The aim of our study was to describe our experience using a Spectra Optia® automated apheresis system in children with sickle cell disease (SCD). We used automated red blood cell exchange (RCE) to treat acute and chronic complications in 75 children with SCD who had a median age of 10 years [7-13]. We analysed 649 exchange sessions. Peripheral venous access was limited in a number of the children, thus requiring a femoral central double‐lumen venous catheter (CVC). We recommend the use of heparin locking, with 500 units in each lumen of a CVC. This method was well tolerated, with few complications during the procedures. For preoperative prevention, all of the patients had achieved a post-RCE HbS level of <30% since this is a mandatory condition imposed by the anaesthesiologist. With a post-RCE Hb level of approximately 10-11 g/dL, a blood exchange volume of ≥32 mL/kg, and an interval between each RCE procedure of ≤30 days, it was able to maintain the residual HbS level below 30%. Despite a target pre‐exchange HbS level of 47%, we did not encounter a single stroke recurrence. Erythrocytapheresis is useful and safe for children with SCD.

Asthma is the most common chronic disease in children. It is characterized by difficulty in breathing and chronic airway inflammation associated with narrowing of the airways, and airway hyperresponsiveness. If left untreated, asthma can lead to respiratory distress and even death. A number of medications are available and prescribed to manage asthma. Yet despite that, only half of the asthmatic patients are able to control their condition. Extracellular vesicles (EVs) play an important role in transporting contents such as nucleic acids, proteins, and lipids to other cells. While EVs have been extensively studied as biomarkers of various pathological states, evidence indicates that they can play protective and therapeutic roles in mitigating diseases such as cancer, cardiovascular disease and asthma. Here we propose to conduct a systematic review that provides a detailed analysis of the therapeutic effect of EVs in mitigating the primary (inflammation, airway hyperresponsiveness) and secondary outcomes (airway remodelling, molecular indices of cellular signalling, and inflammatory mediators in serum) associated with asthma in preclinical studies.

Objective: The objective of this study is to determine the epidemic dynamics and clinical features of COVID-19 in southern Hainan Island, China, and provide experience for other tropical areas of the world. Methods: This retrospective study included confirmed cases of COVID-19 in southern Hainan. All enrolled patients were treated in Sanya, and data on epidemiological and clinical features of the disease and infection prevention and control measures adopted by the local government during the epidemic were collected. Results: Of the 74 cases, 71 (95.95%) were imported from Wuhan, Hubei Province (47, 63.51%), other cities in Hubei Province (11, 14.86%), or provinces other than Hubei and Hainan (13, 17.57%). Three (4.06%) patients were infected in southern Hainan, including one autochthonous case in Sanya. Fifty-four cases (72.97%) were detected in Sanya, and 27 cases (27.03%) were diagnosed in other cities. The rate of severe or critical cases was 28.38% (21/74), and mortality was 2.7% (2/74). The serum lactate levels and base excess of severe-critical patients were higher than those of patients with mild-moderate disease. Multivariate logistic regression analysis showed that chronic conditions were risk factors for severe and critical COVID-19. Seventy-four patients were diagnosed with COVID-19 over a 22-day period in Sanya, and the epidemic period in the city was 48 days. The outbreak was controlled rapidly because the local government adopted strict infection prevention and control measures. Conclusions: The clinical characteristics of COVID-19 in Hainan Island were similar to those reported in other regions. In Sanya, the rate of severe and very severe cases was higher than in other regions; however, most cases were imported, and there was only one autochthonous case. The rapid control of the outbreak in Sanya may be related to the tropical climate, adoption of strict infection prevention and control measures, daily reporting of new cases, increased public awareness about the epidemic, and other emergency actions implemented by the local government.

COVID-19 is an infectious disease spreading through human touch. This study explored the risk perception and knowledge towards COVID-19 infection among Bangladeshi adult participants. Two self-administered online surveys were administered at two different time points from 26-31 March 2020 (Early lockdown) and 11-16 May 2020 (Late lockdown) through social media on 1005 respondents (322 and 683 participants, respectively) during COVID-19 lockdown period in Bangladesh. Univariate and multiple linear regression models were used to examine factors associated with risk perception and knowledge towards COVID-19. The mean knowledge (8.4 vs. 8.1, P=0.022) and risk perception (11.2 vs. 10.6, P < 0.001) scores differ significantly between early and late lockdown. Compared to the early lockdown period, the scores for perceived risk of contracting COVID-19 decreased significantly while public knowledge about COVID-19 was lower but not statistically significant. Female participants who practiced high quarantine particularly those who did so at the public health order during the lockdown reported increased knowledge towards the spread of COVID-19 and perceived high risk of contracting COVID-19. Education intervention using awareness to increase public knowledge and perception towards COVID-19 in Bangladesh should target male participants who practiced low quarantine and are less worried about the spread of such novel coronavirus even as the physical distancing persists.

Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

Neurodegenerative diseases of protein misfolding affect humans and animals. In humans, these diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC). Mineral exposure may be important in the pathogenesis of protein misfolding cascades. The possible association of bentonite, montmorillonite, and mineral risk factors with Alzheimer’s disease, Parkinson’s disease, ALS, and Western Pacific ALS/PDC is analyzed and discussed.

Coronavirus Disease 2019 (Covid-19) was first described in December 2019 in Wuhan, Hubei Province, China; and produced by a novel coronavirus designed as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 has become a pandemic reaching over 1.3 million confirmed cases and 73,000 deaths. Several efforts have been done to identify pharmacological agents that can be used to treat patients and protect healthcare professionals. The sequencing of the virus genome not only has offered the possibility to develop a vaccine, but also to identified and characterize the virus proteins. Among these proteins, main protease (M^pro) has been identified as a potential therapeutic target, since it is essential for the processing other viral proteins. Crystal structures of SARS-CoV-2 M^pro and inhibitors has been described during the last months. To describe additional compounds that can inhibit SARS-CoV-2 M^pro, in this study we performed a molecular docking-based virtual screening against a library of experimental and approved drugs. Top 10 hits included Pictilisib, Nimorazole, Ergoloid mesylates, Lumacaftor, Cefuroxime, Cepharanhine, and Nilotinib. These compounds were predicted to have higher binding affinity for SARS-CoV-2 M^pro than previously reported inhibitors for this protein, suggesting a higher potential to inhibit virus replication. Since the identified drugs have both pre-clinical and clinical information, we consider that these results may contribute to the identification of treatment alternative for Covid-19. Nevertheless, in vitro and in vivo confirmation should be performed before these compounds could be translated to the clinic.

Cardiovascular disease (CVD) is considered to be one of the leading health issues in Thailand. CVD not only contributes to an increase in the number of hospital admissions year on year but also impacts on the rising health care expenditure for the treatment and long-term care of CVD patients. Therefore, this study is aimed at examining the impacts of risk reduction strategies on the number of CVD hospital admissions, Disability-Adjusted Life Years (DALYs) and the costs of hospitalisation. To estimate such impacts a CVD cost-offset model wasapplied using a Microsoft Excel spreadsheet. The number of the mid-year population was classified by age, gender and the CVD risk factor profiles from the recent Thai National Health Examination Survey (NHES) IV. This survey was chosen as the baseline population. The CVD risk factor profiles included age, gender, systolic blood pressure, total cholesterol, and smoking status. The Asia-Pacific Collaborative Cohort Study (APCCS) equation was applied to predict the probability of developing CVD over the next eight-year period. Estimates on the following were obtained from the model: (1.) the CVD events both fatal and non-fatal; (2.) the difference between the projected number of deaths and the actual number of deaths in that population; (3.) the number of patients who are expected to live with CVD; (4.) the DALYs from the estimated number of fatal and non-fatal events; (5.) the cost of hospital admissions. Four CVD risk strategy scenarios were investigated as follows: (1.) the do nothing scenario; (2.) the optimistic scenario; (3.) achieve the UN millennium development goal; and (4.) the worst-case scenario. The findings showed that over the next eight years there are likely to be 3,297,428 recorded cases of CVD; 5,870,049 cases of DALYs; and, approximately ฿57,000 million, ($1.9 billion), is projected as the total cost of hospital admissions. However, if the current health policy can reduce the levels of risk factors as defined in the optimistic scenario or such policy meets the specifications of the UN millennium development goal,there would be a significant reduction in the number of hospital admissions. These are estimated to be a reduction of 522,179 male and 515,416 female cases. With these results it is expected that health care costs would save approximately ฿9,000 million, ($298.3 million), for CVD and 900,000 million of DALYs over the next eight years. However, if there is an upward trend in the risk factors as predicted in the worst-case scenario, then there will be an increase of 428,220 CVD cases; consequently, DALYs cases may rise by 766,029 while the hospitalisation costs may increase by approximately ฿7,000 million, ($232.1 million). Based on our findings, reducing the levels of CVD risk factors in the population will drastically reduce: (1.) the number of CVD cases; (2.) DALYs cases; and (3.) health care costs. Therefore it is recommended that the health policy should enhance the primary prevention programs which would be targeted at reducing the CVD risk factors in the population.

Huntington's disease (HD) is a rare genetic neurodegenerative disorder that causes motor disorders, neuropsychiatric symptoms and a progressing deterioration of cognitive functions. Complex issues resulting from the hereditary nature of HD, the complexity of symptoms and the concealed onset of the disease have a great impact on the quality of life of family carers. The caregivers are called as “forgotten people” in HD family, also in genetic counseling. This study aims to explore the reliability and validity of the Huntington’s Disease Quality of Life Battery for carers (HDQoL-C) within a Polish population. 90 carers recruited from the Enroll-HD study in Polish research centres of the European Huntington`s Disease Network completed a polish translation of the HDQoL-C. Data was subjected to Principle Components Analysis and reliability measures. The Polish version of the shortened versions of the HDQoL–C is similarly valid compared to the original English version and suitable for use within this population. The HDQoL-C has previously demonstrated a wide range of benefits for practitioners in capturing and understanding carer experience and these benefits can now be extended to Polish speaking populations.

Background: To inform global health policies and resources planning, this paper analyzes evolving trends in physical rehabilitation needs, using data on Years Lived with Disability (YLDs) from the Global Burden of Disease Study (GBD) 2017. Methods: Secondary analysis of how YLDs from conditions amenable to physical rehabilitation have evolved from 1990 to 2017, for the world and across countries of varying income levels. Linear regression analyses were used. Results: A 66.2% growth was found in estimated YLD Counts amenable to physical rehabilitation: a significant and linear growth of more than 5.1 billion YLDs per year (99%CI: 4.8–5.4; r² = 0.99). Low-income countries more than doubled (111.5% growth) their YLD Counts amenable to physical rehabilitation since 1990. YLD Rates per 100,000 people and the percentage of YLDs amenable to physical rehabilitation also grew significantly over time, across locations (all p > 0.05). Finally, only in high-income countries Age-standardized YLD Rates significantly decreased (p < 0.01; r² = 0.86). Conclusions: Physical rehabilitation needs have been growing significantly in absolute, per-capita and in percentage of total YLDs, globally and across countries of varying income level. In absolute terms, growths were higher in lower income countries, wherein rehabilitation is under-resourced.

As metabolomics is widely used in the study of disease mechanisms, more and more studies have found that metabolites play an important role in the occurrence of diseases. The aim of this study is to investigate the effects and mechanisms of quercetin in high-fat-sucrose diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) development using nontargeted metabolomics. A rat model of NAFLD was established by feeding with a HFD for 30 and 50 days. Results indicated quercetin exhibited hepatoprotective activity in HFD-induced NAFLD rats in 30 days by regulating fatty acids related metabolites (adrenic acid, etc.), inflammation related metabolites (arachidonic acid, etc.), oxidative stress related metabolites (2-hydroxybutyric acid) and other differential metabolites (citric acid, etc.). However, quercetin couldn’t improve NAFLD in 50 days maybe it couldn’t reverse the inflammation condition induced by long-term high-fat diet. These data indicate that dietary quercetin may be beneficial to NAFLD at early stages. Furthermore, combining metabolomics and experimental approaches opens up avenues of effects and mechanisms of drugs for complex diseases.

Average of 41,900 patients are diagnosed annually with staphylococcus bacterial infection in California, 24,089 patients have Methicillin-resistant Staphylococcus Aureus (MRSA) and 17,810 patients have Methicillin-Sensitive Staphylococcus (MSSA). This paper demonstrates that there is a difference in mortality rate due to staphylococcus infection between males and females (P-value<0.05, CI 95%). Male patient diagnosed with S. aureus has 1.3 chance of mortality incidence than female patient. In addition, MRSA infection rate is 1.4 times MSSA infection (P-value<0.05, CI 95%), but the gap of infection is decreasing; however, mortality of both infections combined are more than threefold greater compared to three decades ago.

Background & Aims: This RCT aimed to investigate the safety and efficacy of MF4637, a medical food comprising highly concentrated, highly purified, long chain (LC) omega-3 fatty acids, (460 mg eicosapentaenoic acid (EPA) and 380 mg docosahexaenoic acid (DHA)) in correcting the omega-3 fatty acid nutritional deficiency present in non-alcoholic fatty liver disease (NAFLD). The potential for MF4637 to reduce liver fat was evaluated in a subset of patients. Methods: 176 subjects with NAFLD were randomised to receive 3 g/d of LC-omega-3 fatty acids (n=87) or placebo (olive oil; n=89) for 24 weeks, in addition to following standard-of-care dietary guidelines for these patients. Thus, interventions were given on top of the dietary advice. The omega-3 index, omega-6:omega-3 fatty acid ratio (primary outcome) and quantitative measurements of red blood cell (RBC) EPA and DHA (secondary outcome) were determined at baseline and study completion. Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) assessment of change in liver fat fraction was conducted in a subset of patients. Results: Of the 176 randomised subjects, 167 were analysed for the primary and secondary outcomes (n=81 in the MF4637 group; n=86 in the placebo group). Supplementation with MF4637 for 24 weeks significantly increased the omega-3 index and absolute values of RBC EPA and DHA, and decreased the omega-6:omega-3 fatty acid ratio in NAFLD patients compared to placebo (p<0.0001). There was a statistically significant reduction in liver fat content within both groups with no difference between them. An inverse relationship between change in absolute RBC EPA+DHA and change in liver fat, AST and ALT levels was seen suggesting that a greater increase in omega-3 content was associated with a reduction for both liver fat content and improvement in liver enzyme levels. Additionally, a significant liver fat-lowering effect of MF4637 compared to placebo was demonstrated in a subset of patients with baseline fatty liver index (FLI) score ≥ 40. There were no serious adverse events related to study interventions. Conclusions: The study results demonstrate that the medical food MF4637, was able to correct the nutritional deficiency of omega-3 in NAFLD patients above and beyond that obtained with nutritional counselling. This demonstrates that MF4637 is beneficial in raising the low omega-3 index observed in these patients. A reduction in hepatic steatosis was demonstrated with both intervention groups although no distinction between groups was seen. Further analyses demonstrate the potential to identify omega-3 sensitive patients using an easily available clinical tool for steatosis prediction.

One of the principal hallmarks of Alzheimer’s disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists either in blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-Epigallocatechin-3-gallate, Quercetin, and Rosmarinic acid) with the amyloid-β(1-40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulate the double-layered structure stability.

Abstract: Cardiovascular Disease (CVD) is the most prevalent disease worldwide, which has been linked to work stress because of poor job design as explained by the Job Demand-Control (JDC) and the Effort-Reward Imbalance (ERI) models. In this paper we explore for the first time relative impact of a specific aspect of organisational climate, Psychosocial Safety Climate (PSC), on any CVD including angina, myocardial infarction, hypertension, and stroke. We used two waves of interview data from Australia, with an average lag of 5 years (excluding baseline CVD, final n = 1223). Logistic regression was conducted to estimate the prospective associations between PSC at baseline on incident CVD at follow-up. It was found that participants in low PSC environments were 59% more likely to develop new CVD than those in high PSC environments. Logistic regression showed that PSC at baseline predicts lower CVD risk at follow-up (OR = 0.98, 95% CI 0.96-1.00), and this risk remained unchanged even after joint adjustment for measures of ERI and JDC. These results suggest that PSC is an independent risk factor for CVD in Australia. Beyond job design this study implicates organisational climate and prevailing management values regarding worker psychological health as the genesis of CVD.

The linear diblock copolymer polystyrene-b-poly(4-vinylpyridine) (PS-P4VP) is an important copolymer recently used in many applications such as optoelectronics, sensors, catalysis, membranes, energy conversion, energy storage devices, photolithography, and biomedical applications. (1) Background: The surface thermodynamic properties of PS-P4VP copolymer are of great importance in many chemical and industrial processes. (2) Methods: The inverse gas chromatography (IGC) at infinite dilution was used for the experimental determination of the retention volumes of organic solvents adsorbed on copolymer surfaces as a function of temperature. This led to the variations of the free energy of interaction necessary to the evaluation of the London dispersive and polar acid-base surface energies, the polar enthalpy and entropy, the Lewis acid-base constants, and the transition temperatures of PS-P4VP copolymer. (3) Results: The application of the thermal Hamieh model led to accurate determination of the London dispersive surface energy of the copolymer that showed non-linear variations versus the temperature highlighting the presence of two transition temperatures. It was observed that the Lewis’s acid-base parameters of the copolymer strongly depend on the temperature and the Lewis base constant of the solid surface was showed to be higher than the its acid constant. (4) Conclusions: Un important effect of the temperature on the surface thermodynamic properties of PS-P4VP was proved and new surface correlations were determined.

A comprehensive design framework is proposed for optimizing sparse MIMO (multiple-input, multiple-output) arrays to enhance multi-target detection. The framework emphasizes efficient utilization of antenna resources, including strategies for minimizing inter-element mutual coupling and exploring alternative grid-based sparse array (GSA) configurations by efficiently separating interacting elements. Alternative strategies are explored to enhance angular beamforming metrics, including beamwidth (BW), peak-to-sidelobe ratio (PSLR), and grating lobe limited field of view. Additionally, a set of performance metrics is introduced to evaluate virtual aperture effectiveness and beamwidth loss factors. The study employs the desirability function and explores optimization strategies for the partial sharing of antenna elements in multi-mode radar applications. A novel machine learning initialization approach is introduced for rapid convergence. Observations include the potential for peak-to-sidelobe ratio (PSLR) reduction in dense arrays and insights into GSA feasibility and performance compared to uniform arrays. The study validates the efficacy of the proposed framework through simulated and measured results. The study underscores the importance of effective sparse array processing in multi-target scenarios and highlights the advantages of the proposed design framework, offering clarity on sparse array efficiency and applicability in processing hardware providing clarity on its advantages over uniform and nonuniform arrays.

Introduction/Aim: Central sensitivity to thyroid hormones refers to the sensitivity of the hypothalamic-pituitary-thyroid (HPT) axis to changes in circulating free thyroxine (fT4). The relationship between fT4 levels and iodine intake is complex. The aim of the present study was to assess central sensitivity to thyroid hormones in pregnancy against iodine intake. Materials & Methods: One thousand one hundred two blood and urine samples were collected from pregnant women (with a mean age+SD of 30.4+4.6 years) during singleton pregnancies; women with known/diagnosed thyroid disease were excluded. Specifically, TSH & fT4 and 24-hour urinary iodine excretion (UI) were measured in each trimester and at two months postpartum. The Thyroid Feedback Quantile-based Index (TFQI) was calculated to assess central sensitivity to thyroid hormones. For the statistical analysis of TFQI by time period, analysis of variance (ANOVA) was used, while Pearson's correlation was used to assess TFQI versus UI. Results: The mean TFQI index ranged from -0.06 (first trimester) to -0.07 (two months postpartum), while the corresponding UI was 141 and 172 μg/L, respectively. The TFQI-UI correlation was negative (Pearson r: -0.325, p: 0.04 and r: -0.399, p: 0.023), for UI values over 250 μg/L, in the first and the third trimester of pregnancy, respectively. Discussion: TFQI is a new index reflecting central sensitivity to thyroid hormones. Lower TFQI indicates higher sensitivity to thyroid hormones. In our sample TFQI was inversely related to iodine intake, in the first trimester of pregnancy (the critical period of organogenesis) and the third trimester (the critical period of fetal growth). Thus, the observed changes in TFQI may reflect different ways of central action of thyroid hormones, according to the phase of pregnancy. The negative association between maternal TFQI (indicative of central sensitivity to thyroid hormone) and urine iodine levels during the third trimester of pregnancy may reflect the combined influence of maternal and fetal thyroid function. Our results are intriguing and have the potential to enhance our comprehension of the changes in the HPT axis’ function via variations in central sensitivity to thyroid hormones and its interplay with nutritional iodine status during pregnancy.

(1)Background: Among new anti-angiogenetic agents being developed and everchanging guidelines indications, the question of benefits/safety ratio remains unclear. (2)Methods: we have conducted a systematic review and meta-analysis of 25 randomized controlled trials (15487 patients), evaluating overall survival – OS, progression free survival– PFS and toxicity (grade ≥3 adverse effects, type and number of all adverse effects. (3)Results: analysis showed improvement of pooled-PFS (HR 0.72, 95%CI 0.66–0.78, I2 = 77%, P<0.00001) regardless of treatment settings (first-line - HR 0.83, 95%CI 0.77-0.90, P<0.00001, recurrent cancer – HR 0.61, 95%CI 0.54-0.68, P<0.00001 or maintenance – HR 0.82, 95%CI 0.67-1.00, P=0.04) and type of anti-angiogenetic drug used (VEGF inhibitors, VEGF-R inhibitors or angiopoietin inhibitors). Improved OS was also observed (HR 0.95, 95%CI 0.91–0.99, P=0.02). OS benefits were only observed in recurrent platinum-sensitive or platinum-resistant cancers. Grade≥3 adverse effects were increased across all trials. Anti-angiogenetic therapy increased the risk of hypertension, infection, thromboembolic/ hemorrhagic events, gastro-intestinal perforations but not the risk of wound related issues, anemia or posterior leukoencephalopathy syndrome. (4)Conclusions: Although angiogenesis inhibitors improve PFS, there is little to no OS benefits. Given the high risk of severe adverse reactions a careful selection of patients is required for obtaining the best results possible.

Oncolytic measles virus (MeV) is a promising anti-cancer treatment. However, the production of high titers of infectious MeV (typically 10⁷–10⁹ TCID₅₀ per dose) is challenging because the virus is unstable under typical production conditions. The objective of this study was to investigate how the multiplicity of infection (MOI) and different media – serum-containing (SCM), serum-free (SFM) and chemically-defined (CDM) – affect MeV production. We infected Vero cells at MOIs of 0.02, 0.2 or 2 TCID₅₀ mL^-1 and the lowest MOI resulted in the largest number of infected cells towards the end of the production period. However, this did not equate to higher maximum MeV titers, which were similar for all MOIs. The medium had a moderate effect, generating maximum titers of 0.89–2.17 × 10⁶, 1.08–1.25 × 10⁶ and 4.58–9.90 × 10⁵ TCID₅₀ mL^‑1 for SCM, SFM and CDM, respectively. Infection at a low MOI often required longer process times to reach maximum yields. Our findings show that SCM, SFM and CDM are equally suitable for MeV production in terms of yield and process time. This will allow MeV production in serum-free conditions, addressing the safety risks and ethical concerns associated with the use of serum.

The Hyper-Torus Universe Model (HTUM) is a novel framework that unifies quantum mechanics, cosmology, and consciousness, proposing that the universe is a higher-dimensional hyper-torus containing all possible states of existence. This paper explores the fundamental concepts and implications of the HTUM, which suggests that the universe is a quantum system in which all possible outcomes are inherently connected, with consciousness playing a crucial role in actualizing reality. The HTUM addresses critical challenges in modern physics, such as the nature of quantum entanglement, the origin of the universe, and the relationship between mind and matter. By introducing concepts like singularity, quantum entanglement at a cosmic scale, and the self-actualization of the universe, the HTUM provides a comprehensive framework for understanding the fundamental nature of reality. This paper discusses the mathematical formulation of the HTUM, its implications for quantum mechanics and cosmology, and its potential to bridge the gap between science and philosophy. The philosophical implications of the HTUM are also examined, including its impact on free will, determinism, and the mind-matter relationship. The HTUM represents a significant shift in our understanding of the universe and our place within it, inviting further research and exploration into the nature of reality and consciousness.

Abstract: This paper outlines the methodology and results for a two species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA) ) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two species (free-drug and bound-drug) mass transport setup including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of drug between the free and bound-drug states. The model is solved by a 2-D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over our previously developed model using the finite-difference method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 hours (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug.

Heat metres are used to calculate the consumed energy in central heating systems. The subject of this article is to prepare a method of predicting a failure of a heat meter in the next settlement period. Predicting failures is essential to coordinate the process of exchanging the heat metres and to avoid inaccurate readings, incorrect billing and additional costs. The reliability analysis of heat metres was based on historical data collected over many years. Three independent models of machine learning were proposed, and they were applied to predict failures of metres. The efficiency of the models was confirmed and compared using the selected metrics. The optimisation of hyperparameters characteristics for each of models was successfully applied. The article shows that the diagnostics of devices does not have to rely only on newly collected information, but it is also possible to use the existing big data sets.

In this study, the optimal condition for the extraction of antioxidants from the fruit Buah Mahkota Dewa (Phaleria macrocarpa) was determined by using Response Surface Methodology (RSM). The optimization was applied using central composite design (CCD) to investigate the three independent variables, namely extraction temperature (^oC), extraction time (minutes) and extraction solvent to-feed ratio (%v/v) on the responses of free radical scavenging activity (DPPH), ferric ion reducing power assay (FRAP), total phenolic content (TPC) and total flavonoid content (TFC).The optimal conditions for the antioxidants extraction were found to be extraction temperature (64^oC), extraction time (66 minutes) and solvent to-feed ratio (75 %v/v) with the highest percentage yield of DPPH, FRAP, TPC and TFC were 86.85%, 7.47%, 292.86 mg/g and 3.22 mg/g respectively. Moreover, the data were subjected to response surface methodology (RSM) and the results showed that the polynomial equations for all models were significant, did not show lack of fit, and presented adjusted determination coefficients (R²) above 99%, proving the yield of phenolic, flavonoid and antioxidants activities obtained experimentally were close to the predicted values and the suitability of the model employed in RSM to optimize the extraction conditions. Hence, in this study, the fruit from P.macrocarpa could be considered to have the strong antioxidant ability and can be used in various cosmeceutical or medicinal applications.

Background: Alzheimer's disease (AD) dementia and Mild Cognitive Impairment (MCI) are currently underdiagnosed in the community. Early detection of cognitive deficits is crucial for timely intervention. FACEmemory®, the first completely self-administered online memory test with voice recognition, has been launched as an accessible tool to detect such deficits. This study aims to correlate FACEmemory subscores with traditional neuropsychological tests and to develop an algorithm to distinguish between cognitively healthy (CH) individuals and those with MCI. Methods: A total of 669 participants (266 CH, 206 with non-amnestic MCI -naMCI-, and 197 with amnestic MCI -aMCI-) were included. Pearson’s correlations were conducted to examine the association between FACEmemory scores, demographics, and cognitive performance on classical neuropsychological tests (the Neuropsychological battery of Ace -NBACE-). Machine learning models were compared to find the best algorithm for distinguishing between CH and MCI (whole MCI, aMCI, and naMCI). Results: FACEmemory scores showed significant correlations (p&lt; 0.001) with memory (r= 0.53), executive functions (r= 0.43), visuospatial/visuoperceptual (r= 0.32), language (r= 0.30), praxis (r= 0.30) and attention (r= 0.26) domains of the NBACE. The best algorithm distinguished between CH and MCI (especially aMCI), with a FACEmemory cutoff score of 44.5, yielding sensitivity and specificity values of 0.81 and 0.72, respectively. Conclusions: FACEmemory is a promising online tool for detecting MCI, particularly aMCI. It could play a key role in reducing underdiagnoses of MCI and AD and supporting early intervention efforts in the community.

Amid the current multi-country mpox outbreak, analyzing monkeypox virus (MPXV) and vaccinia virus (VACV) genomes is vital for understanding evolutionary processes that may impact vaccine efficacy and design. This study aimed to elucidate the phylogenetic relationships and structural features of viral antigens, which are crucial for developing effective vaccines. By aligning 1,903 MPXV genomes from the NCBI Virus repository (released between 2022 and 2024), an increase in phylogenetic diversity was observed compared to previous studies. These genomes grouped into Clade I (25 genomes) and Clade IIB (1,898 genomes), with a new Clade I sub-lineage emerging from samples collected in Sud-Kivu province, Democratic Republic of the Congo. Homology-based modeling of six key neutralization determinants encoded by the highly conserved Clade I MPXV genes revealed several amino acid variants near potential antibody binding sites compared to those of vaccinia and variola virus templates. Despite these structural differences, the long-standing vaccinia vaccines, initially created for smallpox, still play a crucial role in safeguarding humanity against mpox today. The findings have deepened our understanding of disparate evolutionary mechanisms for MPXV and VACV, influencing vaccine efficacy. The workflows for viral genomic analysis and structural modeling in CLC Genomics Workbench will facilitate MPXV research and vaccinology. Finally, this study highlights the critical role of MPXV metagenomic surveillance in identifying viral evolution and potential vaccine resistance.

Objectives: To evaluate the possible long-term cerebral deposition of amyloid-β in PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) and its possible influence on axial and cognitive variables. Methods: Consecutive PD patients treated with bilateral STN-DBS with a long-term follow-up were included. Amyloid-β deposition was evaluated postoperatively through a 18F-flutemetamol positron emission tomography (PET) study. Axial symptoms have been assessed using a standardized clinical-instrumental approach. Speech was assessed by perceptual and acoustic analysis while gait by means of the instrumented timed up and go test (iTUG). Motor severity was evaluated applying the UPDRS part III score and subscores while cognitive functions through a complete neuropsychological assessment. Different stimulation and drug conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, on-stimulation/on-medication conditions (single and dual task). Results: 19 PD patients (male: 11; age: 63.52 years; on-stimulation/on-medication UPDRS-III: 17.05) with a five-year postoperative follow-up were included. Amyloid-β deposition was found in 21% of patients (4/19) with a prevalent involvement of prefrontal, limbic and parietal areas. Compared with patients without amyloid-β deposition, PD patients with positive 18F-flutemetamol PET study showed higher preoperative UPDRS-I (p=.037) score and lower postoperative Raven's matrices scores (p=.05). Conclusions: Our results suggest that in the long-term after STN-DBS a significant percentage of PD patients may present brain amyloid-β deposition. However, larger samples are needed to evaluate the possible role of amyloid-β deposition in the development of axial and cognitive alterations after surgery.

In the textile industry, cotton plays a significant role as the primary raw material. However, cotton farming often faces challenges from various diseases, resulting in reduced productivity and financial losses for farmers. To address this issue, this study proposes a new method for predicting cotton diseases in Internet of Things (IoT)-based applications. The proposed solution combines meta-heuristic techniques with deep learning (DL). The aim of the proposed method leverages IoT, deep learning, and meta-heuristic techniques to detect and classify cotton plant diseases, providing an accurate and efficient solution for farmers and the textile industry. The process begins with capturing high-resolution images of cotton leaves in agricultural fields using a camera. These images are then processed using IoT to identify potential diseases. Noise removal and quality enhancement are performed using a Probabilistic Hybrid Wiener Filter (PHWF). Next, the Modified Dilated U-Net (MDU-Net) model segments significant disease regions from the images. Effective features are extracted from these segments using Improved Local Binary Pattern (ILBP), Gray Level Co-Occurrence Matrix (GLCM), and Gray Level Run Length Matrix (GLRM). Feature dimensionality is reduced by selecting optimal features through a Binary Guided Whale-Dipper Throated Optimizer (BGW-DTO). Classification is carried out using a stacking ensemble model, which combines EfficientNet-B7, ResNet50, VGG19, DenseNet121, and InceptionV3 models. To optimize the ensemble, a Harris whale optimization algorithm determines optimal weight coefficients for each classifier. The optimized ensemble model classifies various diseases, including Army Worms, Powdery Mildew, Bacterial Blight, Aphids, and Target Spots. Using our dataset of cotton plant leaf images, the proposed technique achieves a high accuracy of 99.66%. By integrating IoT sensor data and DL, early detection of cotton plant leaf diseases is enabled.

Due to the extreme complexity of Alzheimer's disease (AD), the aetiology of which is not yet known, nor are there any known effective treatments, mathematical modelling can be very useful. Indeed, mathematical models, if deemed reliable, can be used to test medical hypotheses that could be difficult to verify directly. In this context, it is important to understand how $A\beta$ and $\tau$ proteins, which in abnormal aggregate conformations are hallmarks of the disease, interact and spread. We are particularly interested in this paper in studying the spreading of misfolded $\tau$. To this end, we present four different mathematical models, all on networks on which the protein evolves. The models differ in both the choice of network and diffusion operator. Through comparison with clinical data on $\tau$ concentration, that we carefully obtained with multimodal analysis techniques, we show that some models are more adequate than others to simulate the dynamics of the protein. This type of study may suggest that, when it comes to modelling certain pathologies, the choice of the mathematical setting must be made with great care if comparison with clinical data is considered decisive.

Alzheimer’s disease (AD) is a predominant and incurable chronic debilitating neuro-degenerative disorder occupying more than 60% of all types of dementias. It is inaugurating by a cascade of events initiating from amnesic-type memory impairment and by gradually loss of cognitive and executive capacities, which is an intolerable problem for the patients and their familiars. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated Tau protein aggregate in the brain. These pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis culminating in neurodegeneration and fuelling AD. Thus, at a basic level, abnormality in brain proteins function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is a multifactorial disorder, caused by a combination of age-related changes, genetic, environmental and lifestyle factors that affect the brain over time, its mysterious pathology seems non limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but plethora of substantial and biological processes have been also emerged in its pathogenesis such as — breakdown and/or dysfunction of the blood–brain barrier (BBB); patients’ carriers of the gene variant APOE4; and the immunosenescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) whose have also observed as early markers that may provoke pathogenic pathways that lead or aggravate AD progression and pathology. Notwithstanding, of various pathological pathways, there are numerous substantial AD features that require shedding light on, such as chronic neuroinflammation, decrease glucose utilization and energy metabolism as well as brain insulin resistance (IR). Herein, we come to broadened our understanding & to connect the dots of the multiple comorbidities and their cumulative impact that may have synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement and the role of APOE4 allele and AD-IR pathogenic link - the shared genetics and metabolomics biomarkers between AD and IR disorders. Investment in the future researches brings us closer to know the pathogenesis of AD, and paves the way to build preventive and treatment strategy.

Background/Objectives: This study aimed to evaluate the impact of image enhancement techniques on the interobserver reliability of tear breakup time (TBUT), tear meniscus height (TMH), corneal fluorescein staining (CFS) scoring, and conjunctivochalasis detection using the Smart Eye Camera (SEC), a portable device for anterior segment examination. Methods: A retrospective analysis was conducted on video recordings captured by SEC from 46 patients with dry eye disease (DED). Three video sets were created: unenhanced (G0), mildly enhanced (G3), and strongly enhanced (G7). Three observers—two DED specialists and one general ophthalmologist—assessed TBUT, TMH, CFS scores, and conjunctivochalasis. Interobserver reliability was evaluated using intraclass correlation coefficients (ICCs) for each image set. Results: Interobserver reliability for CFS scores significantly improved with G3, yielding an ICC of 0.8413. In contrast, G7 improved reliability for TBUT measurements (ICC = 0.7381) but led to a notable decrease in reliability for both CFS scoring (ICC = 0.2259) and conjunctivochalasis detection (ICC = 0.0786). Furthermore, the assessment of TMH demonstrated a progressive decline in accuracy with increasing levels of image enhancement. Conclusions: Image enhancement using SEC improves diagnostic consistency between dry eye specialists and general ophthalmologists, especially for TBUT and CFS assessments. However, excessive enhancement may obscure key diagnostic features, indicating the need for careful optimization of image processing techniques depending on the diagnostic focus.

Background: Injecting drug use is a global public health challenge with multifaceted consequences, not only for Injecting Drug Users (IDUs) but also for society at large. Their vulnerability necessitates a deeper exploration of their health information needs, aiming to leverage evidence-based research to shape effective interventions for their well-being. Method: This study employed a qualitative method to gain insights into disease conditions and health information needs of IDUs. Through purposive sampling, 71 in-depth interviews were conducted and thematically analyzed. Results: The study included 43 males and 28 females, predominantly aged 26-35 (59.2%) who had poor socioeconomic status. The most commonly reported disease conditions varied and included malaria, infections and diabetes. Findings revealed a complex understanding of their disease conditions and management practices. Participants emphasized a critical need for access to reliable and comprehensive health information, while also highlighting the significant barriers they face in obtaining this information. Additionally, their preference for receiving health information in video formats, written articles, and through outreach programs underscored their desire for knowledge to make informed decisions. As co-creators and stakeholders in their health, participants expressed a clear demand for sustainable and free healthcare, mosquito nets, and regular outreach programs. Conclusions: While drug use presents a significant public health issue, effective interventions for IDUs require a multifaceted approach that begins with understanding their perspectives and actively involving them as co-creators of their health solutions. Abandoning this population contradicts the Sustainable Development Goals' mandate to ensure no one is left behind. Thus, all stakeholders must prioritize inclusive and participatory approaches to address the complex health information needs of IDUs.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by symptoms such as tremors, dementia, and bradykinesia. Early non-motor signs, including constipation and hyposmia, suggest a potential connection between PD and the gut. The loss of dopaminergic neurons in the substantia nigra is a hallmark of PD, with unknown causes. While current treatments provide symptom relief, there are no therapies to slow the progression of the disease. The gut microbiota plays a role in inflammatory and immune responses and has been implicated in neurological disorders. The connection between gut microbiota and neurodegenerative disease remains unclear. In this paper, we aim to explore the potential link between gut microbiome dysbiosis in PD, focusing on constipation, which is an early symptom of the disease. Our review will examine the evidence that suggests the possibility of chronic intestinal inflammation that may contribute to the development of Parkinson’s disease and implicate further connections with other neurodegenerative diseases.

Sex differences in brain metabolism and their relationship to neurodegenerative diseases like Alzheimer's are an important emerging topic in neuroscience. Intrinsic anatomic and metabolic differences related to male and female physiology have been described, underscoring the importance of considering biological sex in studying brain metabolism and associated pathologies. The hippocampus is a key structure exhibiting sex differences in volume and connectivity. Adult neurogenesis in the dentate gyrus, dendritic spine density, and electrophysiological plasticity contribute to the hippocampus' remarkable plasticity. Glucose transporters GLUT3 and GLUT4 are expressed in human hippocampal neurons, with proper glucose metabolism being crucial for learning and memory. Sex hormones play a major role, with the aromatase enzyme that generates oestradiol increasing in neurons and astrocytes as an endogenous neuroprotective mechanism. Inhibition of aromatase increases gliosis and neurodegeneration after brain injury. Genetic variants of aromatase may confer higher Alzheimer's risk. Oestrogen replacement therapy in postmenopausal women prevents hippocampal hypometabolism and preserves memory. Insulin is also a key regulator of hippocampal glucose metabolism and cognitive processes. Dysregulation of the insulin-sensitive glucose transporter GLUT4 may explain the comorbidity between type II diabetes and Alzheimer's. GLUT4 colocalizes with the insulin-regulated aminopeptidase IRAP in neuronal vesicles, suggesting an activity-dependent glucose uptake mechanism. Sex differences in brain metabolism are an important factor in understanding neurodegenerative diseases and future research must elucidate the underlying mechanisms and potential therapeutic implications of these differences.

Cardiovascular disease (CVD) is a major global health concern. The number of people with CVD is expected to rise due to aging populations and increasing risk factors such as obesity and diabetes. Identifying new molecular markers is crucial for early diagnosis and treatment. Among these, plasma levels of some miRNAs specifically expressed in cardiac and skeletal muscle known as myomiRs, has gained attention for their roles in cardiovascular health. This study analyzed the plasma levels of myomiR-133a, -133b, and -206 in the pathogenesis of cardiovascular diseases. Exploiting of a case-control study design with patients recruited from several nursing homes form Calabria (Southern Italy) characterized by different types of CVD compared to non-CVD controls, we found downregulation of miR-133a in heart failure and miR-133b in stroke, along with the overall decreased expression of miR-133b and miR-206 in CVD patients. In silico functional characterization of their targets and signaling pathways revealed their involvement in critical cardiovascular processes. Although further research is necessary to fully elucidate their mechanisms and clinical utility, the results here reported support the idea that myomiRs could serve not only as biomarkers but also as therapeutic targets, offering new avenues for managing and potentially preventing CVD progression.

Background: Neurocognitive disorders (NCDs) have a variable decline in cognitive function, while loneliness was associated with cognitive impairment and increased dementia risk. In the present study, we examined the associations of loneliness with functional and cognitive status in patients with minor (mild cognitive impairment) and major NCDs (dementia). Methods: We diagnosed mild NCD (n=42) and major NCD (n=164) through DSM-5 criteria on 206 participants aged>65 years using the UCLA 3-Item Loneliness Scale (UCLA-3) to evaluate loneliness, the activities of daily living (ADL) and the instrumental activities of daily living (IADL) scales to measure functional status, and Mini-Mental State Examination (MMSE) to assess cognitive functions. Results: In a multivariate regression model, the effect of loneliness on cognitive functions was negative in major (=-1.05-p<.0001) and minor NCD (=-0.06-p<.01). In the fully-adjusted multivariate regression model (sex-age-education-multimorbidity-depressive symptoms-antidementia drug treatment), the effect of loneliness remained negative for major NCD and became positive for minor NCD (=0.09-p<.001). The effect of loneliness on IADL (=-0.26-p<.0001) and ADL (=-0.24-p<.001) showed a negative effect for major NCD across the different models, while for minor NCD, the effect was positive (IADL:=0.26-p<.0001-ADL:=0.05-p=0.01). Minor NCD displayed different levels of MMSE (=6.68-p<.001), but not ADL or IADL, compared to major NCD for the same levels of loneliness. MANOVA pill’s test suggested a statistically significant and different interactive effect of loneliness on functional and cognitive variables between minor and major NCDs. Conclusions: We confirmed the relationships between loneliness and cognitive and functional status in major NCD, observing a novel trend in minor NCD.

Nonlinear single unit activity (SUA) characteristics are the useful measures to reveal the information processing and transfer features associated with Parkinson’s disease (PD) in the basal ganglia. Most of the state-of-the-art approaches to compute such parameters in continuous and discrete forms are strongly dependent on SUA recording length, noise level and input parameters. Due to the specificity of SUA data collection (mainly short recordings with relatively low signal-to-noise ratio) new techniques to evaluate neuronal nonlinear properties are needed. We have developed an encoding technique based on a mean interspike interval (ISI) value to calculate spike train discrete nonlinear features. The approach to compute mutual information (MI) of isolated neurons with its unstructured activity was also proposed. The proposed technique of SUA nonlinear features evaluation slightly depends on spike train length, has low correlations with other SUA characteristics (firing rate, coefficient of ISI variance and asymmetry index). The derived entropy measure in the subthalamic nucleus has significant positive correlation with PD severity. The proposed approach provides nonlinear features that are slightly dependent on investigated sample size and independent on input parameters. Also, the developed mean ISI based measures reflect the more complex nature of oscillatory activity in the basal ganglia, than it was thought previously. Moreover, MI, unlike entropy, takes into account the position of the spike train elements, which allows us to investigate the amount of information retained after the occurrence of temporary failures. The developed approach may be useful in describing nonlinear features of basal ganglia activity contributing to PD pathophysiology probably associated with impaired information transfer in movement disorders.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

Background/Objectives: Vitamin D’s effect on risk health outcomes is often evaluated using prospective cohort studies. Risk ratios (RRs; e.g., hazard ratios or odds ratios) are determined for incidence for participants with baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations below or above specified values. Serum 25(OH)D concentrations vary over time, thereby diluting the effect of 25(OH)D for long follow-up periods. Inverse relationships between RR and follow-up period have been reported for all-cause mortality rate and cancer incidence rates. Here I evaluate the effect for neurological outcomes. Methods: I analyzed how follow-up period affected results from 10 cohort studies of all-cause dementia, 6 studies of Alzheimer’s disease, and 9 for cognitive impairment with respect to vitamin D deficiency. Results: For all-cause dementia, Alzheimer’s disease, and cognitive impairment, respectively, the linear regression fits are RR = 2.9 – 0.14 × years, r = 0.73, p = 0.02; RR = 2.9 – 0.14 × years, r = 0.69, p = 0.13; and RR = 1.8 – 0.066 × years, r = 0.72, p = 0.03. The regression fit to RR for the shortest follow-up period for each outcome is considered the best estimate of vitamin D deficiency’s effect on risk. Those values are approximately twice that found by averaging all RRs without considering the effect of follow-up period. Conclusions: Vitamin D’s effect on risk of neurological conditions should be determined with relatively short follow-up periods after repeated 25(OH)D measurements as warranted during follow-up.

Periodontal disease, a multifactorial inflammatory condition affecting the supporting structures of the teeth, has been increasingly recognized for its association with various systemic diseases. Understanding the molecular comorbidities of periodontal disease is crucial for elucidating shared pathogenic mechanisms and potential therapeutic targets. In this study, we conducted comprehensive literature and biological database mining utilizing tools such as DisGeNET2R, Romin, and Rentrez R libraries to identify diseases sharing associated genes, proteins, or molecular pathways with periodontitis. Our analysis revealed significant molecular overlaps between periodontal disease and several systemic conditions, including cardiovascular diseases, diabetes mellitus, rheumatoid arthritis, and inflammatory bowel diseases. Shared molecular mechanisms implicated in the pathogenesis of these diseases and periodontitis encompassed dysregulation of inflammatory mediators, immune response pathways, oxidative stress pathways, and alterations in the extracellular matrix. Furthermore, network analysis unveiled key hub genes and proteins that play pivotal roles in the crosstalk between periodontal disease and its comorbidities, offering potential targets for therapeutic intervention. Insights gained from this integrative approach shed light on the intricate interplay between periodontal health and systemic well-being, emphasizing the importance of interdisciplinary collaboration in developing personalized treatment strategies for patients with periodontal disease and associated comorbidities.

This study develops a hybrid machine learning (ML) algorithm integrated with IoT technology to improve the accuracy and efficiency of soil monitoring and tomato crop disease prediction in Anakapalle, a south Indian station. An IoT device collected one-minute and critical soil parameters—humidity, temperature, pH values, nitrogen (N), phosphorus (P), and potassium (K)—essential for assessing soil health and optimizing crop growth. Kendall's correlations were computed to rank these parameters for utilization in hybrid ML techniques. Various ML algorithms including K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Decision Tree (DT), Random Forest (RF), and Logistic Regression (LR) were evaluated. A novel hybrid algorithm, 'Bayesian Optimization with KNN', was introduced to combine multiple ML techniques and enhance predictive performance. The hybrid algorithm demonstrated superior results with 95% accuracy, precision, and recall, and an F1 score of 94%, while individual ML algorithms achieved varying results: KNN (80% accuracy), SVM (82%), DT (77%), RF (80%), and LR (81%) with differing precision, recall, and F1 scores. This hybrid ML approach proved highly effective in predicting tomato crop diseases in natural environments, underscoring the synergistic benefits of IoT and advanced ML techniques in optimizing agricultural practices.

Crohn’s disease (CD) is a chronic inflammatory disease associated with a significant burden in terms of quality of life and health care costs and is frequently associated with several complications, including the development of intestinal strictures. Stricturing CD requires a careful multidisciplinary approach involving medical therapy and surgery, still posing a continuous management challenge; in this context, endoscopic treatment represents a valuable, in-between opportunity as a minimally invasive strategy, endorsed by extensive yet heterogeneous evidence and evolving research and techniques. This review summarizes current knowledge on the role of therapeutic endoscopy in stricturing CD, focusing on evidence gaps, recent updates, and novel techniques intended for optimizing efficacy, safety, and tailoring of this approach in the view of precision endoscopy.

Introduction: Despite its high prevalence and impact on health, metabolic dysfunction-associated steatotic liver disease (MASLD) is inadequately addressed in European primary care (PC), with a large proportion of cases going undiagnosed or diagnosed too late. A multi-country European re-search consortium led a project to design and evaluate a patient-centered, integrated model for MASLD screening, diagnosis and linkage to specialty care for European PC settings. Aim: Based on the lessons from this project, the latest research evidence and existing guidelines for the management of MASLD, we sought to develop a set of practice recommendations for screening, referral and management of MASLD in PC. Methods: The Rand/UCLA modified Delphi panel method, with two rounds, was used to reach consensus on practice recommendations. The international panel consisted of experts from six countries, representing family medicine, gastroenterology, hepatology, cardiology and public health. Initially, fifteen statements were drafted based on a synthesis of evidence from the literature and earlier findings from our consortium. Prior to the consensus meeting, the statements were rated by the experts in a first round. Then, in a hybrid meeting, the experts discussed findings of round one, adjusted the statements and reassessed the updated recommendations in a second round. Results: In round one, there was already a high level of consensus on 10 out of 15 statements. After round 2, there were fourteen statements with a high agreement (>90%). One statement was not endorsed. The approved recommendations addressed the following practice areas: risk screening and diagnosis, management of MASLD – Lifestyle interventions, pharmacological treatment of MASLD/MASH, pharmacological treatment for co-morbidity, integrated care, surgical management and other referrals to specialists. Conclusion: The final set of 14 recommendations focuses on increasing comprehensive care for MASLD in PC. The recommendations provide practical evidence-based guidance tailored to PC practitioners. We expect that these recommendations will contribute to the ongoing discussion on systematic approaches to tackle MASLD and support European PC providers by integrating the latest evidence into practice.

Omega-3 polyunsaturated fatty acids (ɷ-3 PUFAs) offer diverse health benefits, such as supporting cardiovascular health, improving cognitive function, promoting joint and musculoskeletal health, and contributing to healthy aging. Despite their advantages, challenges like oxidation susceptibility, low bioavailability, and potential adverse effects at high doses persist. Nanoparticle encapsulation emerges as a promising avenue to address these limitations while preserving stability, enhanced bioavailability, and controlled release. This comprehensive review explores the therapeutic roles of omega-3 fatty acids, critically appraising their shortcomings and delving into modern encapsulation strategies. Furthermore, it explores the potential advantages of Metal-organic framework nanoparticles (MOF NPs) compared to other commonly utilized nanoparticles in improving the therapeutic effectiveness of omega-3 fatty acids within drug delivery systems (DDS). Additionally, it outlines future research directions to fully exploit the therapeutic benefits of these encapsulated omega-3 formulations for cardiovascular disease treatment.

Despite notable advancements in immunotherapy in the past decades, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a promising, potentially curative treatment modality. Only a limited number of studies has performed a direct comparison of two prevalent rabbit anti-thymocyte globulin (r-ATG) formulations — specifically, Thymoglobuline (ATG-T, formerly Genzyme) and Grafalon (ATG-G, formerly Fresenius). The primary objective of our retrospective analysis was to compare the outcomes of adult patients undergoing matched or mismatched unrelated donor (MUD/MMUD) allo-HCT, with a graft-versus-host disease (GvHD) prophylaxis based on either ATG-T or ATG-G. A total of 87 patients undergone allo-HCT between 2012 and 2022 were included. We observed no significant differences between ATG-T and ATG-G concerning the occurrence of acute graft-versus-host disease (aGvHD), regardless of its severity. Conversely, chronic graft-versus-host disease (cGvHD) occurred less frequently in the ATG-T group compared to ATG-G (7.5% vs. 38.3%, p=0.001). Patients treated with ATG-T manifested a higher incidence of cytomegalovirus (CMV) reactivations (70% vs. 31.9%, p&lt;0.001), with a shorter time between transplant and CMV (&lt;61 days, 77.8% vs. 33.3%, p=0.008) and a higher median CMV copy number (1000 vs. 0, p=0.004). Notably, despite a higher occurrence of CMV reactivations in the ATG-T cohort, most patients were asymptomatic compared to ATG-G (85.7% vs. 43.8%, p=0.005). Finally, we observed no significant differences in terms of 5-year overall survival (OS) and 3-year probability of relapse while comparing ATG-T and ATG-G (32.0% vs 40.3%, p=0.423; 63.9% vs 55.7%, p=0.438, respectively).

Keywords: Echocardiographic alterations; left ventricle; dog; Trypanosoma cruzi; flow patterns; dilated cardiomyopathy; Chagas disease

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

From 2008 to 2024, the Newborn Screening Translational Research Network (NBSTRN), part of the National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Program, served as a robust infrastructure to facilitate groundbreaking research in newborn screening (NBS), rare disease, and genomics. Over fifteen years, NBSTRN developed into a significant international network, supporting innovative research on novel technologies to screen, diagnose, treat, manage, and understand the natural history of more than 280 rare diseases. A key component of these efforts has been the development of resources and expertise for the newborn screening community in ethical, legal, and social issues (ELSI). This paper presents findings from a survey conducted by the NBSTRN team with input from one of theNBSTRN's expert workgroups, the Bioethics and Legal Workgroup. With responses from 88 members of the NBS community including researchers and state NBS programs, the survey found that individuals rely on internal and collegial ELSI resources and highlighted a substantial demand for structured, accessible training and resources. The survey’s insights emphasize the importance of privacy and informed consent in NBS research, and suggested a need for improved collaborative tools and educational programs focused on ELSI for the NBS community. The survey results may inform future efforts in ELSI and NBS research including the development of expanded ELSI tools that leverage digital platforms and consultative services.

Organ-on-a-chip (OOC) is an emerging technology that simulates an artificial organ within a microfluidic cell culture chip. Current cell biology research focuses on in vitro cell culture due to various limitations of in vivo testing. Unfortunately, in vitro cell culture fails to provide an accurate microenvironment, and in vivo cell culture is expensive and has historically been a source of ethical controversy. OOC aims to overcome these shortcomings and provide the best of both in vivo and in vitro cell culture research. The key component of the OOC design is utilizing microfluidics to ensure a stable concentration gradient, dynamic mechanical stress modeling, and accurate reconstruction of a cellular microenvironment. OOC also has the advantage of complete observation and control of the system, which is impossible to recreate in in vivo research. Multiple throughputs, channels, membranes, and chambers are constructed in a polydimethylsiloxane (PDMS) array to simulate various organs on a chip. Various experiments can be performed utilizing OOC technology, including drug delivery research and toxicology. Current technological expansions involve multiple organ microenvironments on a single chip, allowing for studying inter-tissue interactions. Other developments in the OOC technology include finding a more suitable material as a replacement for PDMS and minimizing artefactual error and non-translatable differences.

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

Smoking is a pervasive global health concern associated with a myriad of diseases, but its impact on cellular aging, particularly in relation to telomeres, is increasingly recognized. Telomeres, protective caps at the ends of chromosomes, play a crucial role in maintaining genomic integrity. This review critically examines the existing evidence on the association between smoking and telomere atrophy, exploring the molecular mechanisms involved and the implications for accelerated aging and heightened disease risk. The comprehensive analysis encompasses both cross-sectional and longitudinal studies, elucidating potential gender and age disparities. Insights into the molecular pathways linking smoking to telomere shortening are discussed, along with the broader implications for public health. The review concludes by outlining potential interventions and suggesting future research directions in this critical area.

Delve into the dynamic realms of neuroscience, neurology, and psychiatry with this groundbreaking editorial, unveiling the intricate mechanisms of brain function and dysfunction. Explore the latest advancements in molecular biology, genetics, epigenetics, pharmacology, and neuroimaging that are revolutionizing our understanding of neurological and psychiatric disorders. Uncover the challenges and gaps in translating cutting-edge research into practical clinical applications, aiming to enhance the lives of patients and their families. Discover the pivotal role of neuroplasticity in reshaping the brain's adaptability throughout life, alongside the promising potential of non-invasive brain stimulation techniques like transcranial magnetic stimulation and transcranial direct current stimulation. Embark on a journey of innovation and collaboration as researchers and clinicians strive to bridge the gap between bench and bedside, offering hope for improved diagnosis, prevention, and treatment of complex neurological and psychiatric conditions. Join us in this exploration of transformative ideas and novel interventions that hold the key to a brighter future for individuals and society.

Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disor-ders, even nearly a century after its discovery, due to the elusive nature of its causes. The develop-ment of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system's role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, open-ing new possibilities for treatment. Despite these advancements, conventional treatments for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, under-scoring the need for innovative solutions. This necessity has led to the incorporating of advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions.

The role of inflammation in the pathophysiology of acute myocardial infarction (AMI) is well established. Recognizing inflammation's pivotal role in AMI, this manuscript systematically traces historical studies, spanning from early attempts to the present landscape. Several anti-inflammatory trials targeting inflammation in post-AMI have been performed. The review includes key trials, examining their designs, patient demographics, and primary outcomes. Efficacy and challenges are analyzed, shedding light on the translational implications of trial outcomes. The article also discusses emerging trends, ongoing research, and potential future directions in the field. Practical applications and implications for clinical practice are considered, providing a holistic view of the evolving landscape of anti-inflammatory interventions in the context of AMI.

Extracellular vesicles (EVs), a diverse group of cell-derived exocytosed particles, are pivotal in mediating intercellular communication due to their ability to selectively transfer biomolecules to specific cell types. EVs, composed of proteins, nucleic acids, and lipids, are taken up by cells to affect a variety of signaling cascades. Research in the field has primarily focused on stem-cell derived EVs, with a particular focus on mesenchymal stem cells, for their potential therapeutic benefits. Recently, tissue specific EVs or cell type specific extracellular vesicles (CTS-EVs), have garnered attention for their unique biogenesis and molecular composition because they enable highly targeted cell-specific communication. Various studies have outlined the roles that CTS-EVs play in signaling for physiological function and maintenance of homeostasis, including immune modulation, tissue regeneration, and organ development. These properties are also exploited for disease propagation, such as in cancer, neurological disorders, infectious diseases, autoimmune conditions, and more. The insights gained from analyzing CTS-EVs in different biological roles not only enhance our understanding of intercellular signaling and disease pathogenesis, but also open new avenues for innovative diagnostic biomarkers and therapeutic targets for a wide spectrum of medical conditions. This review comprehensively outlines current understanding of CTS-EV origins, function within normal physiology, and implications in diseased states.

Bacteriophages are viruses obligately infecting bacteria. They constitute the most numerous categories of biological forms populating our biosphere and are highly diverse and capable of infecting almost all bacteria. Phages make use of their host cell molecular machinery to express their own genes as they lack the ability to independently reproduce themselves. The inimitable characteristics of bacteriophages have enabled them to become propitious tools in biotechnology and genetic engineering. Phages show no tropism for mammalian cells but however, can be easily modified to present targeting ligands on their surface as coat protein fusions without any negative impacts on phage structure. These displayed ligands thereupon guide the recognition, interaction, and internalization of the phage into cells wherein efficiency of transfection is directly influenced by the copy number of the ligands used for targeting. Engineered phages are more efficacious for transgene delivery and gene expression in cancer cells when compared to other non-viral gene transfer strategies and are therefore being employed in developing cancer vaccines. The high level of stability as well as resistance of bacteriophages to various environmental conditions have enabled the development of virus-like particles (VLPs) capable of successful deliverance of several therapeutic drug cargos into tumors by selective targeting. Phage display technology has been used in therapy of Alzheimer’s disease and drug delivery into the brain. Exogenous peptides fused into the coat protein of phages enables the display of these peptides on the phage surface to generate combinatorial phage that facilitates their rapid separation using their ability to bind to a specific molecular target. Phage therapy has been shown to be safe in clinical settings when compared to antibiotics as it shows no adverse anaphylaxis nor adverse effects such as the emergence of multi-drug resistant bacteria. This review provides intriguing details of the use of natural and engineered phages in the therapy of diseases such as cancer, bacterial infections, bovine mastitis and dementia in addition to the use of CRISPR-Cas9 technology in generating genetically engineered phages. Further, the use of phage display technology in generating monoclonal antibodies against various human diseases is elucidated.

Diabetic retinopathy (DR), a major complication of prolonged diabetes, poses a significant risk of vision loss. Early detection is critical for effective treatment, yet traditional diagnostic methods by ophthalmologists are time-consuming, costly, and subject to variability. This study introduces a novel approach employing a hybrid Convolutional Neural Network-Radial Basis Function (CNN-RBF) classifier integrated with Multi-Scale Discriminative Robust Local Binary Pattern (MS-DRLBP) features for enhanced DR detection. We implemented advanced image preprocessing techniques, including noise reduction, morphological operations, and Otsu’s thresholding, to optimize blood vessel segmentation from retinal images. Our method demonstrates exceptional performance in screening DR, achieving an average of 96.10% precision, 95.35% sensitivity, 97.06% specificity, and 96.10% accuracy. These results significantly outperform traditional methods and offer a promising tool for remote and efficient screening of DR. Applied to publicly available datasets, this research contributes to the development of accessible, accurate diagnostic methods in ophthalmology, potentially reducing the global burden of diabetic vision loss.

. The Tau protein is associated with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation (p-Tau) and intracellular p-Tau aggregates known as neurofibrillary tangles (NFTs). This is particularly evident in individuals with Down syndrome (DS), who develop Alzheimer’s disease-like (AD) neuropathology early in life with almost complete penetrance, associated with the development of dementia symptoms in their 40s or 50s. Our previous findings have shown that certain forms of p-Tau are present already in childhood in individuals with DS in neuron-derived exosomes, suggesting an early phosphorylation profile in this population that could influence the development of AD pathology. Misfolded p-Tau isoforms are known to be seeding competent and may be responsible for spreading AD pathology in different regions of the brain. This review is focused on the accumulation of p-Tau in the brain of individuals with DS and potential consequences for brain function.

Inflammatory bowel diseases, comprising Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, relapsing and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Ustekinumab (UST) is a monoclonal antibody blocking the p40 subunit of the anti-interleukin (IL) 12/23. Pivotal trials (CERTIFI and UNITI-IM for CD, UNIFI for UC) established the efficacy of UST for the induction and maintenance of remission in both CD and UC, with the most favorable results in naïve patients to biologics. In recent years, a wealth of ‘real-world’ data has emerged supporting positive clinical, endoscopic, and histological outcomes in patients treated with UST, as well as reassuring safety data. More recently, the results of the first head-to-head trials of UST and tumor necrosis factor (TNF) antagonists have been reported. Moreover, a number of studies exploring the role of UST in specific clinical settings, such as perianal CD, postoperative complications and recurrence, extraintestinal manifestations, chronic antibiotic-refractory pouchitis, and pregnancy, have been reported. This review explores results reported to date on UST, including those from pivotal trials, real-world data, and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of UST was also reviewed.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, stands as a significant public health challenge in endemic regions of the Americas. Current treatment options, limited and associated with adverse effects, underscore the need for novel therapeutic approaches. This systematic review comprehensively examines existing research on natural products as potential agents against Chagas disease. Employing a systematic search strategy across diverse databases, studies meeting predefined inclusion criteria were assessed for methodological quality and relevance. The synthesis of findings reveals a spectrum of natural products showcasing promising anti-Trypanosoma cruzi properties. The review discusses the limitations of current evidence, highlights gaps in knowledge, and proposes avenues for future research. By elucidating the landscape of natural products in Chagas disease treatment, this review contributes to the ongoing pursuit of innovative and accessible therapeutic strategies.

Tularemia is a zoonotic disease caused by {\it Francisella tularensis} bacteria, a gram-negative coccobacillus-shaped bacterium. There are multiple transmission routes of the infection to humans such as consumption of contaminated food or water, handling of infected animals or bites from {\it haematophagous} arthropods (such as ticks, deer flies, or mosquitoes). In this study we focus on transmission via the bites of ticks and developed a deterministic model of ordinary and impulsive differential equations to gain insight in the differential effect of prescribed fire on {\it Demacenta variablis} and {\it Amblyomma americanum} ticks and the prevalence of tularemina. We found that prescribed fire differentially reduce the number of the two ticks with {\it A. americanum} reduced the least compare to {\it D. variablis} subsequently leading to differential increase of tularemia new infected cases in humans and rodents. Our result further indicates that the spatial arrangement of burn against unburn areas may not matter as either arrangement led to fewer ticks and reduction in tularemia transmission when prescribed fire was implemented. The results of this study provide important new understandings of the intricate effect of prescribed fire on tick species, and the dynamics of the tick-borne disease, tularemia disease in this study.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder but kidneys are not the only organs involved in this systemic disorder. Individuals with the condition may display additional manifestations beyond the renal system, involving liver, pancreas and brain in the con-text of cystic manifestations, while vascular system, gastrointestinal tract, bones, and cardiac valves in the context of non-cystic manifestations. Despite kidney involvement remain the main feature of the disease, thanks to new generation therapies, early diagnosis and better management of kidney related problems, a new wave of complications must be faced from clinicians who treated polycystic patients. Involvement of the liver represents the most prevalent extrarenal manifestation and grows importance in symptom burden and quality of life. Vascular abnormalities are a key factor for patients’ life expectancy and there’s still de-bate whether to screen or not to screen all patients. Arterial hypertension is often the earliest onset among polycystic patients leading to frequent cardiovascular complications. Although cardiac valvular abnormali-ties is a frequent complication, it rarely leads to relevant problems in the clinical history of polycystic pa-tients. One of the new relevant aspects concern bone disorders, that can exert a considerable influence on the clinical course of these patients. This review aims to provide the “state of art” among extrarenal mani-festation of ADPKD.

The core pathological event in Parkinson’s disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans is still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca2+ oscillations in the absence of the Ca2+-buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple of the risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca2+ oscillations, and (3) providing bioenergetic support.

Little is known about how internal positive psychological resources, such as hope, impact burden in family caregivers of persons with dementia. The current study is novel in that it examined how multiple dimensions of hope impacted perceived burden in a sample of family caregivers of persons with Alzheimer’s disease. The stress process model was used as the theoretical framework for variable specification in this study of one-hundred and fifty-five caregivers. Multiple regression was used to determine if hope-agency and hope-pathway independently contributed to burden. Mediation analysis was used to assess whether hope mediated the relationship between subjective stress and burden. Hope-agency but not hope-pathway influenced burden when other variables were considered. Hope-agency partially mediated the effect of subjective stress on burden. This study provides evidence for the relevance of assessing multiple hope dimensions when working with caregivers. It also speaks to the importance of developing/testing hope-bolstering clinical interventions for this population.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamin-ergic neurons responsible for unintended or uncontrollable movements. Mutations in leu-cine-rich repeat kinase 2 locus, contributes to genetic forms of PD. The fruit fly Drosophila mela-nogaster carrying this mutation (LRRK2-Dm), is an in vivo model of PD that develops motor impairment and stands for an eligible non mammalian paradigm to test novel therapeutic ap-proaches. Dehydrozingerone (DHZ) is a natural phenolic compound isolated from ginger. Pre-sents anti-inflammatory, antioxidant and neuroprotective properties making it a potential therapeutic target for PD. We administered DHZ and its C2-symmetric dimer (DHZ-DIM) at 0.5 and 1mM, for 14 and 21 days, in the LRRK2-Dm, with the aim to assess changes for rescuing motor behavior, brain dopaminergic neurons, mitochondria and synapses (T-Bars). The shorter treat-ment with both molecules revealed efficacy at the higher dose improving climbing behavior with a prevention of dopaminergic neuronal demise. After 21 days, a recovery of the motor disability, dopaminergic neuron loss, mitochondrial damage and T-Bars failure was observed with the DHZ-DIM. Our data indicates that the DHZ-DIM exerts a more potent neuroprotective effect respect to the monomer in LRRK2-Dm, prompting further investigation of these compounds in rodent models of PD.

The crosstalk between gut microbiota, intestinal epithelial cells, and innate and adaptive immune system governs the maintenance of the intestinal homeostasis. Any interference in this tight dialogue and in the processes preserving cellular homeostasis (e.g., autophagy) may dysregulate the immune response and impair the clearance of harmful bacteria favoring the dysbiotic alteration of the microbic flora that leads to chronic inflammation. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders, among them the inflammatory bowel disease (IBD). This review discusses the current knowledge on IBD, from the genetic background of high-risk patients to the molecular mechanisms underlying the disease, the contribution of the microbic flora, and the role of autophagy in intestinal epithelial cells and provides the state of art regarding the targeted-nutritional approaches aimed to restore the beneficial crosstalk between an “anti-inflammatory” microbiota and the host. Analysis of the molecular pathogenesis of IBD will help identify genetic and diet-associated risk factors and thus suggest personalized strategies to prevent and manage the disease to improve quality of life with long-term maintenance of the remission phase.

： Anti-MDA5 antibody bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) &amp;/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD especially with regards to the mortality rate are unknown. We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Thirty-nine (55%) patients presented with DM/PM but 32 (45%) didn’t. Twenty-two of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among 32 patients who didn’t have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio [OR]=1.816, P=0.032), presence of anti-Ro-52 antibody (OR=1.676, P=0.018), elevated C-reactive protein (CRP, OR= 4.354, P&lt;0.001) and carcinoembryonic antigen (CEA, OR=2.625, P=0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p=0.009), CRP (p=0.001), CEA (p=0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR=0.245, P=0.017) and multivariate (OR= 0.058, P=0.036) regressions, indicating that they may be a protective factor from RPILD (OR= 0.543, P=0.008) or fatality (OR= 0.707, P=0.012), which was also demonstrated in subgroup analyses. In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might be conversely a protective factor in anti-MDA5+ patients.

Both brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) have multiple roles in the various aspects of neurons, including cell survival and synaptic function. BDNF and its receptor TrkB express in the central nervous system (CNS) neurons extensively, and contribution of BDNF/TrkB system in neuronal function is evident, thus, its downregulation has been considered to be involved in the pathogenesis of Alzheimer’s disease (AD). GCs, a stress-related molecule, and glucocorticoid receptor (GR) are also considered to be associated with AD, in addition to mental disorders such as depression. Importantly, a growing body of evidence suggest a close relationship between BDNF/TrkB-mediated signaling and GCs/GR system in the CNS. Here, we introduce current studies on the interaction among neurotrophic system and stress in CNS neurons, and discuss their involvement in the pathophysiology of AD.

Crown gall (Agrobacterium tumefaciens), crown/root rot (Phytophthora spp.), root lesion disease (Pratylenchus vulnus), and tree vigor are key traits affecting productivity and quality of walnuts in California. Non-inoculated hybrid rootstocks were analyzed by RNA-seq to examine pre-formed factors affecting these traits. Enrichment analysis of the differentially expressed genes revealed that increased expression of cell wall biogenesis-related genes plays a key role in susceptibility to A. tumefaciens, Phytophthora spp., increased vigor, but not P. vulnus. Analysis of the predicted subcellular loci of the encoded proteins revealed that many gene products associated with vigor and susceptibility were targeted to the plasma membrane and extracellular space, connecting these traits to sustaining barrier function. We observed that RNA processing and splicing, along with predicted nuclear targeting, were associated with resistance to A. tumefaciens, Phytophthora spp., low vigor, but not P. vulnus. Four genes within the J. microcarpa QTL region for resistance to A. tumefaciens and Phytophthora spp. were represented among our transcripts, with two of the genes being differentially expressed in association with resistance to A. tumefaciens and decreased vigor. No differential expression related to Phytophthora spp. or P. vulnus traits was observed in this region. Additionally, the J. microcarpa haplotype expressed more transcripts associated with resistance to A. tumefaciens, Phytophthora spp., and low vigor, but not P. vulnus than the J. regia haplotype. We also report unique and shared hormone and defense responses associated with each trait. This research suggests a link between cell wall biogenesis, vigor, and critical root diseases of walnut.

Background and Objectives: The risk of developing cardiovascular diseases (CVD) in patients suffering from rheumatoid arthritis (RA) is two times higher compared to the general population. The objective of this retrospective study was to determine the type of cardiovascular complications that can appear in men vs. women with rheumatoid arth-ritis. Early diagnosis and initiation of therapeutic measures to reduce the progression rate of rheumatoid arthritis, while also maintaining an active lifestyle, are the most important problems in young patients. Materials and Methods: We included a number of 200 pa-tients, divided in 2 groups according to gender (124 women and 76 men) with rheumatoid arthritis, presenting various stages of disease concomitant with cardiovascular complications. We assessed traditional and non-traditional risk factors, electrocardio-graphic and echocardiographic findings in both groups. Results: All patients presented an atherogenic coefficient over two, indicating a significant risk of atherogenesis. Men had elevated levels of total cholesterol compared with women (≥ 200 mg/dL; 77.6% - men vs. 25.8% - women, p<0.001). The participants presented cardiac arrhythmias, especially in the active stage of RA. Women had an increased risk of atrial fibrillation by 2.308 times compared with men (p=0.020). One of the most important complications in young women was pulmonary arterial hypertension (p=0.007). Conclusion: However, in daily clinical practice, the screening for RA is poorly done. Thus, patients are often undiagnosed, while the risk factors are not assessed and RA patients continue to present an increased risk of developing CVD.

Background: Although lower extremity revascularization is commonly performed in hemodialysis patients, poor prognosis remains a major problem. Protein-energy wasting is reportedly associated with chronic inflammation and advanced atherosclerosis in hemodialysis patients. We investigated the association between the geriatric nutritional risk index (GNRI) as a surrogate marker of protein-energy wasting, C-reactive protein (CRP), and their joint roles in the prediction of amputation and/or mortality. Methods: We enrolled 800 patients successfully underwent lower extremity revascularization. Patients were divided into low, middle and high tertile (T1, T2 and T3) according to GNRI and CRP levels, respectively. Results: Amputation-free survival rates for 8 years were 47.0%, 56.9%, and 69.5% in T1, T2, and T3 of the GNRI, and 65.8%, 58.7%, and 33.2% for T1, T2, and T3 of CRP, respectively (p<0.0001 for both). Declined GNRI [adjusted hazard ratio (aHR) 1.78, 95% confidence interval (CI) 1.24-2.59, p=0.0016 for T1 vs. T3] and elevated CRP (aHR 1.86, 95%CI 1.30-2.70, p=0.0007 for T3 vs. T1) were independent predictors of amputation and/or mortality. In the combined setting of both variables, the risk was 3.77-fold higher (95% CI 1.97-7.69, p<0.0001) in the T1 of GNRI with T3 of CRP than in the T3 of GNRI with T1 of CRP. Conclusions: Patients with pre-procedural decreased GNRI and elevated CRP levels frequently experienced amputation and/or mortality, and a combination of both variables could more accurately stratify the risk.

This study aimed to assess the prevalence and identify risk factors for schistosomiasis among school-aged children in low- and middle-income communities. A retrospective cross-sectional study was conducted, involving the examination of 24 034 children for Schistosoma haematobium ova. Data were analyzed using IBM Statistical Package for the Social Sciences (SPSS) version 27. Logistic regression was employed to determine the factors associated with schistosomiasis. The overall prevalence of schistosomiasis in the study population was 75%, with higher rates observed in rural-dominated areas, particularly Bushbuckridge (73%) and Nkomazi (51%). Age, a history of bilharzia, and the presence of blood in urine were significantly associated with schistosomiasis, while being a female child was found to be a protective factor. This study underscores the importance of implementing robust screening procedures and the necessity for health education to mitigate the high prevalence of schistosomiasis and prevent its further spread.

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

The human gut microbiota (GM) is a complex and dynamic ecosystem that hosts trillions of commensal and potentially pathogenic microorganisms. It is crucial in protecting humans from pathogens and in maintaining immune and metabolic homeostasis. Numerous studies have demonstrated that GM has a significant impact on health and disease, including Alzheimer’s disease (AD). AD is a progressive neurodegenerative disorder characterized by impaired short-term memory and cognitive deficits. Patients with AD have been reported to exhibit abnormalities in GM density and species composition. Oxidative stress (OS) has been implicated in the onset and progression of AD, however, the relationship between OS and gut microbiota in AD onset and progression is not clear. Twendee X®︎ (TwX), an oral supplement consisting of 8 active ingredients, has been shown to prevent dementia in mild cognitive impairment (MCI) in humans and substantially improve cognitive impairment in mouse models of AD. This positive effect is achieved through the potency of the combined antioxidants that regulate OS and therefore similar results cannot be achieved by a single antioxidant ingredient. To examine the impact of long-term OS elevation as seen in AD on the body and GM, we examined GM alterations during the initial OS elevation using a rat 2-week OS loading model, and examined the effects of TwX on OS and GM. Furthermore, using a questionnaire survey and fecal samples, we analyzed the impact of TwX on healthy individuals' gut bacteria and the associated effect on their quality of life (QOL). TwX was found to increase the number of bacteria species and their diversity in GM, as well as butyrate-producing bacteria, which tend to be reduced in AD patients. Additionally, TwX improved defecation condition and QOL. The gut bacteria function as part of the homeostatic function during OS elevation, and prophylactic administration of TwX strengthened this function. The results suggests that the preventative effect of TwX on dementia may involve the GM in addition to the other effects previously demonstrated.

Understanding the genetic architecture of a disease is crucial for development of valid diagnostic and therapeutic interventions. The analysis of genomic variations associated with pathological conditions is the starting point for uncovering disease-causing pathways (candidate processes). However, the complexity of intergenic and genetic-environmental interactions hinders the identification of pathogenic values of genomic changes. Furthermore, heredity, epigenetics and somatic mosaicism make the interpretation of genomic data even more sophisticated. To succeed, a variety of bioinformatic techniques are applied. Here, reviewing own and literature data, knowledge-based prioritization of genomic variations is described. Theoretical basis of the knowledge-based prioritization is given with a special regard to gene ontology, heuristics, hermeneutics (genomic hermeneutics) and analytics. Practical and methodological issues of prioritization using ontology- or pathway-based systems analysis are considered in the light of optimistic and realistic scenarios of cumulative phenotypic effects of the variome (the whole set of genomic variations in an individual or specific set of genomic variations for a phenotypic outcome). In the present communication, copy number variants (CNVs) in children with neurodevelopmental diseases are used as a practical foundation for the prioritization, inasmuch as these genome variations are systematically overlooked in the so-called NGS era. Nonetheless, it is highly likely that the prioritization is applicable to almost all types of genomic variations (e.g. chromosome abnormalities, gene mutations, functional synonymous variants etc.). The present methodology seems to be a valuable addition to current biomedical science widening the opportunities for medical genomics and genetics.

Background: Influenza vaccine is a tool for preventing infection and reducing exacerbations in patients with asthma and chronic obstructive pulmonary disease (COPD). Purpose of this study is to investigate dynamics of CRP and serum cytokines (IL-2, IL-6, IL-10, IL-17) in patients with asthma and COPD, as well as to perform a correlation analysis with the clinical parameters of the disease manifestation. Methods: The study included 34 patients with asthma, 20 patients with COPD vaccinated against influenza during a period of remission from 2 to 4 weeks, both groups being under a basic maintenance therapy, and 26 healthy individuals vaccinated with the trivalent polymer-subunit vaccine Grippol® Plus, containing 5 µg of influenza virus strains and 500 µg of azoximer bromide. Results: Observing patients with asthma and COPD, during a year after the vaccination, has revealed a significant reduction in exacerbations frequency (p < 0.05) and duration (p < 0.05) of the bronchial obstructive syndrome (BF). Before the vaccination the IL-6 level in patients with asthma had a direct moderate correlation with duration of exacerbations of the underlying disease (p < 0.05), along with the number of systemic corticosteroids courses during exacerbations (p < 0.05). In 12 months after the vaccination, while assessing cytokine profile of all study groups, a significant reduction in the level of IL-6 was observed, compared to the baseline values (p< 0.05). Conclusion: Conducted analysis of immunological, clinical, and functional parameters of patients with asthma and COPD has proven for influenza vaccine to be effective in BF patients.

AIM Non-alcoholic　fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα), has been reported to ameliorate liver function among patients with dyslipidemia. However, there are not many reports of the clinical effects of the pemafibrate. This study aims to summarize the experience of using pemafibrate and analyze the effects on liver function in patients with dyslipidemia. METHODS One hundred twelve cases of hyperlipidemia receiving pemafibrate 0.2 mg/day were retrospectively enrolled in this study. Age, gender, BMI, complications, concomitant medications, serum parameters (TG, HDL-C, LDL-C, AST, ALT, γGTP, ALP, platelets, M2BPGi, Cre, eGFR, HbA1c, blood glucose level at any time) were investigated and evaluated. RESULTS Pemafibrate administration significantly improved serum TG and HDL-C, but not in LDL-C. Serum AST, ALT, γGTP, and ALP were also significantly improved. The fib-4 index, a liver fibrosis score, did not change significantly, but M2-BPGi, an index of fibrosis, decreased significantly. No correlation was observed between each lipid parameter and ALT, and ALT decreased independently of the lipid parameters. Conclusions As we expected, pemafibrate demonstrated a lipid-improving effect without adversely affecting hepatic and renal functions. An unexpected finding was the decrease in ALT that was independent of lipid parameters.

Chronic Limb Threatening Ischemia (CLTI) represents the end stage form of peripheral arterial disease (PAD) and is associated to very poor prognosis with high risk of limb loss and mortality. It can be considered very similar to a terminal cancer disease reflecting a large impact on quality of life and healthcare costs. The aim of this study is to offer an overview of the relationship between CLTI, limb salvage and mortality with a focus on the need of a fast-track team-based management, that’s a driver to achieve better survival results. This review can be useful to improve management of this growing impact disease, and promote standardisation of care and communication between specialist and non-specialist health care professionals.

Alzheimer’s disease(AD) progression correlates with the propagation of hyperphosphorylated Tau (pTau) from the entorhinal cortex to the hippocampus and neocortex. Neutral sphingomyelinase2(nSMase2) is critical in the biosynthesis of extracellular vesicles (EVs), which play a role in pTau propagation. We recently conjugated DPTIP, a potent nSMase2 inhibitor, to hydroxyl-PAMAM-dendrimer nanoparticles which can improve brain delivery. We showed that dendrimer-conjugated-DPTIP (D-DPTIP) robustly inhibited pTau spread in an AAV-pTau propagation model. To further evaluate its efficacy, we tested D-DPTIP in the PS19 transgenic mouse model. Unexpectantly, D-DPTIP showed no beneficial effect. To understand this discrepancy, we assessed D-DPTIP’s brain localization. Using immunofluorescence and fluorescence-activated cell-sorting, D-DPTIP was found to be primarily internalized by microglia where it selectively inhibited microglial nSMase2 activity with no effect on other cell types. Furthermore, D-DPTIP inhibited microglia-derived EV release into plasma without affecting other brain-derived EVs. We hypothesize that microglial targeting allowed D-DPTIP to inhibit tau propagation in the AAV-hTau model, where microglial EVs play a central role in propagation. However, in PS19 mice, where tau propagation is independent of microglial EVs, it had a limited effect. Our findings confirm microglial targeting with hydroxyl-PAMAM dendrimers and highlight the importance of understanding cell-specific mechanisms when designing targeted AD therapies.

Arrhythmia is a cardiac condition characterized by an irregular heart rhythm that hinders the proper circulation of blood, posing a severe risk to individuals’ lives. Globally, arrhythmias are recognized as a significant health concern, accounting for nearly 12 percent of all deaths. As a result, there has been a growing focus on utilizing artificial intelligence for the detection and classification of abnormal heartbeats. In recent years, self-operated heartbeat detection research has gained popularity due to its cost-effectiveness and potential for expediting therapy for individuals at risk of arrhythmias. However, building an efficient automatic heartbeat monitoring approach for arrhythmia identification and classification comes with several significant challenges. These challenges include addressing issues related to data quality, determining the range for heart rate segmentation, managing data imbalance difficulties, handling intra- and inter-patient variations, distinguishing supraventricular irregular heartbeats from regular heartbeats, and ensuring model interpretability. In this study, we propose the Reseek-Arrhythmia model, which leverages deep learning techniques to automatically detect and classify heart arrhythmia diseases. The model combines different convolutional blocks and identity blocks, along with essential components such as convolution layers, batch normalization layers, and activation layers. To train and evaluate the model, we utilized the MIT-BIH and PTB datasets. Remarkably, the proposed model achieves outstanding performance with an accuracy of 99.35% and 93.50% and an acceptable loss of 0.688 and 0.2564, respectively.

Self-medication with natural products during disease outbreaks in developing countries poses significant public health challenges yet remains relatively unexplored in the published literature. This study aims to assess the implications of such practices, address the state and quality of evidence, identify gaps in the literature, explore determinants and contributing factors, elucidating the implications, and propose possible solutions. Using a modified systematic literature review methodology, 20 articles were selected from 1,683 reports after applying rigorous selection criteria and quality assessment using the AXIS critical evaluation tool. The findings revealed a dearth of literature concerning the implications of self-medication with natural products during disease outbreaks, highlighting the need for further investigation in this domain. Key determinants included gender, acquisition, and ideological factors, while common side effects comprised diarrhoea, stomach pain, sweating, headache, and nausea/vomiting. Notably, self-medication with natural products was associated with reduced communication with healthcare providers, leading to underreported side effects. It also creates a false sense of safety which may potentially exacerbate the spread of the prevailing disease. In conclusion, the rampant use of natural products for self-medication necessitates increased awareness among the population, encouraging individuals to seek professional medical care and support when faced with disease outbreaks.

Myocardial infarction (MI) is a serious cardiovascular disease that can lead to death. Cardiac troponin I (cTnI) is a biomarker of MI in the circulation system. For detection cTnI protein, many method suffer the same problem, time-consuming. Main drawbacks are time consuming, have tedious operation, require an expensive reader for translating signals, and require non-accessible reagents. Our goal is to create a kit for cTnI protein testing, that the result can easily be read by color difference. The main breakthrough is, the resolution between different concentration can be told by eyes. The result will be future used to create a commercial, potable, convenient, daily-used rapid-test kit. In this study, a cTnI biosensor is proposed that can be read by the naked eye, performs diagnosis based on the pattern color, does not require a reader machine, is easy to operate, and is portable. Our work proposed a device that shortens the diagnosis time, has a quantitative analysis range of 0.32 –200 ng/mL in the human serum matrix, has a 0.32 ng/mL limit of detection (LOD), and shows many advantages comparing to traditional cTnI ELISA plate.

Mycobacterium avium ssp paratuberculosis (MAP) is the causative agent of Johne’s disease (JD) in animals and a suspected cause of Crohn’s disease (CD) in humans. Crohn’s Disease is a progressive, detrimental granulomatous enteritis of which common therapies are targeted to suppressing certain components of the immune system. The efficacy of these treatments can be variable and temporary with no clear process of selection for the individual patient. However, diagnosis of MAP has been elusive in patients with Crohn’s Disease. In animals it can be detected by several different techniques, including bacterial cell culture, polymerase chain reaction (PCR), and immunological targets. To move to an understanding of the possible pathogenicity of MAP and the sup-posed cause of CD in humans, it is necessary to demonstrate the presence of cell wall deficient mycobacterial (CWDM) forms of MAP in blood and tissue cultures from patients with CD. From this, more tailored and accurate therapies can be implemented and be developed to eradicate this infectious organism from humans. Current anti-mycobacterial antibiotics have limited efficacy as MAP is subtly different from tuberculosis. Newer methods, such as vaccination and gut microbiome remediation will be essential as part of combination therapies.

1). BACKGROUND: Cell wall deficient mycobacteria (CWDM) have seldom been isolated in bacterial culture from human subjects. particularly in clinical disease, such as Crohn’s disease. Techniques have focused on the use of polymerase chain reaction (PCR) for the detection of CWDM in association with inflammatory bowel disease. (IBD). This paper is a report of the development of methods to demonstrate the presence of CWDM using the Ziehl-Neelsen (ZN) stain. This is in addition to the detection of the growth of CWDM in fluid media. 2). METHODS: The use of the ZN stain is suitable for the demonstration of CWDM in clinical samples and cultures, when the staining methods that were common prior to the 1970’s, are adopted. Specific culture media are developed and tested in parallel. Alterations in the concentration of basic fuchsin, and changes in the decolourising solutions are necessary. Decolourising solutions such as 20% concentrated sulphuric acid in water are preferable for detection of CWDM in cultures. 3). RESULTS: CWDM can be readily demonstrated using the simple methods outlined in this report. The ability to visualise the presence of CWDM opens the door to the development of specific fluid media for the isolation of CWDM in culture. 4). CONCLUSION: The ZN stain methods optimised for the demonstration of Mycobacterium tuberculosis complex (MTBC) are not suitable for research into infectious causes of inflammatory bowel disease (IBD), as well as for the detection of CWDM in latent tuberculosis. Revisiting the techniques for the detection of CWDM may also refocus attention on inflammatory diseases considered to be idiopathic, but having hallmarks of an infectious process.

Hand, foot and mouth disease (HFMD) is a childhood disease caused by enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16). We hypothesize that capsid loops are important epitopes for EV-A71 and CV-A16. Seven chimeric EV-A71 (ChiE71) involving VP1 BC, DE, EF, GH and HI loops, VP2 EF loop, and VP3 GH loop were substituted with corresponding CV-A16 loops. VP3 GH loop is the most conserved (91.3%) while VP1 BC loop has only 45.5% similarity. Only ChiE71-1-BC, ChiE71-1-EF, ChiE71-1-GH and ChiE71-3-GH were viable. EV-A71 and CV-A16 antiserum neutralized ChiE71-1-BC and ChiE71-1-EF. Mice immunized with inactivated ChiE71 elicited high IgG, IFN-γ, IL-2, IL-4 and IL-10. Neonatal mice receiving passive transfer of WT EV-A71, ChiE71-1-EF and ChiE71-1-BC immune sera had 100%, 80.0% and no survival, respectively, against lethal challenges with EV-A71, suggesting that the substituted CV-A16 loops disrupted EV-A71 immunogenicity. Passive transfer of CV-A16, ChiE71-1-EF and ChiE71-1-BC immune sera provided 40.0%, 20.0% and 42.9% survival, respectively, against CV-A16. One-day-old neonatal mice actively immunized with WT EV-A71, ChiE71-1-BC, ChiE71-1-EF and CV-A16 achieved 62.5%, 60.0%, 57.1% and no survival respectively, after the EV-A71 challenge. Active immunization using CV-A16 provided full protection while WT EV-A71, ChiE71-1-BC, ChiE71-1-EF immunization showed partial cross-protection in CV-A16 lethal challenge with survival rates of 50.0%, 20.0%, and 40%, respectively. Taken together, the EV-A71 VP1 BC loop is essential in immunogenicity of EV-A71 and substitution with CV-A16 VP1 BC loop was insufficient to confer protection against CV-A16. The EF loop maintains the cross-protective immune responses. Disruption of a capsid loop could affect virus immunogenicity, and future vaccine design should include conservation of the enterovirus capsid loops.

Abstract: Pericyte(s) (Pcs) and resident perivascular macrophages (rPVMΦs) are positioned perfectly in the neurovascular unit (NVU) and perivascular spaces to facilitate metainflammation that results in brain endothelial cell activation and dysfunction and neuroinflammation. Their positions within the NVU allow intimate contact with one another as follows: Brain endothelial cells (BECs) and the Pcs via their shared basement membrane and physical contact peg-socket junctions with N cadherins and gap junctions Cx43; Pcs and rPVMΦs intimate contacts. Additionally, rPVMΦs have intimate contact with the astrocyte endfeet (ACef) that form the outermost membrane of perivascular spaces. Importantly, ACef have intimate contact with BECs that have intimate physical contact with neuronal axons and dendrites to complete NVU coupling. The multiplicity of intimate contacts of NVU cells allow for continuous crosstalk communications to provide brain homeostasis. While each of the cells of the NVU play important roles in the development of enlarged perivascular spaces (EPVS), this review focuses on the Pcs and rPVMΦs and discusses each of the intimate contacts and their functional significance in detail with numerous illustrations and transition electron microscopic images to demonstrate their role in the development of EPVS. EPVS are known to be biomarkers for cerebral small vessel disease and impaired glymphatic system waste clearance. Additionally, EPVS associate with mixed dementias of vascular dementia, vascular contributions to cognitive impairment and dementia, and Alzheimer’s disease that results in high economic and psychosocial cost to the global community.

Bibliometric studies on inherited metabolic diseases(IMDs) didn't exist in the literature.Our research aims to conduct a bibliometric study to determine the current status,trending topics,and missing points of publications on IMDs.Between 1968-2023, we conducted a literature search with keyword "inherited metabolic disease" in the SCOPUS-database.We included research articles in medicine written in English,published in the final section.We created our data pool using VoSviewer, SciMAT, and Rstudio software programs for bibliometric parameters of the articles that met the inclusion criteria.We performed bibliometric analysis of the data with R-package "bibliometrix" and BibExcel programs.We included 2702 research articles published on IMDs.Top three countries that have written the most articles in this field are; USA(n= 501), United Kingdom(n=182), and China(n= 172).The most preferred keywords by the authors were;newborn screening(n=54), mutation(n=43), phenylketonuria(n=42), children(n=35), genetics(n= 34) and maple syrup urine disease(n=32).Trending topics were osteoporosis, computed tomography, bone marrow transplantation in the early years of the study, chronic kidney disease, urea cycle disorders, next-generation sequencing, newborn screening, and familial hypercholesterolemia in the final years of the study. This study provides clinicians with a new perspective showing that molecular and genetic studies in inherited metabolic diseases will play an essential role in diagnosis and treatment in the future.

The Coronavirus Disease 2019 (COVID-19) pandemic has had a major impact on the mental and physical health of hospitalized patients. In our study we focused on the onset of symptoms correlated with Post-traumatic stress disorder (PTSD), depression and physical disabilities in patients admitted to the Intensive Care Unit (ICU) because of a severe respiratory distress related to COVID-19 (COVID Group) compared with patients admitted to the same ICU for trauma and other medical conditions than COVID-19 (No-COVID Group). The physical symptoms and the level of disability were evaluated with the Glasgow Outcome Scale-Extended (GOS-E), the Quality of Life after Brain Injury (QOLIBRI) and the 3 levels version of EQ-5D (EQ-5D-3L) questionnaire; psychiatric symptoms were investigated using the Impact of Event Scale-Revised 22-item (IES-R), the Patient Health Questionnaire, 9-Item Version (PHQ-9) and the Generalized Anxiety Disorder Assessment, 7-items version (GAD-7). These questionnaires were administered 6 months after discharge. Patients in the No-COVID Group showed statistically significant more severe scores in all the physical assessments while similar relevant PTSD and depressive symptoms were reported in both groups. The results of the present study underline the psychopathological impact of being hospitalized in ICU because of COVID-19 even after 6 months from discharge ,suggesting the importance of assessing the psychiatric effects of COVID-19 in the long term in order to create supportive measures.

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

With the increment of the aging population in recent years, neurodegenerative diseases exert a major global disease burden, essentially as a result of the lack of treatments that can stop the disease progression. Alzheimer’s Disease (AD) is an example of a neurodegenerative disease, that affects millions of people globally, with no effective treatment. Natural compounds have emerged as a viable therapy to fill a huge gap in AD management, and in recent years, mostly fuelled by the Covid-19 pandemic, RNA-based therapeutics have become a hot topic in the treatment of several diseases. Treatments of neurodegenerative diseases face significant limitations due to the complex and interconnected pathways that lead to their hallmarks and, also due to the necessity to cross the blood–brain barrier. Nanotechnology has contributed to surpass this bottleneck in the treatment of AD, by promoting safe and enhanced drug delivery to the brain. In particular, exosome-like nanoparticles, a hybrid delivery system combining exosomes and liposomes' advantageous features, are demonstrating great potential in the treatment of central nervous system diseases.

(1) Background: This article reviews the available scientific literature on drug-related problems and negative outcomes associated with medications identified by medication review with follow-up for end-stage renal disease and discussed with the physicians; (2) Methods: A systematic review was conducted of the scientific literature retrieved from the following databases: MEDLINE (via PubMed), Web of Science, SCOPUS, Cochrane Library: The Cochrane Central Register and Control Trials (CENTRAL) and Literatura Latinoamericana y del Caribe (LILACS), Medicina en Español (MEDES), and the SciELO bibliographic database (collection of scientific journals). The following terms were used as descriptors and searched in free text: "end-stage renal disease", "medication review", and "drug-related problems” and “negative outcomes associated with medication". The following limits were applied: "humans" and "adults (more than 18 years)”; (3) Results: A total of 59 references were recovered and after applying inclusion/exclusion criteria, 16 articles were selected. Of these selected articles, 15 provided information on drug-related problems and only 1 on negative outcomes associated with medications; (4) Conclusions: It can be concluded that drug-related problems and negative outcomes associated with medication affect patients with end-stage renal disease, mainly those receiving renal replacement therapy. More evidence is needed, especially on negative outcomes associated with medication.

In an era of unparalleled technical advancement, the pharmaceutical industry is struggling to transform data into increased research and development efficiency, and as a corollary, new drugs for patients. Here, we briefly review some of the commonly discussed issues around this counterintuitive innovation crisis. Looking at both industry and science related factors, we posit that traditional preclinical research is front-loading the development pipeline with data and drug candidates that are unlikely to succeed in patients. Applying a first principles analysis, we highlight the critical culprits and provide suggestions as to how these issues can be rectified through pursuit of a Human Data-driven Discovery (HD3) paradigm. Consistent with other examples of disruptive innovation, we propose that new levels of success are not dependent on new inventions, but rather the strategic integration of existing data and technology assets. In support of these suggestions, we highlight the power of HD3, through recently published proof-of-concept applications in the areas of drug safety analysis and prediction, drug repositioning, rational design of combination therapies and the global response to the Covid19 pandemic. We conclude that innovators must play a key role in expediting the path to a largely human focused, systems-based approach to drug discovery and research.

Parkinson's Disease (PD) is a neurodegenerative disorder that affects the motor system of the human body. Currently, the available treatments are limited and often have undesirable side effects. In this context, the aim of this study was to develop a novel combinational formulation of Apomorphine and Quetiapine and evaluate its efficacy in a rat model of PD. The formulation was prepared using the solvent evaporation technique and characterized for its physicochemical properties. The in-vitro drug release was evaluated using the Franz diffusion cell method, and the pharmacokinetics of the combination was studied in rats. The behavioural and biochemical parameters were evaluated in the rats using the Rotarod, pole test, and biochemical assays. The results showed that the developed formulation had satisfactory physicochemical properties and exhibited sustained drug release. The pharmacokinetic studies showed that the combination exhibited a longer residence time than the individual drugs. The behavioural and biochemical parameters showed that the combination was effective in improving motor function and reducing oxidative stress. In conclusion, the developed Apomorphine and Quetiapine combination formulation showed promising results in improving motor function and reducing oxidative stress in rat model of PD. Further studies are required to evaluate the safety and efficacy of the developed formulation in humans.

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NAFLD-NASH-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progress to NASH, liver cirrhosis, and HCC. However, most of NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet (CDMRHFD) for 60 weeks. Treatment of CDMRHFD for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 36-week treatment. Liver nodule emerged at 12 weeks of the treatment, and diameter >2 mm liver tumors developed in all mice at 24 weeks of the treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemistry for NASH-HCC-targeted therapies or HCC prevention strategies.

The current neural networks for tomato leaf disease recognition have problems such as large model parameters, long training time, and low model accuracy. To solve these problems, a lightweight convolutional neural network LBFNet is proposed in this paper.First, a lightweight convolutional neural network LBFNet is established as the base model. Secondly, a three-channel attention mechanism module is introduced to learn the disease features in tomato leaf disease images and reduce the interference of redundant features. Finally, a cascade module is introduced to increase the depth of the model, solve the gradient descent problem, and reduce the loss caused by increasing the depth of the model. The quantized pruning technique is also used to further compress the model parameters and optimize the model performance. The results show that the LBFNet model achieves 99.06% accuracy on the LBFtomato dataset, with a training time of 996s and a single classification accuracy of over 94%. Further training using the saved weight file after quantized pruning makes the model accuracy reach 97.66%. Compared with the base model, the model accuracy was improved by 28%, and the model parameters were reduced by 96.7% compared with the traditional Resnet50. It was found that LBFNet can quickly and accurately identify tomato leaf diseases in complex environments, providing effective assistance to agricultural producers.

Cognitive functions are based on neuronal plasticity, which is provided by various mechanisms involving numerous bioactive molecules, the most important of which are endocannabinoids (eCBs). Over the past three decades, a lot of data have been accumulated on the involvement of eCBs in the mechanisms of memory and other cognitive functions. These functions are impaired in neurodegenerative diseases such as Alzheimer's disease (AD) and temporal lobe epilepsy (TLE). The main pathological feature of neurons in AD and TLE is increased excitability; therefore, an activation of the endocannabinoid system, which controls cellular excitation, may be a promising approach in their therapy. The available information about the effect of (endo)cannabinoids on cognitive functions is contradictory, which may depend on the drugs used, their dose, and the experimental conditions. There is an extensive literature indicating a protective effect of cannabinoids in the treatment of neurodegenerative diseases in humans and in animal models of cognitive deficits. This review, focusing on the recent researches, is devoted to the analysis of the effects of endocannabinoid system activation on cognitive functions in norm and in the brain with neurodegeneration that occurs in AD and TLE diseases. Possible reasons for inconsistencies in the available data are discussed.

Infectious bursal disease (IBD) is a viral poultry disease known worldwide for impacting the economy and food security. The disease is endemic in Nigeria, with reported outbreaks in vaccinated poultry flocks. To gain insight into the dynamics of infectious bursal disease virus (IBDV) evolution in Nigeria, near-complete genomes of four IBDVs were evaluated. Amino acid sequences in the hypervariable region of the VP2 revealed conserved markers (222A, 242I, 256I, 294I and 299S), associated with very virulent (vv) IBDV, including the serine-rich heptapeptide motif (SWSASGS). Based on the newly proposed classification for segments A and B, the IBDVs clustered in the A3B5 group (where A3 are IBDVs with vvIBDV-like segment A and B5 are from non-vvIBDV-like segment B) forming a monophyletic subcluster. Unique amino acid mutations with yet-to-be-determined biological functions have been observed in both segments. Amino acid sequences of the Nigerian IBDVs showed that they are reassortant viruses. Circulation of reassortant IBDVs may be responsible for the vaccination failures observed in the Nigerian poultry population. Close monitoring of changes in the IBDV genome is recommended to nip deleterious changes in the bud, through the identification and introduction of the most appropriate vaccine candidates and advocacy/extension programs for properly implementing disease control.

Malaria is a critical fevered illness caused by Plasmodium parasites transmitted among people through the bites of infected female Anopheles mosquitoes. Public awareness about the disease is important for the control of disease. This article proposes a mathematical model to study the dynamics of malaria disease transmission with the influence of awareness-based control interventions. We found two equilibria of the model, namely the disease-free and endemic equilibrium. Disease-free equilibrium is stable globally if basic reproduction number (R0) is less than unity (R0&lt;1). Some basic mathematical properties of the proposed model, such as nonnegativity and boundedness of solutions, the feasibility of the equilibrium points and their stability properties, have been studied. Finally, we adopted optimal control to minimize the cost of disease control and solve the problem by formulating Hamiltonian functional. The optimal use of insecticides for controlling the mosquito population is determined. Numerical simulations have been provided for the confirmation of the analytical results. We conclude that media awareness with optimal control approach is best for cost-effective malaria disease management.

Background: The birth-cohort phenomenon of peptic ulcers has remained an unresolved mystery for 60 years since it was first reported in 1962. Currently, peptic ulcers are widely studied as an infectious disease caused by Helicobacter pylori, but this etiology cannot explain this phenomenon. A recently published etiological theory identified peptic ulcers as a psychosomatic disease triggered by psychological stress. This new theory addresses all the characteristics, observations/phenomena, controversies, and mysteries of the disease in a series of 6 articles. Methods: In this fourth article of the series, all the possible causes of peptic ulcers collected from literatures were classified into 3 categories, and the mortality rates caused by these categories were superposed to reproduce the fluctuation curves in the birth-cohort phenomenon. Results: The fluctuation curves in the birth-cohort phenomenon were successfully reproduced, with all the details of the phenomenon elucidated. Psychological stress induced by the First World War accounted for the increasing mortality rates in the early 1910s. The high mortality rates between 1910s and 1940s were maintained by a succession of crucial events that led to extensive psychological stress in the population. The end of the Second World War and continuous improvements in living conditions explained the fall in the early 1950s and afterwards. Conclusions: The birth-cohort phenomenon cannot be fully understood unless peptic ulcers are considered a psychosomatic disease triggered by psychological stress. A full explanation of the birth-cohort phenomenon exemplifies the application of a brand-new methodological concept, superposition mechanism, which can be universally applied to understand any life phenomenon and human disease.

Burying and burrowing are promising rodent-typical behaviors to model neuropsychiatric symptoms (NPS). However, the original tests could be insufficient to conclude which NPS are modeled. Here, we propose methodological modifications such as the two-zone configuration and dual analysis in the Marble Burying Test (MB). Also, a new Brief Burrowing Test (BB), a 20 min brief version of the Deacon’s Burrowing Test (DB). We comprehensively studied these behaviors in 12-month-old male and female mice with normal and Alzheimer’s disease (AD)-pathological aging. The results: 1) confirm our precedent report of sexual dimorphism, with enhanced burying in male 3xTg-AD mice; 2) describe for the first time burrowing behavior in 3xTg-AD mice and its sex dependence; 3) regardless of the pattern, MB and BB reflected a goal-directed rather than an indiscriminate digging; 4) using the MB and BB to model anxiety-like behavior it’s not recommended; 5) burying and burrowing represent a repetitive rather than a stereotyped-like or perseverative behavior. In addition: 1) burying and burrowing behavioral patterns are alike, connected by several correlations; 2) the two-zones configuration is a useful tool to assess the intentionality of the burying and burrowing behaviors and to perform a more accurate screening of the NPS modeled by them.