The severity and invasiveness of clinical outcomes from organic responses to trauma are influenced by individual, surgical and anesthetic factors. A stress response elicits neuroendocrine and immune reactions that may lead to multi-organ dysfunction. The degree of neuroinflammatory reflex activation from trauma can increase pro-inflammatory cytokine production, leading to endothelial dysfunction, glycocalyx damage, neutrophil activation and multisystem tissue destruction. A shift in patient treatment towards a neuroinflammatory perspective has prompted a new evaluation protocol for surgical patients, required to understand surgical pathogenesis and its link to chosen anesthesia-surgical methods. This study aims to provide a description of the mechanisms involved in the immune and neuroendocrine response and below is a summary of the main mediators, focusing on video laparoscopic surgeries, by examining its frequency usage by researchers. We performed a narrative review of data from databases like PubMed, MEDLINE, EMBASE, high-impact journals, and studies from the past decade that used inflammatory mediator analysis to compare anesthetic and surgical strategies. Results showed preference for certain biomarkers more sensitive to tissue trauma. These markers display distinct behaviors, temporal fluctuations and their dosages serve as a tool to measure and validate therapeutic approaches in perioperative systemic inflammation.

The standard care for metastatic breast cancer (MBC) is systemic therapies with imbrication of focal treatment for symptoms. Recently, thanks to implementation of radiological and metabolic exams and development of new target therapies, oligometastatic and oligoprogressive settings are even more common, paving the way to a paradigm change of focal treatments role. In fact, according to immunophenotype, radiotherapy can be considered with radical intent in these settings of patients. The aim of this literature review is to analyse available clinical data on prognosis of bone metastases from breast cancer and benefits of available treatments for developing a practical guide for clinicians.

The research reported on this paper was aimed at improving the overall efficiency of a PDO certified artisanal cheese production process. Being a PDO certified foodstuff by the EU, it is considered to have properties and qualities determined by the geographical environment in which is made, with its production taking place in a specific and determined geographical location, in this case the Serra da Estrela region. In that sense, the authors conducted a mapping according to a systemic perspective of the processes involved in the context of manufacturing and distribution of certified Serra da Estrela cheese. Numerous methods were used throughout the process, such as a systemic design analysis, and techniques derived from ethnographic methods, which led to the collection of data in the field and consequently provided the immersion of the researcher in genuine work situations. Critical points were identified and emphasized in the systemic map with the purpose of encouraging initiatives to address and overcome the gaps and inefficiencies detected. The systemic design analysis triggered the development of design work. Observations following an ethnographic approach identified ergonomic risks in cheese making during the process of cutting excess chips, fostering the emergence of musculoskeletal disorders at the wrist. A tool that fits best to the task at hand was developed. A prototype of the new tool enabled collecting feedback from use in the work context, in order to inform product development. The domains of agricultural production and microbiology, considering the specific microorganisms developed trough the ripening process of the cheese, turned out to be aspects of high importance for the issue under focus, contributing to a broader understanding of the ripening process and its risks, simultaneously improving the efficiency and success of cheese production. If it were not for the systemic analysis, which served as a link between the boundaries of distinct domains such as the risk of microorganism contamination, ergonomics, energy efficiency, legislation and regulation policies, transportation challenges and economic viability, approached throughout the research. Simultaneously creating bridges between them, the various problems might not have been detected in the first place, as they are usually addressed in specialized disciplines, predetermined by the restrictions of each specific area of knowledge. As a consequence of the development of this research, which was based on an analysis that sought to establish possible connections between various disciplines and tried to constantly maintain a holistic perspective, making new connections and observing the issues from a new angle, apart from the already established methodologies. All this allowed to lay out the seeds for the development of a plan to tackle the critical points identified by the systemic analysis reported in this paper.

Academics in healthcare grapple with the challenge of efficiently managing time while addressing diverse roles and responsibilities, leading to heightened levels of anxiety and stress within the academic community. The primary objective of this study is to offer a sustainable and systemic solution to the prevalent time-management challenges in healthcare academia, through the development of a predictive model. Employing systemic analysis software and adopting a systemic management approach, we crafted a model to address academic time-management concerns. The dynamics of time allocation for academicians are governed by three fundamental pillars: teaching, research, and administrative tasks. Significantly prioritizing administrative tasks depletes valuable academic time, making time management within academia excessively costly. This occurs as highly skilled individuals find themselves diverted towards administrative duties at the expense of their academic roles diminishing resilience levels. The proposed Timebooster Academic Systemic Model (TASM) advocates for the cultivation of soft skills in academia, en-compassing prioritization, seeking assistance, and addressing tendencies of perfectionism and procrastination. Additionally, TASM recommends the implementation of full automation, delegation of administrative responsibilities, and the mitigation of both overt and covert time-consuming elements. Furthermore, TASM reports on the pivotal role of the academic resilient manager-leaders, who actively contribute to their own satisfaction and academic growth by enhancing collaboration and teamwork. Time-management challenges emerge as a critical determinant of academic well-being and resilience. Systemic models, exemplified by TASM, offer a valuable framework for investigating prioritization concerns, identifying administrative impediments in academic processes, and managing low-value time-consuming elements. The TASM model, along with the systemic philosophy underpinning its design, presents an avenue for advancing the exploration of time-management phenomena within the context of healthcare academia.

This work reviews three frameworks for responding to economic disruption: risk mitigation, systemic recovery, and economic resilience. Specifically, by reviewing extant literature in economics, communication, and other disciplines, we argue that current approaches to understanding resilience in economics largely fail to address ongoing and emergent disruptions to the economic and social world. In response to these issues, we work to synthesize economic frameworks and the communication theory of resilience to forward a new way of examining the overlapping questions of economic resilience related to metatheoretical commitments, analytic contexts, and implications for theory, method, and practice.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease, and organ manifestations, such as lupus nephritis (LN) or skin disease, may be refractory to standard treatment. Therefore, new agents are required to allow for a more personalized therapeutic approach. Recently, several new therapies have been approved internationally, including voclosporine for LN and anifrolumab for moderately to severely active SLE. Here, we report a case of SLE with a predominant and refractory cutaneous manifestation despite treatment with glucocorticoids, hydroxychloroquine, mycophenolate mofetil, and belimumab. Belimumab was switched to anifrolumab, and the patient responded quickly after two infusions (eight weeks) with a reduction of the Cutaneous Lupus Assessment and Severity Index (CLASI) from 17 to 7. In addition, we review the available clinical trial data for anifrolumab with a focus on cutaneous outcomes. Based on phase II and III clinical trials investigating the intravenous administration, a consistent CLASI improvement was observed at 12 weeks. Interestingly, in a phase II trial of subcutaneous anifrolumab application, CLASI response was not different from placebo at 12 weeks but numerically different at 24 and 52 weeks, respectively. Thus, anifrolumab emerges as an attractive new therapeutic option suggesting a possible domain-based approach.

More than 90% of patients affected by mastocytosis are characterized by a somatic point mutation of c-KIT, which induces ligand-independent activation of the receptor and downstream signal triggering, ultimately leading to mast cell proliferation and survival. The most frequent mutation is c-KIT p.D816V, but other rarer mutations can also be found. These mutations often have a very low variant allele frequency (VAF), well below the sensitivity of common next-generation sequencing (NGS) methods used in routine diagnostic panels. Highly sensitive methods are developing for detecting mutations. This review summarizes the current indications on the recommended methods and on how to manage and interpret molecular data for the diagnosis and follow-up of patients with mastocytosis.

This work refers to sustainability (SDG - Sustainable Development Goals) highlighting the idea of ​​harmony of life along the lines of the biological model at various levels and of nature alike, thus defining the concept of bioharmonism. The purpose of this paradigm is to find a way of transition in the contemporary societal change, connecting the natural sciences, more precisely the life sciences, with the social sciences, more concretely along the lines of holistic approaches to the evolution of human society. The objective of this point of view is related to sustainability, resilience and planetary health, which indicates the need to analyse planetary bioharmony and transpose the model to the structure and functionality of human society through the complex, unitary and coherent approach of the bioharmonization process. The study analyses the issue, through: the definition and role of societal bioharmonism, then the argument related to the transition to another world using the proposed path, based on specific notions, principles and laws, and finally, the description of some lines of application of the pillars of bioharmonism. A series of solutions are highlighted that can contribute conceptually to the evolution of contemporary society, to the convergence of anthroposystems with ecosystems by interconnecting the aspects of the biological revolution with those specific to the information age. The solutions aim at societal bioharmonization supported by its specific pillars, which through integration and emergence lead to a dynamic balance. The state of equilibrium, sustainability can be highlighted at a systemic level by the directions of action in which the bioharmonization complementarities that indicate the Environment and biodiversity in the economic equation, the Citizen in the social equation and Science in the political equation will be taken into account.

Tumid Lupus Erythematosus has been the subject of heated debate as to its correct nosographic classification. In particular, its definition has changed over time, depending on the different studies performed. In this review we address the initial definition of TLE, the changes that have taken place in the understanding and placement within the classification of Lupus Erythematosus (LE), and focus on clinical, histopathological, immunophenotypical and differential diagnosis aspects.

Introduction: Pulmonary hypertension (PH) in systemic sclerosis (SSc) can be caused by different pathophysiological mechanisms, including precapillary PH (pulmonary arterial hypertension), post-capillary PH (secondary to left heart diastolic dysfunction), or combined pre- and post-capillary PH. To unmask occult post-capillary PH, fluid loading with saline during right heart catheterization (RHC) is recommended. In the present study, we investigated the response to fluid challenge test (FCT) in patients with SSc who were referred for RHC due to their high likelihood of PH on screening echocardiography. Methods: Demographic data, clinical characteristics, echocardiographic and RHC data, and cardiac magnetic resonance imaging (CMR) results were obtained from the patients' hospital records or by contacting their rheumatologist. A positive FCT was defined as an increase in pulmonary capillary wedge pressure (PCWP) to more than18 mmHg with rapid saline infusion. Patients were followed for a median (IQR) of 15 (7-20) months. Results: Of the total 98 scleroderma patients 34 patients (29 female) were included. The mean age (SD) was 50.6(8.2) years. Baseline RHC data showed that 20 patients had no PH and 14 patients had mild precapillary PH (mPAH). Ten patients (50%) of the patients with no PH and 10 patients (71.4%) with mPAH had a significant increase in PCWP after a fluid loading. There was no statistically significant difference between the patients with positive and negative FCT in terms of the presence of LGE/inflammation on CMR examination. During follow-up, 3 patients died. Mortality was due to SSc-related complications in two patients. Conclusion: This study provides preliminary evidence that FCT may be a useful adjunct to baseline RHC testing to identify SSc patients with latent postcapillary PH. Further studies are needed to confirm these results and determine the optimal role of the fluid challenge test in the clinical management of SSc patients with suspected PH.

To identify factors associated with interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) and build an algorithm to better define this association, for a personalized application in clinical practice. Methods. 78 SSc patients underwent HRCT to assess ILD. Demographic, clinical and laboratory variables were collected, focusing on those associated either directly or indirectly with lung involvement. The discriminant value of each variable was determined using the operating characteristic curves (ROC) and included in a model to estimate the strength of ILD association in SSc. Results. Thirty-three (42.31%) patients showed ILD on HRCT. DLco, M-Borg, GERD-Q, and capillary density were significantly associated with the presence of ILD-SSc. A model including these variables had a coefficient of determination (R2) of 0.697. DLco had an AUC of 0.861 (p<0.001) with a cut-off ≤72.3% (sensitivity 78.8%, specificity 91.1%, +LR 8.86). The m-Borg scale showed an AUC of 0.883 (p<0.001) with a cut-off >2 (sensitivity 84.8%, specificity 82.2%, +LR 4.77), GERD-Q had an AUC of 0.815 (p<0.001) with a cut-off >7 (sensitivity 72.7%, specificity 86.7%, +LR 5.45). The capillary density showed an AUC of 0.815 (p<0.001) with a cut-off ≤4.78 (sensitivity 87.9%, specificity 68.9%, +LR 2.82). Based on the pre-test probability values, these four variables were applied to Fagan's nomogram to calculate the post-test probability of this association. Conclusions. Our study identified four associated clinical factors of ILD in SSc patients. Moreover, their inclusion in an algorithm for the post-test probability, tailored to the specific patients’ characteristics, significantly increases the ability to find out the presence of SSc-ILD.

Background The increasing number of elderly individuals in South Korea, now entering a super-aging era, underscores the growing importance of understanding their specific oral health needs. This study investigated changes in oral health conditions, salivary parameters, halitosis, systemic diseases, and medication usage with aging. Methods This study was retrospectively conducted using the medical records of patients who presented with complaints of xerostomia or halitosis between August 2020 and May 2023. A total of 274 patients (66 males, 208 females, mean age 59.39 ± 16.10 years) were included in this study. Results Aging was found to be significantly associated with the presence of sticky saliva, poor oral hygiene, tongue coating, and halitosis (all p < 0.05). Correlation analyses further revealed significant associations between aging and several conditions, including hypertension (r = 0.495, p < 0.001), diabetes mellitus (r = 0.255, p < 0.001), amlodipine usage (r = 0.249, p = 0.001), osteoporosis (r = 0.195, p = 0.001), cardiovascular disease (r = 0.150, p = 0.013), and the presence of tongue coating (r = 0.205, p = 0.001). Conversely, none of the salivary parameters demonstrated a significant relationship with aging. Furthermore, halitosis did not exhibit significant differences across age groups (all p > 0.05), with the exception of methyl mercaptan levels, which were notably higher among patients in their 20s (p = 0.049). Conclusions The findings of this study can help clinicians develop targeted strategies to address specific oral health challenges associated with aging in elderly patients.

Background: Migraine is the commonest complex neurological disorder affecting over a billion people worldwide. Neuroinflammation has long been considered to play an important role in the pathophysiology of migraine. The main aim of this single-centre, proof of concept, retrospective study was to determine the possible clinical utility of systemic immune-inflammatory response in migraine with and without aura in a hospitalized cohort. We measured the role of universally available serial white blood cell counts to calculate the serial systemic immune-inflammatory indices (SSIIi) and the potential association between aura and SSIIi changes in a cohort of migraine patients admitted to tertiary care center in Melbourne Australia.Main body: We retrospectively assessed patients' medical records presenting to Western Health with migraine over an 18 month period. Patients were classified as either having migraine with aura (MA) or without aura (MO) based on ICHD-3 criteria. Baseline demographics and brain imaging findings in each group were evaluated. Patients with two sets of white blood cell counts during the admission were included in the analysis. SSIIi were calculated as, neutrophil counts x platelet counts / lymphocyte counts. Correlation between SSIIi and MA and MO were assessed using SPSS27.Conclusion: SSIIi were elevated in MA and MO followed by a downward trend in both groups, with MA being statistically significant. This proof-of-concept study suggests the potential role of systemic inflammation in pathobiology of migraine. SSIIi appear to show clinical utility. Further comprehensive ,controlled , multicenter studies are required to clarify the exact role of systemic inflammatory response and the clinical utility of SSIIi in a subset of migraine in the Emergency department setting.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

IBD, encompassing CD and UC, are characterized by chronic gastrointestinal inflammation due to abnormal immune responses to gut microflora. The bidirectional communication between the gut and the brain, known as the GBA, is disrupted in IBD, leading to neurobiological imbalances and affective symptoms. Systemic inflammation in IBD affects the brain's inflammatory response system, hormonal axis, and BBB integrity, influencing gut microbiota and clinical responses to probiotics. This review aims to explore the links between dysregulations in the GBA, serum biomarkers, and the development of MCI and NDDs. The objective is to identify potential correlations and propose future research directions to understand the impact of altered microbiomes and intestinal barrier functions on NDDs. Studies suggest a potential link between IBD and extraintestinal complications such as MCI and NDDs. Mechanisms include systemic inflammation, BBB dysfunction, autoimmune responses, GBA dysfunction, medication effects, and comorbidities. Serum biomarkers, including vitamin D3, C-reactive protein, high-sensitivity C-reactive protein, vitamin B12, homocysteine, serum amyloid, neuron-specific enolase, neurofilament light chain, S100 proteins, brain-derived neurotrophic factor, IL-6, LP-2 associated phospholipase, prostaglandin E2, IL-1β, and TNF-α, have been investigated for their potential to predict MCI but current results are lacking clarity.

Background: Psoriasis is a chronic immune-mediated skin disease in which systemic inflammation plays an important role in the pathogenesis. In recent years, neutrophil-to-lymphocyte ratio (NLR), neutrophil-to-monocyte ratio (NMR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) have been shown to be important indicators of inflammation. In this study, our aim is to investigate NLR, NMR, PLR, and SII levels in psoriasis patients treated with biologic agents. Method: Clinical and biochemical data of 209 patients who received systemic therapy for psoriasis were obtained by retrospectively reviewing their medical records. NLR, NMR, PLR, and SII values were calculated from the hemogram values of the patients. Results: In the third month of follow-up, the mean CRP, NLR, NMR, PLR, and SII values were significantly decreased compared to the baseline values. SII values showed strong positive correlations with NLR, NMR and PLR. Adalimumab, etanercept, and infliximab, which are TNF-α blockers, were observed to be more effective on PLR and NLR and especially NMR. Conclusion: NLR, NMR, PLR, and SII, which are data obtained from routine blood tests, can be used in the monitoring of treatment of psoriasis, especially with TNF- α blockers.

The concept of sustainability and sustainable development, especially systemic sustainable development, still raises controversy in literature. The article makes an attempt to re-examine these concepts from a systems perspective, seeking foundations and applications in the selected sector. It is becoming increasingly clear that sustainability and sustainable development are aimed at integrated economic, social, cultural, political, and ecological factors [1[,[2] (pp.641-642). This causes that the constructive approach to the issue is required, taking into account all the actors, areas and dimensions involved in the pursuit of systemic sustainable development. As a result, both local and global dimensions and the way they interact must be explored in a multi-faceted manner in order to offer a perspective more useful than other analytical approaches, because the systems view is a way of thinking in terms of connectedness, relationships, and context [3]. The article aims to review selected publications and studies so as to form the general idea of systemic sustainable development and define the systemic development of sustainable transport, including in particular the perspective of the actors of the sector, transport providers (passenger, urban) and transport development program, implemented both by local governments and on the European scale. An attempt was made to identify elements of the systemic sustainable development model, setting it in the reality of the following subcategories: “Society”, “Economy” and “Environment” in sectoral terms. It is supposed that, systemic sustainable development is a conglomerate of public administration entities, companies operating in the sector, individual and corporate customers, acting in certain conditions for economic, social and environmental well-being, and a number of their initiatives of major or minor significance, grouped in six sub-areas, undertaken to achieve systemic value in the examined sector, with a positive or negative business/economic, social and environmental impact.

In agriculture, soil-borne fungal pathogens, especially Fusarium oxysporum strains, are posing a serious threat to efforts to achieve global food security. In the search for safer agrochemicals, silica nanoparticles (SiO2NPs) have recently been proposed as a new tool to alleviate pathogen damage including Fusarium wilt. Hollow mesoporous silica nanoparticles (HMSNs), a unique class of SiO2NPs, have been widely accepted as a desired pesticide carrier. However, their role in enhancing the disease resistance and the specific mechanism remain unknown. In this study, three sizes of HMSNs (19, 96 and 406 nm as HMSNs–19, HMSNs–96 and HMSNs–406, respectively) were synthesized and characterized to determine their effects on seed germination, seedling growth, and Fusarium oxysporum f. sp. phaseolus (FOP) suppression in cowpea roots by foliar spray using phenotypes, fresh biomass and disease progression as indicators. The results revealed that three HMSNs exhibited no adverse impacts on seed germination and tended to improve plant growth. Also, they exert their FOP suppression with a size- and concentration-dependent manner. HMSNs–406 possessed the best control effect at a concentration of 1000 mg/L showing an upto 40.00% decline in the disease severity. The Si(OH)4 control was also effective on FOP suppression at a lower concentration of 100 mg/L, whereas its higher concentrations exhibited obviously adverse impacts on FOP control, seed germination and plant growth. Moreover, we conformed that HMSNs posed their Fusarium wilt suppression in cowpea plant by activating SA (salicylic acid)-dependent SAR (systemic acquired resistance) responses rather than directly suppressing FOP. A higher level of SA content and elevated expression of its maker genes of PR-1 and PR-5 in HMSNs–406 treated cowpea roots provided substantial evidences of this mode of action. Other resistance-related genes, as well as defense-responsive enzymes, were also involved in the HMSNs-activated SAR pathway. Overall, for the first time, our results extended a new role of HMSNs as a potent elicitor to serve as a versatile alternative for plant disease protection of low cost, highly efficiency and sustainability.

Patients with sAID are a population at high risk of severe COVID outcomes but evidence on the efficacy of SARS-CoV-2 vaccination in this group of patients is scarce. To investigate the efficacy of SARS-CoV-2 vaccination in patients with systemic autoinflammatory diseases (sAID) receiving interleukin-1 inhibition is important. Vaccination responses from 100 sAID patients most of whom were treated with IL-1inhibitors (N=96) and 100 healthy controls (HC) were ana-lyzed. After 2nd SARS-CoV-2 vaccination, sAID patients showed similar anti-SARS-CoV-2 anti-body responses (mean (SD): 6.7 (2.7)) compared to HC (5.7 (2.4)) as well as similar neutralizing antibodies (85.1 ±22.9% vs. 82.5 ±19.7%). Anti-SARS-CoV-2 antibody responses and neutralizing antibodies were similar in sAID patients after SARS-CoV-2 infection and double vaccination. Furthermore, while antibodies increased after 1st and 2nd vaccination in sAID patients they did not further increase after 3rd and 4th vaccination. No difference was found in antibody responses between anakinra and anti-IL-1 antibody treatments and also the additional use of colchicine or other drugs did not impair vaccination responses. Primary and booster SARS-CoV-2 vaccination lead to protective antibody responses in sAID patients, which are at the same level of vaccination responses in HC and in sAID patients after SARS-CoV-2 infection. Immunomodulatory treatments used in sAID do not seem to affect antibody responses to the SARS-CoV-2 vaccine.

For a long time, a company's Product Development Process (PDP) was seen as supporting the operations department, although PDP decisions and mistakes have a considerable impact on market performance. This is critical even in agriculture where bad habits and practices in the PDP can lead rural producers to great losses. Therefore, this research investigated the effect on the market performance of rural products (banana) in the southern region of Brazil, based on two analyses: (i) how sustainability practices support the PDP phases and (ii) how the phases of the Product Life Cycle Assessment (LCA) mediate sustainability practices and PDP phases. This study presents a quantitative analysis using Confirmatory Factor Analysis (CFA) and hierarchical ordinary least squares (OLS) regression of data obtained from a survey of 110 rural producers who directly participate in the banana production and planning process in southern Brazil. Our results shows that sustainability practices support the PDP, and we confirm that the product development and post-development phase has an effect on market performance. In addition, we identified that in the pre-development phase of the PDP, dealing with rural products (bananas), the maturity stage of the LCA mediates sustainability. In the PDP development phase, we concluded that rural families that develop economic and environmental practices with their products in the market growth phase may have reduced results. As for the post-development phase of the PDP, we conclude that when companies invest in environmental and social practices, there is a complete mediation of the effect, where these practices lose strength if the product is in the introduction and maturity phases in the market. As originality, our study contributed to demonstrate value on the product life cycle for the product development process in agriculture using sustainability practices through a systemic approach, filling the gap in the literature due to the lack of research on these areas seen in an integrated way.

Despite advances in our knowledge of systemic lupus erythematosus (SLE) has increased over time, there are still many challenges in deciphering the precise mechanisms involved in the development and progression of the disease. Recent evidence has raised questions about the effectiveness of the programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during the autoimmune response. Research has ventured into investigate the potential impact of PD-1 on various CD4+ T cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and have been closely related with several autoimmune disorders including SLE. This review aims to highlight the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell response. Additionally, we address the potential of PD-1 or its ligands as a possible therapeutic target in SLE.

Plant activators have emerged as promising alternatives to conventional pesticides for crop disease manage-ment due to their unique mode of action. By priming the plant's innate immune system, these compounds can induce systemic acquired resistance against a broad spectrum of pathogens without directly inhibiting their proliferation. Key advantages of plant activators include prolonged defense activity, lower effective dosages, and negligible risk of developing pathogen resistance. Among the various defensive pathways tar-geted, the salicylic acid (SA) signaling cascade has been extensively explored, leading to the successful devel-opment of commercial activators like benzothiadiazole for widespread application in crop protection. While the action sites of many SA-targeting activators have been preliminarily mapped to different steps along the pathway, a comprehensive understanding of their precise mechanisms remains elusive. This review provides a historical perspective on plant activator development and outlines diverse screening strategies employed across multiple levels, from whole-plant bioassays to molecular and transgenic approaches. We expound on the intricate components, biological relevance, and regulatory circuits governing the SA pathway, while criti-cally examining the structural features, bioactivities, and proposed modes of action of classical activators such as benzothiadiazole derivatives, salicylic acid analogs, and other small molecules. Insights from field trials as-sessing their practical applicability are also discussed. Furthermore, we highlight the current status, challenges, and future prospects in the realm of SA-targeting activator development globally, with a focus on recent en-deavors in China. Collectively, this comprehensive review aims to synthesize existing knowledge and provide a roadmap for future research toward developing more potent and mechanistically understood plant activa-tors that fortify crop immunity against disease.

Background and Objectives: To investigate the relationship between the SII index and the micro-macro complications and death that develop in the first year and the following 3 years, following the calculation of the index in type 2 diabetic retinopathy patients. Materials and Methods: This study was performed retrospectively with 523 type 2 diabetic retinopathy patients admitted to the endocrinology outpatient clinic of our hospital between January 2019 and December 2019. The demographic, and clinical characteristics of the patients were evaluated using descriptive statistics. Shapiro-Wilk test was used for the normal distribution of quantitative data; Mann-Whitney U, Mc Nemar Chi-square, and Cochran's Q tests were used to analyze SII values between groups and complication rates by years; sensitivity and specificity were determined by ROC analysis and considered statistically significant with a significance level of P

Systemic hypertension is not a recognized association in patients with transfusion depended thalassaemia. In patients with high cardio-vascular morbidity due to iron overload and pulmonary hypertension this previously unrecognized disease should not be overlooked.

In the wake of the 2008 financial crisis, the Financial Stability Board (FSB) and the Basel Committee on Banking Supervision (BCBS) created a list of Systemically Important Financial Institutions (SIFIs) with the intention of determining which financial institutions were important enough to the global market that their failure would result in systemic collapse. In this work we create a model that modifies the BCBS's five indicators of size, interconnectedness, cross-jurisdictional activities, complexity, and substitutability and applies these measures of systemic stress to governments. The original application of the model is to track the systemic interdependence of the Eurozone, with particular emphasis on the case of Greece. We anticipate this model can be used in regional fiscal situations beyond the Eurozone.

Background Systemic sclerosis (SSc) is a rare, multisystemic disorder of connective tissue, characterized by widespread inflammation, vascular abnormalities, and both skin and visceral organ fibrosis. Tissue fibrosis is the final phase of a complex biological process of immune activation and vascular damage. Objectives The aim of study was to assess hepatic fibrosis and steatosis in SSc patients by transient elastography (TE). Methods Fifty-nine SSc patients, satisfying the 2013 ACR/EULAR classification criteria, were recruited. Clinical and laboratory findings, modified Rodnan skin score (mRSS), ac-tivity index, video-capillaroscopy, echocardiography, and lung function data were ana-lyzed. Liver stiffness (LS) was measured by transient elastography (TE), with 7 kPa used as the cut-off value for significant liver fibrosis and steatosis. Specifically, values ≥ 238 CAP ≤ 259 dB/m were considered consistent with mild steatosis (S1), 260 ≥ CAP ≤ 290 dB/m with moderate steatosis (S2) and ≥291 dB/m with severe steatosis (S3) Results The median age of patients was 51 years, with a median disease duration of 6 years. Median LS was 4.5 (2.9–8.3) kPa; 41 patients (69.5%) had no evidence of fibrosis (F=0), 16 (27.1%) displayed LS values between 5.2 and 7 kPa; only 2 patients (3.4%) had LS values >7 kPa (F3). The median CAP value for liver steatosis was 223 dB/m (IQR: 164–343). Overall, 39 patients (66.1%) did not show evidence of steatosis (CAP values <238 dB/m); 9 patients (15.2%) showed values consistent with mild (S1) steatosis (CAP value ≥238 ≤259 dB/m); 8 patients (13.5%) had moderate (S2) steatosis (CAP value ≥260 ≤290 dB/m); 3 patients (5.1%) were deemed to have severe steatosis (S3) due to CAP values ≥291 dB/m. Conclusions Only 3.4% of our patient population showed evidence of marked liver fibrosis, which is the same prevalence as that expected in the general population. Likewise, the prevalence of significant steatosis was low (5.1%) and depending on the same variables associated with fatty liver in the general population. TE was shown to be an easy and valuable method for detection and screening of liver fibrosis in SSc patients with no additional risk factors for liver disease.

Soil-borne Trichoderma spp. have been extensively studied for their biocontrol activities against pathogens and growth promotion ability with plants. However, the beneficial effect of Trichoderma on inducing resistance against insect herbivores has been considered only recently. Among diverse Trichoderma species, consistent with previous reports, we showed that root colonization by T. virens triggered induced systemic resistance (ISR) to leaf-infecting fungal pathogens. Whether T. virens induces ISR to insect pests has not been tested before. In this study, we investigated whether T. virens affects jasmonic acid (JA) biosynthesis and defense against fall armyworm (FAW) and western corn rootworm (WCR). Unexpectedly, the results showed that T. virens colonization of maize seedlings grown in autoclaved soil suppressed wound-induced production of JA, resulting in reduced resistance to FAW. Similarly, the bacterial endophyte Pseudomonas chlororaphis 30-84 suppressed systemic resistance to FAW due to reduced JA. Further comparative analyses of the systemic effects of these endophytes when applied into sterile or non-sterile field soil showed that both T. virens and P. chlororaphis 30-84 triggered ISR against hemibiotrophic fungal pathogen Colletotrichum graminicola in both soil conditions, but only suppressed resistance to FAW in sterile soil. In contrast to the effect on FAW defense, T. virens colonization of maize roots suppressed WCR larvae survival and weight gain. This is the first report suggesting the potential role of T. virens as a biocontrol agent against WCR.

Food production is a complex matter, affecting people’s lives, organizations’ profits, and the well-being of the whole planet and has multifaceted ethical considerations surrounding its production, distribution, and consumption. This paper addresses the pressing need to confront ethical challenges within the food system, encompassing issues such as environmental sustainability, food security, and individual food choices for better oral and systemic health of all individuals around the globe. From agricultural practices to global trade and food waste, ethical implications are addressed across various domains, highlighting the interconnectedness of ethical decision-making in the food industry. Central themes explored include the ethical dimensions of food production methods, the impact of global trade on food ethics, and the role of individuals in making ethically informed food choices. Additionally, the paper dives into the spiritual and physical significance of food, particularly through the lens of oral health as a gateway to holistic well-being. Recognizing the complexity of the food ecosystem, the paper calls for serious interventions in legislation and economics to promote ethical protocols and techniques for sustainability reasons. It emphasizes the importance of ethical considerations in food safety management systems, regulatory frameworks, and quality standards. Moreover, the paper underscores the need for a comprehensive approach to address ethical dilemmas and moral values inherent in the food industry and oral health policies, advocating for the adoption of the precautionary principle and ethical decision-making frameworks. The article aims to serve as a call to action for stakeholders across the food industry and the healthcare sector, to prioritize ethical practices, promote transparency, rearrange economic parameters and work towards a more sustainable and equitable food system for inner and outer oral and systemic health and human sustainability for all.

Tumour microenvironment, composed of pro- and anti-tumour immune cells, affects cancer cells behaviour. We aimed to evaluate if tumour-infiltrating lymphocyte (TIL) density and TILs subtypes in core biopsies at diagnosis of breast cancer patients could predict pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably anti-tumour (CD8+, CXCL13+) and pro-tumour (PD-1+, FOXP3+) immune cells. A prospective, non-interventional study including 171 participants undergoing NST was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p=0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p=0.232), Ki-67 (p=0.001), node-negative status (p=0.024), and HER2+/triple negative vs luminal B-like subtype (p&lt;0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

Chemical plants are characterized by the management and operation of various hazardous materials; thus, accident risk is inherently high. Nevertheless, the incidence of chemical accidents in Korea has effectively stabilized, with no marked increase attributable to the implementation of systematic safety management procedures based on process safety management system principles. In June 2023, the Ministry of Employment and Labor in Korea unveiled the Serious Injury and Fatality (SIF) report, meticulously cataloging 4,432 instances of grave accidents spanning six years (2016–2021). The compilation comprises 1,834 and 2,574 cases within the manufacturing and affiliated sectors and the construction sector, respectively. This study provides an overview of each accident, and elucidates the causes, and recommends preventative strategies. The objective was to galvanize companies across various industrial landscapes and fortify their intrinsic safety management protocols by using accident data delineated per sector. Sixteen specific accident cases from the SIF report, all of which occurred in facilities regulated by process safety management (PSM), were investigated. Technical analysis was conducted, focusing on explosion accidents within the organic catalyst packaging process, notable for their unique patterns of occurrence. This analysis extended to an examination of the reproducibility of such accidents. Employing two system analysis methodologies, system theoretic accident model and process and barrier-based systemic cause analysis technique, this study provides insights into the causative factors of the accidents and formulates comprehensive strategies for the prevention of future accidents. The findings will contribute significantly to reducing the risk of accidents within the catalyst packaging domain and assist in the development of robust recurrence prevention measures.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

Introduction: The gastrointestinal tract (GI) is the second most affected organ system in systemic sclerosis or systemic/localized scleroderma (SSc) and is an important topic for research. Approximately 90% of patients with scleroderma exhibit pathology of the GI tract. The systemic scleroderma has the potential to impact any part of the gastrointestinal tract, between the oral cavity and anorectum. The pathological complications of scleroderma adversely impact the health-related quality of life of the affected patients and increase the treatment burden of patients and medical professionals. Study Aim: We summarized the epidemiology, commonly reported clinical manifestations, complications, and available therapies for treating the GI pathology in systemic scleroderma patients. Methodology: We performed a literature review using the keywords "systemic sclerosis," "scleroderma," "GI manifestations in scleroderma," and "GI complications of scleroderma" across databases, including Google Scholar, Medline, Embase, and PubMed. We also analyzed a range of case reports concerning scleroderma manifestations and treatment modalities. Results: Our research revealed the annual incidence of SSc attributing to19.3 cases per million adults in the United States. We found the highest incidence of systemic scleroderma in patients within the age range of 44-55 years. Our results affirmed 5:1 incidence of systemic scleroderma that confirmed the higher impact of this disease condition in females than male populations. We found that the gastrointestinal manifestations of systemic scleroderma predominantly elevate the morbidity and mortality incidence among the affected patients. Esophageal and intestinal manifestations impact 90% and 40-70% of patients with systemic scleroderma. The small bowel hypomotility and small intestinal bacterial overgrowth (SIBO) in systemic scleroderma cases trigger the episodes of malabsorption and malnutrition that eventually add to 50% of the mortality rate. Systemic sclerosis is associated with the high incidence of fecal incontinence that triggers depression and its deleterious mental health manifestations in many clinical scenarios. Conclusion: The gastrointestinal complications in systemic sclerosis potentially deteriorate the daily living activities of the affected patients. The systematic management of the gastrointestinal complications of systemic scleroderma warrants multidisciplinary approaches. Prospective studies should focus on developing targeted therapies for improving the recovery patterns and prognostic outcomes in systemic scleroderma cases.

Systemic sclerosis (SSc) is a progressive autoimmune disorder that mainly affects the skin. There are other clinical manifestations as renal, pulmonary, cardiovascular, and gastrointestinal tract involvements. Based on the skin involvement there are two subtypes of SSc, as limited cutaneous SSc (lSSc) which involves the acral part of the body and diffuse cutaneous SSc (dSSc) resulting in significant skin thickening of the body. The lSSc has usually moderate internal organ manifestations, except for the late-onset pulmonary arterial hypertension (PAH) mainly appearing in this form. In dSSc the severity of the organ manifestations or failure is more intensive such as scleroderma renal crisis (RSC), interstitial lung disease (ILD), myocardial fibrosis, and chronic gastrointestinal dysmotility with consequent malabsorption

Plant-based alternative medicine is normally grounded on empiric cultural perception, as the main objective, these practices intent to either maintain good health or to provide a route to turn-the-tide on a specific disease or ailment. Amongst the thousands of plants that have been used and studied, Neem (Azadirachta indica) seems to have a very interesting tale to tell, since its properties to ward-off certain diseases have overtime, and in a rigorous way, been proven. The preceding concise review is a collection of some of the most relevant studies today, not only focusing on the health benefits obtained by its use, but digging into the molecular mechanisms of how the properties come about. In particular, we take a look over antioxidant properties and how these mediate and mitigate important molecules such as IL-6 and TNF-, leading the way in reducing systematic damage by oxidative stress. Further, we relate this oxidative reduction to other systemic diseases such as cancer and diabetes, as these are currently becoming the most rampant killers. As of yet not all is known about the different ways of extracting or the total composition of an extract, as these may be from different parts of the plant. Therefore, we also allude to an important cautionary view where toxicological effects and conflicting outcomes arise. Overall, presented results show a great potential for the different extracts of Neem as their antioxidant activity can be taken advantage off, and potentially used in modern medicine.

Aim: To investigate inflammation indices and erythropoietin (EPO) levels for their potential role in distinguishing polycythemia vera (PV) from secondary polycythemia (SP), and to compare different parameter combinations in terms of diagnostic accuracy. Methods: This retrospective cohort was created from patients assessed for polycythemia from January 2020 to December 2023. PV diagnosis was made according to the 2016 WHO criteria (n=145). Those who did not fulfill the criteria were defined as having SP (n=84). Results: NLR, PLR and SII were significantly higher in the PV group (p

Current trends in systemic risk literature provide new insights into multi-hazard risks that interact and compound with built environments, creating more significant impacts on socio-economic and human systems. Recurrent natural hazards and extreme weather events are more likely to compound and cascade into more impactful events, especially in vulnerable societies. In small-island communities (SICS), including large archipelagos and Small Island Developing States (SIDS), the long-term impact of multi-, compounding-, and cascading-hazards (MCC hazards) can result in persistent vulnerability and residual risks. This is due to delayed responses, limited resources, poverty, fewer evacuation options, and inadequate markets and infrastructure. Using Ternate, a densely populated small volcanic island in North Maluku, Indonesia, as a case study, this paper assesses the impacts of seven types of natural hazards: flash floods, landslides, extreme weather, extreme waves and abrasion, earthquakes, tsunamis, and volcanic eruptions. The research focuses on the multi-hazard impact on population, land use, and infrastructure exposures in 60 villages in Ternate. The findings highlight population density, land use, and infrastructure exposure to multi-hazard risks, providing valuable information on potential losses in future hazard events.

Systemic lupus erythematosus (SLE) is a chronic idiopathic autoimmune disease affecting various organs. Patients with SLE also present numerous neuropsychiatric manifestations. These neuro-psychiatric manifestations are referred to as neuropsychiatric systemic lupus erythematosus (NPSLE). Neuropsychiatric involvement in patients with SLE was first mentioned by Kaposi more than 100 years ago and is a generic term that refers to neurological and psychiatric symp-toms resulting directly from or as a complication of SLE. NPSLE affects both the CNS and PNS and can manifest as various symptoms, such as cognitive dysfunction, organic brain syndromes, delirium, seizures, headache, and psychosis. NPSLE was previously referred to as ‘lupus cerebri-tis’ or lupus sclerosis. However, these terms are no longer recommended because there is no de-finitive pathological cause for the neuropsychiatric manifestations of SLE.[2]

Psoriasis is a chronic, multisystem, inflammatory disease. The typical clinical cutaneous manifestation of psoriasis is scaly erythema or plaque, limited or widely distributed. However, psoriasis is far beyond the skin involvement and provides many challenges, including associated comorbidities. In this review, we classify psoriasis as cutaneous and systemic psoriasis, according to the clinical diversity and associated comorbid diseases, and recommend classification criteria for psoriasis. The key objective of this novel classification is to raise awareness of the complexity of this multifaceted disease and help to better understand and manage this complex disease comprehensively.

Background: Systemic lupus erythematous (SLE) is an autoimmune, episodic, and chronic disease that can affect multiple organs in the body and consequently it can present with variety of sign and symptoms. Hypercalcemia is a considered to be a rare presentation in patients with systemic lupus erythematous. In this case report we present a patient with SLE flare up who presented with hypercalcemia, which her overlapping manifestations endured a challenging diagnosis of lymphoma.Case Presentation: A 41-year-old man with a ten-year history of SLE presented to us with symptoms of SLE flare up. During laboratory evaluation, high calcium level was detected which was unresponsive to the treatment. Bone marrow revealed marginal B cell lymphoma as the ultimate diagnosis. He was started on R-CHOP chemotherapy regimen, and reported relative improvement in clinical and laboratory conditions during follow-ups.Conclusion: Our case is the first report of concurrent SLE flare up, with a diagnosis of lymphoma and a primary clinical presentation of hypercalcemia. Physicians should be aware of the fact that patients with SLE flare up can present with hypercalcemia and lymphoma as concomitant conditions that needs further exploration.

To examine the role of RNA silencing in defense against viroid, a Dicer-like 2 and 4 (DCL2&4)—double knockdown transgenic tomato line 72E was created. The expression of endogenous DCL2 and DCL4 in line 72E decreased to about a half of the empty cassette line EC. When challenged with potato spindle tuber viroid (PSTVd), 72E allowed significantly higher level of PSTVd accumulation early in infection and showed lethal systemic necrosis. The size distribution of PSTVd-derived small RNA was significantly changed: the numbers of 21 and 22 nucleotides (nt) species in line 72E was approximately 66.7% and 5% of those in line EC, respectively. Conversely, the numbers of 24-nt species increased by 1100%. Furthermore, expression of miR398a-3p and miR398 increased 770–868% in the PSTVd-infected 72E, compared to the PSTVd-infected EC. In parallel, superoxide dismutase (SOD1) in PSTVd-infected 72E showed higher expression levels. In concert with miR398a-3p, SOD1 controls detoxification of reactive oxygen species (ROS) generated in cells. Since high levels of ROS production and its scavenging activity were observed in PSTVd-infected 72E, the lack of full-activity of DCLs was thought to have made the plant incapable to control excessive ROS production and thus resulted in to develop lethal systemic necrosis.

The aims of this study are to determine the oral health status of a rare sample of 19th-century migrant settlers to South Australia, how oral conditions may have influenced their general health, and how the oral health of this group compares with contemporaneous samples in Australia, New Zealand, and Britain. Dentitions of 18 adults and 22 subadults were investigated using non-destructive methods (micro-CT, macroscopic, radiographic). Extensive carious lesions were identified in 17 adults and 4 subadults, from this group 1 subadult and 16 adults had antemortem tooth loss. Sixteen adults showed evidence of periodontal disease. Enamel hypoplastic (EH) defects were identified in 14 adults and 9 subadults. Many individuals with dental defects also had skeletal signs of co-morbidities. South Australian individuals had the same percentage of carious lesions as the British sample (53%), more than other historic Australian samples, but less than a contemporary New Zealand sample. Over 50% of individuals from all the historic cemeteries had EH defects suggesting systemic health insults during dental development were common during the 19th century. The overall oral health of the South Australian settlers was poor but, in some categories, (tooth wear, periapical abscess, periodontal disease), better than the other historic samples.

Background: To assess the prevalence of Hypertension (HTN) in Burning Mouth Syndrome (BMS) patients and to investigate its relationship with sociodemographic factors, pain and the psychological profile. Methods: A case-control study was conducted by enrolling 242 BMS patients and 242 controls matched for age and gender. Sociodemographic and clinical characteristics were recorded, and all the participants completed the numeric rating scale (NRS), the short-form of the McGill pain questionnaire (SF-MPQ), the Hamilton rating scale for anxiety and depression (HAM-A, HAM-D), the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale (ESS). Results: The BMS patients presented a statistically significant higher prevalence of HTN compared to the controls (55% versus 33.5%; p-value: &lt;.001**) and higher median scores of the NRS, SF-MPQ, HAM-A, HAM-D, PSQI and ESS (p &lt; .001**). Multivariate regression analysis in the BMS patients indicated positive correlations between HTN and age, systemic diseases, drug consumption and anxiety (p-value: &lt;.001**) and these predictors were responsible for 11.3% of the HTN variance in the BMS patients, when considered together. Conclusions: The prevalence of HTN was significantly higher in the BMS patients, since ageing, the presence of comorbidities, drug consumption and anxiety were potential predictors. Further studies are needed to better investigate the relationship between BMS and HTN.

Background and Objectives: Zonulin (Zo) is a molecule that has been identified as an intestinal permeability marker in recent years. It has been previously linked to type 2 diabetes mellitus, obesity, and cardiovascular disease, but its role in chronic kidney disease (CKD) remains unclear. This study aimed to investigate the relationship between Zo and systemic inflammation (SI), endothelial dysfunction (ED), and especially renal functions, in patients with CKD. Materials and Methods: One hundred sixty-three participants were enrolled in this study and were divided into two groups (patient and control), according to the presence of CKD. Results: A total of 104 patients with CKD (mean age: 58.9 ±1.4) and 59 control subjects (mean age: 59.0 ±1.1) were included, with similar age (p = 0.934) and gender (p = 0.196) between the groups. In the comparison analysis, plasma Zo levels in the CKD group (166.16 ± 53.54) were significantly higher than those in the control group (143.30 ± 60.92) (p < 0.001). In the correlation analysis, the serum Zo level showed a positive correlation with claudin-3 (r = 0.612, p < 0.001), IL-6 (r = 0.307, p < 0.001), and creatinine (r = 0.313, p < 0.001) and a negative correlation with glomerular filtration rate (GFR) (r = -0.320, p < 0.001) and TC (r = -0.074, p = 0.047). Additionally, according to a linear regression analysis, the Zo level was significantly associated with GFR after adjusting for age and SBP (β value = -0.918, p = 0.012). Conclusion: High serum Zo levels in patients with CKD reflected increased intestinal permeability and were associated with impaired renal function. Moreover, it was thought that Zo level could be associated with SI, but novel clinical studies are needed to elucidate its relationship with ED.

Background: Circulating rare cells participate in breast cancer evolution as systemic components of the disease and thus, are a source of theranostic information. Exploration of cancer-associated rare cells is in its infancy. We determined the validity of a rare-cell detection platform and demonstrated the usefulness of a certain rare cell subset as a novel approach to characterize the breast cancer system. Methods: Linearity of the Rarmax® platform was established using a spike-in approach. The platform includes red blood cell lysis, leukocyte depletion and high-resolution fluorescence image recording. Rare cell analysis was conducted on 28 samples (before and after surgery) from 14 patients with breast cancer, 20 healthy volunteers and 9 non-cancer control volunteers. In-depth identification of rare cells, including circulating tumor cells, endothelial-like cells, erythroblasts and inflammation-associated cells, was performed using a phenotype and morphology-based classification system. Results: The platform performed linearly over a range of 5-950 spiked cells, with an average recovery of 84.6%. Circulating epithelial and endothelial-like cell subsets have been demonstrated to be associated with or independent of cancer with tumor presence. Furthermore, certain cell patterns may be associated with treatment-related adverse effects. The sensitivity in detecting tumor-presence and cancer-associated abnormality before surgery was 50% and 85.7%, respectively and the specificity was 100% and 96.6%, respectively. Conclusion: The present study supports the idea of a cancer-associated rare cell abnormality to represent tumor entities as well as systemic cancer. The latter is independent of the apparent clinical cancer.

Background: In recent years, whole blood parameters and derivatives have been used as prognostic criteria in the course of the disease in various diseases. The prognostic nutritional index (PNI), the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR) have been adapted as an indicator of inflammation and have been widely studied to define the severity of inflammation in some diseases. The aim of this study was to evaluate the relationship between parameters such as NLR, SII, PNI, controlling nutritional status (CONUT) score, nutritional risk index (NRI) and with immunonutrition status and disease activity in patients with ischemic stroke of small vessel, large vessel and other etiologies. Methods: We retrospectively evaluated the records of 1454 consecutive ischemic stroke patients hospitalized in the emergency department of Gaziosmanpasa Education and Research Hospital from 2019 to 2023. Results: Of the 1350 SVO patients included in the study, 58.8% had small vessel, 29.3% had large vessel and 11.9% had other etiologies. There was a significant difference between the 3 etiology groups for PNI and CONUT. The median PNI was 47.03 (41.33-52.85) in the other etiology group, 35.29 (33.69-37.25) in the small vessel group, and 34.11 (30.23-36.87) in the large vessel group. The CONUT median was 5(5-6) in the small vessel group, 5(4-6) in the large vessel group and 4(4-4) in the other etiology group. In addition, CONUT and PNI were also found to be independent risk factors for death. A negative significant correlation was observed between PNI and NLR (r:-0.692), SII (r:-0.591), CONUT (r:-0.685). Significant correlations were observed between CONUT and NLR (r:0.402), SII (r:0.312). Conclusion: PNI and SII were significantly associated with disease activity. PNI, CONUT and NRI as a more accurate prognostic indicator of nutritional status in patients with ischemic stroke of small vessel, large vessel and other etiologies. NLR and SII may be important predictive markers in the course and prognosis of stroke.

Thanks to the Chinese government's strong monetary stimulus initiative, the Chinese stock market has seen a recent surge. A similar scenario in history reminds us that such a surge carries significant potential risks and undermines economic sustainability. This study examines the economic stimulus by the Chinese government during 2008 and 2015 utilizing monetary and real estate policy to stimulate stock market expansion, and identifies a pattern of path dependency in the government's approach to economic challenges. In the context of the fiscal pressures of 2024, the government has again employed an extraordinary level of intervention to catalyze a significant uptick in the stock market. While this has led to a temporary increase in stock market indices, it poses substantial risks. The potential for a stock market bubble, detached from fundamental values, could precipitate a subsequent market collapse. Additionally, the government's market stimulus may be aimed at providing financial support to underperforming state-owned enterprises, which in the long-run will damage China's economic sustainability. There is also a concern that the measures to stimulate the stock market could interlink the bond market and banking sector with the equity, potentially inciting broader systemic risks. Furthermore, the housing market crisis and investors' skepticism towards the extent of China's marketization reforms will also intensify. Overall, we believe that the current round of stock market stimulus is not sustainable and leaves the door open for future risks.

The burden of hepatocellular carcinoma (HCC) continues to pose a significant global health problem. Several systemic therapies have recently been shown to improve survival for patients with unresectable disease. However, evidence is limited to support the use of neoadjuvant or adjuvant systemic therapies in patients with resectable disease, despite the high risk of recurrence. Neoadjuvant and adjuvant systemic therapies are being investigated for their potential to reduce recurrence after resection and improve overall survival. Our review identified various early-phase clinical trials showing impressive preliminary signals of pathologic complete response in resectable disease and others suggesting neoadjuvant therapies, particularly when combined with adjuvant strategies, may convert unresectable disease to resectable and cause significant tumor necrosis, potentially decreasing recurrence rates. The role of adjuvant therapies alone may also have a role in the management of these patients, particularly in reducing recurrence rates. Heterogeneity in trial design, therapies used, patient selection, and a scarcity of randomized phase III trials necessitate the cautious implementation of these treatment strategies. Future research is required to identify predictive biomarkers, optimize the timing and type of therapeutic combinations, and minimize treatment-related adverse effects, thereby personalizing and enhancing treatment strategies for patients with resectable and borderline resectable HCC.

Background: Interstitial lung disease (ILD) is a frequent complication in systemic sclerosis (SSc). So, an increased awareness of this complication is a real need in the clinical setting, because it may affect the prognosis of patients. In particular, an accurate strategy is desirable in order to detect ILD in its stages. So, we investigate the validity of ultrasound (US) in detecting subclinical ILD in SSc, and to determine its potential in disease progression. Methods: 133 patients without respiratory symptoms and 133 healthy controls were included. Borg scale, Rodnan skin score (RSS), pulmonary auscultation, chest radiographs and respiratory function tests (RFT) were performed. An expert rheumatologist performed the lung US. High-resolution CT (HRCT) was also performed. After the baseline assessment, the patients were followed every 3 months for 12 months. Results: A total of 79 of 133 patients (59.4%) showed US signs of ILD in contrast to healthy controls (4.8%) (p=0.0001). The clinical and laboratory variables associated with ILD were anti-centromere antibodies (p=0.005) and RSS (p=0.004). A positive correlation was demonstrated between the US and HRCT findings (p=0.001). Sensitivity and specificity of US in detecting ILD was 91.2% and 88.6% respectively. A good inter-observer reliability was observed (k = 0.72). In the follow-up, a total of 30 patients out of 79 (37.9%) who demonstrated US signs of ILD at baseline, showed changes in the ILD score by US. Conclusions: US showed a high prevalence of subclinical ILD in SSc patients. It demonstrated to be a valid, reliable and feasible tool to detect ILD in SSc and to monitoring the disease progression.

The coexistence of SAH with T2DM is a common comorbidity. In this present study, we investigated the link between altered plasma antioxidant trace elements (ATE: Manganese, Selenium, Zinc and Copper) and fatty acids ratio (FAR: polyunsaturated/saturated) imbalance as transition biomarkers between vascular pathology (SAH) to metabolic pathology (T2DM). Our data revealed strong correlation between plasma ATE and FAR profile which is modified during SAH-T2DM association compared to healthy group. This relationship is mediated by lipotoxicity (simultaneously prominent visceral adipose tissue lipolysis, significant flow of non-esterified free fatty acids release, TG-Chol-dyslipidemia, high association of Total SFA, Palmitic acid, Arachidonic acid and PUFA 6/ PUFA 3; drop in tandem of PUFA / SFA and EPA+DHA); oxidative stress (lipid peroxidation confirmed by TAS depletion and MDA raise, concurrently drop of Zn/Cu-SOD, GPx, GSH, Se, Zn, Se/Mn, Zn/Cu; concomitantly enhance Cu, Mn and Fe); endothelial dysfunction (endotheline-1 increase); athero-thrombogenesis risk (concomitantly raise of ApoB100/ApoA1, Ox-LDL, tHcy and Lp(a)) and inflammation (higher of Hs-CRP, Fibrinogen and Ferritin). Our study open to new therapeutic targets and to better dietary management, such as to establish dietary ATE and PUFA 6 / PUFA 3 or PUFA / SFA reference values for atherosclerotic risk prevention in hypertensive-diabetics patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread inflammation and multi-organ damage. Toll-like receptor 7 (TLR-7) and autophagy have been implicated in SLE pathogenesis. Rice husk silica liquid (RHSL) has shown potential for modulating inflammatory responses, but its effects on SLE have not been thoroughly investigated. This study aims to evaluate the impact of RHSL on immune responses and autophagy in an in vitro model of SLE, focusing on its effects on TLR-7 signaling, cytokine production, and autophagy modulation. RAW264.7 cells and human peripheral blood mononuclear cells (PBMCs) from healthy donors and SLE patients were used. Cells were stimulated with LPS or TLR-7 agonists and treated with RHSL. Cell viability was assessed, and cytokine levels (TNF-α and IL-6) were measured by ELISA. Autophagy-related proteins (LC3II, ATG5-ATG12) were analyzed by Western blotting. The effect of autophagy inhibition was studied using 3-methyladenine (3-MA). RHSL did not affect cell viability but significantly reduced TNF-α production in LPS- and TLR-7 agonist-stimulated RAW264.7 cells and PBMCs. RHSL enhanced autophagy, as evidenced by increased LC3II and ATG5-ATG12 conjugation in both RAW264.7 cells and SLE patient-derived PBMCs. The reduction in TNF-α production by RHSL was attenuated by 3-MA, indicating that autophagy plays a role in this process. RHSL also inhibited the translocation of phosphorylated NF-κB into the nucleus, suggesting a mechanism for its anti-inflammatory effects. RHSL exhibits potential as an immunomodulatory agent in SLE by enhancing autophagy and modulating TLR-7 signaling pathways. These findings suggest that RHSL could offer therapeutic benefits for managing inflammatory responses in SLE and warrant further investigation into its clinical applications.

Systemic Lupus Erythematosus (lupus) and B-cell lymphoma (lymphoma) are serious diseases. Lupus and lymphoma co-occur at higher-than-expected rates and primarily depend on B-cells for their pathology, implicating shared inflammation-related B-cell molecular mechanisms as a potential cause of co-occurrence. We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B-cell RNA-seq data to find shared- and contrasting mechanisms potentially targetable for treatment. We observed 8,562 genes significantly dysregulated in both lupus and lymphoma. Of those genes, we found 5,335 to have a significant immune imbalance, defined as significant dysregulation by both diseases, as determined by IIT. Gene Ontology (GO) term and pathway enrichment of IIT genes yielded immune-related “Neutrophil Degranulation” and “Adaptive Immune System”, validating that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 389 IIT gene products are drug-targetable with established or repurposed drugs. Among our results, we found 40 known and 349 novel lupus targets, along with 151 known and 238 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. We anticipate the IIT algorithm and shared and contrasting gene mechanisms uncovered here will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients.

Background and Objectives: Zonulin is a molecule that has been identified as an intestinal permeability marker in recent years. Zonulin previously linked to Diabetes Mellitus, Obesity and Cardiovascular Disease but but its role in chronic kidney disease (CKD) was unclear. This study aims to investigate the relationship between Zonulin and systemic inflammation (SI), endothelial dysfunction (ED), especially renal functions, in patients with CKD. Materials and Methods: One hundred sixty-three participants were enrolled in this study. All participants were divided into two groups, patient and control groups, according to the presence of CKD (eGFR <60 mL/min/1.73m²). Results: A total of 104 patients with CKD (mean age 58.9 ±1.4) and 59 control subjects (mean age 59.0 ±1.1 ) were included, and age (p =0.934) and gender (p =0.196) were similar between the groups. In the comparison analysis, plasma zonulin levels in the CKD group (166.16 ± 53.54) were significantly higher than the controls group (143.30 ± 60.92) (p <0.001). In the correlation analysis, serum zonulin level showed positive correlation with claudin-3 (r =0.612, p <0.001), IL-6 (r =0.307,p <0.001), creatinine (r =0.313, p <0.001) and negative correlation with eGFR (r =-0.320, p <0.001) and TC (r =-0.074, p =0.047). Additionally, in linear regression analysis, zonulin level was significantly associated to eGFR, after adjustment for age and SBP (β value =-0.918, p =0.012). Conclusion: High serum zonulin levels in patients with CKD reflect increased intestinal permeability and were associated with impaired renal function. Moreover, it was thought that zonulin level could be associated with SI, but novel clinical studies were needed to elucidate its relationship with ED.

Prostate cancer lung metastasis represents a clinical conundrum due to their implication of advanced disease progression and the complexities they introduce in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, the review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, the review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Background: Neuroendocrine tumors (NET) are a rare group of epithelial neoplasm present in gastrointestinal tract (GI) (67.5%), bronchopulmonary tree (25.3-30%), and in 15% of cases, the primary sites cannot be identified. Although endoscopic screening, improvement in pathological techniques, and early detection have shown improvement in NET survival rates, the prognosis of advanced, metastatic, and poorly differentiated NET is very poor. In this study, we aimed to evaluate the effect of Gastrointestinal and pancreatic (GEPs) NETs grade on overall survival. Method: We searched observational studies describing the overall survival or prognostic factors of primary GEP NETs from May 2011 -May 2021 following PRISMA guidelines. Studies describing the effect of primary grade 3 GEP NETs on overall survival were included. Meta-analysis was performed, and pooled hazard ratio and their 95% confidence interval (95% CI) were obtained. The forest plots were created using random-effects models and sensitivity analysis was performed to account for the heterogeneity. Results: Seven studies with 7692 confirmed patients were included. In our meta-analysis grade 3 GEP NET were associated with higher odds of poor survival (pooled HR: 2.73; 95% CI: 1.36–5.47; p = 0.005), with 92% heterogeneity between studies (p < 0.0001). To account for heterogeneity, sensitivity analysis was performed by removing two outlying studies (Fathi et al. and Foubert et al.) on funnel plots. The results after sensitivity analysis did not change and still showed significant association of grade 3 with poor survival (pooled HR: 4.53; 95% CI: 3.54–5.78; p < 0.00001), with no heterogeneity between studies (p = 0.72; I2 = 0%). Conclusion: Our meta-analysis found that grade 3 GEP NETs are associated with poor survival and additional future studies are needed to identify other risk factors associated with poor survival in GEP NETs to improve mortality.

The human oral microbiome refers to an ecological community of symbiotic and pathogenic microorganisms found in the oral cavity. The oral cavity is a suitable environment that provides various kinds of biological niches such as teeth, tongue, and oral mucosa. The oral cavity is the gateway between the external environment and the human body, maintaining oral homeostasis, protecting the mouth, and preventing disease. On the flip side, the oral microbiome plays an important role in triggering, development, and progression of oral and systemic diseases. Currently, disease diagnosis through the analysis of the human oral microbiome has been realized with the recent development of innovative detection technology, and is overwhelmingly promising compared to the previous era. It has been found that patients with oral diseases and systemic diseases have variations in the oral microbiome compared to normal subjects. This narrative review provides insight into the pathophysiological role that oral microbiome plays in influencing oral and systemic diseases, and updates the knowledge related to the oral microbiome over the past 30 years. A wide range of updates was provided with the latest knowledge of the oral microbiome to help researchers and clinicians in both academic and clinical aspects. The microbial community information can be utilized in non-invasive diagnosis and help develop a new paradigm in precision medicine, which will benefit human health in the era of post-metagenomics.

Background: Skin- (SSM) and nipple-sparing (NSM) mastectomies are frequently performed surgeries with a considerable risk for post-operative hematoma or seroma. Tranexamic acid (TXA) is a potent antifibrinolytic drug commonly used in many surgical fields but rather novel in plastic and specifically breast surgery. This study investigates the influence of TXA in patients undergoing SSM or NSM with expander-based reconstruction (EbR) on post-operative outcomes. Methodology: A retrospective study was conducted on 132 patients undergoing uni- or bilateral SSM or NSM with EbR between May 2015 and March 2022. Patients receiving systemic TXA treatment for 48 hours following a standardized protocol were compared to those who received no treatment. Multivariable linear regression was performed to identify influencing factors and quantify their effect on drainage volume, duration of drain placement, length of hospital stay, post-operative bleeding, and seroma formation. Results: 132 patients underwent a total of 155 mastectomies (72 in the TXA group, 83 in the control group). TXA significantly reduced drainage volume (-22.3ml, P=0.011). Duration of drain placement and length of hospital stay were significantly shorter in the TXA group (P&lt;0.001 and P=0.001). No significant side effects were reported. Conclusion: TXA is a safe drug if administered respecting the well-defined contraindications. Systemic TXA administration significantly reduces drainage volume in patients undergoing SSM or NSM and should encourage surgeons to reconsider using drains in post-operative protocols. Duration of drain placement and length of hospital stay were significantly reduced in the TXA group but other factors like resection weight might have a more substantial impact.

Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by a variety of both signs and symptoms; it mainly affects women of childbearing age, with an estimated prevalence of 24/100,000 people in Europe and North America. SLE is often described as an antibodies-driven disease as its clinical manifestations are usually associated with the presence or the absence of specific antibodies. Objectives To evaluate clinical manifestations in patients with SLE and to assess the relationship with the presence of specific antibodies by using real-world data. Methods A retrospective study was performed; the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus were used to classify patients with SLE. Data concerning serological profiles (which included Antinuclear antibodies – ANA, anti dsDNA, anti-Ro/SS-A, anti-La/SS-B, anti-Sm) were gathered along with medical records of clinical manifestations. Complement levels were also tested for possible clinical correlations. χ² or Fisher's exact tests were utilized to establish associations between autoantibodies and symptoms. The odds ratios (OR) and their 95% confidence intervals (CI) were computed. No correction was made for multiple testing; only a p-value 0.01 ≤ was considered significant. Results One-hundred and twenty-seven patients (n=127, mean age 53.43 ±14.02) were enrolled in this study. Anti-dsDNA antibodies were found to be statistically significant for both malar rash and proteinuria; anti-Ro/SSA antibodies showed an association with photosensitivity and pericarditis; furthermore, a strong association was found between anti-Ro antibodies and proteinuria, but only if anti-dsDNA antibodies were present as well. Patients who tested positive for anti-La/SSB antibodies correlated with a threefold increase in the risk of developing pericarditis. Lastly, anti-Smith appeared to be associated with NPSLE as well as an increased risk for both autoimmune haemolytic anemia and thrombocytopenia. Conclusions In our study, many associations confirmed those found in previous studies; however, new relationships between antibodies and clinical manifestations were found thus indicating the need for additional evaluations to assess these correlations further.

Systemic sclerosis (also known as scleroderma) is a chronic fibrosing autoimmune disease with both skin and multisystem organ involvement. Scleroderma has the highest mortality among all rheumatic diseases. The pathophysiology mechanism of systemic sclerosis is a progressive self-amplifying process, which implicates the widespread microvascular damage, followed by a dysregulation of innate and adaptive immunity and inflammation, and diffuse fibrosis of the skin and visceral organs. Fibrosis of internal organs is a hint for systemic sclerosis, moreover associated with interstitial lung disease (SSc-ILD) is a complex process. We report a case of a 56 years old female, diagnosed with Systemic Sclerosis 16 years ago. The systemic and clinical manifestations, respiratory functional tests, radiological aspects and specific therapy were discussed.

Various studies have addressed the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, cancer has a systemic impact which targets various organs thus challenging the overall physiology of the host. So, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern the systemic role of neutrophils, we monitored their number and function at different stages of tumor growth in Dalton’s lymphoma mice model. Notably, we observed a gradual increase in neutrophil count in blood and their infiltration in vital organs of tumor bearing mice. In parallel, we observed damaged histoarchitecture with significant alterations in biochemical parameters that aggravated with tumor progression. We next examined systemic impact of neutrophil by assessing neutrophil elastase, myeloperoxidase, and matrix metalloproteinases (MMP-8 and MMP-9) wherein we found their upregulated expression and activity in tumor condition. Taken together, our results demonstrate high infiltration and hyperactivation of neutrophils which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.

The contemporary treatment for metastatic castration-sensitive prostate cancer (mCSPC) has evolved significantly, building on successes in managing metastatic castration-resistant prostate cancer (mCRPC). Although androgen deprivation therapy (ADT) alone has long been the cornerstone of mCSPC treatment, combination therapies have emerged as the new standard of care based on recent advances, offering improved survival outcomes. Landmark phase 3 trials demonstrated that adding chemotherapy (docetaxel) and androgen receptor pathway inhibitors to ADT significantly enhances overall survival, particularly for patients with high-volume, high-risk, or de novo metastatic disease. Despite these advancements, a concerning gap between evidence-based guidelines and real-world practice remains, with many patients not receiving recommended combination therapies. The challenge in optimizing therapy sequences, considering both disease control and treatment burdens, and identifying clinical and biological subgroups that could benefit from personalized treatment strategies remains. The advent of triplet therapy has shown promise in extending survival, but the uro-oncology community must narrow the gap between evidence and practice to deliver the most effective care. Current research is focused on refining treatment approaches and utilizing biomarkers to guide therapy selection, aiming to offer more personalized and adaptive strategies for mCSPC management. Thus, aligning clinical practices with the evolving evidence is urgently needed to improve outcomes for patients facing this incurable disease.

Lupus, also known as systemic lupus erythematosus (SLE), is a chronic autoimmune disease that can lead to inflammation and damage to multiple organs and tissues in the body. The symptoms vary from patient to patient, which makes the disease manifest very differently, resulting in difficulty in diagnosing and treating patients. Some may experience fatigue, hair loss, joint pain, and more. In the past, a general approach of blanket immunosuppression was commonly used to treat lupus. These immunosuppressive drugs would broadly target the immune system and focus on reducing symptoms. However, recent research has shown that selective immunotherapies such as monoclonal antibodies (anifrolumab and belimumab) which target specific components of the immune system are more effective in managing lupus because of their ability to reach specific cells in the immune system rather than easing symptoms. Anifrolumab blocks the activity of type I interferons, while belimumab neutralizes BLyS to reduce the production of autoantibodies, the root cause of SLE.¹⁻² This paper will introduce the immunology of the disease, explore how the more traditional approach of blanket immunosuppressive drugs work compared to the newer selective immunotherapies, and review the results from the clinical trials of anifrolumab and belimumab.

A Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disease characterized by a complex interplay of genetic, molecular, and cellular factors. It is considered a multifactorial disorder influenced by genetic susceptibility, environmental triggers, and dysregulated immune responses. Understanding the molecular and cellular mechanisms driving SLE pathogenesis has been instrumental in developing targeted therapies to manage the disease and improve patient outcomes. In this essay, we will delve into the intricate molecular and cellular processes underlying SLE and examine the key lessons learned from human therapies.

The coronavirus disease (COVID-19) is a respiratory tract infection caused by the new virus SARS-CoV-2. In March 2020, the World Health Organization (WHO) declared a worldwide COVID-19 pandemic. Since then, there has been a rush to find preventative or curative treatment. This arrived with the appearance of the COVID-19 vaccine, months after the declaration of the pandemic. In the setting of global COVID-19 immunization, there have been reports of rare skin immune-mediated diseases (IMD) after COVID-19 vaccination, particularly systemic sclerosis. Systemic sclerosis (SSc) is the most reported new onset IMD following messenger RNA (mRNA) COVID-19 vaccination. The pathogenesis of SSc is not fully understood, and the diagnosis is based on clinical symptoms. We report a 54-year-old male, with no prior history of autoimmune disorder, with rapid and progressive skin thickening (Modified Rodnan skin score 30/51), weeks after his mRNA COVID-19 vaccination. Antinuclear antibodies (ANA) showed a strongly positive nuclear fine-speckled pattern, but no SSc autoantibodies were found. The patient was diagnosed with SSc based on the persistence of autoantibodies and the clinical criteria according to the 2013 American College of Rheumatology/European League Against Rheumatism classification. Due to the proximity of the two events, we hypothesized a cross-reaction between COVID-19 vaccination and, in genetically predisposed patients, an emergence of systemic sclerosis. Our case suggests a potential relationship between the mRNA COVID-19 vaccine and new-onset autoimmune diseases. Physicians should be aware of this possible association.

Trichoderma spp. are widely used in plant disease control as biocontrol agents. Inducing plant disease resistance is an important biocontrol mechanism of Trichoderma. It is of great significance to explore the factors involved in the surface recognition and interaction of Trichoderma with plants. Hydrophobin is a small molecular protein rich in cysteine in higher filamentous fungi and has been found to participate in the morphogenesis and interaction of fungi with other organisms. In this study, the type II hydrophobic protein-coding gene Thfb6 from T. harzianum TH33 was cloned and heterologously expressed in Escherichia coli BL21 (DE3). The purified recombinant protein Thfb6 induced a hypersensitive response in tobacco leaves, a burst of reactive oxygen species, and an accumulation of callose, phenolic substances, and lignin in tobacco, indicating that Thfb6 can induce an early defense reaction in tobacco. Thfb6 also enhanced the systemic resistance of tobacco against tobacco mosaic virus. The rate of lesion number reduction by treatment with Thfb6 could be up to 36.02%. Thfb6 increased the activity of tobacco defense-related enzymes, including phenylalanine ammonia-lyase (PAL), polyphenol oxidase, and peroxidase, which were all more than three times the control after 3–5 days post treatment of Thfb6. The transcription of resistance-related genes, including the PAL gene, non-expresser of pathogenesis-related gene1 (NPR1), and basic pathogenesis-related gene 1 (PR1-b), were upregulated after Thfb6 treatment. The relative expression levels of the PAL and NPR1 genes were highest on the third and fourth days after Thfb6 treatment, at 5.5 times and 8.3 times that of the control, respectively. The relative expression level of PR1 on the sixth day after Thfb6 treatment was 5.3 times that of the control. These results indicate that the improvement of defense-related enzyme activity and the induced expression of disease-resistance-related genes were the main mechanisms by which Thfb6 induced systemic resistance in tobacco.

Background: The systemic inflammatory index (SII) is a new inflammatory marker that has been the subject of various studies in diseases with chronic inflammation. Diabetic nephropathy is also a disease that goes with chronic inflammation. We aimed to evaluate the relationship be-tween SII and diabetic nephropathy. Methods: Patients with diabetes who applied to our outpatient clinic are included in the study. Diabetic patients are divided into two groups: those with diabetic nephropathy and those with-out. In addition, healthy individuals who applied to our clinic for general check-ups during these dates are included as control group. The SII values and other characteristics of the three study groups are compared. Results: The median SII value for those with DKI was 584 (178-4819); for those without DKI, it was 282 (64-618); and for the control group, it was 236 (77.5-617) (p<0.001). SII was significantly and positively correlated with BMI, weight, blood glucose, HbA1c, CRP and creatinine, and neg-atively correlated with glomerular filtration rate (GFR) value. The SII value higher than 336 has 75% sensitivity and 70% specificity in detecting DKI. Conclusion: The SII value could predict diabetic kidney injury in diabetics and it could be used as an adjunctive diagnostic tool.

Programmed-death-1 (PD-1) receptor plays a major physiological role in maintainance of im-mune tolerance, and, by interaction with its ligands (PD-L1 and PD-L2), prevents the develop-ment of multiple immune-mediated diseases. There is growing evidence of an important role of PD-1/PD-L1 pathway in pathogenesis of psoriasis. 84 subjects with psoriasis were included into the study, together with 29 healthy subjects as a control group. 28 of psoriatic patients were treated with biologice therapy (TNF-alpha, interleukin (IL)-12/23 or IL-17 inhibitors). Amounts of PD1 and PD-L1 positive T-cells in peripheral blood were evaluated using flow cytometry. Significantly lower levels of peripheral blood mononuclear cells (PBMCs) with the expression of PD-1 and PD-L1 were found in psoriatic patients when compared to healthy individuals, i.e. CD3/PD1, CD3/PDL1, CD4/PD1, CD4/PDL1, CD8/PDL1, CD19/PD1, CD19/PDL1 positive cells. Biologic treatment resulted in elevation of CD3/PDL1, CD8/PDL1 and decrease of CD8/PD1 posi-tive PBMCs. Our results confirm previous observations of disrupted PD-1/PD-L1 pathway in psoriasis, and that this disturbances may play an important role in development of the disease. Biologic drugs may reverse several abnormalities observed within this pathway, which may ex-plain their excellent efficacy in the treatment of psoriasis. Further research should be conducted to fully explain the results obtained.

Although man is still rapidly evolving, he has not co-evolved with all of the modern chemicals made by man, including those in cosmetic products. Care must be taken when formulating products so that commonly used ingredients, such as polyethylene glycol, can be substituted with safer ingredients to which man has adapted and that will not cause irritation and inflammation. This is especially important given that induction of skin inflammation will cause systemic inflammation. A review of the literature and of commercially available products was made to highlight techniques and products that remediate inflammation or induce inflammation. Many skin care products contain chemicals that induce irritation and inflammation that may lead to chronic, systemic inflammation. Well studied natural products, especially skin identical chemicals, may offer an advantage compared to recent man-made chemicals in cosmetic and topical formulations and help to reduce skin inflammation as well as skin derived systemic chronic inflammation.

The use of fluoride (F^-) for decreasing the prevalence and incidence of tooth decay was the greatest worldwide preventive public health measure of the 20th century. There have been controversial reports about the benefits of the use of F^-, because in small amounts it helps prevent dental caries, but in high concentrations it can be potentially toxic and harmful to dental and systemic health. Since the mid-20th century, F^- has been studied by toxicologists, looking at its deleterious effects in human populations. During the last decade, the interest on the undesirable effects has resurfaced because of the knowledge that it interacts with the cellular system, even in low doses, with a very small safety margin. Acute ingestion of toxic amounts of fluoride can cause corrosive gastric mucosa injury. Also respiratory effects such as bleeding, pulmonary edema, tracheostomy and shortness of breath, have been observed in individuals who inhale hydrogen fluoride. Some researchers had shown that F^- is an oxidizing agent and a well-known reversible enzymatic inhibitor that interferes with the enzyme activity of at least 80 proteins, can altered the intracellular redox equilibrium, lipid peroxidation, as well as, alteration in the gene expression and apoptosis induction. The primary purpose of this review is to examine findings of the action of inorganic F^-, and an overview of hard and soft tissue disturbances, known as fluorosis. The goal of this review is to enhance understanding of the mechanisms by which F^- affects cells with an emphasis on human tissue-specific events.

Focusing on the implementation of the 2003 UNESCO Convention for the Safeguarding of the Intangible Cultural Heritage (ICH), this article highlights the fact that the cataloging procedures, the way records are stored, and the metadata models used during recording, visualization, and storage of ICH expression elements, vary from country to country. Especially in these days of great uncertainty, war conflicts, and the systemic risks that may arise, it is vital to clarify what techniques will be used in the storage of ICH to ensure its unhindered preservation and dissemination over time across the globe. Using the systems thinking approach indicated for cases of great complexity, the process followed in Greece for depositing a new element in its local repository is described to demonstrate the need for a well-defined process by UNESCO, which must be followed worldwide and which has not been defined so far. What are the potential challenges not only in determining the type of data but also in choosing the best metadata model to use in each case when capturing this data? What technologies must be used for storing digital cultural heritage in such a way that will preserve it over time, defying physical and technological hazards? The article finally suggests how Blockchain Technologies (BT) can be effectively used to store the global ICH and ensure its continuity in future generations by creating a decentralized worldwide network between the heritage stakeholders.

Cancer has emerged as a systemic disease which targets various organs thus challenging the overall physiology of the host. Recently, we have shown that hyperactive neutrophils infiltrate various organs of tumor bearing host and contribute significantly to gradual systemic deterioration. Therefore, taming neutrophils via potent immunomodulators could be an appropriate therapeutic approach in regulating systemic damage. Tinospora cordifolia (TC), an Ayurvedic panacea, is known for its immense medicinal values in traditional literature and recent reports have also documented its strong immunomodulatory potential. However, whether TC can regulate neutrophils to exert its therapeutic effectiveness has not been deciphered so far. To discern this, we utilized murine model of Dalton’s Lymphoma (DL) wherein, we have earlier reported heightened infiltration of neutrophils and their hyperactivation. Our findings showed that TC treatment significantly reduced neutrophil count in peripheral blood and their infiltration in vital organs of tumor bearing host. Further, it ameliorated neutrophil hyperactivation by down regulating the expression of its key cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), MMP-8, MMP-9 and cathepsin G (CSTG) at early and mid stage of tumor growth. In addition, TC treatment prevented histopathological alterations and restored the normal serum enzyme levels at different stages of tumor growth. Importantly, TC treatment also showed significant reduction in tumor burden which was accompanied by a remarkable increase in survival of the tumor-bearing mice. We conclude that Tinospora cordifolia could limit systemic damage via regulating neutrophil infiltration and hyperactivation which can further lead to cancer control at both prophylactic and therapeutic level.

Objectives: To determine the prevalence of controlled systemic hypertension and its associated risk factors among the hypertensive patients who attended the clinic at Mbeya Zonal Referral Hospital in Tanzania. Methods: A descriptive cross-sectional quantitative study was used determine the prevalence of co to 252 hypertensive patients were recruited during clinic visit from September to November 2020 and participant was randomly selected interviews using structured self-administered questionnaires. Data was analyzed using chi square test to find the risk factors associated with controlled hypertension. Results: Among 252 participants, 94(39.7%) individuals with controlled hypertension giving the prevalence of controlled hypertension. The proportion of females with controlled hypertension was slightly higher than male (49 females to 45 males). The prevalence of uncontrolled hypertension was 152(60.3%) participants. The prevalence of controlled hypertension was higher among patients who have regular clinic visit (p< .05) and have daily adherence to their anti-hypertensive medication. A similar trend was observed among participants without financial challenges to attend clinic, short duration of illness, higher level of education and there was no association between age, sex, marital status, smoking, alcohol consumption, having health insurance and having chronic illness. Conclusion: Prevalence of controlled hypertension is higher among patients who have regular clinic visit and have daily adherence to their anti-hypertensive medication. Also, it is higher among participants without financial challenges to attend clinic so they can have regular clinic visit and checkup. Reinforcement on regular drug intake and clinic visit, good nutrition and reduced salt intake and modifying lifestyles of patient with hypertension is important.

The human body supports the growth of a wide array of microbial communities in various niches, such as the oral cavity, gastro-intestinal and urogenital tracts and on the surface of the skin. These host associated microbial communities include yet-un-cultivable bacteria and are influenced by various factors. Together, these communities of bacteria are referred to as the human microbiome. Human oral microbiome consists of both symbionts and pathobionts. Deviation from symbiosis among the bacterial community leads to “dysbiosis”—a state of community disturbance. Dysbiosis occurs due to many confounding factors that predispose to a shift in the composition and relative abundance of microbial communities. Dysbiotic communities have been a major cause for many microbiomes related systemic infections. Such dysbiosis is directed by certain important pathogens called the “keystone pathogens” that could modulate community microbiome variations. One such persistent infection is oral infection, mainly periodontitis, where a wide array of causal organisms has been implied to systemic infections such as cardio vascular disease, diabetes mellitus, rheumatoid arthritis and Alzheimer’s disease. The keystone pathogens co-occur with many yet-cultivable bacteria and their interactions lead to dysbiosis. This has been the focus of recent research. While immune evasion is one of the major modes that lead to dysbiosis, new processes and new virulence factors of bacteria have been shown to be involved in this important process of that determine disease or health state. This review focuses on such dysbiotic communities, their interactions and their virulence factors that predispose the host to other systemic implications.

The glucocorticoid receptor alpha (GRα), a pivotal component of the ancient glucocorticoid (GC) signaling system that emerged nearly 450 million years ago, has been instrumental in directing vertebrate evolution and is essential for survival, regulating fertility and fetal development, the function of every organ and circulating cells, metabolism, immune responses, and adaptation to stress. While its anti-inflammatory properties have been recognized since the mid-20th century, GRα’s broader role as the master regulator of homeostatic corrections, particularly in health and critical illness, has only recently been fully appreciated.GRα orchestrates three key phases of homeostatic correction: the Priming Phase, where it rapidly activates early immune responses, mobilizes energy reserves, and prepares the body to mount an immediate defense against various physiological stressors, including infection and injury. During this phase, GRα enhances glucose metabolism, supports mitochondrial function, and facilitates the release of key immune cells to the site of damage, ensuring the body is equipped to handle the initial assault. The Modulatory Phase follows, in which GRα fine-tunes the inflammatory response to prevent excessive tissue damage. By balancing pro- and anti-inflammatory signals, GRα helps contain the immune response, preventing the harmful effects of prolonged inflammation while maintaining immune surveillance. This phase also involves the regulation of oxidative stress, vascular tone, and the preservation of cellular integrity to protect vital organs from injury. Finally, in the Restorative Phase, GRα plays a critical role in resolving inflammation and initiating tissue repair. During this phase, GRα supports cellular regeneration, promotes the clearance of apoptotic cells and debris, and restores anatomical and physiological balance. It aids in rebuilding tissue architecture and returning the neuroendocrine-immune system to its baseline state, ensuring long-term recovery and stability.Throughout these phases, GRα manages complex interactions, including recently discovered co-regulation with pro-inflammatory transcription factors, while also regulating mitochondrial function to ensure bioenergetic and metabolic stability during stress. In critically ill patients, depletion of bioenergetic and micronutrient reserves severely impairs GRα’s capacity to regulate immune responses, heightening the risk of morbidity and mortality.This review, in light of this new understanding, underscores the need to re-evaluate current glucocorticoid (GC) treatment strategies, emphasizing the incorporation of micronutrient support to optimize GRα function across all phases of homeostatic correction. This integrated therapeutic approach has the potential to enhance both immediate immune responses and long-term recovery in critically ill patients, offering a more comprehensive strategy for managing the complex pathobiology of critical illness. Furthermore, this integrative approach could decrease glucocorticoid dose and duration requirements and potential side effects.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a broad array of clinical signs. In this study, we aimed to use intravenous immunoglobulins (IVIG), called intacglobin, as a monotherapy to manage SLE in three patients. Laboratory investigations for SLE diagnosis were performed, including the detection of anti-nuclear antibodies (ANA) and SLE confirmation by detecting high titers of anti-dsDNA antibodies. C3 and C4 serum levels were assessed, as well as the determination of immunoglobulins. The SLEDAI score was measured to determine whether a significant degree of disease activity existed and as a prognostic value. The evaluation of any chest infection was performed by chest-X-ray. The patients were treated with five–ten g/day of IVIG for six consecutive days, followed by five–ten g/month. Immunological evaluation demonstrated that patients presented with a flare of SLE with high titers of ANA and anti-dsDNA antibodies, low C3 and C4, and elevated immunoglobulin levels. The SLEDAI score falls from 10 to below 3, and chest infections in some patients are cleared up. The postulated mechanisms of action of IVIG demonstrated that it could be used as an immunosuppressor, immunomodulator, and antimicrobial agent in patients with SLE.

Diabetes may cause an increase blood levels of cytokines inducing a rising of C reactive protein (PCR) and fibrinogen stimulating a subclinical inflammation which lead to adhesive molecules expression and to endothelial disfunction. A comprehensive panel of type 1 diabetes mellitus (T1DM) interleukins polymorphisms is not provided yet. As chronic periodontitis (CP) is considered the sixth complication of DM, a clarification is needed about the inflammatory role managed by single nucleotides polymorphisms (SNPs). The goal of this review is to focus on the significant diversity of SNPs in T1DM patients with and without CP. After a digital search on PubMed and Scopus with reference to the last 5 years, 21 items were enrolled. Several ILs were analyzed. T1DM still needs to be thoroughly explored regarding the ILs polymorphisms panel, however the last 5 years have led to the increased independence of this condition, causing autonomous inflammatory effects which requires further investigations. CP and T1DM association in children and adolescents represents a severe gap in literature that should be filled, the scarce presence of studies also about adults serves as a motivation for ulterior clinical researches

The ongoing conflict in Syria and Iraq has caused many residents of these countries to flee. This study explored how these refugees cope with traumatic experiences from pre-migration to post-migration phases and how they develop resilience experiences at the individual, familial, and community levels. Data were collected through individual interviews and analyzed using Interpretative Phenomenological Analysis. A discussion of the findings revealed (1) a cumulative effect of prolonged adversity from pre-migration to resettlement phases; (2) the impacts of post-migration context as it facilitates refugees’ adjustment or leads to re-traumatization through increased marginalization; and (3) finally, an overview of refugees’ ongoing survival. Clinical implications are presented along with policy implications and future directions for research.

Background: Since the introduction of the SLICC criteria in 2012, biopsy-proven lupus nephritis (LN) has been the only independent diagnostic criterion for systemic lupus erythematosus (SLE). This was reaffirmed by the EULAR/ACR in 2019, emphasizing the importance of renal biopsy in LN. However, the current classification lacks specific histopathological criteria for defining LN. This study describes the histological findings of patients with LN, compares them with those of other glomerular diseases, and evaluates their diagnostic accuracy. Methods: This retrospective cohort included 731 kidney biopsies. The patients were divided into two groups: a LN group and a control group comprising patients with membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, pauci-immune glomerulonephritis, and proliferative glomerulonephritis. Sensitivity and specificity analyses were conducted for various histopathological features. Results: We identified five features strongly correlated with LN: mesangial proliferation, subendothelial deposits, C1q staining ≥ 1+, dominant IgG, and ≥ 4 positive immunofluorescence elements. Combined, these features yielded an area under the ROC curve of 0.94 (95% CI: 0.91–0.95). In membranous nephropathy, histological features such as mesangial deposits, C1q positivity, and ≥ 4 positive immunofluorescence elements effectively distinguished class V LN from non-lupus membranous nephropathy, with an area under the ROC curve of 0.85 (95% CI: 0.76–0.93). Conclusion: The combination of mesangial proliferation, subendothelial deposits, C1q staining ≥1+, dominant IgG, and ≥ 4 positive immunofluorescence elements offer good accuracy for diagnosing renal involvement in SLE. In the absence of pathognomonic features, combined criteria are valuable diagnostic tools, particularly when other SLE criteria are lacking.

The La Oroya metallurgical complex reveals a process of structural or power pathology, where economic and environmental social policies lead to a citizenry without systemic freedom, characterized by environmental contamination (PAMA executed on average 67%, some processes with 0%) and sanitary (plumbosis 8.39 to 10.28 μg / dL), the economic dependence of this industry is also observed, which caused the weakening of the communities to maintain autonomy over their own destinies.The Doe Run Peru, operated the metallurgical complex, creating added value to the extractive-export chain of mineral concentrate, but also took advantage of the legal loopholes, the little coordination between the State institutions and the little authority of the supervisory institutions to get the most out of it, complying with the law in some cases, but without moral quality in some others, such as health in the oroinos.Government institutions must have strong links that provide a normative framework with prospects with sustainable development, where the beneficiary is society and not only certain interest groups. The economic benefits of the metallurgical complex operation are multiple, which begin with labor, the purchase and sale of materials and services, the collection of taxes and energy.

This study aimed to compare the effects of a permanent ischemic stroke model (focal ischemia by thermocoagulation of pial vessels) on sensorimotor function (cylinder test and adhesive removal test), behavioral tasks (novelty habituation memory-open field task), and cerebral infarct size in adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats over 42 days after the occurrence of stroke. We observed that the stroke caused asymmetry in the front paws and delayed adhesive removal. These effects were spontaneously reduced in WKY rats, but not in SHR. Short- and long-term novelty habituation memories were abolished by stroke in WYK and SHR. On the 3rd day after stroke, the size of the focal cerebral infarct was the same in WKY and SHR. However, on the 7th day, the infarct size decreased in WKY rats, but not SHR. These results suggested that SAH impairment of sensorimotor recovery in rats subjected to cerebral ischemia could be related to augmented focal cerebral infarct size. Moreover, the behavioral tasks used in this study were unaffected by Systemic Arterial Hypertension. Our results highlight the need for animal models of comorbidities in stroke research.

Service-Learning (SL) is a methodology that links students directly with reality. It strengthens the development of different competencies in students as they participate in activities associated with community service. The objective of this work is to analyze the SL methodology as an effective pedagogical practice to promote the development of generic competencies in university students. This research is a systematic review. The articles were selected according to the Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the eligibility criteria proposed by the PICOS strategy (population, interventions, comparators, outcomes and study design) based on 71 records of scientifically identified articles in the Web of Science (WoS) Journal Citation Report databases. Publications between 1999 and 2022 were considered. The literature review allowed the selection of seven articles showing the results of qualitative, quantitative and mixed research. The results reveal that the application of SL enhances the learning of professional and transversal competencies such as teamwork, appreciation and respect for diversity and multiculturalism, ethical commitment, critical and self-critical capacity, social responsibility, among others. It is concluded that this pedagogical practice effectively consolidates the development of these competencies, and that the success of its application depends on the commitment of teachers, students and community partners.

Phosphorus (P) is an essential plant macronutrient; however, its availability is often limited in soils. Plants have evolved complex mechanisms for efficient phosphate (Pi) absorption, which are responsive to changes in external and internal Pi concentration, and orchestrated through local and systemic responses. To explore these systemic Pi responses, here, we identified AtMYB44 as a phloem-mobile mRNA, an Arabidopsis homolog of Cucumis sativus MYB44, that is responsive to the Pi-starvation stress. qRT-PCR assays revealed that AtMYB44 was up-regulated and expressed in both shoot and root in response to Pi-starvation stress. The atmyb44 mutant displayed higher shoot and root biomass, compared to wild-type plants, under Pi-starvation conditions. Interestingly, the expression of PHOSPHATE TRANSPORTER1;2 (PHT1;2) and PHT1;4 was enhanced in atmyb44 in response to a Pi-starvation treatment. A split-root assay showed that AtMYB44 expression was systemically regulated, under Pi-starvation conditions and, in atmyb44, systemic controls on PHT1;2 and PHT1;4 expression were moderately disrupted. Heterografting assays confirmed graft transmission of AtMYB44 transcripts, and PHT1;2 and PHT1;4 expression was decreased in heterografted atmyb44 rootstocks. Taken together, our findings support the hypothesis that mobile AtMYB44 mRNA serves as a long-distance Pi response signal, which negatively regulates Pi transport and utilization in Arabidopsis.

Background: We previously developed a refined, tumor selective adenovirus, Ad5NULL-A20, har-boring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6 positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 hours post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6 selective manner, whilst cell killing me-diated by oncolytic Ad5NULL-A20 was αvβ6 selective. Biodistribution analysis following intrave-nous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor: liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20 based virotherapies efficiently target αvβ6 integrin positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic ap-plications, enabling tumor selective overexpression of virally encoded therapeutic transgenes.

(1) Background: The aim of this study was to analyze the relationship between the serum levels of soluble transferrin receptor (sTfR) and interleukin 4 (IL-4), and disease activity and organ mani-festations in SLE patients. (2) Methods: We studied 200 SLE patients and 50 controls. We analyzed disease activity, organ involvement, serum sTfR, IL-4, and interleukin-6 (IL-6) levels, and antinu-clear and antiphospholipid antibody profiles. (3) Results: The median serum levels of sTfR (p>0.000001) and IL-4 (p<0.00001) were higher in the study group than in the controls. SLE patients, compared to the controls, had significantly lower HGB levels (p<0.0001), a lower iron concentration (p=0.008), a lower value of total iron-binding capacity (TIBC) (p=0.03), and lower counts of RBC (p=0.004), HCT (p=0.0004), PLT (p=0.04), neutrophil (p=0.04), and lymphocyte (p<0.0001). Serum sTfR levels were negatively correlated with lymphocyte (p=0.0005), HGB (p=0.0001) and HCT (p=0.008), and positively correlated with IL-4 (p=0.01). Elevated serum sTfR >2.14 mg/dL was associated with an increased risk of myocardial infarction (OR: 10.6 95 CI 2.71–464.78; p=0.001), ischemic heart disease (OR: 3.25 95 CI 1.02–10.40; p=0.04), lung manifestations (OR: 4.48 95 CI 1.44–13.94; p=0.01), and hematological manifestations (OR: 2.07 95 CI 1.13–3.79; p=0.01), and with a reduced risk of neuropsychiatric manifestations (OR: 0.42 95 CI 0.22–0.80; p=0.008). Serum IL-4 was negatively correlated with CRP (p=0.003), and elevated serum IL-4 levels > 0.17 mg/l were associated with a reduced risk of mucocutaneous manifestations (OR: 0.48 95 CI 0.26–0.90; p=0.02). (4) Conclusions: In SLE patients, elevated serum levels of sTfR were associated with an increased risk of cardiovascular, pulmonary, and hematological manifestations, and with a decreased risk of neuropsychiatric manifestations. In contrast, elevated serum IL-4 levels were associated with a decreased risk of mucocutaneous manifestations.

Objective: Meningococcal meningitis (MM) is an acute, severe respiratory infectious disease caused by Neisseria meningitidis and remains an important cause of morbidity/mortality in children. Immunization with meningococcal vaccine (MV) is the most effective measure to control and prevent the transmission of MM. In this study, in order to support the appropriate use of various MVs in the prevention of MM, the effects of MVs, especially single-dose and inter-booster administered, on inflammatory parameters in

Background. Neoplastic diseases and infections have become the leading causes of death in SLE in recent decades. Cancers and infections were also precipitating factors in the development of catastrophic APS. Case summary. We describe two patients: one of them had definite antiphospholipid syndrome (APS) and melanoma and the other had definite systemic lupus erythematosus (SLE) with APS, melanoma, infiltrative tuberculosis and severe Herpes Zoster (HZ). Management of patients with SLE concurrent with APS is a rather difficult task in rheumatology practice. In addition to kidney damage and cardiovascular disease, infections and malignancies are a significant cause of death in this cohort. The risk of malignancy in SLE is of considerable interest, since the immune and genetic pathways underlying the pathogenesis of this disease, as well as the immunosuppressive therapy, can significantly alter the risk. Both patients still had reliable APS, confirmed by triple-positive aPL. Both were at high risk of thrombosis. Patients ' adherence to treatment with direct oral anticoagulants and relapse of thrombosis on the background of rivaroxaban were noted. Conclusion. The cases where cancer or tuberculosis develops in the presence of rheumatic diseases are not so common and complicate the possibilities of therapeutic approaches, limiting the use of drugs that are not regulated by clinical recommendations.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is located in the KIT gene. We report a rare case of a boy, born at term, presenting already at birth with generalized subcutaneous nodules, on the face, scalp, trunk, back, hands, and feet. The spleen, liver and inflammatory markers were normal at birth. Tryptase was significantly elevated. Bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical, and inguinal adenopathy while the skin nodules persisted especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation, however compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Globally, gastric cancer is a major cause of cancer mortality, with a 5-year survival rate of 32% for locally advanced and metastatic gastric cancer. This systematic literature review summarized the clinical, safety, and humanistic outcomes associated with systemic regimens given as first line therapy for locally advanced and metastatic gastric cancer. The search included articles published in English in PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and the American Society of Clinical Oncology meeting library, from inception to April 2022. Phase II and III randomized controlled trials conducted among western populations diagnosed with stage III and IV locally advanced and metastatic gastric cancer were included. Two investigators independently reviewed the studies, conducted data extraction, and assessed risk of bias in accordance with PRISMA guidelines. Twenty-four randomized controlled trials totaling 8,705 patients were included. Median overall survival ranged from 5.0-13.1 months, median progression-free survival ranged from 2.0-7.7 months, and objective response ranged from 13.0-64.1%. Two studies reported higher quality of life outcomes. Grade 3 and 4 adverse events were reported in most studies. Improvement in clinical outcomes can be seen in recently published randomized controlled trials for locally advanced and metastatic gastric cancer.

Background: To evaluate the effect of systemic erythropoietin, as well as oral steroids, in the management of recent onset non-arteritic anterior ischemic optic neuropathy (NAION). Method: Ninety-nine eyes of 99 patients diagnosed with NAION within 5 days of onset were included in this single masked randomized clinical trial. Thirty-four patients were randomized into group 1 (systemic erythropoietin), group 2 (oral steroids), and group 3 (control). Group A received 10,000 units of erythropoietin twice a day for three days. Group B received oral prednisone 75 mg daily for two weeks followed by a tapering dose (70 mg for 5 days, 60 mg for 5 days, and 5 mg reductions thereafter every 5 days). Functional and structural outcomes were analyzed at 3 and 6 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measure, and mean deviation (MD) of visual field (VF) test and peripapillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. Results:The mean BCVA (±SD) at the time of presentation was 1 ± 0.56, 1.01 ± 0.6, and 0.94 ± 0.47 logMAR in groups A, B, and C, respectively (P = 0.140); corresponding values were 0.72 ± 0.45, 0.83 ± 0.46, and 0.78 ± 0.4 logMAR (P = 0.417), and at 6-month follow-up, they were 0.70 ± 0.44, 0.73 ± 0.35, and 0.75 ± 0.39 logMAR, respectively (P = 0.597). Fifty-five percent of patients in group A vesus 34.3% in group B, and 31.2% in group C had an improvement of at least 3 lines in the BCVA values at the 6th-month follow-up visit. (P= 0.04) The mean deviation (MD) at the time of presentation was 19.67 ± 6.2, 20.83 ± 4.83, and 18.94 ± 6.92 decibels (db), respectively (P= 0.483).The corresponding values at month 3 were 18.22 ± 7.5, 19.82 ± 7.15, and 17.65 ± 7.22 db, (P = 0.848); and at month 6 they were 16.56 ± 7.08, 18.15 ± 6.57, and 15.9 ± 5.97 db, respectively. (P = 0.699) PRNFLT at presentation was 189 ± 58, 193 ± 64, and 199 ± 62 micrometers, respectively (P = 0.779), which decreased to 110 ± 45, 127 ± 37, and 119 ± 37 at month 3 (P = 0.423). The corresponding values for month 6 were 88 ± 12, 74 ± 25, and 71 ± 18, respectively (P = 0.041). Conclusion: The findings of our study indicate the beneficial effects of systemic erythropoietin in preserving the function and structure of the optic nerve in recent onset NAION.

Reactive oxygen species (ROS) are a major risk factor for the development of oxidation and inflammation. Ryegrass (pasture), a natural dietary fiber source, acts as an antioxidant with well-known anti-inflammatory properties. The current study aimed to examine the alkaline phosphatase (ALP)-dependent Kelch-like-ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) signaling pathway that facilitates the anti-oxidative and anti-inflammatory properties of pasture and its protective effects on ileal permeability, systemic inflammation, nutrient absorption, liver dysfunction, growth performance, intestinal organ development, and metabolic syndrome in commercial diet-challenged geese. The lipopolysaccharides (LPS), ALP, ROS, and tight junction proteins were determined from the ileum tissues, and the antioxidant enzymes, immunoglobulins, and metabolic syndrome were determined from liver tissues via Enzyme-linked immunosorbent assay (ELISA) kits. While the Nrf2 and LPS/ROS/Keap1-induced inflammatory cytokines were determined by the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. The intestinal morphology was examined by Hematoxylin and Eosin (H&E) staining to determine nutrient absorption in ileal tissues. Pasture-dependent ALP activity significantly ameliorated commercial diet-induced LPS and ROS-facilitated ileal barrier dysfunction and systemic inflammation. The pasture supplementation induced nutrient absorption by influencing intestinal organ development. Our biochemical assays showed that the activation of Nrf2 significantly increased antioxidant enzymes and immunoglobulins, and decreased Keap1 and malondialdehyde (MDA) concentrations in the liver tissues after pasture supplementation. The correlation analysis of ALP, LPS, ROS, and Keap1-Nrf2 pathway-dependent antioxidant enzymes with other host markers showed that pasture supplementation induced intestinal barrier function via reducing LPS/ROS-induced intestinal permeability and systemic inflammation in the ileum and liver tissues. Pasture intake might attenuate LPS/ROS-induced gut permeability, systemic inflammation, and metabolic syndrome and augment gut barrier functions, nutrient absorption, immunity, and growth performance, possibly by its Keap1-Nrf2 pathway-dependent antioxidant properties.

Stroke is one of the leading cause of adult disability and the second leading cause of death worldwide. The immune system actively participates in the pathobiological process of AIS, during the index event and during the repair process despite the limited attention drawn to this aspect in the existing stroke guidelines globally. The similar clinical course and similar circulating innate and adaptive immune cell counts in AIS and COVID-19 has created a renewed interest in these easily available biomarkers innate and adaptive immunological changes in AIS with potential diagnostic, prognostic, and therapeutic implications. The current scoping review aimed to assess the significance of circulating neutrophil and lymphocyte counts and their ratio (NLR) in AIS and explore their association with post-stroke recovery trajectory. The Arksey and O'Malley methodological framework was employed to review the published papers on the neutrophil-lymphocyte ratio (NLR) and AIS in late November 2020. Only studies published in English from 2000-2020 were included in this scoping review. Fifty-three published papers were reviewed. This review's key finding is that a canonical inflammatory response occurs in AIS just as in the case of COVID-19 and neurological involvements well described in the recent literature. An excessive circulating innate immune cells (neutrophils) and reduced circulating adaptive immune cells (lymphocytes ) are associated with poorer outcomes during the acute interventions ( reperfusion therapies) as well as the recovery trajectory. Main representatives of innate and adaptive immunity follow a canonical course in AIS and COVID-19. Exaggerated circulating innate ( elevated neutrophils and elevated NLR) and reduced adaptive immune response (lymphopenia) correlate with the worse outcome in AIS and COVID-19. This scoping review's findings make the strongest case for a systems biology-based approach to the standard operating procedures in stroke care urgently.

Purpose of review: This review investigates the oral microbiome's composition, functions, influencing factors, connections to oral and systemic diseases, and personalised oral care strategies. Recent findings: The oral microbiome is a complex ecosystem consisting of bacteria, fungi, archaea, and viruses that contribute to oral health. Various factors, such as diet, smoking, alcohol consumption, lifestyle choices, and medical conditions, can affect the balance of the oral microbiome and lead to dysbiosis, which can result in oral health issues like dental caries, gingivitis, periodontitis, oral candidiasis, and halitosis. Importantly, our review explores novel associations between the oral microbiome and systemic diseases including gastrointestinal, cardiovascular, endocrinal, neurological conditions, autoimmune diseases, and cancer. We comprehensively review the efficacy of interventions like dental probiotics, xylitol, oral rinses, fluoride, essential oils, oil pulling, and peptides in promoting oral health by modulating the oral microbiome. Summary: This review emphasizes the critical functions of the oral microbiota in dental and overall health, providing insights into the effects of microbial imbalances on various diseases. It underlines the significant connection between the oral microbiota and general health. Furthermore, it explores the advantages of probiotics and other dental care ingredients in promoting oral health and addressing common oral issues, offering a comprehensive strategy for personalized oral care.

Background and Objectives: Thyroid disease has been associated with autoimmune disorders. As systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations spanning across all organ systems, the relationship of SLE with thyroid disorders needs investigation. In particular, the relationship of SLE with autoimmune thyroid disease has attracted the interest of the research community. The aim was to evaluate the relationship of SLE with autoimmune thyroid disease. Materials and Methods: A cohort of 45 consecutive patients, mean age 47,97 years (range 21-79 years) and 45 age and sex-matched controls were prospectively studied over a period of 12 months for the presence of thyroid disease and the prevalence of antithyroid antibodies. Results: Four patients (8.9%) were found to suffer from primary hypothyroidism, 5 (11.11%) from subclinical hypothyroidism and 1 (2.22%) from hyperthyroidism, whereas 1 (2.22%) of the controls had primary hypothyroidism and 1 (2.22%) had hyperthyroidism. Five patients (11.11%) had a thyroid hormone profile compatible with the presence of euthyroid sick syndrome. Thyroid peroxidase (TPOab) and thyroglobulin (Tgab) antibodies were detected in 20/45 and 15/45 of the SLE population and in 7/45 and 5/45 of the controls, respectively (p&lt;0.05, chi square test). Conclusions: In conclusion, the incidence of clinical thyroid disease is greater amongst SLE patients than in a control population and in a significant number of these patients antithyroid antibodies are detectable. Thus, a subset of lupus patients appears to be predisposed to the development of thyroid disease and this should be considered when evaluating patients with SLE.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) and is considered one of the leading causes of mortality. Multiple immunological pathways are involved in the pathogenesis of SLE, which makes it imperative to deepen our knowledge about this disease's immunopathological complexity and explore new therapeutic targets. Since an altered redox state contributes to immune system dysregulation, this document briefly addresses the role of oxidative stress (OS), oxidative DNA damage, antioxidant enzymes, mitochondrial function, and mitophagy in SLE and LN. Although adaptive immunity's participation in the development of autoimmunity is undeniable, increasing data emphasize the importance of innate immunity elements, particularly the Toll-like receptors (TLRs) that recognize nucleic acid ligands, in inflammatory and autoimmune diseases. Here, we discuss the intriguing role of TLR7 and TLR9 in developing SLE and LN. Also included are the essential characteristics of conventional treatments and some other novel and little-explored alternatives that offer options to improve renal function in LN.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curable for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists or/and to downstage patients who are beyond Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine Kinase Inhibitors (TKIs) can be used as a bridging systemic therapy to LT in patients with contraindication to locoregional liver-directed therapies. Immune Checkpoint Inhibitors (ICIs) treatment can be utilized either as a monotherapy or as a combination therapy with Bevacizumab or TKIs prior to LT. Acute rejection post liver transplantation is a concern in the context of ICIs treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Ustekinumab is a fully human IgG1k monoclonal antibody that binds with high affinity and specificity to the p40 subunit of interleukins (IL-) 12 and 23, inhibiting their activity by preventing binding to their receptors. The European extension of the patent (Supplementary Protection Certificate) of ustekinumab expired on July 20, 2024. Biosimilar alternatives to ustekinumab are now an additional option for treating patients. The efficacy data for this drug in moderate-to-severe psoriasis, obtained both from clinical trials and indirect comparisons through meta-analyses, are superior to those of etanercept and adalimumab, and its safety profile is more favorable than that of tumor necrosis factor (TNF) inhibitors. Several ustekinumab biosimilars have already been approved by regulatory agencies: between October 2023 and July 2024, Wezlana® (Amgen ABP 654), Uzpruvo® (Alvotech AVT04) and Pyzchiva® (Samsung/Bioepis SB17) have been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). SteQeyma® (Celltrion Healthcare CT-P43) has been approved by the EMA in August 2024. Several other potential biosimilar candidates are under development, including FYB202 (Formycon), BAT2206 (Bio-Thera), DMB-3115 (Dong-A ST), QX001S (Qyuns Therapeutic), BFI-751 (BioFactura), NeuLara (Neuclone), ONS3040 (Oncobiologics), and BOW090 (Epirus Biopharmaceuticals). In most cases, these monoclonal antibodies are expressed in cell lines (e.g. Chinese Hamster Ovary, CHO) different from those used for the originator (Sp2/0 spleen cell murine myeloma); of note, the cell line of origin is not a requirement for biosimilarity in the totality-of-evidence comparison exercise and may facilitate the production and reduce the immunogenicity of biosimilars originated in CHO cultures. This narrative review will summarize the available data on characteristics of the full comparability exercises and comparative clinical trials of these drugs.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by debilitating symptoms including skin and visceral fibrosis, systemic skin hardening, Raynaud's phenomenon and other vascular dysfunctions, and immune abnormalities. The disease poses a significant medical challenge with no cure currently available. As such, SSc is designated as an intractable disease in Japan, with patients receiving government subsidies for medical expenses. Oxidative stress (OS) is implicated in the pathogenesis of SSc and the antioxidant combination Tweendee X®︎ (TwX) has shown promising results in mitigating OS-related conditions. HOCl-induced SSc-mice are known to exhibit similar skin and visceral fibrosis, vascular disorders, and autoimmunity observed in human. In a study done using these mice, Twx demonstrated a significant reduction in lung and skin fibrosis compared to untreated HOCl-induced SSc mice. TwX also significantly reduced advanced oxidized protein products (AOPP) in serum, Col-1 gene expression and the activation of B cells involved in autoimmunity. SSc is a disease state in which autoimmune abnormalities, fibrosis, and vascular disorders are intertwined, and therefore for a treatment to be effective it needs to address multiple issues. Thus the efficacy of TwX may stem from its strong antioxidant capacity to regulate OS, which cannot be achieved by a single antioxidant on its own. In other studies, targeting other OS-related conditions, TwX was safe and proved to be effective at prevent dementia in humans with mild cognitive impairment and to significantly improve cognitive impairment in Alzheimer's (AD) mouse models. TwX may offer a new approach to antioxidant treatment for SSc, to address multiple abnormalities that are characteristic of the disease.

Non-systemic oral drugs, which do not get absorbed through the gastrointestinal membrane, are an important group of compounds for targeting diseases residing within the gastrointestinal lumen. However, they require a set of design principles not sufficiently covered by traditional druglikeness metrics, such as Lipinski’s Rule of 5. These druglikeness metrics fail to accurately identify true negative outcomes; such is the requirement for novel cheminformatic based approaches for the discovery of non-systemic small molecules. One such example of these newer metrics is the fraction of SP3-hybridised carbon atoms (fSP3) which has shown promising application as an identifier of poor oral-bioavailability. Herein, we discuss the application of fSP3 in the drug discovery process in a number of case studies, including our own work discovering non-systemic fructose scavengers for the treatment of fructose malabsorption.

Systemic sclerosis is an autoimmune disease characterized by organ fibrosis and vasculopathy. Almost all patients suffer from Raynaud’s phenomenon (RP). Currently, several imaging techniques are available; nailfold video capillaroscopy (NVC) is the most widely available, but flow quantification is not possible with NVC. Novel imaging techniques are of interest in this population. We performed a single-center feasibility study using Micro Vascular Imaging (MVI) as a novel imaging technique for flow quantification of small fingertip vessels. We compared a group of 20 healthy controls (HCs) with 20 Systemic Sclerosis (SSc) patients. In HCs, flow measurements assessed with MVI were statistically significantly higher in individual fingers and combined for all fingers (p&lt;0.0001). As a cut-off value to discriminate HCs from SSc, a peak systolic (PS) flow velocity of &lt;6.9 cm/s and an end-diastolic (ED) flow velocity of &lt;2.68 cm/s was determined. Test characteristics for PS flow velocity showed moderate sensitivity (0.69, 95% CI 0.58-0.78) but high specificity (0.88, 95% CI 0.79-0.93). Similar test characteristics for ED flow velocity were obtained. The optimal cut-off point was estimated at &lt;2.68 cm/s, sensitivity was moderate (0.65, 95% CI 0.53-0.75), specificity was 0.80 (95% CI 0.70-0.87). Here, we present the first study on the use of MVI to assess blood flow in the fingertips with high specificity in SSc patients. Future studies need to investigate correlations with the risk for organ complications, such as digital ulcers or pulmonary arterial hypertension.

Both scleroderma and immunoglobulin G4-related disease (IgG4-RD) are systemic fibro-inflammatory diseases characterised by lymphoplasmacytic infiltrates. IgG4-RD and systemic Sclerosis (SSc) may share common pathophysiological mechanisms, but no examples of co-occurrence of the diseases have been found. Autologous haematopoietic stem cell transplantation (AHSCT) is implemented in selected rapidly progressive SSc with high risk of organ failure. However, existing guidelines are based on clinical trials that do not represent the entire patient population and exclude critically ill patients with no therapeutic alternatives. Examples of AHSCT in IgG4-RD are absent. We report the case of AHSCT in a female patient with overlapping progressive diffuse SSc and sinonasal IgG4-RD. Despite immunosuppressive therapy, IgG4-RD developed and clinically manifested shortly before AHSCT. Lacking therapeutic alternatives, after 11 years of SSc therapy, the 44-year-old successfully underwent AHSCT. The 63-month follow-up showed regression of symptoms. Only after surgical treatment (bilateral ethmoidectomy, sphenoidotomy, intranasal buccal antrostomy) the initially progressive clinical course of IgG4-RD remained indolent.

Systemic lupus erythematosus (SLE), the prototype of systemic autoimmune diseases is characterized by extreme heterogeneity with a variable clinical course. Renal involvement may be observed and affects the outcome. Hydroxychloroquine is the cornerstone of lupus treatment. Conventional immunosuppressive therapy includes corticosteroids, methotrexate, azathioprine, cyclosporine and tacrolimus. Cyclophosphamide and mycophenolate mofetil may also be used. However, despite conventional immunosuppressive treatment flares occur and broad immunosuppression is accompanied by multiple side effects. Flare occurrence, target organ involvement, side effects of broad immunosuppression, increased knowledge of the pathogenetic mechanisms involved in SLE pathogenesis as well as the availability of biologic agents has led to the application of biologic agents in SLE management. Biologic agents targeting various pathogenetic paths have been applied. B cell targeting agents have been used successfully. Belimumab, a B cell targeting agent has been approved for the treatment of SLE. Rituximab, an anti-CD20 targeting agent is also used in SLE. Anifrolumab, an interferon I receptor targeting agent has beneficial effects on SLE. In conclusion, biologic treatment is applied in SLE and should be further evaluated with the aim of a good treatment response and a significant improvement in quality of life.