species, microbial clusters and correlations tests were performed. According to periodontal condition, Gingivitis - dental biofilm-induced in reduced periodontium and stage III periodontitis were found to have the highest diversity of cryptic microorganism species. Based on the experimental condition these findings showed that there are genera related to disease conditions and others related to healthy conditions, with species that could be related to different chronic diseases being highlighted as comorbidities periodontitis and OSA. The cryptic microorganisms within the oral microbiota of patients with periodontitis and OSA are present as potential pathogens, promoting the development of dysbiotic microbiota, and the occurrence of chronic diseases, which have been previously proposed to be common risk factors for periodontitis and OSA. Understanding the function of possible pathogens in the oral microbiota will take more research.

In Japan, the prevalence of low birth weight (LBW) has been estimated to be approximately 10%, which is the highest among developed countries. This high prevalence might affect the prevalence of LBW-associated diseases in the adult population of Japan. Recently, LBW has been recognized as a contributing factor to post-adaptive focal segmental glomerulosclerosis (FSGS) in adulthood; however, few reports to date have evaluated the clinical and pathological characteristics of post-adaptive FSGS. A 13-year-old girl was referred to our hospital owing to mild proteinuria, which was detected at a school urinary screening. She was born at a gestational age of 23 weeks, with a very LBW of 630 g. Dipstick urinalysis revealed grade (2+) proteinuria. Her serum creatinine level was 1.02 mg/dL, and she was diagnosed as having stage 2 chronic kidney disease (CKD). Her serum uric acid level was 7 mg/dL. Her mother and 16-years old brother had hyperuricemia, too. A percutaneous renal biopsy leads to a diagnosis of FSGS. After 3 years of treatment with an angiotensin receptor blocker, her proteinuria decreased. However, her serum creatinine level was 1.07 mg/dL, and she still had stage 2 CKD. We considered that in this patient, the first hit was her LBW, and the second hit was hyperuricemia. The second hit might be associated with the development of CKD. The birth history of patients is not usually confirmed by nephrologists. Our case demonstrates that obtaining information regarding the preterm birth and LBW of patients is important in the diagnosis of noncommunicable diseases, because school urinary screening is not routinely performed in countries other than Japan.

Background: Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in non-diabetic adults, accounting for up to one-third of biopsy diagnostics in some regions. A watchful waiting strategy has been adopted to accurately assess the success of MGN. In this study, we predict prognostic risk factors for primary MGN patients for effective intervention and prognosis. Materials and Methods: This is a retrospective study design involving 125 biopsy-proven MGN subjects on follow-up from January 2012 to October 2019 in Hospital Serdang and Hospital Kuala Lumpur, Malaysia. Result and Conclusion: After the median follow-up of 36 (15.0-57.0) months, 26 (20.8%) consisting of 17 (13.6%) primary MGN and 9 (7.2%) secondary MGN subjects achieved complete remission while 17 (13.6%) and 10 (8.0%) of primary and secondary MGN subjects respectively achieved spontaneous remission. Subjects with nephrotic range proteinuria have 2.917 odds more at risk of primary MGN while subjects with hypertension have 2.417 odds risk of primary MGN compared to those with no hypertension at presentation. Multiple logistic regression models retained only factors directly associated with MGN with only nephrotic range proteinuria associated with primary MGN. Those with nephrotic range proteinuria were 3.04 times the odds of primary MGN when compared with those without nephrotic syndrome (95% C. I = 1.089, 8.472). The nephrotic syndrome could be used to determine the prognosis in patients with primary MGN especially those at risk of end-stage kidney disease.

: Over time, we have come to recognize a very complex network of physiological changes enabling wound healing. An immunological process enables the body to distinguish damaged cells and begin a cleaning mechanism by separating damaged proteins and cells with matrix metallopro-teinases, a complement reaction, and free radicals. A wide variety of cell functions help to rebuild new tissue, dependent on energy provision and oxygen supply. Like in an optimized "biorector," disturbance can lead to prolonged healing. One of the earliest investigated local factors is the pH of wounds, studied in close relation to the local perfusion, oxygen tension, and lactate concentration. Granulation tissue with the wrong pH can hinder fibroblast and keratinocyte division and pro-liferation, as well as skin graft takes. Methods for influencing the pH have been tested, such as occlusion and acidification by the topical application of acidic media. In most trials, this has not changed the wound's pH to an acidic one, but it has reduced the strong alkalinity of deeper or chronic wound. Energy provision is essential for all repair processes. New insights into the metabolism of cells have changed the definition of lactate from a waste product to an indispensable energy provider in normoxic and hypoxic conditions. Neovascularization depends on oxygen provision and lactate, signaling hypoxic conditions even under normoxic conditions. An appropriate pH is necessary for successful skin grafting; hypoxia can change the pH of wounds. This review describes the close interconnections between the local lactate levels, metabolism, healing mechanisms, and pH. Furthermore, it analyzes and evaluates the different possible ways to support metabolism, such as lactate enhancement and pH adjustment. The aim of wound treatment must be the optimization of all these components. Therefore, the role of lactate and its influence on wound healing in acute and chronic wounds will be assessed.

Experiences of homelessness, although widely varied, are characterized by extensive time in public spaces, often outdoors. However, there has been little empirical research about the ways in which environmental factors affect individuals experiencing homelessness (IEHs). Therefore, the purpose of this study was to use an environmental justice approach to understand how cardiopulmonary health of IEHs is affected by episodic poor air quality in Salt Lake County. It was hypothesized that people who had experienced unsheltered homelessness and those who had been experiencing homelessness for longer periods of time would report greater health difficulties from poor air quality exposure. Through a combination of in-person semi-structured interviews with IEHs (n = 138) and access to corresponding state-based service provider databases, researchers examined both overall descriptives of and relationships between types (sheltered and unsheltered) and duration (chronic and non-chronic) of homelessness. More than 61% of IEHs reported physical reactions to air pollution, 37% reported air pollution-related emotional stress, and more than 89% had sought medical attention for a condition related to air pollution. Findings indicate that while IEHs report a number of health effects related to poor air quality, there were no significant differences between individuals based on either sheltered status or duration of their experiences of homelessness. This study provides an initial empirical inquiry to understand how environmental disamenities negatively influence IEHs, as well as noting that sheltered status and duration of homelessness are less impactful than originally hypothesized.

This study applies a cluster analysis to identify typical physical activity (PA) and sedentary behaviour (SB) patterns in people with chronic obstructive pulmonary disease (COPD) before starting pulmonary rehabilitation (PR). We implemented an observational design which assessed baseline data on objectively measured PA and SB from the STAR (Stay Active after Rehabilitation) study. 355 persons wore a accelerometer (Actigraph wGT3X) for seven days before the start of their PR. Sociodemographic and disease-related parameters were assessed at the start of PR. We applied cluster analysis and compared groups applying univariate variance analyses. Data was available for 326 persons (31.6% women; age ø = 58 yr.). Cluster analysis revealed four movement clusters with distinct PA and SB patterns: sedentary non-movers (28.5%), sedentary occasional movers (41.7%), sedentary movers (19.6%), and sedentary exercisers (10.1%). The four clusters showed very different levels of moderate PA before rehabilitation (Ø daily minutes: 9; 28; 38; 70). Notably, all four clusters displayed considerably long average sitting time per day (Ø daily minutes: 644; 561; 490; 446). The groups differed significantly in disease-related parameters of GOLD severity, FEV1, CAT, and 6-Min-Walk-Test. In addition to PA promotion, PR programs should consider the reduction of sitting time as a valuable goal.

One of the most common complications of neurogenic bladder secondary to spinal cord injury (SCI) is urinary incontinence, possibly related to bladder-emptying methods and changes in quality of life. This study aimed to identify the occurrence of this complication in adults with SCI and analyze its relationship with bladder-emptying methods, satisfaction, and lifestyle. This is a quantitative, exploratory, cross-sectional study. The variables were collected using the Bowel and Bladder Treatment Index during a telephone interview with 290 participants from February to November 2021. According to the results, 70% of the participants were male and 74.1% performed clean intermediate catheterization (CIC) as the main bladder-emptying method. Moreover, 55.6% were considered incontinent in the last year. Emptying by normal urination and bladder reflex triggering had a statistically significant relationship with urinary incontinence. A statistical association was observed between all the variables of satisfaction and lifestyle with urinary incontinence. Although CIC reduced urine leakage, a considerable number of participants still presented with frequent urine leakage. Urinary incontinence negatively altered satisfaction with the bladder-emptying method, effectiveness of bladder management, quality of life, and personal and social relationships.

Spinal cord injuries (SCI) can result in sensory and motor dysfunctions, which were long-considered permanent. Recent advancement in electrical neuromodulation has been proven to restore sensorimotor function in people with SCI. These stimulation protocols, however, were mostly invasive, expensive, and difficult to implement. In this study, transcutaneous electrical stimulation (tES) was used to restore over-ground walking of an individual with 21 years of chronic paralysis from a cervical SCI. After a total of 66 weeks of rehabilitation training with tES, which included standing, functional reaching, reclined sit-up, treadmill walking and active biking, significant improvement in lower-limb volitional movements and overall light touch sensation were shown by International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) score. By the end of the study, the participant could walk in a 4-meter walking test with the aid of a walking frame and ankle foot orthoses. The success in the sensorimotor recovery of our study participant sheds light on the future of non-invasive neuromodulation treatment for SCI paralysis.

Nasal nitric oxide (nNO) is a gas synthesized by the inducible and constitutive NO synthase enzyme in the airway cells of the nasal mucosa. Like lung nitric oxide, it is thought to be associated with airway inflammation in various respiratory diseases in children. The aim of our review was to investigate the current state of use of nasal nitric oxide measurement in children. A comprehensive search was conducted using the Web of Science and PubMed databases specifically targeting publications in the English language, with the following keywords: nasal NO, children, allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). We describe the use of nNO in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, primary ciliary dyskinesia (PCD), and cystic fibrosis (CF) based on the latest literature. CONCLUSION: nNO is a noninvasive, clinically applicable test for use in pediatric allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, PCD and CF. It can be used as a complementary method in the diagnosis of these respiratory diseases and as a monitoring method for the treatment of allergic rhinitis, acute and chronic rhinosinusitis.

Abstract Sickle cell anaemia (SCD) is a life-threatening haematological disorder which is predominant in sub-Saharan Africa and is triggered by a genetic mutation of the β-chain haemoglobin gene resulting in the substitution of glutamic acid with valine. This mutation leads to the production of an abnormal haemoglobin molecule called haemoglobin S (HbS). When deoxygenated, haemoglobin S (HbS) polymerizes and results in a sickle-shaped red blood cell which is rigid and has a significantly shortened life span. Various reports have shown a strong link between oxidative stress, inflammation, the immune response, and the pathogenesis of sickle cell disease. The consequence of these processes lead to the development of vasculopathy (disease of the blood vessels) and several other complications. The role of the immune system, particularly the innate immune system, in the pathogenesis of SCD has become increasingly clear in recent years of research, However, little is known about the roles of the adaptive immune system in this disease. This review examines the interaction between the immune system, inflammation, oxidative stress, blood transfusion, and their effects on the pathogenesis of sickle cell anaemia

Aim: This study aimed to evaluate the sociodemographic, behavioral, and biological profile and its relationship with the emergence of chronic non-communicable diseases in riverside populations in the Xingu region, Pará, Brazil. Methods: Characteristics related to health indicators and which risk factors are considered most important were also analyzed. This is a cross-sectional, exploratory, and descriptive study. The sample consisted of riverside people over 18 years of both sexes. The sample size (n.86) was calculated with a confidence level of 95% and a sample error of 5%. To divide the groups, the K-means clustering algorithm was adopted through an unsupervised method and the values were expressed as median. For continuous and categorical data, the Mann-Whitney and Chi-square tests were used, respectively, and the significance level was set at p<5%. To classify the degree of importance of each variable, the multi-layer perceptron algorithm was applied. Results: Based on this information, the sample was divided into two groups: the group with low or no education, with bad habits and worse health conditions, and the group with opposite characteristics. The risk factors considered for cardiovascular diseases and diabetes in the groups were low education (p < 0.001), sedentary lifestyle (p < 0.01), smoking, alcoholism, body mass index (p < 0.05) and the waist-hip ratio, with values above the expected, in both groups. Conclusions: The factors considered important to have a good health condition or not were the educational and social conditions of these communities and a part of the riverside population was considered healthier than the other.

Providing patient-centered care to manage chronic pain and opioid use disorder (OUD) is associated with improved health outcomes. However, adopting a holistic approach to providing care is often challenging in rural communities. This study aims to identify and contrast challenges to providing patient-centered care from the perspective of patients and providers. A participatory design approach was adopted to elicit the perceptions of providers and patients with lived experiences of chronic pain and OUD in Jefferson County, Wisconsin. Two focus groups were conducted with each stakeholder group to identify problems that participants face with respect to chronic pain management and OUD and possible solutions. Four interviews were conducted with providers experienced in chronic pain management. Analysis of focus group sessions and interviews show consensus among patients and providers that lack of behavioral health and recovery resources create barriers to effectively manage OUD and chronic pain. However, there was discordance among the two groups about other barriers such as patient and provider attitudes, tapering approach, and access to medications for OUD. This tension among patients and providers can influence patients’ retention in therapy. More efforts are needed to mitigate stigma among providers in rural communities and support psychosocial needs of patients.

Natural cycles underpin the very stuff of life. In this commentary we consider unnatural cycles: that is, anthropogenic activities which have a circularity, but whose nature is to have a detrimental effect on human health, exacerbating existing problems. Natural cycles have feedback loops, some of which have recently come to light, with an understanding that everything is connected in some way. In health, feedback loops are imperative in homeostatic mechanisms. However, in the unnatural cycle the feedback loops serve to reinforce (and in some cases amplify) negative problems. We offer a commentary on an unnatural cycle moving from air quality to lung function and back to air quality; we call this the lung disease unnatural cycle. We suggest where links occur, and where wider consideration of interactions between various disciplines can lead to breaking this unnatural (or vicious) cycle, changing it to a healthy cycle where individual health can be improved, along with better global scale outcomes. We suggest that many activities within this unnatural cycle occur within silos. However, the improved cycle incorporates joint activities at geological, health, and financial levels, to the mutual benefit of all, breaking the unnatural cycle, and improving health, life and financial costs.

Is it possible to measure the dispersion of ex-ante chances (i.e. chances “before the event”) among people, be it gambling, health, or social opportunities? We explore this question and provide some tools, including a statistical test, to evidence the actual dispersion of ex-ante chances in various areas with a focus on chronic diseases. Using the principle of maximum entropy, we derive the distribution of the risk to become ill in the global population as well as in the population of affected people. We find that affected people are either at very low risk like the overwhelming majority of the population but still were unlucky to become ill, or are at extremely high risk and were bound to become ill.

Background and Objectives The socioeconomics working group of the European ME/CFS Research Network (EUROMENE) has conducted a review of the literature pertaining to GPs’ knowledge and understanding of ME/CFS. Materials and Methods A MEDLINE search was carried out. The papers identified were reviewed following the Synthesis Without Meta-analysis (SWiM) methodology, and were classified according to the focus of the enquiry (patients, GPs, database and medical record studies, evaluation of a training programme, and overview papers), and whether they were quantitative or qualitative in nature. Results 33 papers were identified in the MEDLINE search. The quantitative surveys of GPs demonstrated that a third to a half of all GPs did not accept ME/CFS as a genuine clinical entity and, even when they did, they lacked confidence in diagnosing or managing it. Patient surveys indicated that a similar proportion of patients was dissatisfied with the primary medical care they had received. These findings were consistent with the findings of the qualitative studies that were examined, and have changed little over several decades. Conclusions Lack of knowledge and understanding of ME/CFS among GPs is widespread, and the resultant diagnostic delays constitute a risk factor for severe and prolonged disease. Failure to diagnose ME/CFS renders problematic attempts to determine its prevalence, and hence its economic impact.

The European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) was established after a successful grant application to the European Cooperation is Science and Technology (COST). This network aimed to assess the existing knowledge and/or experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in the European countries and worldwide, and to enhance coordinated research and health care provision in this field. The EUROMENE proposal, was based on the establishment of interrelated working groups (WGs), where the participants contributed with specific knowledge and viewpoints according to their specialties and/or areas of interest. In this paper we outline the work of a multidisciplinary team of researchers, including epidemiologists, clinicians, statisticians, biomedical scientist and heath economists, who set out their recommendations to guide data acquisition for ME/CFS research, aiming to standardise data collection and improve epidemiological research.

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically ‘exhausted’ in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

Extramedullary hematopoiesis is a compensatory response in chronic hemolytic anemia, such as thalassemia, and can lead to spinal cord compression. This case report describes a 36-year-old woman with β-thalassemia who presented with lower extremity motor deficiency, pelvic paresthesia, and bladder dysfunction. The patient had a history of low back pain, bilateral lower limb weakness, and poor compliance with iron chelation therapy. MRI revealed compression of the spinal cord due to extramedullary hematopoiesis. Surgical intervention was not feasible, and the patient underwent hypertransfusion and iron chelation therapy. Neurological symptoms improved, but urinary retention persisted. The patient continues to receive iron chelation treatment and undergoes transfusions. Extramedullary hematopoiesis is a common complication in thalassemia and requires an individualized treatment approach.

Gout is at least 3 times more prevalent in men than in women. However, concurrent with rising total gout prevalence, complex factors, including comorbidities, diet and lifestyle, and aging, have promoted higher gout prevalence in females. This narrative review focuses on summarizing recent developments in the landscape of gout in women, and mechanisms involved. New knowledge on sex hormone effects on both urate-excreting and urate-reabsorbing transporters, and higher hypertension and chronic kidney disease prevalence in women compared to men, may help explain why gout incidence rises robustly after menopause in women to approach that in men. Racial and ethnic factors, risk profiles based on heritable genetic polymorphisms of urate transporters, and diet, body mass index, and lifestyle factors differ according to sex. In addition, sex differences in clinical phenotypes and outcomes of gout and non-gout illnesses include more frequent comorbidities, more pain and disability during gout flare, different perceptions of disease burden, and more frequent severe cutaneous hypersensitivity reaction to allopurinol in women. Significantly, women with gout also have poorer COVID-19 outcomes than do men. Collectively, such findings support the potential clinical benefits of tailoring gout and hyperuricemia treatment according to sex.

Leukemia cutis (LC) is defined as leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and in T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis and treatment of leukemic skin involvement in different types of leukemia

Background Total serum bile acids (TSBA), liver-spleen scan and dynamic liver functional tests, in our case the antipyrine clearance (Ap Cl), have been long adopted. The aim of our study was that of assessing whether some diagnostic tests, scarcely performed due to the novel techniques implementation, were reliable diagnostic tools. Methods Data extracted from records of two well-matched for age and gender populations was retrospectively analysed. Specifically, 17 patients with biopsy-proven chronic hepatitis were confronted with 17 subjects suffering from liver cirrhosis. Clinical, laboratory and instrumental findings, such as the Child-Pugh classification, the number connection test for evaluating hepatic encephalopathy, prothrombin time, serum albumin levels, TSBA concentration, Ap Cl determination, abdominal ultrasound and liver-spleen scan imaging as well as endoscopy features were evaluated. Results Cirrhotics showed a median concentration of TSBA increased respect to that of patients with chronic hepatitis, independently from gender, 20.1 versus 12.24 micromol/L, P= 0.0054. The median AP Cl value of the patients with liver cirrhosis was reduced confronted with that of patients with chronic hepatitis, specifically, 13.92 opposed to 18.3 mcg Ap/dL, P= 0.045. Furthermore, the median liver-spleen scan score was higher in cirrhotics than in chronic hepatitis patients, i.e., 3.47 versus 1.47, P= 0.000. The AUROCs of TSBA levels and of the liver-spleen scan scores for differentiating patients with liver cirrhosis from those with chronic hepatitis were 0.82 and 0.96, respectively. When was applied a new predictive model, combining the previous ones, the AUROC to discriminate patients belonging to the two populations was 0.98. The best cut-off of the new index was 26, with a sensitivity and specificity of 100.00% and 82.35%, respectively, correctly classifying 91.18% of the patients. Discussion Both TSBA and liver-spleen scan were high discriminant as well as their combination, while Ap Cl showed some limitations as reliable diagnostic tool. TSBA and liver-spleen scan have been too soon and unnecessarily overlooked.

Objective: This study aimed to examine the relationship between health structure disparities and hospitalizations and deaths among the pediatric population in different regions. Method: The study employed an ecological time series design, utilizing population-based secondary data ob-tained from DATASUS, from the Brazilian Ministry of Health. The data included in this study encompassed the population aged zero to 19 years, health establishments, physicians working in health establishments, hospitalizations, and deaths related to Morbidities listed in the Interna-tional Classification of Diseases. The focus was explicitly on individuals diagnosed with Cere-bral Palsy and other paralytic syndromes. The data for this study were gathered from January 2018 to December 2021. TABNET was used for data collection, and Excel for tabulation and anal-ysis. Results: Analysis of health structure data across regions revealed notable disparities, par-ticularly in the North and Northeast regions, compared to other regions. These discrepancies prompted a decision to conduct a comparative assessment between these regions and the rest of the country. Conclusion: In the North region, a significant 50% difference in hospitalizations based on residence versus a place of care was observed for individuals with Cerebral Palsy and other paralytic syndromes, indicating the necessity for relocation to access appropriate medical treatment.

Asthma is the most prevalent cause of chronic respiratory diseases. Herein, we evaluate asthma burden in Mexico based on results from the Global Burden of Disease (GBD 2019) study 2019. Using data from the GBD 2019, we estimated asthma prevalence, incidence, mortality, and disability-adjusted lived years (DALYs) counts and crude and age-standardized rates per 100,000 people with a 95% uncertainty interval (UI) by sex and age at the national and subnational levels in Mexico from 1990 to 2019. At the national level, asthma affected 3.35 million (95% UI, 2.59-4.37) people, with 606.0 thousand (433.0-811.1) new incident cases and 1,655 (3-1,931) deaths during 2019. Asthma caused a slightly higher burden in females and affected mainly age groups between 1 and 14 years of age. The burden of asthma gradually decreased from 1990 to 2010. However, during the last decade (2010-2019), prevalence increased by 8.2%, as did incidence by 11.3%, whereas mortality and DALYs decreased by 23.3 and 1.6%, respectively. Finally, the burden of asthma displayed a heterogeneous pattern of disease at the subnational level. In conclusion, asthma causes a significant health loss in Mexico that differentially affects the population distributed among the states of the country, thus causing health disparities that should be addressed to provide sustainable asthma diagnosis and control to reduce its burden, especially at early stages of life.

Chronic hepatitis B infection remains a significant worldwide health burden, placing persons at risk for hepatocellular cancer and hepatic fibrosis. Chronic hepatitis B virus (CHB) infection is characterized by elevated levels of immunosuppressive regulatory T cells (Tregs), which can inhibit the function of effector T cells and lead to an insufficient immune clearance response against HBV in the host. Theoretically, suppression of Treg functionality and percentage could increase anti-HBV reactivity in CHB-infected patients, although this has not yet been explored. We attempted to enhance our previously established anti-CHB protocol utilizing the GM-CSF+IFN-α+rHBVvac regimen (GMI-HBVac) by incorporating Mafosfamide (MAF), which has been utilized in anticancer therapy in the past. Intravenous administration of MAF to rAAV8-1.3HBV-infected mice resulted in a dose-dependent reduction of Tregs in the blood, rebounding to pretreatment levels 10 days later. To determine the efficacy of anti-CHB, 2ug/ml MAF was combined with the GMI-HBVac in an HBV-infected animal model as an anti-Treg treatment. When rAAV8-1.3HBV-infected mice were immunized with MAF+GMI-HBVac, peripheral blood Tregs decreased significantly, leading to dendritic cell activation, HBV-specific T cell proliferation, and upregulation of IFN-gamma producing CD8+T cells. In addition, MAF+GMI-HBVac vaccination stimulates T cell infiltration in HBV-infected liver. These conditions may contribute to an enhanced immune response and the clearance of HBV-associated antigens, including serum HBsAg, serum HBcAg, and HBcAg+ hepatocytes. Overall, this is the first indication that MAF was utilized as an adjuvant to deplete Tregs and paired with GMI-HBVac as a unique therapeutic vaccine regimen against established CHB mice to produce a functional cure, as seen by the remarkable clearance of HBsAg.

Background: To date, FM using middle ear packing has rarely reported. In this study, we hypothesized that middle ear packing with dexamethasone soaked gelfoam and fibrin glue over the fat graft could promote the success rate of TMP closure regardless of perforation size. Methods: Between January 2005 and July 2020, a total of 209 patients who underwent fat myringoplasty due to chronic TMP at tertiary referral center were encountered and analyzed. The success rate and audiologic outcome was analyzed. Results: The mean successful TM closure rate was 88.0 %. The success rate by different age generation was not significant difference. The size of the perforation grade showed no significant difference. The perforation site by anterior or posterior was not significant. The preoperative mean threshold of AC, BC and ABG were 55.71, 12.98 and 42.73 dB respectively. The postoperative mean threshold of AC, BC and ABG were 23.67, 12.98 and 10.69 dB. The change of preoperative and postoperative hearing showed statistically significant. Conclusion: From our results, the simple trimming of the perforation edge and middle ear packing with external ear canal packing using fibrin glue induced the stable adhesion between the remnant TM and the fat graft.

Microbiome First Medicine is a suggested 21st century healthcare paradigm that prioritizes the entire human, the human superorganism, beginning with the microbiome. To date, much of medicine has protected and treated patients as if they were a single species. This has resulted in unintended damage to the microbiome and an epidemic of chronic disorders [e.g., noncommunicable diseases and conditions (NCDs)]. Along with NCDs came loss of colonization re-sistance, increased susceptibility to infectious diseases, and increasing multimorbidity and polypharmacy over the life course. To move toward sustainable healthcare, the human micro-biome needs to be front and center. This paper presents microbiome-human physiology from the view of systems biology regulation. It also details the ongoing NCD epidemic including the role of existing drugs and other factors that damage the human microbiome. Examples are provided for two entryway NCDs, asthma and obesity, regarding their extensive network of comorbid NCDs. Finally, the challenges of ensuring safety for the microbiome are detailed. Under Microbiome First Medicine and considering the importance of keystone bacteria and critical windows of development, changes in even a few microbiota-prioritized medical decisions could make a significant difference in health across the life course.

Background: The purpose of this article is to update the diagnostic assessment, therapeutic approach, and 12-18 month follow up of patients added in the Italian Lombardy ADHD Register. Methods: Data on patients evaluated by the 18 Regional ADHD Reference Centres in the ten year period from 2011 to April 2021 were analysed. Results: 4091 of 5934 added patients received a diagnosis of ADHD. In 20.3% of cases, there was a family history of ADHD. 2879 children (70.4%) had at least one comorbidity disorder, the most common of which was learning disorder (39%). Nearly all (95.9%) received at least one psychological prescription, 17.9% of them almost one pharmacological treatment, and 15.6% a combination of both. Values of ≥5 of the Clinical Global Impressions- Severity (CGI-S) are more commonly presented by patients with a pharmacological prescription than with a psychological treatment (p < .0001). A significant improvement was reported in half of the patients followed after 1 year, with Clinical Global Impressions- Improvement (CGI-I ≤ 3). In all, 233 of 4091 are 18 year old patients. Conclusion: A ten year systematic monitoring of models of care was a fruitful shared and collaborative initiative in order to promote significant improvement in clinical practice, providing effective and continuous quality of care. The unique experience here reported should spread.

After reviewing cancer theories, cancer treatment development histories, randomized clinical trial's performance, cancer treatment strategy, trial follow-up times, and conducting numerous simulations using existing data, the authors found: (1) medical treatments come with three to four lethal factors: treatment side-effects, emotional distress and chronic dress, lack of exercises or physical inactivity, and excessive nutrition in some cases; (2) clinical trial exaggerates the benefits of fast-acting treatments and underestimates the slow-delivering adverse side effects as a result of statistical averaging, interfering effects of personal lifestyle factors, and insufficient follow-up times; (3) the benefits of medical treatments are limited by chain comparison, where surgery sets up a negative standard relative to the best way for resolving cancer; (4) the strategy of destroying the tumor is unworkable; (5) medical treatments can turn natural cancer growth curve into approximately doubly exponential curve; (6) multiple factor non-medical measures are much more powerful than medical treatments in controlling cancer growth and metastasis rates; and (7) cancer early diagnosis and over treatments are bad strategies that have great adverse impacts on cancer patients. Based on huge increases in cancer growth rate constants, substantial of loss of organ functional capacity, and severe systemic aging-like cellular damages, the authors concluded that medical treatments promote cancer growth and metastasis rates and shorten patient lives in most cases, and the claimed benefits are caused by triple biases of clinical trials. The authors believe that the better strategy for ending the global cancer epidemic is abandoning clinical trails as the research model, changing caner treatment strategy from killing cancer cells to slowing down cancer growth rates by using multiple factors optimization approach in personalized medicine.

Plants and its corresponding botanical preparations have been used for centuries due to their remarkable potentialities in both treatment and prevention of numerous affections. Hundreds of biologically active constituents are present in each whole plant matrice, working in synergism and conferring both its own protection against invaders and even providing promissory bioactive effects for human beings. The worldwide population has devoted increasing attention and preference by medicinal plants use for health promotion and disease prevention, and more recently for oxidative-stress related disorders protection. Indeed, oxidative stress-related disorders, like cardiovascular and (neuro) degenerative disorders, and even cancer have raised exponentially. Although oxidative stress is in itself intrinsic to our own metabolism, allarming sources of free radicals are daily affecting us. In fact, plant-derived bioactives present a broad spectrum of biological effects, and its antioxidant, anti-inflammatory and more recently anti-aging effects have been considered a hot topic among the medical and scientific community. Nonetheless, and although its numerous biological effects, it should not also be forgotten that some bioactive molecules are prone to oxidation and can even exert pro-oxidant effects. In this sense, the objective of the present review is to provide a detailed overview on plant-derived bioactives in oxidative stress-related disorders. Specifically, the role of phytochemicals as antioxidants and pro-oxidant agents is carefully addressed, as is its therapeutic relevance in disease prevention. Finally, an eye-opening look in overall evidence in humans is also ensured.

Boldine, a major aporphine alkaloid found in Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in Renovascular hypertension (RVH). The activation of the Renin-Angiotensin System (RAS) is crucial in the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n=5/group) were treated with boldine (50mg/kg/day, gavage) for 6 weeks after 2K1C surgery (pressure≥180mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. α-SMA and Col III were used as markers of kidney damage; ED-1 and Osteopontin (OPN) as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced UProt/UCrea ratio, plasma TBARS and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1 and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.

Pigmented corn is a gramineae food of great biological, cultural and nutritional importance for many Latin American countries, with more than 250 breeds in the American continent. It confers a large number of health benefits due to its diverse and abundant bioactive compounds. In this narrative review we decided to organize the information on the nutrients, bioactive compounds and phytochemicals present in pigmented corn, as well as their effects on human health. Phenolic compounds and anthocyanins are some of the most studied and representative compounds in these grasses, with a wide range of health properties, mainly the reduction of prooxidant molecules. Carotenoids are a group of molecules belonging to the terpenic compounds, present in a large number of pigmented corn breeds, mainly the yellow ones, whose biological activity incorporates a wide spectrum. Bioactive peptides can be found in abundance in corn, having very diverse biological effects that include analgesic, opioid, antihypertensive, etc. activity. Other compounds with biological activity found in pigmented corn are resistant starches, some fatty acids, phytosterols, policosanols, phospholipids, ferulic acid and phlobaphenes, as well as a great variety of vitamins, elements, and fibers. This review aims to disseminate and integrate the existing knowledge on compounds with biological activity in pigmented corn, in order to promote their research, interest and use by scientists, nutrition professionals, physicians, industries and the general population.

Punica granatum L., commonly known as pomegranate, is a typical fruit of Asia, Mediterranean countries, Middle East and USA areas. While in the ancient time pomegranate was considered an ornamental plant, nowadays numerous scientific studies have highlighted its antioxidant and anti-radical activities, up to consider pomegranate as a “superfood”. Pomegranate presents a high content of natural bioactive compounds (NBCs) and its consumption appears to exert numerous healthy beneficial effects, in particular, in several pathological conditions, namely in patients affected by metabolic syndrome, cancer, nephrolithiasis, urinary tract infections and neurodegenerative diseases. Moreover, recent studies pointed out the possible beneficial action of pomegranate on oral health. For these reasons, the utility of pomegranate in internal medicine and in dentistry represents a promising field, as it could permit the development of innovative natural adjuvant therapies, able to empower the standard pharmaceutical therapies.

Sphingosine 1-phosphate (S1P) is a signaling lipid molecule involved in various cellular processes. It is important to develop a quantitative method for S1P to determine endogenous levels and to investigate its functions. Especially since S1P is a tiny lipid component of most biological samples, highly sensitive analysis by LC-MS/MS is required. The main challenge in S1P analysis by chromatography is peak broadening due to the presence of a polar phosphate and zwitterion formation in S1P. In this study, we used hydrogen fluoride (HF) to efficiently remove a phosphate and then analyzed the surrogate, sphingosine, as a sharp peak by LC-ESI-MS/MS. We optimized the dephosphorylation reaction in terms of reaction time, temperature, and HF concentration. Multiple reaction monitoring (MRM) for dephosphorylated form of S1P and C17-S1P as internal standard at m/z transition 300.4&gt;282.4 (quantification ion), 300.4&gt;262.4 (qualification ion), 286.3&gt;268.2 (internal standard). This method was validated by essential parameters such as specificity, linearity, range, LOQ, LOD, accuracy, precision, and repeatability. To confirm this new method, we quantified S1P levels in various serum products (100.02 ~ 284.38 nM). To apply the method in vivo, we analyzed S1P in plasma and kidney tissues obtained from a chronic kidney disease (CKD) mouse model. S1P levels were increased only in CKD kidney tissue but not in plasma. In conclusion, by applying the dephosphorylation step with HF, we established a new sensitive LC-MS/MS quantitative method for S1P that can be applied to biological samples.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, multi-target drugs have been proposed to treat complex diseases including NASH; however, their manufacturing pro-cesses remain time- and cost-intensive and inefficient. Therefore, to overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. Through such platform, we designed a tetra-specific compound, C-192, targeting Glucagon-like peptide 1 (GLP-1), Glucagon (GCG), Fibroblast growth factor 21 (FGF21), and Interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine–choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumula-tion, and the non-alcoholic fatty liver disease activity score. Our results collectively provide clin-ical feasibility of UniStac for developing multi-specific drugs, and C-192 as an innovative thera-peutic opportunity for severe NASH, as it exerts synergistic effects across multiple targets.

Uncontrolled chronic inflammation results in cardiovascular disease and early death. In this review, we studied the impact of rheumatoid arthritis on the cardiovascular system, including the early and accelerated development of atherosclerosis, and its clinical manifestations, focusing on the inflammatory mechanisms leading to arterial wall damage, rapid atherosclerotic plaque formation, and thrombosis. Furthermore, the influence of medications used to treat rheumatoid arthritis on the cardiovascular system. The influence of chronic inflammation and medicaments on traditional cardiovascular risk factors is not the main subject of this review. We found that uncontrolled chronic inflammation and some medications directly impact all stages of atherosclerosis. In conclusion, reducing inflammation and maintaining long-term remission in rheumatoid arthritis may pre-vent early atherosclerosis. We believe that this review will encourage a better interdisciplinary approach for these patients and further research in this field.

BACKGROUND: diabetic foot ulcers (DFU) represent the main cause of major amputations and hospitalizations in diabetic patients. Aim of this study was to assess safety and cost-efficacy of intramuscular injection of peripheral blood mononuclear cells (PBMNCs), in diabetic patients with no-option chronic limb-threatening ischemia (CLTI) and small artery disease (SAD). METHODS: a retrospective study was carried out on a series of types 2 diabetic patients with DFU grade Texas 3 and no-option CLTI and SAD. All patients had undergone at least a previous revascularization and were allocated in a surgery waiting-list for major amputation. The principal endpoint evaluated at 90 days was a composite of TcPO2 values at the first toe ≥30 mmHg and/or TcPO2 increase of at least 50% from baseline and/or ulcer healing. Secondary endpoint were individual components of the primary endpoint, any serious and non-serious adverse events, direct costs at one year. RESULTS: the composite endpoint was achieved in 9 patients (60.0 %); one patient (6.7%) healed within 90 days and 26.7% and 46.7% showed TcPO2 ≥30 mmHg and a TcPO2 increase of at least 50% at 90 days, respectively. At 1-year, three (20.0%) patients underwent a major amputation (all diagnosed SAD grade III). One patient died after seven months, and seven patients (46.7%) healed. The overall median and mean cost per patient were 8,238±7,798€ and 4,426[3,798;8,262]€, respectively. CONCLUSIONS: the use of PBMNCs implants in no-option CLTI diabetic patients with SAD seems to be of help in reducing the risk of major amputation.

Kidney diseases are a global health problem, and their frequency is continuously increasing. Available treatments provide limited kidney protection. The protective effect of the green tea polyphenol epigallocatechin-3-gallate (EGCG) in several diseases have been extensively investigated. Experimental and clinical studies have shown that the antioxidant, anti-inflammatory, and anti-apoptotic properties of EGCG are promising for the treatment and/or prevention of kidney diseases. This review analyzes the available evidence on the effects, and the likely protective mechanisms of action, of EGCG in a broad spectrum of kidney diseases, including acute kidney injury, drug-induced nephrotoxicity, kidney stone disease, diabetic nephropathy, chronic kidney disease, and kidney fibrosis.

A chronic activated pro-inflammatory cytokine network (“inflamm-aging”) may amplify the neurodegenerative effects of a fall induced brain trauma in geriatric subjects. Our research aimed to evaluate how a trained machine learning algorithm may predict recent antecedent falls based only on specific serologic cytokines network analysis and how the consequences of these falls can be substantiated on standard head MRIs. All 279 subjects included in our study were selected from the ADNI1 dataset and all had a mild cognitive impairment diagnostic at the ADNI1 study baseline. A “train group” was built and included 14 subjects with a history of a recent, simple, standing-level fall. These were carefully matched with 14 similar subjects without any antecedent trauma. The “test group” included 251 subjects, all without any history of recent fall. The machine learning algorithm (classic C4.5 decision tree) was trained to detect a pattern of variation in 23 clinically relevant cytokines in relation with an antecedent fall. Changes in five cytokines (matrix metalloproteinase-7, eotaxin-1, interleukin-3, interleukin-8 and matrix metalloproteinase-9) were used for fall prediction in the “test” group. Once trained, the algorithm predicted a recent fall in 119 cases from the test group. The mean brain ventricular volume that was significantly different between fall/non-fall subgroups (41645.5±10337.2 vs 27127.3±6749.4 mm3, p=0.005) remained significant in the test group, after prediction between (41544.24±17343.4 vs 34553.5±10543.2 mm3, p=0.042). The hippocampus mean volume was also significantly different between in the test group (6297.3±1080.1 vs 6745.9±1123.7, p=0.0015). A significant brain ventricular difference was observed in the “65<y.o.” subgroup (p=0.04). If confirmed by larger prospective studies, our findings may increase the precision of the neuro-cognitive assessments in geriatric subjects.

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study conducted through cross-sectional survey. Each received a 13-point questionnaire, investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs 2019 (9161 patients): post-EVAR surveillance, treatment for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased [1484 (16.2%) vs 1014 (14.3%), p=0.0009; 1401 (15.29%) vs 959 (13.52%), p=0.0006; and 1558 (17.01%) vs 934 (13.17%), p<0.0001, respectively]; while revascularization or major amputations for chronic limb-threatening ischemia, and urgent revascularization for symptomatic carotid stenosis significantly increased [1204 (16.98%) vs 1245 (13.59%), p<0.0001; 355 (5.01%) vs 358 (3.91%), p=0.0007; and 153 (2.16%) vs 140 (1.53%), p=0.0009, respectively]. Conclusions: The suspension of elective activities during the COVID-19 pandemic caused a significant reduction in asymptomatic carotid stenosis revascularization, treatment for Rutherford 3 peripheral arterial disease, post-EVAR surveillance. Contestually, we observed a significant increase in urgent revascularization for symptomatic carotid stenosis, and revascularization or major amputations for chronic limb-threatening ischemia.

Pediatric obstructive sleep apnea (OSA) has significant negative effects on health and behavior in childhood including depression, failure to thrive, neurocognitive impairment, and behavioral issues. It is strongly associated with an increased risk for chronic adult disease such as obesity and diabetes, accelerated atherosclerosis, and endothelial dysfunction. Accumulating evidence suggests that adult-onset non-communicable diseases may originate from early life through a process by which an insult applied at a critical developmental window causes long-term effects on the structure or function of an organism. Recently, much attention has been paid to the role of epigenetic mechanisms in the pathogenesis of adult disease susceptibility. Epigenetic mechanisms that influence adaptive variability include histone modifications, non-coding RNAs, and DNA methylation. This review will highlight what is currently known about the phenotypic associations of epigenetic modifications in pediatric OSA and will emphasize the importance of epigenetic changes as both modulators of chronic disease and potential therapeutic targets.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease associated with airways inflammation and lung parenchyma fibrosis. The primary goals of COPD treatment are to re-duce symptoms and risk of exacerbations, therefore pulmonary rehabilitation is considered the key component of managing COPD patients. Oxidative airway damage, inflammation and re-duction of endogenous antioxidant enzymes are known to play a crucial role in the pathogenesis of COPD. Natural antioxidants have also recently been considered as they play an important role in metabolism, DNA repair and fighting the effects of oxidative stress. In this paper we evaluated the response of 105 elderly COPD patients to pulmonary rehabilitation (PR), based on high or low vegetable consumption, by analyzing clinical parameters and biological measure-ments at baseline and after completion of the three weeks PR. We found that high vegetable in-take in normal diet, without any specific intervention, can increase the probability to success-fully respond to rehabilitation (65.4% of responders ate vegetables daily vs. 40.0% of Non-Responders, p=0.033). Three weeks of pulmonary rehabilitation are probably too short to reveal a reduction of the oxidative stress and DNA damage, but are enough to show an im-provement in the patient's inflammatory state.

Patients with chronic obstructive pulmonary disease (COPD) often require frequent hospitalization due to worsening symptoms. Preventing prolonged hospital stay and readmission becomes a challenge for healthcare professionals treating patients with COPD. Although the integration of health and social care supports greater collaboration and enhanced patient care, organizational structure and poor leadership may hinder the implementation of patient-oriented goals. This paper presents a case of a 64-year-old chronic smoker with severe COPD who was to be discharged on long-term oxygen therapy (LTOT). It further highlights the healthcare decisions made to ensure the patient’s safety at home and further provides a long-lasting solution to the existing medical and social needs. The goal was accomplished through a discharge plan that reflects multidisciplinary working, efficient leadership, and change management using Havelock’s theory. While COPD is characterized by frequent exacerbation and hospital readmission, it was emphasized that most failed discharges could be attributed to bureaucratic organizational workflow which might not be in the patient’s best interest. It was further demonstrated that healthcare professionals are likely to miss the window of opportunity to apply innovative and long-lasting solutions to the patient’s health condition in an attempt to remedy the immediate symptoms of COPD

Chronic obstructive pulmonary disease (COPD) is a respiratory disease associated with airways inflammation and lung parenchyma fibrosis. The primary goals of COPD treatment are to re-duce symptoms and risk of exacerbations, therefore pulmonary rehabilitation is considered the key component of managing COPD patients. Oxidative airway damage, inflammation and re-duction of endogenous antioxidant enzymes are known to play a crucial role in the pathogenesis of COPD. Natural antioxidants have also recently been considered as they play an important role in metabolism, DNA repair and fighting the effects of oxidative stress. In this paper we evaluated the response of 105 elderly COPD patients to pulmonary rehabilitation (PR), based on high or low vegetable consumption, by analyzing clinical parameters and biological measure-ments at baseline and after completion of the three weeks PR. We found that high vegetable in-take in normal diet, without any specific intervention, can increase the probability to success-fully respond to rehabilitation (65.4% of responders ate vegetables daily vs. 40.0% of Non-Responders, p=0.033). Three weeks of pulmonary rehabilitation are probably too short to reveal a reduction of the oxidative stress and DNA damage, but are enough to show an im-provement in the patient's inflammatory state.

Chikungunya virus is a re-emerging mosquito-borne alphavirus. Outbreaks are unpredictable and explosive in nature. Fever, arthralgia, and rash are common symptoms during the acute phase. Diagnostic tests are required to differentiate chikungunya virus from other co-circulating arboviruses, as symptoms can overlap, causing a dilemma for clinicians. Arthritis is observed during the sub-acute and chronic phases, which can flare up, resulting in increased morbidity that adversely affects activities of daily living. During the 2019 chikungunya epidemic in Thailand, cases surged in Bangkok in the last quarter of the year. Here, we demonstrate the chronic sequelae of post-chikungunya arthritis in one of our patients 1 year after the initial infection. An inflammatory process involving edema, erythema, and tenderness to palpation of her fingers' flexor surfaces was observed, with positive chikungunya IgG and negative IgM tests and antigen. The condition produced stiffness in the patient’s fingers and limited their range of motion, adversely affecting daily living activities. Resolution of symptoms was observed with a short course of an anti-inflammatory agent. More research is required to determine whether sanctuaries enable chikungunya virus to evade the host immune response and remain latent, flaring up months later and triggering an inflammatory response that causes post-chikungunya arthritis.

Nutrition therapy is the best solution to human chronic diseases, especially beer and barley which play an important role in human health and civilization. We demonstrated the actional mechanism of functional ingredients in beer and barley to combat chronic diseases, based on PubMed, google, CNKI, and ISI Web of Science databases from 1997 to 2024. Beer is rich in functional ingredients that is a complex of barley malt and hops; the health effect of beer against 26 chronic diseases is highly similar to that of barley, due to molecular mechanism of polyphenols (phenolic acids, flavonoids), melatonin, minerals, bitter acids, vitamins, and peptides. The ancient German Beer Purity Law provides much scientific basis today, especially indirectly supporting the human one cell disease theory. Low purine beer can be produced by enzymatic and biological degradation and adsorption of purines as well as dandelion addition. Functional beer with low purine and high active ingredients made from Beer Purity and barley malt as well as functional foods addition will be the key and important development direction, such as ginger beer and ginseng beer, especially coix-lily beer at the ancestors ca. 9000 years ago. This review paper not only reveals the actional mechanism of beer overcoming human chronic diseases, but also provides scientific basis for the development of functional beer for the prevention and treatment of human chronic diseases.

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Although initially described as a tumor-cytotoxic agent, over time, it has also been recognized as an essential pro-inflammatory cytokine implicated in the pathogenesis of different autoimmune diseases, such as multiple sclerosis (MS). Several studies have shown an increase in TNF expression both in acute and chronic active MS brain lesions, as well as its involvement in maintaining a chronic inflammatory intrathecal process known as “compartmentalized inflammation”, which contributes to disease progression and disability accumulation in MS, even more than acute inflammatory activity. Indeed, high TNF levels were observed in the serum and cerebrospinal fluid of subjects with MS and correlated to disease severity, promoting axonal damage and, consequently, neurodegeneration. In this review we discuss the current knowledge of TNF and its receptors involvement in MS progression, focusing on disability progression independent of relapse activity (PIRA), meant as the disability accumulation evident in relapsing MS patients not related to acute inflammatory events.

The incidence of chronic enteropathies (CE), in particular food-responsive enteropathies (FRE) in dogs, is on the rise in veterinary practice. The symptoms of these digestive disorders cannot be alleviated with the use of commercial hypoallergenic feeds. The applicability of novel substrates in hypoallergenic dog feeds is limited, and edible insects could pose a viable alternative. Insects have a high nutritional value, and their potential can be harnessed to design personalized nutrition strategies. However, the use of insects in animal feeds should be rigorously tested. The aim of this study was to analyze the applicability of edible insects as a source of dietary protein for companion animals, including the current and future prospects. Canine food formulas should be evaluated in a clinical setting. The role edible insects in pet diets and the efficacy of this substrate in animal nutrition should be examined in advanced clinical trials in gastroenterology, histology, immunology, and microbiology. These efforts are required to guarantee the safety and efficacy of innovative insect-based feeds and to increase their popularity among veterinary practitioners, pet food producers, and animal owners.

Malnutrition is prevalent in patients with chronic kidney disease (CKD), especially those on hemodialysis. Recently, our group described that a new oral nutritional supplement (ONS) for malnourished (or at-risk) hemodialysis patients with a "similar to the Mediterranean diet" model, improved caloric and protein intake, nutritional status and inflammation and oxidation biomarkers. Our aim in this study was to evaluate whether the new ONS, including probiotics, may produce changes in miRNAs expression and its target genes in malnourished hemodialysis patients, compared to individualized diet recommendations. We conducted a randomized, multicenter, parallel-group study in malnourished hemodialysis patients divided in 3 groups (1: Control -C- individualized diet 2: Oral nutritional supplement -ONS- + placebo -ONS-PL- and 3: ONS + probiotics -ONS-PR). Study registration: NCT03924089. The trial was open to the ONS diet or individual dietary advice, but double-blind for the intake of probiotics supplements. MiRNAs and gene expression levels were analyzed by RT-qPCR at baseline and after 3 and 6 months. We observed that the expression of miR-29a and miR-29b increased significantly in patients with ONS-PR at 3 months in comparison with baseline, stabilizing at the sixth month. Moreover, we observed differences between studied groups, where miR-29b expression levels were elevated in patients receiving ONS-PR compared to the control group in the third month. Regarding the gene expression levels, we observed a decrease in the ONS-PR group compared to the control group in the third month for RUNX2 and TNFα. TGFB1 expression was decreased in the ONS-PR group compared to baseline in the third month. PTEN gene expression was significantly elevated in the ONS-PR group at 3-months in comparison with baseline. LEPTIN expression was significantly increased in ONS-PL group at 3-month intervention compared to baseline. The new Oral Nutritional Supplement associated with probiotics; increases the expression levels of miR-29a and miR-29b after 3 months of intervention, modifying the expression of target genes with anti-inflammatory and anti-fibrotic actions. This study highlights the potential benefit of this Oral Nutritional Supplement, especially associated with probiotics, in malnourished patients with chronic renal disease on hemodialysis.

Haemolytic anaemia represents a risk factor for the development of pulmonary hypertension (PH), currently classified as World Health Organization group 5 PH and data regarding appropriate therapeutic strategy are limited. A total of 28 patients, 85.7% with thalassemia and 14,3% with sickle cell disease, with a diagnosis of PH confirmed by right heart catheterization, were included in the study. The patients were divided into three groups according to haemodynamics and overall diagnostic approach: 42,9% had precapillary PH (Pulmonary Arterial Hypertension -PAH group), 25% post-capillary PH and 32.1% Chronic Thromboembolic PH (CTEPH) (29% of b-thalassemia and 50% of SCD patients). The therapeutic approach in each group and its impact on the outcome and haemodynamics was recorded. PAH-specific drug therapy received 82.1% of patients and Balloon Pulmonary Angioplasty (BPA) was performed in 6 patients with CTEPH. There were statistically significant differences in baseline mPAP and PVR values between the CTEPH-haemolytic anaemia group and other groups. PAH-specific drug therapy resulted in haemodynamic improvement for PAH-group. Patients who underwent BPA improved Pulmonary Haemodynamics. Median survival time was 162 months and the survival rate was 1yr-100%, 2,3,4,5,6 years 96%, 9yrs 90% and 13yrs 78%. In patients with haemolytic anaemia, the wide spectrum of induced PH highlights the importance of a correct diagnosis. BPA in CTEPH patients and specific-PAH drug therapy for PAH patients represent potential therapeutic strategies, however the management should be offered in expert PH centers under patients’ individualized approach.

The aim of the present study was to investigate whether chronic undernutrition modifies the response to rostafuroxin in juvenile rats. Chronic undernutrition was induced in male rats using a multideficient diet known as Regional Basic Diet (RBD), mimicking alimentary habits in impoverished regions worldwide. Animals were given RBD – or a control/CTRL normal diet for rodents – from weaning to 90 days, and rostafuroxin (1 mg/kg body mass) or vehicle were orally administered during the last 30 days. Undernourished rats became hypertensive at 55–60 days of age (tail-cuff recording). During the last two days, the rats were hosted in metabolic cages to measure food/energy, water, Na⁺ ingestion, and urinary volume. Blood and kidneys were collected after euthanasia. Rostafuroxin increased food/energy and Na⁺ intake in CTRL and RBD rats but had opposite effects on Na⁺ balance (intake minus urinary excretion): negative in CTRL and positive in RBD. The drug normalized the decreased plasma Na⁺ concentration found in RBD rats, increased urinary volume in RBD but not in CTRL, and decreased and increased urinary Na⁺ concentration in the RBD and CTRL groups, respectively. Rostafuroxin decreased the ouabain-sensitive (Na⁺+K⁺)ATPase and increased the ouabain-resistant, furosemide-sensitive Na⁺-ATPase from proximal tubule cells in both groups, and normalized the systolic blood pressure in RBD without effect in CTRL rats. We conclude that chronic undernutrition modifies the response of blood pressure, caloric metabolism, Na⁺ distribution in liquid compartments, mobilization of Na⁺ from non-osmotic compartments, Na⁺ and water balance, and activity of renal Na⁺-transporting ATPases to rostafuroxin.

According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are 4 main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans by undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.

The aim of the present study was to investigate whether chronic undernutrition modifies the response to rostafuroxin in juvenile rats. Chronic undernutrition was induced in male rats using a multideficient diet known as Regional Basic Diet (RBD), mimicking alimentary habits in impoverished regions worldwide. Animals were given RBD – or a control/CTRL normal diet for rodents – from weaning to 90 days, and rostafuroxin (1 mg/kg body mass) or vehicle were orally administered during the last 30 days. Undernourished rats became hypertensive at 55–60 days of age (tail-cuff recording). During the last two days, the rats were hosted in metabolic cages to measure food/energy, water, Na+ ingestion, and urinary volume. Blood and kidneys were collected after euthanasia. Rostafuroxin increased food/energy and Na+ intake in CTRL and RBD rats but had opposite effects on Na+ balance (intake minus urinary excretion): negative in CTRL and positive in RBD. The drug normalized the decreased plasma Na+ concentration found in RBD rats, increased urinary volume in RBD but not in CTRL, and decreased and increased urinary Na+ concentration in the RBD and CTRL groups, respectively. Rostafuroxin decreased the ouabain-sensitive (Na++K+)ATPase and increased the ouabain-resistant, furosemide-sensitive Na+-ATPase from proximal tubule cells in both groups, and normalized the systolic blood pressure in RBD without effect in CTRL rats. We conclude that chronic undernutrition modifies the response of blood pressure, caloric metabolism, Na+ distribution in liquid compartments, mobilization of Na+ from non-osmotic compartments, Na+ and water balance, and activity of renal Na+-transporting ATPases to rostafuroxin.

The ageing of the population is growing significantly and will challenge healthcare systems. Chronic diseases in the older population require a change in service delivery, and new technologies can be a key element in ensuring the viability and sustainability of these systems. However, the generation gap and the physical and cognitive decline commonly associated with the older generation are barriers to the transition to these models of care. Despite this, there has been a trend towards digital healthcare, which has many potential benefits for the older population. Numerous studies have assessed the acceptability of new technologies for older people in health care. These studies highlight the importance of perceived usefulness, compatibility, ease of use and personalisation of the technology. Personalisation is necessary to ensure that the system is useful for users, and different characteristics such as country of origin, gender, age or comfort with the technology should be taken into account. A person-centred approach in the development of new health technology systems is essential to ensure that applications can be better tailored to the needs of different ageing populations. Many organisations have dedicated time and resources to ensure a person-centred approach in the development of new health technology systems, and putting the individual first is the best way forward in digital health. This article presents the work carried out in this regard in the framework of the European TeNDER project together with an analysis of the results obtained in terms of satisfaction, usefulness and usability by end users.

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans. Increasing data suggest that CVD is closely related to lipid metabolism and signaling. This study aimed to assess whether circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as biomarkers of CVD. For this objective, the evolution of the plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) was monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS²) in different rat models of CVD, i.e. angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there was modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4), LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after correction for multiple testing. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in the 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on isolated human pulmonary smooth muscle cells with an increase in their proliferation. This study demonstrates that circulating LPA species are increased in rats with PH and may contribute to the pathophysiology of this disease. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest.

Current pharmacological treatments of Fibromyalgia (FM) are merely symptom palliative, as clinical trials have so far failed to provide overall benefits without associated harms. Polypharmacy often leads to patient´s health deterioration and chronic drug use to an eventual lack of patient´s response. Emerging evidence support that physiotherapy treatments based on mechanical triggers improve FM symptoms and therefore could be used for therapeutic purposes by themselves, or in combination with current pharmacological treatments, as part of integrative medicine programs. However, a paucity of studies rigorously and systematically evaluating this possibility exists. This study uses scores from validated standardized questionnaires, algometer pressure point threshold (PPT) readings and responses from a custom self-developed questionnaire to determine the impact of a pressure-controlled manual protocol on FM hyperalgesia/allodynia, fatigue and patient´s quality of life. The results show that patient´s baseline sensitivity to pain inversely correlates with treatment response in FM. Moreover, patients presenting comorbid ME/CFS do not seem to respond to the applied therapy as those presenting FM only. Thus, pre-treatment PPTs and ME/CFS comorbidity may serve as indicators to predict patient´s response to physiotherapy programs based on mechanical triggers, as the one evaluated here. These unexpected findings grant further explorations including the study of gene expression profiles associating to patient´s treatment response in the blood collection of samples generated by this study.

Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments but also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation by their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with an oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Despite the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Beside an introductory chapter and a peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated to the regulation of cysteine cathepsins by redox balance and by oxidants (e.g. Michael acceptors, reactive oxygen and nitrogen species).

The worldwide competition to vaccinate against COVID-19 has highlighted the importance of immunization measures in containing the virus. Saudi Arabia, like the rest of the globe, must assess socio-demographic subtleties, chronic illnesses, vaccination effects, and public health policy implications as it navigates this complicated environment. This cross-sectional study examined Saudi COVID-19 vaccine in many ways. It examined the socio-demographic makeup of vaccine recipients, the prevalence of chronic conditions in this population, vaccine administration patterns, post-vaccination side effects, and vaccine-infection rates. A questionnaire-based online survey of 401 participants ensured gender, nationality, age, weight, and educational diversity. We analyzed vaccine manufacturer choice for each dosage, side effects after the first and second doses, and chronic diseases in the sample. Pfizer/BioNTech vaccines are preferred for all three doses, reflecting worldwide vaccination acceptance patterns. Side effects were not significantly different between vaccination kinds. Interestingly, immunization reduced infection rates, demonstrating the efficacy of COVID-19 vaccines. The data fills important information gaps and illuminates Saudi COVID-19 vaccination kinetics. These data support the global preference for mRNA vaccines, demonstrating the faith in this breakthrough technology. They also sponsor COVID-19 vaccine safety and effectiveness studies. The dramatic drop in infection rates among vaccinated people shows how vaccinations suppress the pandemic. These findings inform Saudi Arabia's immunization efforts. As booster doses become more common, long-term vaccination research is crucial. Vaccine reluctance, especially in certain demographics, must be addressed. Due to vaccines' protective potential, equitable vaccine distribution and large immunization programs are essential for herd immunity and pandemic management. This thorough cross-sectional study helps policymakers and healthcare practitioners build successful and inclusive COVID-19 immunization regimens in Saudi Arabia.

Long-acting (LA) drug-delivery system (DDS) successes are linked to their abilities to harness biocompatible polymers and materials for sustained and predictable release of therapeutic agents over an extended period of time. For human immune deficiency virus type one (HIV-1) infections, LA DDSs hold great promise in closing the gaps of daily oral therapy for treatment and prevention. Examples are Cabenuva, Apretude and Sunlenca, which have been shown to be safe and effective. Alternative promising drug delivery technologies such as implants, prodrugs, vaginal rings, and microarray patches are being explored to further meet patients’ needs. We posit that improved physicochemical properties of the formulation payloads and material chemistry design with optimal drug release kinetics holds the potential to optimize release profiles. Furthermore, for the treatment and prevention of HIV-1 infection, the landscape of LA medicines now in clinical or preclinical development offers hope that the strategic design of polymers will further improve upon controlled delivery of drugs to simplify dosing schedules.

Background. IgA nephropathy (IgAN) is associated with chronic inflammation. Platelet-related parameters, such as platelet (PLT) count, platelet-to-albumin ratio (PAR) and platelet-to-lymphocyte ratio (PLR), were examined as potential prognostic indicators for renal and cardiovascular (CV) outcomes in IgAN. Methods. 150 IgAN patients were devided into two groups based on the cut-off value of PAR. All-cause mortality, major CV events and end-stage renal disease were the primary combined endpoints. Secondary endpoints, such as CV or renal endpoints, were also analyzed separately. Results. The patient’s mean age was 43.7 ± 13.5 years, and the follow-up time was 124 ± 67 months. The K-M curve showed that PLR, PAR and PLT were strongly associated with primary combined (p = 0.002, p = 0.004, p = 0.001) and renal outcomes (p < 0.001, p < 0.001, p < 0.001), but not with CV outcomes in IgAN. However, when combined with left ventricular hypertrophy (LVH) or metabolic syndrome (MetS) PAR was found to be a significant predictor of both primary (p < 0.001, p < 0.001) and secondary outcomes (p = 0.001 and p = 0.038; p = 0.001 and p = 0.015). Additionally, PLR correlated with microalbuminuria (r = -0.165, p = 0.033) and LVH (r = -0.178, p = 0.025), while PLT correlated with eGFR (r = 0.158, p = 0.040). Conclusion. Elevated PAR and PLR may predict progression to end-stage kidney disease, but in combination with LVH and MetS, they showed CV events also in IgAN. The determination of PAR and PLR can be useful and cost-effective parameters for assessing both cardiovascular and renal risks in CKD.

Ecological changes evoke many felt losses and types of grief. These affect sustainability efforts in profound ways. Scholarship on the topic is growing, but the relationship between general grief research and ecological grief has received surprisingly little attention. This interdisciplinary article applies theories of grief, loss, and bereavement to ecological grief. Special attention is given to research about “non-death loss” and other broad frameworks about grief. Dynamics related to both local and global ecological grief are discussed. Kinds of potential losses arising out of ecological issues are clarified with the frameworks of tangible/intangible loss, ambiguous loss, nonfinite loss, and shattered assumptions. Various possible types of ecological grief are illuminated by discussing the frameworks of chronic sorrow and anticipatory grief/mourning. Earlier scholarship about disenfranchised ecological grief is augmented by further distinctions about various forms it may take. The difficulties in defining complicated or prolonged grief in ecological context are discussed, and four types of “complicated ecological grief” are explored. Based on the findings, three special forms of ecological loss and grief are named and discussed: transitional loss and grief, lifeworld loss, and shattered dreams. The implications of the results for ecological grief scholarship, counselling and coping are briefly discussed. The results can be used by psychological and healthcare professionals and researchers, but also by members of the public who wish to reflect on their eco-emotions.

Background: This study analyzes sex-based differences in renal structure and response to the Angiotensin-Converting Enzyme (ACE) inhibitor enalapril in a mouse model of atherosclerosis. Methods: ApoE-/- mice (8 weeks old) received enalapril (5 mg/kg/day, subcutaneous) or PBS as a control for an additional 14 weeks. Each group consisted of six males and six females. Results: Females exhibited elevated LDL-cholesterol levels, while males presented higher creatinine levels and proteinuria. Enalapril effectively reduced blood pressure in both groups, but proteinuria decreased significantly only in females. Plaque size analysis and assessment of kidney inflammation revealed no significant sex-based differences. However, males displayed more severe glomerular injury, with increased mesangial expansion, mesangiolysis, glomerular foam cells and activated parietal epithelial cells (PECs). Enalapril mitigated mesangial expansion, glomerular inflammation (particularly in females), and the hypertrophy of PECs in males. Conclusion: This study demonstrates sex-based differences in the response to enalapril in a mouse model of atherosclerosis. Males exhibited more severe glomerular injury, while enalapril provided renal protection, particularly in females. These findings suggest potential sex-specific considerations for ACE inhibitor therapy in chronic kidney disease and atherosclerosis cardiovascular disease. Further research is needed to elucidate the underlying mechanism behind these observations.

A relatively loud sound is audible when a vibrator is attached to the aural cartilage. This form of conduction is referred to as cartilage conduction (CC). In Japan, a new type of hearing aid has been developed using CC and is available in clinical practice since 2017. A clinical study conducted prior to its launch demonstrated its benefits, particularly in patients with aural atresia who were unable to use air-conduction hearing aids. Several studies have been published on the benefits of CC hearing aids since their introduction in clinical practice. Most of the patients included in these studies had canal stenosis or aural atresia, and the purchase rates of CC hearing aids in these patients were relatively high. However, the number of patients with open ears was small, with overall poor results in the trials, with the exception in patients with continuous otorrhea. CC hearing aids are considered a good option for compensating hearing loss in ears with canal stenosis or atresia in both bilateral and unilateral cases. However, CC hearing aids are not currently considered the first choice for patients with an open ear,.

Background: Portable oxygen concentrators (POCs) have shown efficacy in delivering adequate oxygen for various patient scenarios; however, there is a lack of research on POCs’ efficacy across different respiratory rates specifically among COPD patients. Methods: This bench study was conducted using the IngMar Medical Active Servo Lung 5000 attached to flexible tubing, which simulated an adult patient’s nares. An oxygen analyzer (Maxtec Handi+) was connected to the tubing 6 inches below the nares to estimate the inspired oxygen concentration at the adult trachea. A standard nasal cannula was placed in the simulated patient nares, which was also attached to each POC. The IngMar Lung was programmed to simulate a COPD patient at the following respiratory rates: 15, 20, 30, and 40 breaths/min. POC devices were then compared to an oxygen wall outlet and a standard oxygen concentrator (non-portable CAIRE device). The POCs included the CAIRE FreeStyle Comfort (with Autosat), CAIRE FreeStyle Comfort (without Autosat), Inogen G4, Inogen G5, Phillips SimplyGo Mini, GCE Zen-O lite, Drive Medical iGo2, and Kingon POCs. Descriptive statistics and ANOVAs were computed to determine statistically significant differences between POCS and control devices (wall oxygen and standalone oxygen concentrator). Results: Across most respiratory rate scenarios, the wall oxygen and standalone oxygen concentrator (control group) resulted higher oxygen measurements compared to the POCs. Among the POCs on setting 2, the highest oxygen measurement for 15, 30, and 40 breaths/min was the CAIRE FreeStyle Comfort with AutoSat on sensitivity 5 (24.43%, 24.81%, and 25.0%, respectively). On setting 2, the 20 breaths/min highest oxygen measurement was the Inogen G4 (24.43%). For setting 5, the highest oxygen measurement for 15 breaths/min and 40 breaths/min was the CAIRE FreeStyle Comfort without AutoSat (31.56% and 26.13%, respectively), while the highest oxygen measurement for 20 breaths/min was the Inogen G5 (30.26%), and the highest oxygen measurement for 30 breaths/min was the CAIRE FreeStyle Comfort with AutoSat on sensitivity level 5 (27.89%). Conclusions: The oxygen administered through the wall and the standalone CAIRE oxygen concentrator all delivered higher oxygen levels compared to the POCs (with the exception of the 40 breaths/min scenario on setting 2). However, among the POCs, the CAIRE Freestyle Comfort with AutoSat, CAIRE Freestyle Comfort without AutoSat, and the Inogen G4 all performed the best among the various breathing rate scenarios.

Geriatric decisional capacity assessment is a complex medico-legal activity that evaluates normal subjects involved in specific civil matter like wealth transfer, access to treatment or voluntary hospitalization. Our objective was to evaluate how geriatric extrajudicial capacity exams impacted a general psychiatric unit over a decade. We also assessed the value of a surrogate biomarker (neutrophils to lymphocyte ratio) as a screening factor in the capacity assessment process. 72 cases were assessed in one psychiatric unit over a decade (2009-2018). As population was fast ageing, the total number of capacity exams per year doubled in time. None of the subjects had an active diagnostic of severe cognitive impairment or active psychiatric disease. The percentage of subjects receiving an “absence of capacity” conclusion remained constant over time (approx. 20% of all cases). 81% of the subjects within this subgroup had a clinical diagnostic of mild cognitive impairment compared to 46% in the “presence of capacity” subgroup (p&lt;0.001). The surrogate biomarker neutrophils to lymphocyte ratio was significantly higher in the “absence of capacity” subgroup, mainly related to a cognitive impairment diagnostic. The ratio has to be validated by larger studies before to be included in the capacity assessment process as an early screening tool.

ME/CFS (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome) is a chronic, complex, heterogeneous disease that affects millions and lacks both diagnostics and treatments. Big data, or the collection of vast quantities of data that can be mined for information, has transformed the understanding of many complex illnesses like cancer (1,2) and multiple sclerosis (3,4), by dissecting heterogeneity, identifying subtypes, and enabling the development of personalized treatments. It is possible that big data can reveal the same for ME/CFS. Solve M.E. developed and launched the You + ME Registry to collect longitudinal health data from people with ME/CFS, people with Long COVID (LC) and control volunteers using rigorous protocols designed to harmonize with other groups collecting data from similar groups of people. The Registry is an invaluable resource because it integrates with a symptom tracking app, as well as a biorepository, to provide a robust and rich dataset that is available to qualified researchers. Accordingly, it facilitates collaboration that may ultimately uncover causes and help accelerate the development of therapies.

The is a sequential article to an initial review suggesting that Microbiome First medical approaches to human health and wellness could both aid the fight against noncommunicable diseases and conditions (NCDs) and help to usher in sustainable healthcare. This current review article specifically focuses on public health programs and initiatives and what has been termed by medical journals as a catastrophic record of recent failures. Included in the review is a discussion of the four priority behavioral modifications (food choices, cessation of two drugs of abuse, and exercise) advocated by the World Health Organization as the way to stop the ongoing NCD epidemic. The lack of public health focus on the majority of cells and genes in the human superorganism, the microbiome, is highlighted as is the “regulatory gap” failure to protect humans, particularly the young, from a series of mass population toxic exposures (e.g., asbestos, trichloroethylene, dioxin, polychlorinated biphenyls, triclosan, bisphenol A and other plasticizers, polyfluorinated compounds, herbicides, food emulsifiers, high fructose corn syrup, certain nanoparticles, endocrine disruptors, obesogens). The combination of early life toxicity for the microbiome and connected human physiological systems (e.g., immune, neurological), plus a lack of attention to the importance of microbial rebiosis has facilitated rather than suppressed, the NCD epidemic. This review article concludes with a call to place the microbiome first and foremost in public health initiatives as a way to both rescue public health effectiveness and reduce the human suffering connected to co-morbid NCDs.

Approximately 240 million people are chronically infected with hepatitis B virus (HBV), despite four decades of an effective HBV vaccine. During chronic infection, HBV forms two distinct templates responsible for viral gene transcription: (1) episomal covalently closed circular (ccc)DNA and (2) host-genome integrated viral templates. Multiple ubiquitous and liver-specific transcription factors are recruited onto these templates and modulate viral gene transcription. This review details the latest developments in antivirals that inhibit HBV gene transcription, and their impact on the stability of viral transcripts. Notably, nuclear receptor agonists exhibit potent inhibition of viral gene transcription from cccDNA, small molecule inhibitors repress HBV X protein-mediated transcription from cccDNA and small interfering RNAs and single-stranded oligonucleotides result in transcript degradation from both cccDNA and integrant templates. These antivirals mediate their effects by reducing viral transcripts abundance, eventually leading to loss of surface antigen expression, and can potentially be added to the arsenal of drugs with demonstrable anti-HBV activity. Thus, these candidates deserve special attention for future repurposing or further development as anti-HBV therapeutics.