Aim. The purpose of the work was the development of a machine learning model for diagnosing the stage of liver fibrosis in patients with chronic viral hepatitis C according to the data of routine clinical examination. Materials and methods. A total of 1240 patients with chronic viral hepatitis C was examined. A set of data obtained from 689 patients balancing by the stage of liver fibrosis was used for developing and testing machine learning models. 9 routine clinical parameters were selected as the most important predictors for determining the likelihood of liver fibrosis the 3–4 stages presence: age, height, weight and body mass index of the patient, the number of platelets in the clinical blood test, levels of alanine transaminase, aspartate transaminase, gamma-glutamyltransferase, and total bilirubin in a biochemical blood test. Results. The accuracy of the developed method for determining the 3–4 stages of liver fibrosis in patients with chronic viral hepatitis C in comparison with the «gold standard» of diagnosis (liver biopsy) was 80.56% (95% CI: 69.53–88.94%), sensitivity — 66.67%, specificity — 94.44%. Conclusion. The developed method is an alternative to more expensive and geographically inaccessible studies. The method does not require the purchase of additional equipment or software, as well as additional laboratory tests, when used in real clinical practice. The introduction of the method into clinical practice can help to solve the problem of low material and territorial availability of diagnostic tests and allow determining the stage of liver fibrosis in patients with chronic viral hepatitis C.

(1) Background: The goal of the study was to evaluate psychological tolerance and health-related quality of life (QOL) in head and neck (HN) cancer patients treated with definitive accelerated radiotherapy (DART); (2) Methods: Seventy-six recurrence-free patients eligible for the study, who were treated with DART in the CAIR-2 phase III clinical study (median of follow-up=47 months), completed EORTC QLQ-C30 with H&N35 module, Hospital Anxiety and Depression Scale (HADS) and Visual–Analog Scales (VAS) of pain in HN and the neck / arm area.; (3) Results: The most dominating symptoms measured with QLQ-C30 were: fatigue (44/100), sleeplessness (39/100), financial problems (38/100) and pain (32/100). Within H&N35 the highest scores were reported on the subscales of sticky saliva (60/100), mouth dryness (65/100) and increased intake of painkillers (50/100). Pain (VAS) was reported by 87% (HN area) and 78% (shoulder) of the patients, with a mean score of 3/10. One-third reported depressive mood (HADS≥15 points) with an average score of 12.5/42 p. The depressed group, who smoked more as compared to non-depressed before DART (96% vs 78%) and required steroids treatment (85% vs 58%) during DART, also scored significantly worse on 23 of 35 subscales of QLQ-C30 and H&N35 and experienced more intense pain (VAS). Women, and less advanced patients scored better in several aspects of the quality of life; (4) Conclusions: Patients treated with DART struggle with low quality of life and persisting treatment-related symptoms including constant pain. HNC survivors, especially those, who are depressed, may require additional psychosocial, rehabilitation and medical intervention programs..

Background and objectives: Since 2013, highly effective direct-acting (DAA) chronic hepatitis C (CHC) antiviral therapy became available, which has cure rates of over 95%. For choice of optimal CHC treatment, assessment of hepatitis C virus (HCV) genotype (GT) and liver fibrosis stage are necessary. Information about distribution of these parameters among CHC patients in Baltic states and especially in Ukraine is scarce. This study was performed to obtain epidemiological data regarding CHC GT and fibrosis stage distribution for better planning of resources and prioritization of patients for DAA drug treatment according to disease severity in high-income (Baltic states) and lower-middle income (Ukraine) countries. Materials and Methods: This was an epidemiological, retrospective, cross-sectional study that included 1451 CHC patients. Demographic and disease information from medical charts was collected for each patient during a single visit. Results: Most frequent suspected mode of viral transmission was blood transfusions (17.8%), followed by injection drug use (15.7%); however, in 50.9% of patients exact mode of transmission was not clarified. In Ukraine (18.4%) and Estonia (26%) transmission by the injection drug use was higher than in Lithuania (5%) and Latvia (5.3%). Distribution of HCV GT among patients with CHC was as follows: GT1 - 66.4%; GT3 - 28.1; and GT2 - 4.1%. The prevalence of GT1 was the highest in Latvia (84%), and the lowest in Ukraine (63%, p<0.001). Liver fibrosis stages were distributed as follows: F0 - 12.2%, F1 - 26.3%, F2 - 23.5%, F3 – 17.1% and F4 - 20.9%. Cirrhosis (F4) was more prevalent in Lithuanian patients (30.1%) than in Estonians (8.1%, p <0.001). Conclusions: This study contributes to the knowledge of epidemiological characteristics of HCV infection in the Baltic states and Ukraine. The data regarding the patterns of HCV GT and fibrosis stage distribution will be helpful for the development of national strategies to control HCV infection in the era of DAA therapy.

Beyond plasma glucose-lowering in patients with type 2 diabetes, sodium- glucose cotransporter 2 inhibitors (SGLT2i) significantly reduced the hospitalization for heart failure (HF) and retarded the progression of chronic kidney disease (CKD). Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), and is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2i have shown an improvement in endothelial dysfunction, as assessed by flow-mediated vasodila-tion, in individuals at high risk for CVD. Along with an improvement of endothelial dysfunction, SGLT2i showed improvements in oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity such as advanced glycation end products signaling and nitric oxide bioavailability. The improvements in endothelial dysfunc-tion and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy which cause HF and in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2i might have been largely induced by the improvement of vascular endothelial function by SGLT2i.

This study aimed to evaluate the proliferation and migration of fibroblast cells derived from chronic wounds and investigate the impact of low-level laser therapy (LLLT) on their growth and migration. A total of 60 dermal samples were obtained from three sites of chronic pressure ulcers and diabetic ulcers in 20 patients. Following collection in the operating room, the dermal samples were isolated using the procedure described by Freshney RI. Fibroblasts from the wound base (Site 1) exhibited a slow proliferation rate and a decrease in proliferative capacity. Fibroblasts from wound margins (Site 2) and adjacent healing skin (Site 3) could be successfully isolated and maintained for multiple generations without any morphological changes. Fibroblasts from chronic wounds at Sites 2 and 3 showed slower proliferation rates and reduced migration capabilities compared to normal dermal fibroblasts (control samples). The fibroblast cells were exposed to LLLT at different energy levels (2.5, 3, and 3.5 J/cm2). The laser-treated groups demonstrated a significantly higher increase in cell count compared to the control sample, with the highest increase observed at an energy level of 3 J/cm2. These findings suggest that LLLT at an energy level of 3 J/cm2 could effectively enhance fibroblast migration, indicating its potential as a therapeutic intervention for chronic wounds.

In chronic hepatitis C (CHC) patients, interferon-based treatments showed toxicity, limited efficacy, and psychiatric manifestations. Direct-acting antiviral (DAA) agents appeared safer, though it remains unclear if they may exacerbate or foster mood symptoms in drug-naïve CHC patients. We evaluated 62 CHC patients’ mental status, before and 12 weeks after DAA therapy, by assessment scales and psychometric instruments. We subdivided patients into two groups, CHC patients with (Group A) or without (Group B) a current and/or past psychiatric history. After DAA treatment, Group A patients showed low anxiety and improved depression, no variation in self-report distress, but worse general health perceptions. No significant difference emerged from coping strategies. Depression and anxiety improved in Group B, and no change emerged from total self-reported distress, except for somatization. Moreover, Group B increased problem-focused strategies for suppression of competing activities, and decreased strategies of instrumental social support. Contrarily, Group B reduced significantly emotion-focused strategies, such as acceptance and mental disengagement, and improved vitality, physical and social role functioning. DAA therapy is safe and free of hepatological and psychiatric side effects in CHC patients, regardless of current and/or past psychiatric history. In particular, patients without a psychiatric history also remarkably improved their quality of life.

Background. Rheumatoid arthritis (RA) is a chronic inflammatory and autoimmune disorder which affects the joints in the wrists, fingers, and knees. RA is often associated with depressive and anxiety symptoms as well as chronic fatigue syndrome (CFS)-like symptoms.Aim. To examine the association between depressive symptoms (measured with the Beck Depression Inventory, BDI), anxiety (Hamilton Anxiety Rating Scale, HAMA), and CFS-like (Fibro-fatigue Scale) symptoms and immune-inflammatory, autoimmune, and endogenous opioid system (EOS) markers, and lactosylceramide in RA. Methods. The serum biomarkers were assayed in fifty-nine RA and fifty-nine patients without increased psychopathology (PP) and fifty healthy controls.Results. There were highly significant correlations between the BDI, FF, and HAMA scores and severity of RA, as assessed with the DAS28-4, clinical and disease activity indices, the number of tenders and swollen joints, and patient and evaluator global assessment scores. A common latent vector (reflective model) could be extracted from the PP and RA-severity scales, which showed excellent psychometric properties. Partial least squares analysis showed that 69.7% of the variance in this common core underpinning PP and RA symptoms could be explained by the regression on immune-inflammatory pathways, rheumatoid factor, anti-citrullinated protein antibodies, CD17, and mu-opioid receptor levels. Conclusions. Depression, anxiety, and CFS-like symptoms due to RA are reflective manifestations of the phenome of RA and are mediated via the effects of the same immune-inflammatory, autoimmune, and EOS pathways and lactosylceramide that underpin the pathophysiology of RA. These PP symptoms are clinical manifestations of the pathophysiology of RA.

Background: Clinical trails have revealed that patients with depression generally accompanied with learning and memory impairment, which critically impact on individual’s health and development. Danggui-Shaoyao-San (DSS), a famous Chinese complex prescription, significantly overcame depression and relieved cognitive disorder based on previous research and publication. However, its effectsand potential mechanism against chronic restraint stress (CRS) remained unknown. Methods: CRS animal model was established and mice were divided to six groups while they were oral administrated with Danggui-Shaoyao-San at doses of 1.25, 2.5 and 5 g/kg for 14 days. Emotional and cognitive performances were detected by behavior tests, meanwhile neural plasticity and its molecular mechanism were examined by Dil staining, western blot and immunofluorescence. Results: DSS treatment dose-dependently improved locomotion ability in open filed test, overcame depression behavior in forced swimming test and elevated plus maze test, enhanced learning and memory ability in Morris water maze test. CRS decreased number of total spines and mushroom spines, while DSS treatment dose-dependently restored these by Dil staining. Expression of BDNF and GluR1 were significantly down-regulated in CRS group, which were significantly normalized by DSS. Conclusions: DSS treatment dose-dependently reversed CRS-induced cognitive impairments by inducing structural remodeling of neurons.

Chronic diseases are still known as incurable diseases, and we suspect that the medical research model is unfit for characterizing chronic diseases. In this study, we examined accuracy and reliability required for characterizing chronic diseases, reviewed implied presumptions in clinical trials and assumptions used in statistical analysis, examined sources of variances normally encountered in clinical trials, and conducted numeric simulations by using hypothetical data for several theoretical and hypothetical models. We found that the sources of variances attributable to personal differences in clinical trials can distort hypothesis test outcomes, that clinical trials introduce too many errors and too much inaccuracies that tend to hide weak and slow effects of treatments, and that the means of treatments used in statistical analysis have little or no relevance to specific patients. We further found that a large number of uncontrolled co-causal or interfering factors normally seen in human subjects can greatly enlarge the means and the variances of the experimental errors, and the use of high rejection criteria (e.g., low p values) further raises the chances of failing to find treatment effects. As a whole, we concluded that the research model using clinical trials is wrong on multiple grounds, under any of our realistic theoretical and hypothetical models, and that misuse of statistical analysis is most probably responsible for failure to identify treatment effects for chronic diseases and to detect harmful effects of toxic substances in the environment. We proposed alternative experimental models involving the use of single-person or mini optimization trials for studying low-risk weak treatments.

This study investigates the therapeutic potential of new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner's chronic unpredictable mild stress model of depression in 48 male Wistar rats was used a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group receiving saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to intact animals. These results suggest that Compound I has a reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. Recently, we generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

Takotsubo syndrome (TTS) is a cardiomyopathy that presents clinically as a transient and reversible left ventricular wall motion abnormality (LVWMA) that can recover spontaneously within hours to weeks. Studies have shown that it mainly affects older people. Postmenopausal women in particular have an increased prevalence. Physical and emotional stress are widely discussed and generally recognized trigger factors. As age also appears to play a major role in the development of TTS, this review will take a closer look at age- and gender-specific aspects. First and foremost, postmenopausal women and the associated lower oestrogen concentration should be mentioned here. Another important role is played by the hypothalamic-pituitary-adrenal (HPA) axis and the associated glucocorticoid-dependent negative feedback and the resulting immune response. Inflammaging is another term that is increasingly used in connection with TTS. In the following, these risk factors are considered in more detail and linked to the increased sympathetic activity as a possible consequence of chronic stress. Based on the imbalance between the sympathetic and parasympathetic nervous system, we venture an explorative proposal and would like to present a new possible therapeutic approach.

Bioactive lipids are involved in cellular signalling events with links to human disease. Many of these are involved in inflammation under normal and pathological conditions. Despite being attractive molecules from a pharmacological point of view, detection and quantification of lipids has been a major challenge. Here, we have optimised a liquid chromatography dynamic multiple reaction monitoring targeted mass spectrometry (LC-dMRM-MS) approach to profile eicosanoids and fatty acids in biological samples. In particular, by applying this analytic workflow to study a cellular model of Chronic Myeloid Leukaemia (CML), we found that intra- and extra-cellular 2-Arachidonoylglycerol (2-AG), intracellular Arachidonic Acid (AA), and extracellular Prostaglandin F_2α (PGF_2α), 5-Hydroxyeicosatetraenoic acid (5-HETE), Palmitic acid (PA, C16:0) and Stearic acid (SA, C18:0) were altered in response to immunomodulation by type I Interferon (IFN-I), a currently approved treatment for CML. Our observations indicate changes in eicosanoid and fatty acid metabolism with potential relevance in the context of cancer inflammation and CML.

We investigated whether cigarette smoking and dietary acid load (DAL) are associated with the risk of chronic obstructive pulmonary disease (COPD) in middle-aged healthy Korean men. Healthy men without diagnosed chronic disease (40-64 yrs) from the KNHANES-VI (2013–2015) included in the analysis (n=774) were subdivided by smoking status and DAL levels as estimated by the net endogenous acid production (NEAP) quartile. Current smokers tended to have a higher risk of COPD than non-smokers before and after the adjustment. When divided by the DAL quartile, the Q4 tended to have a higher risk of COPD than the Q1. Additionally, current smokers with lower (Q2), modest (Q3), and highest NEAP scores (Q4) showed more than 4-fold higher risks of COPD than the non-smokers with the lowest NEAP scores (Q1). Ex–smokers with higher NEAP scores (Q3 and Q4) showed more than 4-fold higher risks of COPD than the Q1. Interestingly, the risk of COPD was also more than 6-fold higher in non-smokers with the highest NEAP scores compared to the Q1. NEAP scores and smoking status synergistically increased the risk of COPD in middle-aged healthy Korean men. It suggests that DAL levels are an important factor for the prevention and management of COPD.

The introduction of ventricular shunts dramatically changed the outcome and quality of life of hydrocephalic patients. However, shunt surgery continues to be associated with numerous adverse events. Headache is one of the most common complications after shunt operation. It is often over a prolonged duration, the symptoms resemble migraine, and pain does not respond to medication. We propose invasive peripheral nerve stimulation as a possible solution in the treatment of patients suffering from chronic headache associated with shunted hydrocephalus. A young woman with daily holocephalic headache with diffuse pain exacerbated by lying down. Imaging revealed panventricular enlargement and possible stenosis of the aqueduct. When a ventriculoperitoneal shunt was placed, clinical symptoms resolved. Nevertheless, she gradually exacerbated after a second valve replacement due to wound infection. Imaging revealed decompressed ventricles and appropriate shunt placement. The diagnosis of chronic post-intracranial disorder headache was set. Therefore, occipital nerve stimulation was applied and considering that the patient had not a total response, bilateral parietal stimulation was added. Three months after the combined PNS she experienced total remission of headache. Combined PNS eases refractory headaches much more than occipital nerve stimulation alone and could be considered as a solution for shunted hydrocephalus associated headache.

Employment implies economic independence, social inclusion, non-discrimination and impacts people’s life in areas beyond work. Therefore, for persons with disabilities (PwD), that include persons with chronic diseases (PwCD), equal employment opportunities must be provided and reasonable accommodation (RA) in employment carefully designed. The objectives of this study done in Slovenia were: (i) to translate and adapt RA Factor Survey (RAFS; Dong et al., 2010); (ii) to examine psychometric properties of its expanded Slovenian modification Aspects of RA survey (ARAS); (iii) to find out the views of professionals in the field by ARAS; (iv) to present Slovenian model of employment rehabilitation concerning PwD and PwCD. ARAS was developed with the collaboration of professionals performing focus groups, it consists of three parts Influencing factors, Contents areas and Barriers with 78 items. Data were collected from 140 professionals and underwent descriptive statistics and factor analysis. The results showed that the key factors for RA implementation are attitude and support of employer/organization. Other important factors are employee and his/her employment, the conditions to implement RA, and the awareness of employee and work environment. ARAS might be used as a framework to assist in the development, improvement, and implementation of RA in practice. This is discussed in the broader context of equal opportunities for employment of PwD including PwCD and the welfare model in Slovenia.

Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae Lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote gut microbiota homeostasis, however, its role in renoprotection remains unknown. This study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8-week 2% NaCl-feeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, PLR significantly alleviated CKD-associated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and down-regulating the canonical Wnt / β-catenin pathway. Further, PLR rescued gut microbiota dysbiosis and protected high salt-induced gut barrier dysfunction. We found enrichment of Akkermansia and Bifidobacterium after PLR intervention, the relative abundance of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was at least partially exerted through gut microbiota reestablishment and down-regulation of the Wnt / β-catenin pathway. Our study provides evidence for new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.

Hemodialysis (HD) patients experience significant psychological stress related HD. Coping strategies are utilized to help these patients cope with this stress. Prevalence of different types of coping strategies in relation with differential levels of HD-related stress scores and by demographics were assessed. HD patients aged 18 years and above who were seeking regular treatment in a specific HD-unit of a hospital in the upper Midwest, were surveyed between March 2020 and July 2020. Descriptive statistics, correlational analyses, and regression analyses were performed. Females could be expected to have emotional coping scores 8 units greater than males, as B = 8.017 for sex in the model, p =.000. Females could be expected to have coping scores 6.4 points higher than males when adjusted for stress levels, as: B = 6.351, p =.001 for sex in the model. For each 1point increase in Stress Score, the Coping Score could be expected to: increase 6.8 points when adjusted for Sex, where B = 6.751 and p =.000. Increased prevalence of emotional pre-occupation was only observed among female patients which increased with the increase in stress. Psychological interventions in female HD patients should be strongly considered in addressing emotional pre-occupation coping.

There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B6, and vitamin B12) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD=-0.50, 95% CI -0.95 to -0.05, p=0.029) and folic acid (SMD=-0.37, 95% CI -0.65 to -0.09, p=0.009), and higher homocysteine (SMD=0.78, 95% CI 0.48 to 1.07, p˂0.001) and cysteine concentrations (SMD=0.34, 95% CI 0.02 to 0.66, p=0.038). Additionally, COPD was associated with significantly higher ADMA (SMD=1.27, 95% CI 0.08 to 2.46, p=0.037), SDMA (SMD=3.94, 95% CI 0.79 to 7.08, p=0.014), and ornithine concentrations (SMD=0.67, 95% CI 0.13 to 1.22, p=0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways which can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036)

Background and Objectives: Elders’ needs are rarely examined beforehand, and thus, although technology-based tools can enhance self-management, acceptability rates are still low. This study aimed to examine and compare self-reported needs, priorities, and preferences of elders with heart failure (HF), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD) toward technology use to enhance self-management. Materials and Methods: A convenience sample of 473 participants over 60s (60.5% females), diagnosed with HF (N=156), DM (N=164), or COPD (N=153) was recruited. They were administered a questionnaire about the usefulness of technology in general and in specific areas of disease management. Results: Most participants (84.7%) admitted that technology is needed for better disease management. This was equally recognized across the three groups both for the overall and specific areas of disease management (in order of priority: ‘Information’, ‘Communication with Physicians &amp; Caregivers’, and ‘Quality of Life &amp; Wellbeing’). Sociodemographic differences were found. Cell phones and PCs were the devices of preference. The four common features prioritized by all three groups were related to ‘information about disease management’ (i.e., monitoring symptoms, reminders for medication intake, management and prevention of complications), whereas the fifth one was related to ‘communication with physicians and caregivers (i.e., in case of abnormal or critical signs). The top disease-specific feature was also monitoring systems (of respiratory rate or blood sugar or blood pressure, oxygen), whereas other disease-specific features followed (i.e., maintaining normal weight for HF patients, adjusting insulin dose for DM patients, and training on breathing exercises for COPD patients). Conclusions: Elders in these three samples seem receptive to technology in disease management. mHealth tools, incorporating both common and disease-specific features and addressing different chronic patients, and being personalized at the same time, could be cost-saving and useful adjuncts in routine clinical care to improve self-management.

Chronic Myeloid Leukemia, resulting due to chromosomal aberration t(9;22) through formation of oncogenic BCR-ABL fusion oncogene. Modern BCR-ABL inhibitors, called TKIs, have revolutionized CML treatment. CML has three stages: chronic, accelerated, and blast crisis. TKIs work well in CP-CML, where patients survive as long as the normal population, but they don't work in AP- and BC-CML. Even with advances in treatment, BC-CML has an average overall survival of less than a year, giving oncologists little time to clinically intervene. Oncologists can delay or prevent CML advancement by detecting patients at risk of disease progression early and making timely treatment decisions, especially with third and fourth generation TKIs. However, no universal molecular biomarkers exist to diagnose CML patient groups at risk of disease progression. A recent study found that all BC-CML patients have mutant FANCD2. Our study was designed to detect mutant FANCD2 in AP-CML (early progression phase) to investigate its potential as a novel biomarker of early CML progression from chronic phase to accelerated phase due to the urgent need for such a biomarker. Our study comprised of 123 CP-CML (control group) and 60 AP-CML patients (as experimental group) from Hayatabad Medical Complex, Peshawar, Pakistan, from Jan 2020 to July 2023. DNA was extracted from the patients and FANCD2 gene was sequenced using Illumina next generation sequencer (NGS) Illumina MiSeq sequencer. NGS analysis revealed a unique splice site mutation in FANCD2 gene (c. 2022-5C>T). This mutation was detected in all CP-CML patients but in none of CP-CML. The mutation was confirmed by Sanger sequencing. FANCD2 is member of Fanconi anemia (FA-) pathway gene involved in DNA repair and genomic instability. Therefore, our studies show that FANCD2 (c. 2022-5C>T) mutation as a very specific molecular biomarker for early CML progression. We recommend to clinical validate this biomarker is prospective clinical trials.

Background and Objectives: This study aimed to evaluate the effects of subtalar joint axis-based balance exercises on the anterior talofibular ligament (ATFL) thickness, ankle strength, and ankle stability after an arthroscopic modified Broström operation (AMBO) for chronic ankle instability (CAI). Materials and Methods: The study included 47 patients diagnosed with CAI who underwent AMBO and were randomly divided into three groups: control (n=11), general balance exercise (n=17), and subtalar joint axis balance exercise (n=19), regardless of the affected area. Participants in the exercise rehabilitation group performed exercises for 60 min twice a week for 6 weeks, starting 6 weeks after AMBO. ATFL thickness, ankle strength, and ankle dynamic stability were measured using musculoskeletal ultrasonography, Biodex, and Y-balance test, respectively, before and after treatment. Results: Compared with the remaining groups, the subtalar joint axis balance exercise group had reduced ATFL thickness (p = 0.000), improved ankle strength for eversion (p = 0.000) and inversion (p = 0.000), and enhanced ankle stability (p = 0.000). Conclusions: The study results suggests that subtalar joint axis-based balance exercises may contribute to the early recovery of the ankle joint after AMBO.

Adverse childhood experiences are known to program children for disrupted biological cycles, premature aging, microbiome dysbiosis, immune-inflammatory misregulation, and chronic disease multimorbidity. To date, the microbiome has not been a major focus of deprogramming efforts despite its emerging role in every aspect of ACE-related dysbiosis and dysfunction. This article examines: 1) the utility of incorporating microorganism-based, anti-aging approaches to combat ACE-programmed chronic diseases (also known as noncommunicable diseases and conditions, NCDs) and 2) microbiome regulation of core systems biology cycles that affect NCD comorbid risk. In this review microbiota influence over three key cyclic rhythms (circadian cycles, the sleep cycle, and the lifespan/longevity cycle) as well as tissue inflammation and oxidative stress are discussed as an opportunity to deprogram ACE-driven chronic disorders. Microbiota, particularly those in the gut, have been shown to affect host-microbe interactions regulating the circadian clock, sleep quality, as well as immune function/senescence and regulation of tissue inflammation. The microimmunosome is one of several systems biology targets of gut microbiota regulation. Furthermore, correcting misregulated inflammation and increased oxidative stress is key to protecting telomere length and lifespan/longevity and extending what has become known as the healthspan. This review article concludes that to reverse the tragedy of ACE-programmed NCDs and premature aging, managing the human holobiont microbiome should become a routine part of healthcare and preventative medicine across the life course.

Background. Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous systemic syn-drome that often coexists with multiple comorbidities. In high-complex COPD patients the role of the Cumulative Illness Rating Scale (CIRS) as a risk predictor of COPD exacerbation is not known. Objective. To determine the effectiveness of the CIRS score in detecting the association of comorbidities and disease severity with the risk of acute exacerbations in COPD patients. Methods. 105 adults with COPD were included in this prospective study. All participants at baseline had at least 2 moderate exacerbations or 1 leading to hospitalization. The primary outcome was a composite of moderate or severe COPD exacerbation during 12-months follow-up. Results. CIRS indices (CIRS total score, Severity Index and Comorbidity Index) showed a positive correlation with mMRC, CAT and a negative correlation with FEV1, FVC, FEV1/FVC. The three CIRS indices were able to predict the 12-month rate of moderate or severe exacerbation (CIRS-Total Score: Hazard Ratio (HR) = 1.12 (95% CI: 1.08-1.21); CIRS-Severity Index: HR = 1.21 (95% CI: 1.12-1-31); CIRS-Comorbidity Index = 1.58 (95% CI: 1.33-1.89)). Conclusions. Among patients with COPD, comorbidity number and severity, assessed by the CIRS score, influence the risk in moderate to severe exacerbations. The CIRS score also correlates with the severity of respiratory symptoms and lung function

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dis-autonomy tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2-vaccination of healthy controls (N = 89, 71 females, mean/ median age 39/ 49 years) were compared with corresponding values of PACVS-affected persons (N= 191, 159 females, mean/median age: 40/39 years) exhibiting chronic fatigue/dis-autonomy (≥ three symptoms for ≥ five months after last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases of 11 receptor-antibodies (by 25 - 50 %, p < 0.0001), increases in two receptor-antibodies (by 15 - 25 %, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p &lt; 0.0001) by increased angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/ml, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/ml, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/ml, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers

The HSP70 and HSP90 family members belong to molecular chaperones that exhibit protective functions during the cellular response to stressful agents. We investigated whether the exposure of rats to chronic mild stress (CMS), a validated model of depression, affects the expression of HSP70 and HSP90 in the prefrontal cortex (PFC), hippocampus (HIP) and thalamus (Thal). Male Wistar rats were exposed to CMS for 3 or 8 weeks. The antidepressant imipramine (IMI, 10 mg/kg, i.p., daily) was introduced in the last five weeks of the long-term CMS procedure. Depressive-like behavior was verified by the sucrose consumption test. The expression of mRNA and protein was quantified by real-time PCR and Western blot, respectively. In the 8-week CMS model, stress alone elevated HSP72 and HSP90B mRNA expression in the HIP. HSP72 mRNA was increased in the PFC and HIP of rats not responding to IMI treatment vs. IMI responders. The CMS exposure increased HSP72 protein expression in the cytosolic fraction of the PFC and HIP, and this effect was diminished by IMI treatment. Our results suggest that elevated levels of HSP72 may serve as an important indicator of neuronal stress reactions accompanying depression pathology and could be a potential target for antidepressant strategy.

The TeNDER project aims to improve the Quality of Life (QoL) of chronic patients through an integrated care ecosystem. This study evaluates the Health Recommender System (HRS) developed for the project, which offers personalized recommendations based on data collected from a set of monitoring devices. The list of notifications covered different areas of daily-life such as physical activity, nutrition, and sleep. We conducted this case of study to evaluate the effectiveness and usability of the HRS in providing accurate and relevant recommendations to users. Evaluation process consisted on survey administration for QoL assessment, and the satisfaction and usability of the HRS. The four-week pilot study involved several patients and caregivers, and demonstrated that the HRS was perceived as user-friendly, consistent, and helpful, with a positive impact on patients’ QoL. However, the study highlights the need for improvement in terms of personalization of recommendations.

This retrospective study aimed to compare risk factors for vascular calcification (VC) between pre-hemodialysis (HD) and prevalent HD adult patients while investigating associations with calcification biomarkers. Baseline data from 30 pre-HD and 85 HD patients were analyzed, in-cluding iPTH, vitamin D, FGF-23, fetuin-A, sclerostin and VC scores (Adragao method). Preva-lence of VC was similar in both groups, but HD patients had more frequent VC scores ≥6. Pre-HD patients were older, with higher prevalence of hypertension and less frequent use of calcium phosphate binders. Both groups showed similar patterns of hyperphosphatemia, low vitamin D, and iPTH. Fetuin-A levels were higher in pre-HD, while FGF-23 was elevated in HD patients. Higher VC risk in pre-HD patients was associated with male gender, older age, lower fetuin-A and higher sclerostin, lower ferritin and no vitamin D treatment, while in HD patients with higher sclerostin, FGF23 and urea, and lower iPTH. Conclusion. Progression of CKD from the pre-HD to the HD stage is accompanied by a decreased effect of the inhibitor and an increase in the promoter VC. However, mineral imbalance, hormonal regulation, treatment options, and patient-specific fac-tors should be considered. Further studies are needed to elucidate the underlying pathways.

Healthy life style is associated with decreased risk of chronic kidney disease (CKD) and mortality in the general population. However, there is no definitive evidence on the benefits of physical activity and other health-related behaviors in the early-stage CKD. This study aimed to explore the association between health-related behaviors and end-stage renal disease (ESRD) and mortality in the early stages of CKD. The National Health Insurance Service (NHIS) database from January 1st, 2009 to December 31st, 2016 was used to screen 83,470 subjects with early stage CKD. Cox proportional hazard regression analysis was used to evaluate the association between health-related behaviors and ESRD and death. Kaplan-Meier curves for mortality and ESRD were plotted according to the physical activity, smoking status and alcohol consumption pattern. Risk of death decreased significantly in subjects who engaged in sufficient physical activity (adjusted Hazard Ratio (HR) 0.73; 95% CI: 0.64-0.83; p < 0.001). Risk of ESRD and death increased significantly in the current smoker with adjusted HR of 1.44 (95% CI: 1.06-1.95; p < 0.02) and 1.61 (95% CI: 1.44-1.80; p < 0.001) respectively. Therefore, systematic interventions to encourage physical activity and smoking cessation need to be actively considered in the early stages of CKD.

BACKGROUND&AIMS: Hepatitis B virus (HBV) infection remains a major public health problem. The interaction between HBV and the host inflammatory response is an important factor contributing to liver damage and disease development. We compared the correlation between the subclinical index and PBMCs concentration in two groups of pregnant women (HBsAg positive), which are different in HBV DNA concentration in Vietnam. METHODS: The Hierarchical cluster analysis (HCA) was run with 20 different clustering methods on data collected from 80 Vietnamese pregnant women and their babies (60/80 cord blood). RESULTS: In the high viral load group (HBV DNA ≥ 5x10^7 copies/ml), a strong correlation between CBMCs with serum maternal Haemoglobin concentration and maternal platelet and maternal ALT. Their R values are: -0.88, 0.82, and 0.84 with p=8.97E-03, 2.41E-02 and 1.75E-01, respectively. CONCLUSIONS: We found a significant correlation shift of subclinical index between the two groups, which may be important in diagnosing pregnant women with chronic hepatitis B virus infection.

Vascular calcification (VC) is associated with increased cardiovascular risks in patients with chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors, like empagliflozin, can improve cardiovascular and renal outcomes. We assessed the expression of Runt-related transcription factor 2 (Runx2), interleukin (IL)-1β, IL-6, AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor (Nrf2), and heme oxygenase 1 (HO-1) in inorganic phosphate–induced VC in mouse VSMCs to investigate the mechanisms underlying empagliflozin’s therapeutic effects. We evaluated biochemical parameters, mean artery pressure (MAP), pulse wave velocity (PWV), transcutaneous glomerular filtration rate (GFR), and histology in an in vivo mouse model with VC induced by an oral high-phosphorus diet following a 5/6 nephrectomy in ApoE−/− mice. Compared to the control group, empagliflozin-treated mice showed significant reductions in blood glucose, MAP, PWV, and calcification, as well as increased calcium and GFR levels. Empagliflozin inhibited osteogenic trans-differentiation by decreasing inflammatory cytokine expression and increasing AMPK, Nrf2, and HO-1 levels. Empagliflozin mitigates high phosphate–induced calcification in mouse VSMCs through the Nrf2/HO-1 anti-inflammatory pathway by activating AMPK. Animal experiments suggested that empagliflozin reduces VC in CKD ApoE−/− mice on a high-phosphate diet.

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers. The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network. We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which we established in CFAS-D patients. PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks. MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA. The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease. Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus. In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

Background: This practice guideline was developed by the Chronic Kidney Disease (CKD) Task Force, which was composed of clinical and methodological experts. The Saudi Arabian Ministry of Health and its Health Holding Company commissioned this guideline project to support the realization of the Vision 2030's healthcare transformation pillar. Methods: The guideline synthesis was guided by the GRADE-ADOLOPMENT methodology. Results: The final adoloped guideline addressed 12 clinical questions on blood pressure management in patients with CKD through a set of recommendations and performance measures. The recommendations included antihypertensive agents in children, non-renin angiotensin system inhibition (Non-RASi) vs RASi in adults, intensive vs standard blood pressure targets, early vs late assessment for kidney replacement therapy (KRT), late vs early preparation strategy for KRT, CKD symptoms during assessment for KRT or conservative management, initiation of KRT in patients with deteriorating CKD, choice of KRT modality or conservative management in certain CKD patient groups, changing or discontinuing KRT modalities, review frequency for KRT or conservative management, and Information, education and support. Conclusions: These conditional recommendations were based on low to very low certainty of evidence that highlights the need for high-quality randomized trials comparing different antihypertensive agents in patients with CKD.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS. New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure. Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion. The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance - capillary ischemia-reperfusion - which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.

Platelet-activating factor (PAF) is a phospholipid-derived inflammatory mediator, triggering various inflammatory conditions, including eosinophil activation and recruitment. Despite the unclear mechanism underlying the formation and maintenance of nasal polyp in chronic rhinosinusitis with nasal polyps (CRSwNP), there is strongly indication of its association with type 2 inflammation. This study aimed to quantify PAF-associated gene expression, examining enzymes involved in PAF synthesis (lysophosphatidylcholine acyltransferase 1 (LPCAT1), LPCAT2, LPCAT3, and LPCAT4), and PAF degradation (PAF acetylhydrolases 1 B2 (PAFAH1B2), PAFAH1B3, and PAF acetylhydrolases 2 (PAFAH2)), and PAF receptor (PTAFR). Transcriptomic analysis encompassed CRSwNP, including eosinophilic CRS (ECRS) (n=9), nonECRS (n=8), and a subgroup of ECRS with aspirin exacerbated respiratory disease (Asp) (n=3) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria. Gene expression profiles from nasal polyps in CRSwNP patients and the uncinate process in normal subjects (controls) (n=6) were analyzed using bulk RNA barcoding and sequencing (BRB-seq). Hierarchal analysis, utilizing the average linkage method with iDEP1.1, clarified the relationship between Differentially Expressed Genes (DEG) expressions and cluster formation. Two clusters (cluster 1 (n=11) and cluster 2 (n=9)) of CRSwNP divided by hierarchal analysis showed distinct gene expression profiles in the specific pathway of “cytokine-cytokine receptor interaction” in KEGG pathway and upregulated type 2 inflammatory gene expression in cluster 2. In CRSwNP subclassification of ECRS, nonECRS, and Ctrl, PTAFR was only upregulated in ECRS and nonECRS. In cluster analysis, cluster 1 showed significant downregulation of LPCAT2 and upregulation of PTAFR expression, while cluster 2 showed significant upregulation of LPCAT1, PAFAH1B2, and PTAFR and downregulation of PAFAH2 expression. These findings suggest that cluster 2, characterized by severe type 2 inflammatory gene expression, manifest a prominent PAF-associated pathophysiology. Understanding this high PAF-associated pathophysiology in cluster 2 could provide valuable insights into the treatment and management of CRSwNP.

Various autoimmune diseases, including autoimmune hypothyroidism (AHT), are associated with a higher risk of developing mood disorders throughout life. Depression is accompanied by the changes in the levels of inflammatory and trophic factors, including interleukines (IL-1beta, IL-2, IL-6), interferon alpha (IFN-alpha), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and brain derived neurotrophic factor (BDNF). Similar disturbances in the cytokine profile are seen in AHT patients and their relatives. Disclosure of the relationship between the co-existence of depression and autoimmune subclinical thyroiditis indicates that the pathomecha-nism of depression may be related to the changes in the immune system, it is possible that both conditions may be caused by the same immune processes. The above hypothesis is indirectly sup-ported by the observations that the treatment with both antidepressants and levothyroxine leads to a decrease in the levels of proinflammatory cytokines with an increase in BDNF concentrations, simultaneously correlating with an improvement in the clinical parameters. However, so far there are no long-term studies determining the causal relationship between depression, thyroid auto-antibodies, and cytokine profile, which could bring us closer to understanding the interrelation-ships between them and facilitate the use of an adequate pharmacotherapy, not necessarily psy-chiatric. We consider the above issues insufficiently investigated but of great importance. This ar-ticle is an overview of the available literature as well as an introduction to our research project.

Patients with chronic (CM) and high frequency episodic migraine (HFEM) report cognitive complaints that contribute to migraine burden. Although, there is little evidence about the ef-fects of migraine treatments on these symptoms. Objective: To evaluate the effect of preventive treatment on the impact of cognitive symptoms, specifically the ability to concentrate, in individuals with CM and HFEM. Methods: Prospective cohort study in patients with CM and HFEM initiating treatment with botulinum toxin (BT) or anti-CGRP/R monoclonal antibodies (mAbs). Patients were evaluated at baseline and after 3 months of treatment, using a headache diary and a question about the im-pact of migraine attacks on concentration (never, rarely, sometimes, often, and always). Results: 108 patients (105 females, 44.3 years of age on average), 75% with CM and 27% with HFEM were included, 55 received a first session of BT and 53 received 3 injections of a monthly mAb. In both groups, there was a significant decline on the impact of migraine in concentration (related samples Wilcoxon signed rank test <0.001) compared to baseline. Reduction in monthly headache days was the main predictor of any concentration improvement, while treatment group, age, ongoing medication with topiramate or baseline medication overuse were not sig-nificant. Conclusion: Preventive treatment of HFEM or CM with drugs not acting on central nervous sys-tem is associated with a decrease of the impact of migraine attacks on concentration, predicted by the decline in headache days. These results indicate that migraine preventive treatment also improves non-pain symptoms, which is relevant given the contribution of cognitive complaints to the impact of headache attacks

Burnout is common in many countries and is associated with several other problems, such as depression, anxiety, insomnia and memory deficits, and prospectively it predicts long-term sick-leave, cardiovascular disease and death. Clinical burnout or its residual symptoms often last several years and a common assumption is that recovery takes a long time by nature despite full time sick-leave and absence of work stress. Literature suggests models that hypothetically explain the development, but not maintenance, of the syndrome. Based on cognitive and behavioral principles and stress theory this paper describes a theoretical model explaining how clinical burnout can develop and be maintained. While the development of clinical burnout is mainly explained by prolonged stress reactions and disturbed recovery processes due to work related stressors, maintenance of the syndrome is particularly explained by prolonged stress reactions and disturbed recovery processes due to the new context of experiencing burnout and being on sick-leave. Worry about acquired memory deficits, passivity and excessive sleep, shame, fear of stress reactions, and the perception of not being safe are examples of responses that can contribute to the maintenance. The model has important implications for research and how to intervene clinical burnout.

Background: The assessment of the incidence and characteristic of acute and chronic post-operative endophthalmitis (POE) after cataract surgery in Poland during 2010 - 2015. Patients and methods: All hospitalizations of patients, in the National Database of Hospitalizations, who underwent cataract surgery alone or in combined procedures in Poland between January 2010 and December 2015, with a billing code of endophthalmitis, were selected. Acute endophthalmitis was identified if symptoms occurred within 1 - 42 days from the cataract surgery and chronic endophthalmitis if symptoms occurred ≥ 43 days after cataract surgery, respectively. Results: In total, 1331 cases of POE after 1,218,777 cataract extractions were identified. The overall incidence of POE decreased from 0.125% in 2010 to 0.066% in 2015. In multiple logistic regression analyses, increasing age was significantly associated with acute POE, while type II diabetes mellitus, extracapsular cataract extraction and one-day surgery were significantly associated with chronic POE. The combined cataract surgery and male sex were significant risk factors for both acute and chronic POE. A total of 62.51% of all eyes affected by POE received antibiotic treatment and 37.49% had vitrectomy treatment. Conclusions: During the study period, the total incidence of post-operative endophthalmitis after cataract surgery decreased significantly.

Introduction: Wound healing is a complex cascade involving the orchestration of inflammatory cells, skin fibroblasts, keratinocytes, and endothelial cells. These cells achieve tissue repair through an interchange of cytokines and growth factors through a controlled inflammation, angiogenesis, and remodeling process. Disruptions in the wound-healing process by comorbid conditions lead to significant morbidity and mortality. Stem cell therapy has emerged as a new strategy to facilitate the wound healing process. Stem cells harvested from different sources can be used for wound repair and regeneration (endothelial progenitor cells, bone marrow, adipose tissue, dermal and inducible pluripotent stem cells). We aimed to review clinical, translational, and primary literature on stem cell therapies in chronic wounds and summarize practical clinical applications to dermatological care. Materials and Methods: A comprehensive search of Pubmed, Embase, Web of Science, Google Scholar, and Cochrane Library was conducted for studies relating to stem cells and wound healing. Duplicate results were removed using Covidence. Titles and abstracts were screened by two independent researchers (BF and KR), with discrepancies resolved through discussion and mutual agreement. Articles were excluded if they were review-type or commentary-type articles. Results: A total of 22,454 articles were retrieved from the search. Deduplication removed 905, and automation removed an additional 18,363 articles. After an initial screening of titles and abstracts, 170 articles remained. Full-text screening resulted in an additional 126 articles being removed, leaving 44 included studies. Discussion: Stem cells used for wound repair and regeneration include endothelial progenitor stem cells and adult stem cells, in the forms of bone marrow-derived mesenchymal stem cells, adipose tissue stem cells, and inducible pluripotent stem cells. Among these sources, adipose tissue-derived mesenchymal stem cells (AD-MSCs) are ideally used due to the abundant supply of fat tissue, ease of isolation, extensive proliferative capacities ex vivo, and their ability to secrete pro-angiogenic factors. AD-MSCs have been used to enhance wound healing in peripheral arterial disease, diabetic wounds, hypertensive ulcers, bullous diabeticorum, venous ulcers, and postsurgical wounds after Mohs micrographic surgery. These cells have been delivered to the tissue topically, with scaffolds, combined with plasma-rich proteins, and through atelocollagen in various human studies. These approaches, when combined with local wound care practices, resulted in decreased pain, shorter wound healing times, and better cosmesis. Conclusions: Stem cell transplantation is a potential therapeutic approach in the wound healing process. Transplanted stem cells do not only differentiate into multiple skin cell types but also provide cytokine and growth factors required for wound healing resulting in increased angiogenesis. Thus, this approach may be regarded as an attractive option for intractable wounds that cause major clinical problems, especially chronic lower leg wounds. It can also be used after Mohs micrographic surgery for defects left to heal by secondary intention. Stem cell application may reduce the overall cost burden on the healthcare system and improve the quality of life for patients.

The management of wounds is a significant issue that impacts individuals, healthcare systems, and society at large. This study evaluates Rigemed D (RD), a novel compound extracted from Bovine Colostrum with a unique combination of 20 different growth factors and exosomes, known for its exceptional properties in promoting cell proliferation and regeneration. This study aims to determine the effects of different doses of RD on cell survival (using CCK8) and to assess its antioxidant effect using the Comet assay in the presence of hydrogen peroxide (H2O2) on two human cell types, fibroblasts and immortalised keratinocytes (HaCat cell line). The study results revealed that RD, at doses of 1, 1.5, and 2 % v/v, significantly improved cell viability four, six, and 12 times, respectively, compared to the control group (p < 0.00001). Furthermore, the Comet assay showed a two-fold reduction in DNA damage in RD-treated cells at 2% v/v without and with H2O2 (p < 0.001). The effect of RD on cell proliferation and migration was evaluated using a scratch assay on fibroblasts and HaCat cells. The findings demonstrated a four-fold increase in cell proliferation and migration at 1 and 24 hours (p < 0.001). Immunohistochemistry confirmed this claim (p < 0.001). Also, angiogenesis induction of RD was assessed on human vein umbilical endothelial cells (HUVEC), showing that RD significantly enhanced the proliferation of endothelial HUVEC cells (p < 0.0001). In conclusion, RD is a promising vitalising compound with exceptional capabilities in promoting cell proliferation, migration, and regeneration. It also shows a significant antioxidant effect and has the potential to support all phases of wound healing involving cell proliferation, re-epithelialisation, angiogenesis, and tissue maturation. Hence, the present formulation presents a promising foundation for developing a 3D bio-printed membrane, potentially expediting the wound healing process.

Fibromyalgia is a complex and often misunderstood chronic pain disorder. It is characterized by widespread musculoskeletal pain, fatigue, and heightened sensitivity, and has evolved in diag-nostic criteria and understanding over the years. Initially met with skepticism, fibromyalgia is now recognized as a global health concern affecting millions of people, with a prevalence trans-cending demographic boundaries. The clinical features and diagnosis of fibromyalgia encompass a range of symptoms beyond pain, including sleep disturbances and cognitive difficulties. The study emphasizes the importance of a comprehensive evaluation for accurate diagnosis, considering the shift from tender point reliance to a more holistic approach. Etiology and pathophysiology involve genetic predisposition, neurotransmitter dysregulation, central sensitization, and immune system involvement. Risk factors such as gender, age, family history, and comorbid conditions contribute to susceptibility. The impact on quality of life is profound, affecting physical and social aspects, often accompanied by mood disorders. Management approaches include pharmacological interventions, non-pharmacological therapies, lifestyle modifications, and alternative treatments. The study also delves into emerging research, exploring advances in neurobiological understanding, brain imaging, genetic markers, glutamate modulation, cannabinoids, gut microbiome, and digital health tools for fibromyalgia manage-ment. Overall, this study provides a nuanced and up-to-date overview of the complexities sur-rounding fibromyalgia, aiming to enhance understanding and support for individuals grappling with this challenging condition.

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

Chronic stress is a major risk factor for various psychiatric diseases, including depression; it induces a range of cellular and structural adaptations, culminating in altered neurocircuitry and subsequent depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive behavior. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders.

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

Chronic Hepatitis B (CHB) Virus infection is major etiological factor for liver cirrhosis and/ or liver cancer. The viral protein, major contributor in predisposition of chronicity and Hepatocellular Carcinoma (HCC) is Hepatitis B x (HBx) protein. Its dynamic subcellular distribution to an extent determines its multifactorial role. It is a regulatory protein which modulates viral as well as host machinery in favours to HBV persistence. An insight on HBx stabilising factors is critical for therapeutic purpose. The precise role of HBx in the pathogenesis of Chronicity of HBV is not known. Summary: This review comprehensively summarizing different mechanisms and their regulation by HBx protein with respect to chronicity and HCC emphasising viral persistence. Key Messages 1. HBx is a key protein for viral persistence. 2. Dynamic subcellular distribution of HBx determines its function. 3. HBx modulates cellular machinery to favours HBV survival. 4. HBx affects various intermediary mechanisms contributing to disease progression. 5. HBx may be a potent target to prevent the disease progression towards HCC.

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

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

Aims: A community-based multi-component intervention (increasing awareness of the importance of physical activity in chronic illness management through reading comic books, training regarding warm-up stretching exercises, identifying facilitators and barriers to exercise through photosharing, supporting self-reflection and development of action plans) was developed to promote physical activity (PA) among patients with diabetes and hypertension. This study aimed to evaluate the efficacy of this intervention on health behaviour (walking) and health outcomes. Design: A non-randomized controlled trial with waitlisted control and pre- and post-measures. Setting: Community centres for the elderly. Participants: A total of 204 older adults with diabetes and/or hypertension were recruited. They were assigned to either the intervention group (IG) or waitlisted to the control group (CG). Intervention: Under the supervision of a nurse, six weekly group meetings were arranged in community centres for the elderly in which the participants freely exchanged their views regarding the barriers and facilitators of regular physical activity. Participants were encouraged to take photos in their neighbourhood or at home and brought these photos to share at the group meetings. The photos showed both the barriers and the facilitators to PA. In the last meeting, each participant worked out a plan to perform PA in the coming four weeks. Measures: PA referred to the number of steps taken per day and it was measured by a Garmin Accelerometer at baseline, Week 6 and Week 10. Other measures included the nine-item Self-Efficacy Scale for Exercise - Chinese version (SEE-C), the 23-item Chinese Barriers to Exercise Scale and Senior Fitness Tests. Generalised Estimating Equations (GEE) models compared the outcomes over time between IG and CG. Results: A statistically significant difference in the changes in the average number of steps taken daily between the two groups at Week 10 (mean difference = 965.4; 95% confidence interval: 92.2, 1838.6, p = 0.030) was observed, although the difference at Week 6 was non-significant (mean difference = 777.6; 95% confidence interval: −35.3, 1590.5, p = 0.061). IG participants also showed significant improvements in lower body strength (mean difference = 0.967; 95% confidence interval: 0.029, 1.904, p = 0.043) and lower limb flexibility (mean difference = 2.068; 95% confidence interval: 0.404, 3.731, p = 0.015) at Week 10 compared to CG participants. Conclusion: This multi-component intervention improved the participants’ physical activity level and physical fitness, particularly in lower limb flexibility and body strength.

Mindfulness-based interventions (MBIs) have been shown to improve health and well-being in adolescents with chronic illnesses. Because they are most often delivered in person in a group setting, there are several barriers that limit access to MBIs for youth with limited mobility or who cannot access in-person MBIs in their communities. The objective of this study was to determine if eHealth is a viable platform to increase accessibility to MBIs for teens with chronic illnesses. This study reports the qualitative results of a mixed method randomized trial describing the experience of the Mindful Awareness and Resilience Skills for Adolescents (MARS-A) program, an 8-week MBI, delivered either in person or via eHealth. Participants were adolescents between the ages of 13 and 18 with a chronic illness recruited at a tertiary pediatric hospital in Toronto, Canada. Individual semi-structured post-participation audio-video interviews were conducted by a research assistant. A multiple-pass inductive process was used to review interview transcripts and interpret emergent themes from the participants’ lived experiences. Fifteen participants completed post-participation interviews. Four distinct themes emerged from participants in both the in-person and eHealth groups: creation of a safe space, fostering peer support and connection, integration of mindfulness skills into daily life and improved well-being through the application of mindfulness. Results from this study suggest that eHealth may be an acceptable and feasible mode of delivery for MBIs in adolescents with chronic illnesses. EHealth should be considered in future studies as a promising avenue to increase access to MBIs in this population.

Vitamin D deficiency and insufficiency are highly prevalent in CKD affecting over 80% of hemodialysis (HD) patients and require therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level &gt; 30 ng/mL. 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value &gt;30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week – by 15 patients (68.18%), in the fourth week – by 18 patients (81.18%) and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)2D levels was observed during the study, however, only 2 patients (9.09%) achieved a concentration of 1,25(OH)2D above 25 ng/mL – the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia, and one new episode of hyperphosphatemia were observed. In conclusion, our study showed that the administration of a high therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients.

Background: The annual mortality of patients with untreated chronic thromboembolism pulmonary hypertension (CTEPH) is approximately 50% unless a timely diagnosis is followed by adequate treatment. In pulmonary embolism (PE) survivors with functional limitation the diagnostic work-up starts with echocardiography. It is followed by lung scintigraphy and right heart catheterization. However, noninvasive test providing diagnostic clues to CTEPH, or ascertain this diagnosis as very unlikely, would be extremely useful since the majority of post PE functional limitations is caused by deconditioning. Methods: Patients after acute PE underwent a structured clinical evaluation with electrocardiogram, routine laboratory tests including NT-proBNP and echocardiography. The aim of study was to verify whether the parameters from echocardiographic or perhaps electrocardiographic examination and NT-proBNP concentration best determine the risk of CTEPH. Results: A total (n = 261, male n = 123) patients after PE were included into the study, in group of 155 patients (59.4%) with reported functional impairment 13 patients (8.4%) had CTEPH and 7 PE survivors had chronic thromboembolic pulmonary disease (CTEPD) (4,5%). Echo parameters differed significantly between CTEPH/CTEPD cases and other symptomatic PE survivors. Patients with CTEPH/CTEPD had also higher level of NT-proBNP (p = 0.022) but concentration of NT-proBNP above 125 pg/ml did not differentiate patients with CTEPH/CTEPD (p>0.05). Additionally, proportion of patients with right bundle brunch block registered in ECG was higher in group with CTEPH/CTED (23.5% vs. 5.8%, p = 0.034) but there were no differences between other ECG characteristics of right ventricle overload. Conclusion: Screening for CTEPH/CTEPD should be performed in patients with reduced exercise tolerance compared to pre PE period, It is not effective in asymptomatic PE survivors. Patients with CTEPH/CTED had predominantly abnormalities indicatingchronic thromboembolism in the echocardiographic assessment. NT-proBNP and electrocardiographic characteristics of right ventricle overload proved to be insufficient in predicting CTEPH/CTEPD development.

Background: Acute kidney disease (AKD) is a known risk factor for increased mortality and evolution towards chronic kidney disease (CKD) in adults. The data regarding children are scarce. The purpose of our study is to explore the risk factor for AKD and impact of AKD following an acute kidney injury (AKI) episode in children on mortality and new-onset CKD. Methods: We retrospectively evaluated 736 children with ages between 2 and 18 years old with AKI admitted in a tertiary care hospital from the west Romania over a 9 years period. Results: AKD incidence following AKI was 17%. Patients that developed AKD were older, with higher baseline serum creatinine values, urea, C reactive protein and lower proteins, haemoglobin and sodium. They were more often exposed to sepsis, critical illness and nephrotoxic medications and presented certain susceptibilities like CKD, neoplasia, anemia, heart failure, arterial hypertension, stem cell transplant and female gender. AKI causes that increased the risk of AKD were intrinsic ones. AKD increased the overall mortality by three times. The factors that independently increased the risk of evolution towards CKD were AKD, acute tubular necrosis and higher baseline serum creatinine values. Conclusions: AKD is an independent risk factor for mortality and new-onset CKD in children.

The spectrum, intensity and overlap of symptoms between FGIDs and other gastrointestinal disorders characterize patients with FIGDs, who are incredibly different in their backgrounds. An additional challenge with regard to the diagnosis and treatment's applicability is the ongoing expansion of the risk factors believed to be connected to these disorders. Many cytokines and inflammatory cells have been found causing the continuous existence of low-inflammation, which is thought to be a basic pathophysiological process. The idea of the gut-brain axis has been created to offer a basic framework for the complex interactions that occur between the nervous system and intestinal functions, including the involvement of the gut bacteria. In this review paper, we intend to promote a hypothesis that FGIDs, should be seen through the perspective of the network of the neuroendocrine, immunological, metabolic and microbiome pathways. Hypothesis arises from an increased understanding of chronic inflammation as a systemic disorder, being omnipresent in chronic health conditions. Better understanding of inflammation role in the pathogenesis of FGIDs can be achieved by clustering markers of inflammation with data indicating symptoms, comorbidities, and psycho-social factors. Finding subclasses among related entities of FGIDs, may reduce patient heterogeneity and help clarify pathophysiology for better treatment.

This narrative review aims to summarize evidence regarding the current utilization and future applications of neuromodulation in patients with headaches, with special attention paid to migraine and chronic cluster headache. We performed a narrative review of the literature to identify studies that detail the effectiveness of neuromodulation therapies in the treatment of headache syndromes. The literature was refined to predominantly focus on systematic reviews published in the last year that have the most robust reporting of research done on this topic. Patients with headache face several challenges, including medication overuse, cost burden, non-compliance to medications due to inability to tolerate side effects, or treatments that are ineffective. Neuromodulation is an emerging field that encompasses implantable and non-implantable technologies that intervene on the signaling and perception of pain. In recent years, this technology has been used as an analgesic, and has been shown to be effective for treatment-resistant headache, particularly when used in patients with migraine and chronic cluster headache.

Laboratory analyses reveal significant differences between vaccinated and unvaccinated patients in parameters like C-reactive protein, ferritin, and white blood cell counts. Univariate and multivariate Cox proportional hazards regression analyses identify several factors influencing mortality, including comorbidities, pneumonia development, and various inflammatory markers.

With enhanced life expectancy and ageing global populations, the prevalence of multimorbidity continues to increase. However, there is a dearth of evidence linked to multimorbidity diagnoses, treatments and health outcomes which remains a concern for future proofing optimal healthcare services. Generating evidence is critical to managing multimorbidity, promoting public health and minimizing health inequalities via effective healthcare policies that improve quality of life for vulnerable populations. This study assessed meta-epidemiology of multimorbidity to report the gaps in scientific knowledge and clinical practice. A systematic methodology was designed and published in PROSPERO (CRD42022347308) to report meta-epidemiology analyses using databases including PubMed, Web of Science, ScienceDirect, EMBASE, The Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials and MEDLINE for studies published between the 1^st of January 1980 - 31^st December 2022. A random-effects model was used to estimate the pooled proportion of multimorbidity in adults. Forest plots, pooled odds ratios and statistical heterogeneity metrics were used to assess the association between multimorbidity and investigated factors. Funnel plots and Egger’s regression were used to detect and correct for publication bias. Our findings identified women to be 0.32 times more likely to have multimorbidity in comparison to males. In regard to ethnicity, white people were 0.47 times less likely to develop comorbidities than black people. People who identified as a drinker or unmarried were more likely to develop comorbidities than those who are non-drinkers or married, respectively. Regardless of smoking status, people were equally likely to have comorbidity. In terms of environmental influences, people in rural areas were found to be 0.2 times less likely to have comorbidity in comparison to those living in urban areas. Interestingly, people with a higher education level were 0.57 times more likely to develop comorbidities than those with only a high school education. It is evident that multimorbidity has a significant burden globally and impacts the provision of care necessitated across populations given its association with several social determinants of health. Robust research and healthcare policies are required to better manage multimorbidity in patients. An example of such intervention includes employing prevention programs to reduce risk and incidence of multimorbidity within at-risk populations.

Feline immunodeficiency virus (FIV) is a lentivirus in the family Retroviridae that infects domestic cats resulting in an immunodeficiency disease featuring a progressive and profound decline in multiple sets of peripheral lymphocytes. Despite compelling evidence of FIV-associated immunopathology, there are conflicting data concerning the clinical effects of FIV infection on host morbidity and mortality. To explore FIV-associated immunopathogenesis and clinical disease, we experimentally inoculated a cohort of 4 specific pathogen free kittens with a biological isolate of FIV clade C and continuously monitored these animals along with 2 uninfected control animals for more than 13 years, from the time of inoculation to the humane euthanasia endpoint. Here we report the results obtained during the late asymptomatic and terminal phases of FIV infection in this group of experimentally FIV-infected cats.

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

Abstract: The purpose of this review is to summarize recent knowledge on the main processes that occur during wound healing, including the responses of various cell types and the molecular mechanisms involved. Particular attention is also dedicated to new therapies often involved in the resolution of wounds, whether acute or chronic. Awareness of these dynamics is important for the various professional figures who are confronted with these kinds of problem daily. However, the study of the healing mechanisms has yet to be defined in detail, in fact there are alterations of variously coordinated events which lead to a delayed resolution or, as in the case of keloids, to pathological states consisting in the excessive formation of scars with consequences yet to be seen. to define. Therefore, it is necessary to know the most feasible approaches and the most effective therapies.

There is a need for a modified Global Physical Activity Questionnaire (GPAQ) to estimate physical activity levels more accurately in populations. We aimed to develop a modified GPAQ and examine its construct validity among adults in Kerala state, India. We incorporated locality-specific, metabolic equivalent task (MET)-based activities into the original GPAQ and administered this modified GPAQ among randomly selected 451 individuals (age ≥20 years) residing in the Trivandrum district of Kerala. Construct validity was assessed using Generalized Linear Models by examining the association of total moderate-to-vigorous physical activity (MVPA) MET-minutes per week estimated by the modified GPAQ with clinical measures. The mean age of participants was 45.4 (SD: 14.1) years and 52.6% were female. Increasing total MVPA MET-minutes per week was associated with decreasing weight (β=-0.011 kg, 95% CI: -0.020, -0.002), waist circumference (β=-0.013 cm, 95% CI: -0.023, -0.004), and systolic blood pressure (β=-0.009 mmHg, 95% CI: -0.015, -0.002), independent of age, sex, education, occupation, current smoking, current alcohol use, and fruit and vegetable intake. The validity coefficients and associations between total MVPA MET-minutes per week and theoretical constructs of physical activity were in agreement with those predicted, providing evidence of construct validity for the modified GPAQ.

This study aimed to clarify the relationship between the joint and ligament structures of the subtalar joint and degeneration of the subtalar articular facet. We examined 50 feet from 25 Japanese cadavers. The number of articular facets, joint congruence, and intersecting angle were measured for the joint structure of the subtalar joint, and the footprint areas of the ligament attachments of the cervical ligament, interosseous talocalcaneal ligament (ITCL), and anterior capsular ligament were measured for the ligament structure. Also, subtalar joint facets were classified into Degeneration (+) and (-) groups according to degeneration of the talus and calcaneus. No significant relationship was identified between the joint structure of the subtalar joint and degeneration of the subtalar articular facet. In contrast, footprint area of the ITCL was significantly higher in the Degeneration (+) group than in the Degeneration (-) group for the subtalar joint facet. These results suggest that the joint structure of the subtalar joint may not affect degeneration of the subtalar articular facet. Degeneration of the subtalar articular facet may be related to the size of the ITCL.

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, hormonal secretion, cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane followed by transportation of various cargo molecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin dependent and independent endocytosis, caveolar pathway and receptor mediated endocytosis have been attributed in a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.

The long-term impact of treatment of dogs with steroid-responsive enteropathy (SRE) on the fe-cal microbiome and metabolome has not been investigated. Therefore, this study aimed to evaluate the fecal microbiome and metabolome of dogs with SRE before, during, and following treatment with standard immunosuppressive therapy and an elimination diet. We retrospec-tively selected samples from 9 dogs with SRE enrolled in a previous clinical trial, which received treatment for 8 weeks, and had achieved remission as indicated by the post-treatment clinical scores. Long-term (1 year) samples were obtained from a subset (5/9) of dogs. Samples from 13 healthy dogs were included as controls (HC). We evaluated the microbiome using 16S rRNA sequencing and qPCR. To evaluate the recovery of gut function, we measured fecal metabolites using an untargeted approach. While improvement was observed for some bacterial taxa after 8 weeks of treatment, several bacterial taxa remained significantly different from HC. Seven-ty-five metabolites were altered in dogs with SRE, including increased fecal amino acids and vitamins, suggesting malabsorption as a component of SRE. One year after treatment, however, all bacterial species evaluated by qPCR and 16S rRNA gene sequencing, and all but thirteen me-tabolites were no longer different from healthy controls.

Assessment of cardiac function is the leading parameter when evaluating the state of the cardiovascular system of patients undergoing chronic hemodialysis. The aim of the paper: to assess the state of the cardiovascular system of these patients using new sensitive echocardiography and Doppler techniques and thus advance the prevention of cardiovascular disease.Method: Twenty children with end-stage renal insufficiency on chronic hemodialysis and twenty healthy controls underwent echocardiographic monitoring using standard Doppler and tissue Doppler imaging. Structural and functional changes in the left ventricle were evaluated.Results: Patients on hemodialysis had significantly greater left ventricular mass indices compared to the controls (p<0.001). The patients on hemodialysis had preserved systolic function – their fractional shortening, ejection fraction and Sm (systolic myocardial velocity) did not differ significantly compared to the controls (p>0.05). Early diastolic function in children on hemodialysis was also preserved: the E/A and Em/Am ratio did not differ significantly from the control group (p>0.05). Children on hemodialysis exhibited impaired late diastolic function (compliance index), that is, considerably higher E/Em compared to controls (p<0.00). Myocardial Performance Index values showed statistically significant elevation in children on hemodialysis compared to the control group (p<0.001).Conclusion: Tissue Doppler in tandem with conventional Pulsed Doppler can provide additional information on left ventricular filling pressures (E/Em) in children on hemodialysis. It is therefore recommended to perform routine measuring of Em waves and the E/Em ratio, not only in order to evaluate myocardial relaxation and ventricular filling pressures, but primarily to stratify risk and provide a prognosis.

Background: The myeloid-epithelial-reproductive tyrosine kinase (MERTK) is involved in hepatic steatosis, inflammation and liver fibrosis. Here we evaluated the association between the MERTK rs4374383 single nucleotide polymorphism (SNP) and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. Methods: We performed a retrospective study (repeated measures design) in 208 patients who had liver stiffness measurement (LSM), which was assessed by transient elastography No patient had cirrhosis at baseline (LSM≥12.5 kPa). Results: At baseline, 53.8% were male, the median age was 47.1 years, 13.5% reported a high intake of alcohol, 10.1% were prior injection drug users, 85.3% were infected by HCV genotype 1, and 22.6% had previously failed antiviral therapy (pegylated-interferon-alpha/ribavirin). During a median follow-up of 46.6 months, 26 patients developed cirrhosis. The rs4374383 G carriers had a higher risk of increasing LSM (adjusted arithmetic mean ratio (aAMR)=1.14; p=0.006) and a higher likelihood of having an increase in LSM greater than 5 kPa (ΔLSM≥5 kPa) [adjusted odds ratio (aOR)=2.37; p=0.029], and greater than 7 kPa (ΔLSM≥7 kPa) [aOR=3.24; p=0.032], after controlling for confounding. The SNP’s association with cirrhosis progression was close to statistical significance (aOR=2.18; p=0.070). Conclusions: MERTK rs4374383 A carriers had a lower risk of liver fibrosis progression than G carriers, supporting the hypothesis that this SNP seems to have a critical role in the pathogenesis of liver disease in HCV-infected patients.

Objective: To estimate for the first time the burden of serious fungal infections in Romania; Methods: Data derived from the World Health Organization (WHO), National Institute of Statistics, Romanian public health agencies and non-profit health organizations and published annual reports on local epidemiology were used in the present study. When no data was available, specific at-risk populations were used to calculate frequencies of serious fungal diseases, using previously published epidemiological parameters. All data refer to the year 2016; 3) Results: The estimated number of serious fungal infections in Romanian population was 435,930 in 2016. Recurrent vulvovaginal candidiasis accounts for up to 80% of total cases (more than 350,000 women annually). Concerning the HIV related infections, among 14349 infected persons, Pneumocystis pneumonia occurred in about 10% of late presenters (30 cases in 2016), while cryptococcal meningitis is rarely diagnosed (less than 20 cases). Annually, the total number of oesophageal candidiasis and oral thrush cases in HIV-positive patients may be as high as 1229 and 3066, respectively. In immunocompromised and cancer patient population, the annual incidence of candidaemia is 295, and at least 158 invasive aspergillosis cases and 4 mucormycosis cases occur yearly. With 4,966 critical care beds and approximately 200,000 abdominal surgeries performed, the estimated annual incidence of candidaemia and Candida peritonitis is 689 and 344, respectively. The annual incidence of pulmonary tuberculosis is still high in Romania (12,747 cases). Thus, the prevalence of post-TB chronic pulmonary aspergillosis is estimated to be 8.98/100,000 (1768 cases). The prevalence of chronic obstructive pulmonary disease (COPD) and asthma in adults is 6% and 6.5%, respectively. Therefore, allergic bronchopulmonary aspergillosis prevalence is estimated at 29,387 and severe asthma with fungal sensitisation at 38,731 cases annually. 4) Conclusions: Not being on the list of reportable diseases, the number of patients presenting with severe mycoses in Romania can only be roughly estimated. Based on local reports and prevalence estimation, we consider that at least 2.2% of Romanians suffer a serious form of fungal disease.

The lymphocyte function–associated antigen-1 (LFA-1) (also CD11a/CD18 and αLβ2), is just one of many integrins in the human body, but its significance derives from its exclusive presence in leukocytes. In this review, we summarize the studies relating LFA-1 and its major ligand ICAM-1 (CD54) with cancer, through the function of lymphocytes and myeloid cells on tumor cells. We consider how LFA-1 mediates the interaction of leukocytes with tumors and the role of ICAM-1 in tumor dynamics, which can be independent of its interaction with LFA-1. A more detailed examination of LFA’s role within B-cell chronic lymphocytic leukemia is made. Finally, we discuss the role of LFA-1-harboring exosomes in tumor growth and metastasis.

In service economy, scholars and practitioners focus on the development and the appliance of innovative services. The importance of service innovation is rising in many sectors and among different organizations. Several disciplines (e.g. marketing, management, operations research, etc.) focus on this innovation, a concept widely used, but with different definitions. In this paper, service innovation has been analyzed according to SD Logic and a service ecosystem perspective. Literature still call for a deeper understanding of how new or renewed resources’ combination affect the shaping of service ecosystems. To contribute to fill this gap, the study explores the practices that different actors, internal and external to a healthcare service ecosystem, enact to co-create value in novel ways that is service innovation. The paper is structured as follows. In the next section, the main academic contributions on service research have been reviewed, focusing on healthcare service innovation. Follows, the research method and the discussion of research findings. Finally, theoretical and managerial implications have been detailed and an agenda for future research suggested. The paper offers interesting insights to develop new or renewed practices that foster the reshaping and maintaining of a healthcare service ecosystem. Some recommendations are included to support managers in the development of service innovation strategies.

The study comprehensively evaluated the prognostic roles of PLR, NLR, MLR, BLR, and ELR in patients with acute exacerbation chronic obstructive pulmonary disease (AECOPD). 619 patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics containing laboratory findings of the AECOPD patients and the blood cell counts (CBCs) of the healthy volunteers were collected. Compared with the healthy volunteers, PLR, NLR, and MLR were elevated in COPD patients in stable condition, and were further ele-vated during exacerbation. ELR showed the opposite trend. PLR, NLR, and MLR were all posi-tively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more serious airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while Elevated ELR was associated with decreased in-hospital mortality in AECOPD. A nomogram was construct to predict in-hospital mortality in AECOPD. The nomo-gram had a C-index of 0.850 (95% CI: 0.799 – 0.901) with good predictive value and clinical ap-plicability. In summary, PLR, NLR, MLR, and ELR served as predictors for clinical outcomes in patients with AECOPD.

Background: In 2014 the World Health Organization (WHO) warned of an emerging world-wide crisis of antibiotic resistant microorganisms. In response, government and professional organizations recommended that health care systems adopt antimicrobial stewardship programs (ASPs). In the United States, the Centers for Medicare Services (CMS) mandated antimicrobial stewardship in the hospital inpatient setting. Effective January 1, 2020, the Joint Commission required ambulatory centers that prescribe antibiotics, such as wound centers, to institute an ASP. Chronic wounds often remain open for months, during which time patients may receive multiple courses of antibiotics and numerous antimicrobial topical treatments. The wound clinician plays an integral role in reducing antimicrobial resistance in the outpatient setting: antibiotics prescribed for skin and soft tissue infections are among the most common in an outpatient setting. One of the most challenging aspects of antimicrobial stewardship in treating chronic wounds is the inaccuracy of bacterial and infection diagnosis. Methods: Joint Commission lists five elements of performance (EP): (1) Identifying an antimicrobial stewardship leader, (2) establishing an annual antimicrobial stewardship goal, (3) implementing evidence-based practice guidelines related to the antimicrobial stewardship goal, (4) providing clinical staff with educational resources related to the antimicrobial stewardship goal, and (5) collecting, analyzing, and reporting data related to the antimicrobial stewardship goal. This article focuses on choosing and implementing an evidence-based ASP goal for 2020. Discussion: Clinical trials have demonstrated the ability of fluorescence imaging (MLiX) to detect clinically significant levels of bacteria in chronic wounds. Combined with clinical examination of signs and symptoms of infection, the MLiX procedure improves the clinician’s ability to diagnose infection and can guide antimicrobial use. In order to satisfy the elements of performance, the MLiX procedure was incorporated into the annual ASP goal for several wound care centers. Clinicians were educated on the fluorescence imaging device and guidelines were instituted. Collection of antimicrobial utilization data is underway.

This review provides insight into the role that obesity, but especially mediators of the adipose tissue, have in both renal disease and transplantation. In particular, we focus on the functions of leptin and adiponectin, inflammatory mediators with widely known clinical implications, as well as on the role of arachidonic acid-derived eicosanoid metabolites. These latter compounds, epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETEs) acids, which modulate the liberation of cytokines in the adipose tissue, are generated in the epoxygenase pathway of arachidonic biotransformation via CYP450 enzymes. There is accumulating evidence suggesting that EETs and HETEs may have a critical role in the onset and outcome of chronic kidney disease and renal transplantation. Finally, we also discuss the reported effect that the presence of genetic variants in leptin, adiponectin, EETs and HETEs-related genes may cause in renal patients and recipients. The levels of cytokines of the adipose tissue and related compounds play a remarkable role in both renal disease and transplant. Accordingly, novel therapeutic strategies are being developed based on the modulation of their concentrations in patients with various diseases.

Ankle sprains are exceedingly common injuries in both athletes and general population. They account for 10 to 30% of all sports injuries. Although the vast majority of lateral ankle ligamentous injuries respond successfully to conservative management, the absolute number of those that progress to chronic lateral ankle instability (CLAI) remains considerably important. This condition is characterized by persistent symptoms and may be associated with short-term and long-term complications and functional deficits. There is still a lack of ideal postoperative management of CLAI patients. Furthermore, an evidence-based rehabilitation phasing does not exist and most of the published studies regarding this subject suggest some protocols based on a wide variety of functional assessment scores and other modalities which are not accurate enough. Moreover, the literature that assesses the ability to return to work (RTW) and return to sport (RTS) in general population and athletes operated for CLAI shows most commonly aggregated results with global rates of RTW or RTS without describing a detailed timeline based on the readiness of patients to return to each level of activity. Although stress radiographs and MRI have been assessed as potential tools to improve postoperative management of CLAI patients, the first modality is limited by its low sensitivity to detect laxity and the second one by its static character and its inability to predict the healing process phase nor the mechanical properties of the repaired/reconstructed ligaments. Bioelectrical impedance, mechanical impedance and near-infrared spectroscopy are non-invasive methods of measurement that could be potential assessment tools to help surgeons improve the postoperative management of patients after CLAI surgery.

Obesity induces inflammation in the hypothalamus and adipose tissue, resulting in metabolic disorders. A novel hypothalamic neuropeptide, neurosecretory protein GM (NPGM), was previously identified in the hypothalamus of vertebrates. While NPGM plays an important role in lipid metabolism in chicks, its metabolic regulatory effects in mammals remain unclear. In this study, a novel Cre driver line, NPGM-Cre, was generated for cell-specific manipulation. Cre-dependent overexpression of Npgm led to fat accumulation without increased food consumption in NPGM-Cre mice. Chemogenetic activation of NPGM neurons acutely promoted feeding behavior and chronically resulted in a transient increase in body mass gain. Furthermore, the ablated NPGM neurons exhibited a tendency to be glucose intolerant, with infiltration of proinflammatory macrophages into the adipose tissue. These results suggest that NPGM neurons may regulate lipid storage and inflammatory responses, thereby maintaining glucose homeostasis.

Cadmium (Cd) is a pervasive, toxic environmental pollutant that preferentially accumulates in tubular epithelium of the kidney. Current evidence suggests that the cumulative burden of Cd here leads to progress loss of the glomerular filtration rate (GFR). In this study, we have quantified changes in estimated GFR (eGFR) and albumin excretion (Ealb) in according to levels of blood Cd ([Cd]b) and excretion of Cd (ECd) after adjustment for confounders. ECd and Ealb were normalized to creatinine clearance (Ccr) as ECd/Ccr and Ealb/Ccr. Among 482 residents of Cd-polluted and non-polluted regions of Thailand, 8.1% had low eGFR and 16.9% had albuminuria, (Ealb/Ccr)×100 ≥ 20 mg/L filtrate. In the low Cd burden group, (ECd/Ccr) ×100 &lt; 1.44 µg/L filtrate, eGFR did not correlate with ECd/Ccr (β = 0.007), while an inverse association with ECd/Ccr was found in the medium (β =−0.230) and high-burden groups (β =−0.349). Prevalence odds ratios (POR) for low eGFR were increased in the medium (POR 8.26) and high Cd burden groups (POR 3.64). Also, eGFR explained a significant proportion of Ealb/Ccr variation among those with middle (η2 0.093) and high [Cd]b tertiles (η2 0.132), but did not with low tertile (η2 0.001). With adjustment of eGFR, age and BMI, POR values for albuminuria were increased in the middle (POR 2.36) and high [Cd]b tertiles (POR 2.74) and those with diabetes (POR 6.02) and hypertension (2.05). These data argue that ECd/Ccr of 1.44 µg/L filtrate (0.01−0.02 µg/g creatinine) could determine a Cd threshold level from which protective exposure guidelines should be formulated.

IHepatitis C virus (HCV) has a high genetic diversity, with seven genotypes with 86 subtypes. This genetic variability confers persistence in the infection and escape of the immune system with evolution to cirrhosis and cancer. Environmental factors can contribute to different disease progression, being essential to assess the viral genotype in the infection and discuss the environmental particularities of Eastern Amazon, and the frequencies of Liver fibrosis between different HCV genotypes in patients living in a region of the Brazilian Eastern Brazilian Amazon. Consists in an observational cross-sectional study. Sociodemographic and clinical data of 76 individuals diagnosed with Hepatitis C between 2019 and 2020 in public health services were selected. Data collected was tabulated in Microsoft Excel 2010TM spreadsheets and analysed in GraphPad Prism 5.0TM. Liver fibrosis was associated with genetic subtypes. Subtype 1b was predominant (42.1%), followed by 1a (13%) and 3a (1.3%). 69.7% of participants had chronic hepatitis, with mild fibrosis (F1/F2) being the most prevalent (38.1%). Severe fibrosis was detected in 75% of individuals infected with the subtype 1b, that is associated with more severe disease. We suggest further studies, to assess other communities in the region, as well as the monitoring of these patients with Liver Elastography to determine the disease evolution and its better management.

Temporomandibular joint disorders (TMD) are characterized by their multifactorial etiology and pathogenesis. A 3-year prospective study was conducted in a Portuguese TMD department to study the prevalence of different TMD signs and symptoms and their association with risk factors and comorbidities. Five hundred ninety-five patients were included using an online database: EUROTMJ. Most patients were female (80.50 %), with a mean age of 38.20±15.73 years. The main complaints were temporomandibular joint (TMJ) clicking (13.26%), pain (12.49%), and masticatory muscle tension (12.15%). The main clinical findings were myalgia (74%), TMJ clicking (60-62%) and arthralgia (31-36%). Risk factors such as clenching (60%) and bruxism (30%) were positively associated with TMJ pain and myalgia. Orthodontic treatment (20%) and wisdom tooth removal (19%) were positively associated with TMJ clicking, while jaw trauma (6%) tracheal intubation (4%) and orthognathic surgery (1%) were positively associated with TMJ crepitus, limited man-dibular range of motion and TMJ pain, respectively. 42.88% of TMD patients had other associated chronic diseases, most of them were mental behavioral or neurodevelopmental disorders (33.76%), namely, anxiety (20%) and depression (13%). The authors also observed a positively association of mental disorders with the degree of TMJ pain and myalgia. Online database seems to be a relevant scientific instrument for healthcare providers who treat TMD. The authors expect that EUROTMJ database can serve as a milestone for other TMD departments.

Klotho (KL) is a glycosyl hydrolase and aging-suppressor gene. Stress is a risk factor for depression and anxiety that are highly comorbid with each other. The aim of this study was to determine KL is regulated by estrogen and plays an important role in sex differences in stress resilience. Our results showed that KL was regulated by estrogen in rat hippocampal neurons in vivo and in vitro and was essential for estrogen-mediated increase in the number of presynaptic vesicular glutamate transporter 1 (Vglut1) positive clusters on the dendrites of hippocampal neurons. The role of KL in sex differences in stress responses was examined in rats using three-week chronic unpredictable mild stress (CUMS). CUMS produced a deficit in spatial learning and memory, anhedonic-like and anxiety-like behaviors in male but not female rats, which was accompanied by a reduction in KL protein levels in the hippocampus of male, but not female rats. This demonstrated the resilience of female rats to CUMS. Interestingly, knockdown of KL protein levels in the rat hippocampus of both sexes caused a decrease in stress resilience in both sexes, especially in female rats. These results suggest that regulation of KL by estrogen plays an important role in estrogen-mediated synapse formation, and KL plays a critical role in the sex differences in cognitive deficit, anhedonic-like and anxiety-like behaviors induced by chronic stress in rats, highlighting an important role of KL in sex differences in stress resilience.

Background: Though tyrosine kinase inhibitors managed to reach outstanding responses in the treatment of Chronic Myeloid Leukemia, resistance is still a challenging point, occurring in approximately 10–20% of the cases, due to several mechanisms. STAT5 expression has been strictly linked to resistance and disease progression and may thus represent a significant target to overcome resistance to TKI in CML. The aim of the study is to explore the in vitro antineoplastic role of the STAT5 inhibitor Pimozide in association with 2nd and 3rd generation inhibitors on chronic myeloid leukemia cells. Methods: The cytotoxic effect was evaluated by the Trypan blue dye exclusion test. K562 cell lines were exposed to pimozide alone and in association with ponatinib and dasatinib at different concentrations to explore the drugs association effect and the in vitro cytotoxic concentrations. Conclusions: Pimozide showed a synergic effect when associated with ponatinib and dasatinib in survival inhibition of K562 cell lines. This results are of note and pave the way for a possible in vivo associations.

Objective: Elucidate the main clinical aspects of the CANOMAD spectrum. Methods: Bibliographical review trough databases (PubMed, Google Scholar, Orphanet, Oxford Academic) of articles from 1985 (1) to 2019 and later selection of the most applicable of the above, in order to construct a non-systematic review. Conclusion: CANOMAD is a chronic-ataxic autoimmune neuropathy associated with IgM monoclonal gammopathy. The correct diagnosis of this rare and multi-faceted disease will help optimal treatment.

Hepatitis C virus (HCV) represents a challenging global health threat in ~200 million infected individuals. Clinical data suggests that only ~10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts a myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence that includes, but not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here, we discussed a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.

Myeloperoxidase (MPO) belong to the family of heme containing peroxidases, produced mostly from polymorphonuclear neutrophils. The active enzyme (150 kD) is the product of MPO gene located on long arm of chromosome 17. The primary gene product undergoes several modifications like removal of introns and signal peptide and leads to the formation of enzymatically inactive glycosylated apoproMPO which complexes with chaperons, producing active proMPO by the insertion of heme moiety. The active enzyme is a homodimer of heavy and light chain protomers. This enzyme is released into extracellular fluid after oxidative stress and different inflammatory responses. MPO is the only type of peroxidase using H2O2 to oxidize several halides and pseudohalides to form different hypohalous acids. So the antibacterial activities of MPO involve the production of reactive oxygen and reactive nitrogen species. Controlled MPO release at the site of infection is of prime importance for its efficient activities. Any uncontrolled degranulation exaggerates the inflammation that can also lead to tissue damage even in absence of inflammation. Several types of tissue injuries and pathogenesis of several other major chronic diseases like rheumatoid arthritis, cardiovascular diseases, liver diseases, diabetes and cancer have been reported to be linked with myeloperoxidase derived oxidants. So the enhanced level of MPO activity is one of the best diagnostic tool of inflammatory and oxidative stress biomarkers among these commonly occurring diseases.

This review was written with the aim of examining the effects that caused an insult such as a wound to an organ such as the skin. Before examining the cellular mechanisms relating to wound healing, the reader is invited to read the structure of the skin as a necessary basis for understand-ing the final aim of this review. The structure of the skin as a basis for understanding the phe-nomena relating to wound healing is addressed taking into account updated literature that ad-dresses the numerous problems of the skin microenvironment. Starting from this awareness, the paragraph dedicated to wound healing becomes complicated when this phenomenon is not im-plemented and therefore the problems dedicated to chronic wounds, keloids and hypertrophic scars are addressed, pathologies that are still difficult to understand and treat today.

To investigate the impact of electrode structure on Electrical Stimulation Therapy (EST) for chronic wound healing, this study designed three variants of flexible microelectrodes (FMs) with Ag-Cu coverings (ACCs), each exhibiting distinct geometrical configurations: hexagonal, cross-shaped, and serpentine. These were integrated with PPY@PDA/PANI (3/6) hydrogel dressings. Comprehensive animal studies, coupled with detailed electrical and mechanical modeling and simulations, were conducted to assess their performance. Results indicated that the serpentine-shaped FM outperformed its counterparts in terms of flexibility and safety, exhibiting minimal thermal effects and a reduced risk of burns. Notably, FMs with metal coverings under 3% demonstrated promising potential for optoelectronic self-powering capabilities. Additionally, simulation data highlighted the significant influence of hydrogel non-uniformity on the distribution of electrical properties across the skin surface, providing critical insights for optimizing EST protocols when employing hydrogel dressings.

The EPA has banned PFOA and PFOS as persistent organic pollutants, but their residues in environment should not be underestimated. Based on the demand for healthy aquaculture and safe aquatic products, it is necessary to explore alleviative methods for the toxicity of PFOA and PFOS to fish. This study is the first to investigate the protective effects of Lactobacillus rhamnosus against oxidative damage, neurotoxicity, and gut microbial dysbiosis induced by PFOA and PFOS in adult zebrafish. The results showed that L. rhamnosus effectively alleviated PFOA- and PFOS-induced oxidative stress by restoring superoxide dismutase (SOD), catalase (CAT), and lactate dehydrogenase (LDH) levels. Both PFOA and PFOS caused intestinal tissue damage, and the degree of damage is PFOA+PFOS>PFOS>PFOA. L. rhamnosus can restore damaged intestinal villi and lymphocyte numbers and also have a restorative effect on intestinal tissue damage. The up-regulated proportion of beneficial Firmicutes and Actinobacteria was also found after L. rhamnosus feeding. These findings provide new insights for L. rhamnosus to alleviate the toxicity of PFOA and PFOS to zebrafish and promote the progress of research on the successful use of probiotics in freshwater aquaculture.

Chronic Chagas Cardiomyopathy (CCC) results from infection with the protozoan parasite Trypanosoma cruzi and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H/HeN mice chronically infected with T. cruzi JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC. We utilized electrocardiography (ECG) to monitor T. cruzi-infected mice and determine whether ECG markers could be correlated with cardiac function abnormalities. We found that the C3H/HeN:JR combination frequently displayed early onset CCC indicators, such as sinus bradycardia and right bundle branch block, as well as prolonged PQ, PR, RR, ST and QT intervals in the acute stage. Our model exhibited high levels of cardiac inflammation and enhanced iNOS expression in the acute stage, but denervation did not appear to have a role in pathology. These results demonstrate the potential of the C3H/HeN:JR host:parasite combination as a model for CCC that could be used for screening new compounds targeted at cardiac remodeling and for examining the potential of anti-parasitic drugs to prevent or alleviate CCC development and progression.

Keywords: chronic lymphocytic leukemia; older patient, Bruton tyrosine kinase, BCL2, cost-effectiveness Bruton tyrosine kinase inhibitors (BTKi) and the BCL2 inhibitor venetoclax, with or without the anti CD20 monoclonal antibody Obinutuzumab, represent the preferred options for the first-line therapy of CLL because they are more effective and may improve quality of life. However, pa-tient’s inclusion criteria were heterogeneous across trials designed for older patients and the identification of CLL-specific parameters identifying unfit patients at risk of developing drug-specific adverse events are required to guide treatment choice. Due to inclusion/exclusion criteria in trials, higher discontinuation rates with BTKi were reported in real-world studies and registry analyses provided useful information on factors predicting for earlier discontinuation in a real-world setting. Though targeted agents were shown to be cost-effective treatments in high-income countries, the out-of-pocket expenses may limit accessibility to these drugs and the overall expenditure for new drugs in CLL is projected to increase substantially posing an issue for sustainability. This being said, the choice of a finite duration treatment based on venetoclax containing regimens or treatment until progression with BTKi is today possible in high- income countries and the therapy choice drivers are represented by coexisting medical conditions rather than age, by patient expectations, logistics and sustainability.

Glitter particles are considered a model of microplastics, which are used in a wide range of products. In this study, we evaluated the toxicity of green and white glitter dispersions on the embryonic development of the sea urchins Echinometra lucunte, Arbacia lixula, and the mussel Perna perna. The Toxicity Identification and Evaluation (TIE) approach was used to identify possible chemicals related to toxicity. Glitter dispersions were prepared using 0.05% ethanol. The tested dispersions ranged from 50 to 500 mg/L. The white glitter was composed of a vinyl chloride-methyl acrylate copolymer. The effective concentrations of green glitter to 50% embryos (EC50) were 246.1 (235.8 – 256.4) mg/L to A. lixula, 23.0 (20.2 - 25.8) mg/L to P. perna and 105.9 (61.2 - 150.2) mg/L, whereas the EC50 of white glitter to E. lucunter was 272.2 (261.5 – 282.9) mg/L. The EC50 for P. perna could not be calculated; however, the lowest effect concentration was 10 mg/L. The filtered suspension of green glitter had Ag levels exceeding the legal standards for marine waters. TIE showed that metals, volatiles, and oxidant compounds contribute to toxicity. The results showed that glitter may adversely affect marine organisms; however further studies are necessary to determine its environmental risks.

Abstract. The increasing frequency of isolation of methicillin-resistant Staphylococcus aureus (MRSA) limits the chances of effective antibacterial therapy of staphylococcal diseases and results in development of persistent infection such as bacteremia and osteomyelitis. The aim of this study was to identify features of the MRSAST239 0943-1505-2016 (SA943) genome, that contribute to the formation of both acute and chronic musculoskeletal infections. The analysis was performed using comparative genomics data of the dominant epidemic S. aureus lineages namely ST1, ST8, ST30, ST36, ST239. SA943 genome encodes proteins that provide resistance to the host immune system, suppress immunological memory and form biofilms. The molecular mechanisms of adaptation responsible for development of persistent infection were as follows: amino acid substitution in PBP2 and PBP2a, providing resistance to ceftaroline; loss of a large part of prophage DNA and restoration of nucleotide sequence of beta-hemolysin, that greatly facilitates escape of phagocytosed bacteria from phagosome and formation of biofilms; dysfunction of the AgrA system due to the presence of psm-mec and several amino acid substitutions in the AgrC; partial deletion of nucleotide sequence in genomic island vSAβ resulting in the loss of two proteases of Spl - operon; deletion of SD repeats in SdrE amino acid sequence.

Chronic venous insufficiency (CVI) is a lifelong, moribund, and debilitating disease process with tremendous personal and financial costs. At its core, CVI involves blood pooling in the lower extremities secondary to inadequate venous blood return, resulting in venous hypertension and incompetence of the one-way valves in the lower extremity veins. As venous circulation slows, metabolic demands of the cells in the lower extremities increase, leading to stasis dermatitis, infection, cellular death, and venous ulceration. This case study aims to report the efficacy of dehydrated amniotic membrane allograft (DAMA) applications to a chronic right lateral ankle ulcer resulting from chronic venous insufficiency. The patient in this study received DAMA applications weekly for six weeks. Upon examination at the initial application, the wound was wet and macerated due to drainage with significant hemosiderosis and lipodermatosclerosis consistent with a Venous Clinical Severity Score (VCSS) of 2. Upon inspection at the final visit, the wound was closed, with a VCSS of 0. This case study demonstrates that the application of DAMA has the potential to act as an effective barrier to cover and accelerate wound closure time. Future non randomized and randomized controlled trials may further establish standardized protocols for DAMA application in venous ulceration, help create treatment algorithms to predict wound closure endpoints, and encourage innovation that may further accelerate healing time.

Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerful therapeutic opportunity to CML patients. However, a definitive cure can only be achieved when only CRISPR-edited cells are selected. A gene-trapping approach combined with CRISPR technology would be an ideal approach to ensure this. Here, we have developed a CRISPR-Trap strategy that efficiently inserts a donor gene trap (SA-CMV-Venus) cassette into the BCR-ABL1-specific fusion point in the CML K562 human cell line. The trapping cassette interrupts the on-cogene coding sequence and expresses a reporter gene that enables the selection of edited cells. Quantitative expression analyses showed significantly higher level of expression of the BCR-Venus allele coupled with a drastically lower level of BCR/ABL expression in Venus+ cell fractions. Functional in vitro experiments showed cell proliferation arrest and apoptosis in selected Venus+ cells. Finally, xenograft experiments with the selected Venus+ cells showed a large reduction in tumour growth, thereby demonstrating a therapeutic benefit in vivo. This study is a proof of concept for the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms.

Background: Chronic kidney disease, one of the most common diseases in the world, is characterized by irreversible impairment of the kidney’s metabolic, excretory, and endocrine functions. During end-stage renal disease, patients require renal replacement therapy, such as hemodialysis (HD). Protein-energy wasting is a common health problem among HD patients. However, this study aims to assess the nutritional status of HD patients at two HD centers in Jeddah, Saudi Arabia, and to determine its associated factors. Methods: A cross-sectional study was conducted at two different Dialysis Centers in Jeddah, Saudi Arabia; 211 female and male HD patients. Malnutrition was recognized using the Modified-SGA (M-SGA) comprising two parts: medical history and physical examination. Sociodemographic and health status for all patients were also determined. Patients were classified based on their M-SGA score into two groups: normal and malnourished. Results: Overall, 54.5% of the participants showed malnutrition. Unemployment, low muscle strength and mass, high level of medication use, and high dialysis vintage were positively (P&lt;0.05) associated with malnutrition. Conclusion: The M-SGA score indicates a high prevalence of malnutrition among HD patients. These results show the importance of regular assessment and follow-ups for HD patients ensuring better health and nutritional status.

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treat-ment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provided limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory conditions and experi-mental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model of human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, including podocyte loss. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by targeting NOTCH signaling pathway. JQ1 inhibited the gene expression of the NOTCH effec-tors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

The paradigm of the Somatic Mutation Theory (SMT) is failing and a new paradigm is in the making but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast cancer is well compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that breast cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.

Designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation is Science and Technology (COST) (https://www.cost.eu/cost-actions/what-are-cost-actions/ ) - COST action 15111 - from 2016 to 2020. The main goal of the Cost Action was to assess the existing fragmented knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries, and to enhance coordinated research and health care provision in this field. We report on the recommendations for clinical diagnosis, heath services and care for people with ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries and 55 European health professionals and researchers, who have been informed by people with ME/CFS (https://www.cost.eu/actions/CA15111/#tabs|Name:overview).

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.