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.

Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be largely explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.

RNA interference (RNAi) has become a widely utilised method to study gene function, yet despite this, many of the mechanisms surrounding RNAi remain elusive. The core RNAi machinery is relatively well understood, however many of the systemic mechanisms, particularly double stranded RNA (dsRNA) transport, are not. Here, we demonstrate that dsRNA binding proteins in the serum contribute to systemic RNAi, and may be the limiting factor in RNAi capacity for species such as spiny lobsters where gene silencing is not functional. Incubating serum from a variety of species across phyla with dsRNA led to a gel mobility shift in species where systemic RNAi has been observed, with this response being absent in species where systemic RNAi has never been observed. Proteomic analysis suggested lipoproteins may be responsible for this phenomenon, and may transport dsRNA to spread the RNAi signal systemically. Following this, we identified the same gel shift in the slipper lobster Thenus australiensis and subsequently silenced the insulin androgenic gland hormone, marking the first time RNAi has been performed in any lobster species. These results pave the way for inducing RNAi in spiny lobsters, and better understanding the mechanisms of systemic RNAi in Crustacea, as well as across phyla.

Cryptocurrencies like Bitcoin rely on a proof-of-work system to validate transactions and prevent attacks or double-spending. A new proof-of-work is introduced which seems to be the first number theoretic proof-of-work unrelated to primes: it is based on a new metric associated to the Collatz algorithm whose natural generalization is algorithmically undecidable: the inflation propensity is defined as the cardinality of new maxima in a developing Collatz orbit. It is numerically verified that the distribution of inflation propensity slowly converges to a geometric distribution of parameter $0.714 \approx \frac{(\pi - 1)}{3}$ as the sample size increases. This pseudo-randomness opens the door to a new class of proofs-of-work based on congruential graphs.

There is a lack of studies on the level of stress and health of families of workers in road transport. This study aimed to evaluate the perceived stress level and Family Effectiveness of family members of road transport workers. A quantitative study was carried out with family members of road transport workers in the southern region of Brazil. For the data collection, a sociodemographic form, the Perceived Stress Scale (PSS), and the Evaluation of Family Effectiveness Strategies were used. The data were analyzed by simple frequency, Spearman correlation coefficient (ρ) (p < 0.05), and descriptive analysis from the perspective of the Systemic Organization. 49 family members of road transport workers were participants. Perceived stress was higher in family members who had more than nine years of schooling, the targets of Control and Growth were higher in the evaluation of Family Effectiveness. The Control target was also higher in families with more than three people. The Coherence dimension had higher levels in families with health problems and whose income was less than $792.00 US dollars per month. In the Individuation dimension, income over $792.00 had better results. The Maintenance dimension of the system was higher in families whose drivers’ activity was as an intercity driver, as well as in the Stability target. In conclusion, the social factors such as schooling, income, diseases, type of worker activity in road transport, and number of people in the family influenced perceived stress and Family Effectiveness, which demonstrates the need to increase the promotion of health care of the families of road transport workers.

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

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: 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.

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

Stroke represents one of the most important causes of morbidity ( eighty million patients with disabling of ongoing effects of stroke at a given time, globally) and mortality (the second leading cause of death) worldwide. Innovative systems biology-based approach is likely to increase the understanding of the underpinning of acute stroke promise to enhance stroke prevention, acute treatment, and neurorehabilitation. Recent growing body of evidence with shared pathobiology with COVID-19 and the critically important role of inflammation in the context of stroke points to far-reaching consequences of acute stroke, just as in the case of COVID-19 ( post-acute event issues as well as long term issues ) . So far, stroke typically defined by late-appearing disease manifestation by the range of stroke subtypes as defined by the WHO or American Stroke Association. This definition neglects the underlying pathobiological mechanisms such as low-grade chronic inflammation and already compromised vascular system. Diseases such as stroke is hardly a simple result of a single problem, but rather a complex cascade of pathobiological processes and interactions in a complex biochemical environment. The evidence of changes in innate immunity and adaptive immunity during the index event of acute stroke and recovery over next 3-12 months can be easily elicited with simple bedside blood tests such as neutrophil-lymphocyte ratio (NLR) with well over 300 published papers including several systematic reviews and meta-analyses confirming this. Global standard operating procedures (SOP) of stroke care dictated by the national and international stroke guidelines at present. It is imperative to explore the evidence of systems biology approach in current stroke guidelines. This is likely to be a key turning point in managing stroke across the continuum (prevention, management of acute event and rehabilitation).

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.

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.

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.

A ~3-kb deletion-type DNA copy-number variation (CNV, esv3587290) located at intron 7 of the VANGL1 gene (1p13.1, MIM*610132) has been proposed as a genetic factor for developing lupus nephritis (LN) in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: cSLE patients with (N=39) or without (N=27) LN, as diagnosed by renal biopsy (N=17), proteinuria (N=33), urinary protein:creatinine ratio >0.2 (N=34), and erythrocyturia and/or granular casts in urinary sediment (N=16). For esv3587290 CNV genotyping, we performed an end-point PCR assay with breakpoint confirmation by Sanger sequencing. We also determined the allelic frequencies of the esv3587290 CNV in 181 deidentified ethnically-matched individuals (reference group). The obtained genotypes were tested for Hardy-Weinberg equilibrium (HWE) by c2 test. Associations between LN and esv3587290 CNV were tested by calculating the Odds Ratio (OR) and using Pearson's c² tests with a 95% confidence interval and P≤0.05. The esv3587290 CNV allele (OR 0.108, 95% CI 0.034-0.33, P=0.00003) and the heterozygous genotype (OR 0.04, 95% CI 0.119-0.9811, P=0.002) showed a significant protective effect against LN development. Finally, we characterized the precise breakpoint of the esv3587290 CNV as NG_016548.1(NM_138959.3):c.1314+1339_1315-897del (https://databases.lovd.nl/shared/variants/0000918418#00025811) in our population. This report supports the notion that a broad genetic heterogeneity underlies the susceptibility for developing LN.

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.

Anti-DNA antibodies are hallmark autoantibodies produced in systemic lupus erythematosus (SLE), but their pathogenetic roll is not fully understood. Accumulating evidence suggests that some anti-DNA antibodies enter different types of live cells and affect the pathophysiology of SLE by stimulating or impairing these cells. Circulating neutrophils in SLE are activated by type I interferon or other stimuli and primed to release neutrophil extracellular traps (NETs) on additional stimulation. Anti-DNA antibodies are also involved in this process and may induce NET release. Thereafter, they bind and protect extracellular DNA in the NETs from digestion by nucleases, resulting in increased NET immunogenicity. This review discusses the pathogenetic role of anti-DNA antibodies in SLE, mainly focusing on recent progress in the two research fields concerning antibody penetration into live cells and NETosis.

(1) Background: This case presents a rare and challenging clinical scenario involving a 50-year-old female patient diagnosed with Inflammatory Carcinoma, a particularly aggressive and rapidly growing form of breast cancer. The disease is characterized by heat, redness, swelling and noticeable changes in the breast's skin texture, resembling the skin of an orange (peau d'orange). This case is important because it contributes to the limited clinical literature on such aggressive forms of breast cancer.; (2) Methods: The multidisciplinary approach was employed. Diagnostic procedures such as imaging tests, biopsy, and histopathological examination were performed to confirm the diagnosis of Inflammatory Carcinoma and assess the extent of the disease. The presence of the HER2 protein on the tumor cells supported the selection of a combination therapy involving systemic chemotherapy and targeted biological therapy.; (3) Results: The patient responded positively to the combination therapy consisting of systemic chemotherapy and targeted biological therapy. The aggressive nature of Inflammatory Carcinoma, characterized by rapid growth and distinct skin changes, was effectively addressed. The presence of the HER2 protein on the tumor cells indicated the potential efficacy of the combination therapy in aggressive forms of breast cancer.; (4) Conclusions: This case highlights the critical importance of a multidisciplinary approach in managing complex cases of breast cancer, especially rare and aggressive subtypes like Inflammatory Carcinoma. The positive response of the patient to the combination therapy involving systemic chemotherapy and targeted biological therapy demonstrates the potential for favorable outcomes in aggressive disease presentations.

The oral cavity is the gateway for microorganisms into your body where they disseminate not only to the directly connected respiratory and digestive tracts, but also to the many remote organs. Oral microbiota, traveling to the end of the intestine and circulating our body through blood vessels, not only affect a gut microbiome profile, but also many systemic diseases. By gathering information accumulated from the era of focal infection theory to the age of revolution in microbiome research, we propose a pivotal role of “leaky gum”, as an analogy of “leaky gut”, to underscore the importance of the oral cavity in systemic health. The oral cavity has unique structures, the gingival sulcus (GS) and the junctional epithelium (JE) below the GS, which are rarely found anywhere else in our body. The JE is attached to the tooth enamel and cementum by hemidesmosome (HD), which is structurally weaker than desmosome and is thus vulnerable to microbial infiltration. In the GS, microbial biofilms can build up for life, unlike the biofilms on the skin and intestinal mucosa that fall off by natural process. Thus, we emphasize that the GS and the JE are the weakest leaky point for microbes to invade human body, making the leaky gum just as important as, or even more important than, the leaky gut.

The nature of the sustainability crisis is characterized by high levels of complexity, thus it is not amenable to be approached from the linearity or reductionist paradigm. Emergence is a multilevel phenomenon that is characterized by qualitative novelty and is recognized as an important attribute of complex systems produced by self-organized processes, unveiled from a holistic stance. This conceptual-analytical article explores the emergence phenomenon and questions whether it can be a way of enhancing the solution process to meet the sustainability challenges. Emergent properties or behaviors emerge only when the system parts interact in a wider whole. Moreover, a systemic approach is proposed as an intermediary component in the process of emergence of creative and wise solutions to the wicked problems of unsustainability. This requires observation and entails analyzing open systems as a whole and recognizing the impact of traversing macro- and micro- scales on causal and creative emergence. The study also emphasizes synergies between emergence and creativity aimed at sustainability. Sustainable development requires leapfrogging past conventional practices, in an accelerated way, and the emergence phenomenon at play between systems levels, coupled with purposefully structured creative processes, holds the potential for catalyzing sustainable development efforts.

Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Sequons within κ light chains are predominantly observed in framework region 3. Sequons within λ light chains are mainly located in complementarity determining region 3, at residues near the interfaces with light or heavy chain partners in homodimeric free light chains or antibodies, respectively. We suggest that N-glycosylation of λ light chains may lead to decreased stability of protein complexes, thus promoting unfolding that can lead to aggregation. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Overall, there is no clear structural rationale for why N-glycosylation of κ light chains is associated with amyloidosis. Better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk.

Candida spp. is rarely found in the etiology of neonatal early-onset sepsis (EOS). However, candidemia is associated with increased mortality and morbidity, as in late-onset sepsis. Congenital candidiasis may present as mucocutaneous infection or, more rarely, as a systemic infection in term and preterm infants. Material and methods: Case reports of two cases of congenital systemic candidiasis (CSC) produced by Candida albicans and a review of the data in the literature. Results: Both neonates were male, born vaginally, with risk factors for congenital candidiasis. One of the infants was born at term and presented with an almost generalized maculopapular rash at birth; C. albicans grew in the blood culture sampled at 36 hours; parenteral fluconazole was started immediately, and no complications were noted. The other infant was born preterm, at 28 weeks of gestation, and presented signs of respiratory distress on the 4th day of life after initial successful treatment of the respiratory distress syndrome with surfactant and non-invasive respiratory support. C. albicans was present in the neonatal blood and gastric aspirate cultures, and in the maternal vaginal cultures (all sampled at birth); parenteral fluconazole therapy was administered for 30 days as investigations revealed both liver and renal involvement and the infant development bronchopulmonary dysplasia. Conclusion: As data in the literature suggests, despite occurring at any gestational age, CSC may present various clinical pictures, the rash may mimic many other neonatal conditions, and the systemic dissemination cannot be distinguished from bacterial EOS. Careful anamnesis and a high index of suspicion are important for the prompt recognition and treatment of CSC, optimizing the short- and long-term outcomes.

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

B and T lymphocytes demonstrate important alterations in patients with Systemic Lupus Erythematous (SLE), with significant up-regulation of Double Negative (DN) B cells. Aim of this study was to evaluate correlation of T cell immunity changes with the distinct B cell-pattern SLE. In the present study, Flow cytometry was performed in 30 patients with SLE, on remission, and 31 healthy controls, to detect DN B cells (CD19+IgD-CD27-) and a wide range of T lymphocyte subpopulations, based on the presence of CD45RA, CCR7, CD31, CD28, CD57, defined as naive, memory and advanced differentiated/senescent T cells. Both B and T lymphocytes were significantly reduced in SLE patients. However, the percentage of DN B cells were increased, compared to HC, 12.9(2.3-74.2) vs. 8(1.7-35), p=0.04. Distribution of CD4 and CD8 lymphocytes demonstrated a shift to advanced differentiated subsets. The population of DN B cells had significant positive correlation with most of early differentiated T lymphocytes, CD4CD31+, CD4CD45RA+CD28+, CD4CD45RA+CD57-, CD4CD45RA-CD57-, CD4CD28+CD57-, CD4CD28+CD57+, CD4 CM, CD8 CD31+, CD8 NAÏVE, CD8CD45RA-CD57-, CD8CD28+CD57-, CD8CD28+CD57+. Multiple Regression analysis revealed CD4CD31+, CD8CD45RA-CD57- and CD8CD28+CD57- cells as independent parameters contributing to DN B cells, adjusted R2=0.534, p<0.0001. The predominance of DN B cells in patients with SLE is closely associated with early differentiated T lymphocyte subsets, indicating a potential causality role of DN B cells in T lymphocyte activation.

Systemic lupus erythematosus (SLE) myocarditis is presumed to be rare but associated with ad-verse outcomes. If SLE diagnosis has not previously been established, its clinical presentation is often unspecific and difficult to recognize. Furthermore, there is a lack of data in the scientific literature regarding myocarditis and its treatment in systemic immune-mediated diseases, leading to its late recognition and undertreatment. We present the case of a young woman whose first lupus manifestations included acute perimyocarditis, among other symptoms and signs that provided clues to the diagnosis of SLE. Transthoracic and speckle tracking echocardiography were helpful in detecting early abnormalities in myocardial wall thickness and contractility while waiting for cardiac magnetic resonance (CMR). Since the patient presented with acute decompensated heart failure (HF), HF treatment was promptly started in parallel with immunosuppressive therapy, with a good response. In the treatment of myocarditis with heart failure, we were guided by the echocardiographic findings, biomarkers for myocardial injury N-terminal pro b-type natriuretic peptide (NT-proBNP) and hs-troponin I, biomarkers for systemic inflammation erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and biomarkers for SLE disease activity (Complement C)3, C4, and anti-dsDNA levels.

In this study, we wanted to discuss the acute coronary syndromes in the pregnant womens which are very important for life ofthe fetus. Spontaneous coronary artery dissection and management, which is the most common cause of acute coronary syndrome in pregnant women is also discussed. About 300 articles were examined and 35 articles which published in high quality journals with high level of evidence were chosen and this review was prepared.

Background: The present work aimed to estimate the economic impact of PTSD following COVID-19 in a population of patients affected by systemic autoimmune disease (SAD) using a cost-of-illness approach and accounting for the perspective of society. Methods: Considering data collected from SAD patients enrolled in a specialized outpatient clinic in the Tuscany region, Italy, generalized-linear-models and LASSO logistic regression were used to evaluate the impact of PTSD on costs and its relevance as possible predictors of being a high-cost patient, respectively. Results: Considering 301 SAD patients, 161 (51.2%) of whom diagnosed with PTSD, the overall costs were 3,670 [890;40,529] Euro per patient/year among patients with PTSD and 2,736.7 [283;21,078] Euro per patient/year among those without PTSD (P-value<0.001), with differences mainly attributable to significantly greater direct non-healthcare and indirect costs. PTSD was estimated to increase overall costs (β=0.296 (0.140), P-value=0.035), direct non-healthcare (β =1.193 (0.392), P-value =0.002) and indirect costs (β =3.741 (1.136), P-value =0.001). PTSD diagnosis was also significantly associated with the likelihood of being a high-cost patient. Conclusions: Findings from the present study offer a novel perspective on the economic impact of COVID-19 and provide valuable data for policymakers to better understand demand for healthcare services and associated costs.

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.

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.

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.

Background: The aim of this study has been to investigate if inflammatory biomarkers such as the systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have any correlation with the recurrence of pleomorphic adenomas (PA) in patients afflicted by this disease. Methods: A retrospective multicentre study involving two Italian centres, the Maxillofacial Sur-gery at the Policlinico Federico II in Naples and the ENT and Maxillofacial Surgery at the IRCCS G. Pascale National Cancer Institute in Naples, has been performed. The study, involving 608 pa-tients who had received a diagnosis of PA, was conducted between January 2000 and January 2020. A Receiver Operating Characteristic (ROC) curve was used to calculate the optimal cut-off values for the SII, PLR and NLR. A linear regression model (LRM) and a non-linear logistic re-gression model (NLRM) were realized with respect to the NLR, PLR and SII. Results: The highest performance was achieved by the NLR (cut-off 2.960) with the AUC = 0.91, with an accuracy of 96.1%, sensitivity of 78.4% and specificity of 97.2%, PPV = 64.4% and NPV = 98.6%. The LRM and NLRM including all the haematological parameters did not increase the per-formance in terms of recurrence detection. Conclusion: The NLR is an excellent support tool in predicting the recurrence of PA with a cut-off of 2.960. It can be a good reference point for surgical decision-making and follow-up in clinical practice.

Background. Minimally invasive surgery via right mini-thoracotomy has become the standard of care for the treatment of mitral valve disease worldwide, particularly at high volume centers. In recent years, the spectrum of indications has progressively shifted and extended to fragile and higher risk patients, also addressing more complex mitral valve disease and ultimately including patients with native or prosthetic infective endocarditis. The rationale for the adoption of the minimally invasive approach is to minimize the surgical trauma, promote an earlier postoperative recovery and reduce the incidence of surgical wound infection and other nosocomial infections. The aim of this retrospective observational study is to evaluate the effectiveness and the early and late outcome in patients undergoing minimally invasive surgery for mitral valve infective endocarditis. Methods. Prospectically collected data regarding minimally invasive surgery in patients with mitral valve infective endocarditis were entered into a dedicated database for the period between January 2007 and December 2022 and retrospectively analyzed. All comers during the study period underwent a preoperative evaluation based upon clinical history and anatomy for the allocation to the most appropriate surgical strategy. Selection for the mini-thoracotomy approach was primarily driven by a thorough transthoracic and especially transesophageal echocardiographic evaluation, coupled with total body and vascular imaging. Results. During the study period, 92 patients underwent right mini-thoracotomy to treat native (80/92, 87%) or prosthetic (12/92, 13%) mitral valve endocarditis at our institution, representing 5% of the patients undergoing minimally invasive mitral surgery. Twenty-six (28%) patients had undergone previous cardiac operations, whereas 18 (20%) presented preoperatively with complications related to endocarditis, most commonly systemic embolization. Sixty-nine and 23 patients, respectively, underwent early surgery (75%) or were operated on after the completion of targeted antibiotic treatment (25%). A conservative procedure was feasible in 16/80 (20%) patients with native valve endocarditis. Conversion to standard sternotomy was necessary in a single case (1.1%). No cases of intraoperative iatrogenic aortic dissection were reported. Four patients died perioperatively, accounting for a thirty-day mortality of 4.4%. Causes of death were refractory heart or multiorgan failure and/or septic shock. New onset stroke was observed postoperatively in one case (1.1%). Overall actuarial survival rate at 1 and 5 years after operation was 90.8% and 80.4%, whereas freedom from mitral valve reoperation at 1 and 5 years was 96.3% and 93.2%, respectively. Conclusions. The present study shows good early and long-term results in higher-risk patients undergoing minimally invasive surgery for mitral valve infective endocarditis. Total body, vascular and echocardiographic screening represent the key points to select the optimal approach and allow the extension of indications for minimally invasive surgery to sicker patients, including active endocarditis and sepsis.

Background: Systemic-to pulmonary collaterals (SPC) are common in congenital heart disease (CHD). Particularly in single ventricle anatomy and Fontan circulation, SPC can both complicate the postoperative course and lead to clinical deterioration in the long term. Treatment of SPC is controversial. The aim of our study was (1) to analyze retrospectively patients who underwent SPC embolization using Concerto™ Helix nylon-fibred microcoils (CHM) and (2) to describe the interventional technique. Methods: In this a single-center retrospective observational cohort study, we analyzed clinical and imaging data of all patients who underwent transcatheter embolization of SPC using CHM from January 2016 to December 2023. Results: In 38 consecutive patients (65.8 % male, median age 41 months, range 2 – 490), a total number of 141 CHM had been implanted into 64 SPC in 49 procedures. The majority were arterial SPC (n = 59/64) originating from the thoracic aorta or its branches; 5/64 were veno-venous SPC. Primary closure succeeded in all procedures. The CHM diameters ranged from 3 to 8 mm, with 5 mm being the most commonly used diameter. The mean coil / SPC ratio was 2.6 (range 1.3 – 5.3). CHM implantation was performed via 4 French sheaths. Both detachment and stable positioning was simple and safe. Neither non-target embolization nor coil migration occurred. One complication occurred with a minor vascular injury without clinical relevance. Conclusion: CHM are easy to use and appropriate for SPC embolization in all age groups, including infants, with a low complication rate. The coils are particularly suitable for closure of collaterals with small diameter or tortuous course.

Aim: To evaluate the clinical findings of glucose 6 phosphate dehydrogenase(G6PD) and pyruvate kinase(PK) deficiency in prolonged jaundice. To determine whether systemic-immune-inflammation index(SII), neutrophil-to-lymphocyte ratio(NLR) and platelet-to-lymphocyte ratio (PLR) can be used in the diagnosis of neonatal prolonged jaundice. Methods: In full term neonates with hyperbilirubinemia who were admitted to Medicine Hospital between January 2019 and January 2024 with the complaint of jaundice, 167 infants with a serum bilirubin level above 10 mg/dL, whose jaundice persisted after the 10th day, were included in the study. Results: G6PD was negatively correlated with NLR, SII, age, and Hct. There was a negatively poor correlation between G6PD and NLR and a negatively moderate correlation between G6PD and SII when adjusted for age and Hct. PK showed no significant correlation with G6PD, NLR, PLR, SII, age, and Hct. A linear relationship was observed between G6PD and SII and NLR. Conclusions: NLR and SII can be easily calculated in the evaluation of prolonged jaundice in G6PD deficiency has a considerable advantage. NLR and SII levels may contribute by preventing further tests for prolonged jaundice and regulating its treatment. It may be useful to form an opinion in emergencies and in the early period.

This study comprehensively explores Serbia's Disaster (Risk) Management System, aiming to critically evaluate its inherent strengths and weaknesses. Using descriptive-analytical methods and qualitative interpretation, SWOT analysis was applied to collect data from scientific papers, books, and institutional reports. This study delves deeply into the nuances of Serbia's Disaster Management Framework, revealing a nuanced landscape of strengths, weaknesses, and strategic improvement opportunities. Identified strengths underscore a robust foundation characterized by proficient professionals, state-of-the-art technology, and cohesive teamwork, all pivotal for effective emergency preparedness and response. Conversely, weaknesses underscore pressing imperatives for enhancements in regulatory enforcement, resource allocation, and infrastructure upgrades, presently hampering the framework's efficacy and response readiness. This research contributes to the ongoing discourse on disaster risk management and serves as a catalyst for further scholarly inquiry and policy formulation. By mapping out the structure of Serbia’s Disaster (Risk) Management Framework and integrating diverse data sources, the study enriches theoretical models and lays the groundwork for practical policy interventions. Its findings, including precise recommendations for policy reform and strategic improvements, provide valuable insights for policymakers, emergency management experts, and stakeholders seeking to enhance disaster preparedness and response capabilities on both national and global scales.

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.

Washing hands, social distancing and staying at home are the preventive measures set in place to contain the spread of the COVID-19, a disease caused by SARS-CoV-2. These measures, although straightforward to follow, highlight the tip of an imbalanced socio-economic and socio-technological iceberg. Here, a System Dynamic (SD) model of COVID-19 preventive measures and their correlation with the 17 Sustainable Development Goals (SDGs) is presented. The result demonstrates a better informed view of the COVID-19 vulnerability landscape. This novel qualitative approach refreshes debates on the future of SDGS amid the crisis and provides a powerful mental representation for decision makers to find leverage points that aid in preventing long-term disruptive impacts of this health crisis on people, planet and economy. There is a need for further tailor-made and real-time qualitative and quantitative scientific research to calibrate the criticality of meeting the SDGS targets in different countries according to ongoing lessons learned from this health crisis.

We examine the global legal entity identifier (LEI) system for the identification of participants in financial markets. Semi-structured interviews with data professionals reveal the many ways in which the LEI can improve both business process efficiency and counterparty and credit risk management. Larger social benefits, including monitoring of systemic financial risk, are achievable if it becomes the accepted universal standard for legal entity identification. Our interviews also review the substantial co-ordination and investment barriers to LEI adoption. To address these, a clear regulatory-led road map is needed for its future development with widespread application in regulatory reporting.

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.

Climate changes challenges people’s life and sustainability. Environmental problems seem to derive from human behavior. Dentistry has a high environmental footprint that needs to be controlled worldwide. Thus, the change of behavior of dentists is a necessary condition to improve the environmental situation. In this study we use a system dynamics approach to analyze pro-environmental behavior in dentists. Systemic modelling in this case, allow us to make a clear prediction of how the population of non-eco dentists will change in the future if certain factors will be affected and how much time will be needed by the system of a group of dental professionals to become eco- dentists. The ECODENT model was designed with Vensim software. It was based on the influence of WOM (word of mouth) spread of information among colleagues and stakeholders (e.g. patients, auxiliary staff and community) and other factors such as dental income, state support, CaPex and OpEx, education hours, level of urbanization and time to react. By changing each one of them we can observe the changes in the groups of non-eco and eco dentists as well as the flow of the phenomenon. It is tested that by augmenting WOM parameter, state economic support or education hours, while diminishing CaPex and OpEx, changes in pro-environmental behaviors of dentist will be reported in a shorter time. The ECODENT model can be used to further study pro-environmentalism in different dental groups and associations and design relevant eco-friendly educational programs.

The immunization of healthcare workers in the early stages of the rollout of COVID-19 vaccines was prioritized in order to ensure uninterrupted medical care provision. At the same time the increasing number of available COVID-19 vaccines may trigger hesitancy towards the decision to get vaccinated. Thus, accumulating reliable information on the adverse events following immunization may educate and urge the general population to receive a COVID-19 vaccine. The present study aimed to evaluate the adverse events (AEs) following immunization with any of the available COVID-19 vaccine among Bulgarian healthcare workers (HCWs). A cross-sectional study among HCWs in Plovdiv, Bulgaria was conducted in the period March – September 2021. Through a semi-structured online questionnaire, the participants reported the adverse events following the administration of the first and second dose of a COVID-19 vaccine. A total of 253 respondents, vaccinated with one of the available vaccines against COVID-19 took part in the study. Of them 71.9% were females, and 75.9% received mRNA-based vaccines, while 24.1% received a viral-vector based vaccine. Overall 91.6% and 82.6% of all participants reported at least one local AE after the first and second dose of a COVID-19 vaccine. The share of respondents reporting at least one systemic AE after the first and second dose of a COVID-19 vaccine was 59.7% and 62.4% respectively. The most common local AE was pain at the injection spot (84.0%), while the most common systemic AEs were fatigue (54.9%), chills (43.2%), and headache (41.7%). The mRNA-based vaccines versions seem to cause higher prevalence of local AEs, while the vector-based vaccines were linked with increased prevalence of systemic AEs. Female HCWs and the younger age group were associated with an increased risk of adverse events generally. Our results added more evidence that mRNA-based and viral-vector based vaccines are generally safe. The reported adverse events were mild, although they occurred in a high share of the respondents. No serious AEs attributable to the vaccines were reported.

Maternal intake of the polyunsaturated fatty acids omega-3 (n-3 PUFA) and omega-6 (n-6 PUFA) impacts hippocampal neurogenesis during development, an effect that may extend to adulthood by altering adult hippocampal neurogenesis (AHN). n-3 PUFA and n-6 PUFA are precursors of inflammatory regulators that potentially affect AHN and glia. Additionally, n-3 PUFA dietary supplementation may present a sexually dimorphic action in the brain. Therefore, we postulated that dietary n-6/n-3 PUFA balance shapes the adult DG in a sex-dependent manner influencing AHN and glia. We test our hypothesis by feeding adult female and male mice with n-3 PUFA balanced or deficient diets. To analyze the immunomodulatory potential of the diets, we injected mice with the bacterial endotoxin lipopolysaccharide (LPS). LPS reduced neuroblast number, and its effect was exacerbated by the n-3 PUFA deficient diet. The n-3 PUFA deficient diet reduced the DG volume, AHN, microglia number and surveilled volume. Diet effect on most mature neuroblasts was exclusively significant in female mice. Colocalization and multivariate analysis revealed an association between microglia and AHN, and the sexual dimorphic effect of diet. Our study reveals that female mice are more susceptible than males to the effect of dietary n-6/n-3 PUFA ratio on AHN and microglia.

Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Although many small molecules have been proposed as inhibitors of amyloid formation, few have been successful in clinical trials. Amyloid formation is complex and several individual steps could be targeted by small molecules. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light chain dimers, the precursor proteins for AL amyloidosis are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidogenesis.

This paper proposes a novel concept within Quantum Natural Language Processing (QNLP) to encode the interpersonal metafunction of Systemic Functional Linguistics (SFL), particularly tenor, into quantum circuits by treating Japanese honorifics seriously. Because of English language bias in the literature, the incorporation of nuanced aspects of interpersonal communication evident in languages, such as the aforesaid Japanese, remains under-developed and overlooked. Utilizing lambeq, monoidal categories, and string diagrams, this study extends lambeq’s quantum computing framework to capture not only grammar but also social context—specifically the roles and relationships that define interpersonal interactions in quantum circuits. This approach represents a significant step toward that end simply by defining the honorific type h in lambeq. This innovative strategy exposes the capability of quantum circuits to model the complex structures of language, moving beyond grammar and even semantics—the horizontal, textual dimension of language—to embrace the vertical, hierarchical dimension of human communication and social interaction. Through this lens, the paper underscores the potential of QNLP to transcend traditional linguistic analysis, advocating for a broader and more nuanced understanding of language that includes not only what is said but also the social persona of the interlocutors. An algorithm for parsing Japanese grammar into pregroup diagrams containing the h type is introduced along with a codebase for other researchers to use and to which to contribute. Lastly, a toy experiment is performed to demonstrate that the circuits generated from these pregroup diagrams are suitable for Quantum Machine Learning (QML) applications.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on development of oral therapies with improved efficacy and safety compared to available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways, such as AhR, PDE-4 and Jak-STAT. Topical tapinarof, an AhR modulator, and roflumilast, a PDE-4 inhibitor, have exhibited favorable efficacy and safety outcomes have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis and specially on those that are currently under evaluation and development for the treatment of psoriasis.

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.

Nutrition support is increasingly recognized as a clinically relevant aspect of the intensive care treatment of cardiac surgery patients. However, evidence from adequate large-scale studies evaluating its clinical significance for patients’ mid- to long-term outcome remains sparse. Considering nutrition support as a key component in the perioperative treatment of these critically ill patients, led us to review and discuss our understanding of the metabolic response to the inflammatory burst induced by cardiac surgery. In addition, we discuss how to identify patients who may benefit from nutrition therapy, when to start nutritional interventions, present evidence about the use of enteral and parenteral nutrition and the potential role of pharmaconutrition in cardiac surgery patients. Although the clinical setting of cardiac surgery provides advantages due to its scheduled insult and predictable inflammatory response, researchers and clinicians face lack of evidence and several limitations in the clinical routine, which are critically considered and discussed in this paper.

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.

Vitamin D plays an important role in maintaining healthy mineralized skeleton. It is also consid-ered an immunomodulatory agent that regulate the innate and adaptive immune systems. Multi-ple observational studies have demonstrated the association between low level of serum 25-hydroxyvitamin D [25(OH)D] and presence and severity of several rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthropathies and oste-oarthritis (OA). Nevertheless, the specific benefits of vitamin D supplement for treatment and prevention of rheumatic diseases are less accepted as the results from randomized clinical trials are inconsistent, although some conceivable benefits of vitamin D for improvement of disease ac-tivity of RA, SLE and OA have been demonstrated in meta-analyses. It is also possible that some individuals might benefit from vitamin D differently from others since inter-individual difference in responsiveness to vitamin D supplementation has been observed in genomic studies. Although the optimal level of serum 25(OH)D is still debatable, it is advisable it is advisable that patients with rheumatic diseases should maintain serum 25(OH)D level at least 30 ng/mL (75 nmol/L) to prevent osteomalacia, secondary osteoporosis and fracture, and possibly 40 – 60 ng/mL (100 – 150 nmol/L) to achieve maximal benefit from vitamin D for immune health and overall health.

The aim was to study alterations of bacterial communities in patients undergoing hip or knee arthroplasty to assess the impact of chlorhexidine gluconate soap decolonisation and systemic antibiotic prophylaxis. A Swedish multicentre, prospective collection of samples obtained from elective arthroplasty patients (n=83) by swabbing anterior nares, skin sites in the groin and the site of planned surgery, before and after arthroplasty surgery, was analysed by 16S rRNA (V3-V4) gene sequencing and a complementary targeted tuf gene sequencing approach to comprehensively characterise alterations in staphylococcal communities. Significant reductions in alpha diversity was detected for both bacterial (p=0.04) and staphylococcal (p=0.03) groin communities after arthroplasty surgery with significant reductions in relative Corynebacterium (p=0.001) abundance and S. hominis (p=0.01) relative staphylococcal abundance. In nares, significant reductions occurred for S. hominis (p=0.02), S. haemolyticus (p=0.02), and S. pasteuri (p=0.003) relative to other staphylococci. S. aureus colonised 35% of anterior nares before and 26% after arthroplasty surgery. S. epidermidis was the most abundant staphylococcal species at all sampling sites. No bacterial genus or staphylococcal species increased significantly after arthroplasty surgery. Application of a targeted tuf gene sequencing approach provided auxiliary staphylococcal community profiles and allowed species-level characterisation directly from low biomass clinical samples.

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 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.

Objective: The current study aimed to delineate the relationship of furin with inflammation while cervical intraepithelial neoplasia progresses to cancer. Study Design:This cross-sectional study included 81 women who required colposcopic examinations. The study groups were formed based on pathological results: Group I included women with cervical intraepithelial neoplasia (CIN) I (n=30); Group II included women with CIN II-III (n=28); and Group III included women with cervical cancer (CC) (n=23). Furin, ki-67, and p16 levels were evaluated based on immunostaining intensity. The inflammatory indices were calculated parallel with the literature from routine blood samples retrieved within one week before the procedure. Results:Furin expression gradually increased from CIN I to CIN II-III and from CIN II-III to CC, respectively (p < .001, p = .005). The NLR, MLR, PLR, and SII were significantly higher in the CC group (p < .001). ROC curve analysis unveiled that NLR, MLR, PLR and SII predicted the presence of CC with a cutoff value of 2.39 for NLR (sensitivity: 91.3%, specificity: 63.8%, AUROC: 0.79, p < .001); a cutoff value of 0.27 for MLR (sensitivity: 78.3%, specificity: 72.4%, AUROC: 0.77, p = .009); a cutoff value of 123 for PLR (sensitivity: 100%, specificity: 41.4%, AUROC: 0.70, p = .04); and a cutoff value of 747 for SII (sensitivity: 69.6%, specificity: 90.7%, AUROC: 0.71, p = .014). Conclusion:Furin expression increased gradually in parallel to the severity of cervical intraepithelial neoplasia. The inflammatory indices were higher in the presence of CC and denoted good discrimination ability for predicting cervical cancer.

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.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing in-creased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play im-portant roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB de-pendence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter en-dothelial function or the contractile response to phenylephrine in these arteries. In contrast, CIH exposure increased the systemic arterial pressure, and enhanced the contractile response to phenylephrine while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta, without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. Neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. This systematic review provides an overview on the value of NfL in early detection of neuropathy, central nervous system involvement, monitoring of neuropathy progression, and treatment effect in systemic amyloidosis. A literature search in PubMed, Embase and Web of Science was performed on 14-02-2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene variant (TTRv) carriers. Only studies containing original data were included. Included were twelve full-text articles and six abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has potential to be used for early detection of neuropathy, monitoring treatment effect, and monitoring disease progression in patients with systemic amyloidosis.

Irrational belief is a product of complex personality traits and Machiavellianism Intelligence. The present study is conducted to trace the significance of predictive nature of personality characteristics and Machiavellianism Intelligence (Mach Intelligence) on irrational beliefs among chronically ill older people. The research method is cross-sectional with correlational design, purposive sampling with a total of 200 chronically ill older people aged between 40–60 years with disease type such as Systemic lupus erythematosus, Complicated Diabetes, Glomerulonephritis and Chronic Heart Failure. The analysis revealed that personality characteristics and irrational belief subscales such as worrying, rigidity, problem avoidance and Mach Intelligence are significantly positively correlated; however, Emotional irresponsibility has significant negative correlation with personality characteristics and Mach Intelligence. Gender differences revealed that males are high on all the subscales of personality characteristics, irrational beliefs (except emotional irresponsibility) and Mach Intelligence as com-pared to female chronically ill older people. Predictive analysis also revealed that overall personality characteristics explained a total of 67% variance in irrational beliefs. Moreover, Mach Intelligence predicts irrational beliefs. Future health related recommendations should be planned accordingly.

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.

People from Black and Asian backgrounds are more likely to die from Covid-19 but less likely to be vaccinated, threatening to exacerbate health inequalities already experienced by ethnic minority groups. Literature suggests that mistrust rooted in structural inequality may be a key barrier to Covid-19 vaccine uptake. We need to better understand how structural inequalities influence vaccine confidence. Understanding and addressing these processes is likely to lead to longer-term impacts than information alone. We draw on health and sociological theories of structure and agency to inform our understanding of structural factors. We conducted qualitative interviews and focus groups with 22 people from London and surrounding areas in December 2021 to March 2022. Fifteen participants were members of the public from ethnic minority backgrounds and 7 were professionals working with the public to address concerns and encourage vaccine uptake. Our findings suggest that people from ethnic minority backgrounds make decisions regarding Covid-19 vaccination based on a combination of how they experience external social structures (including political authority, social positioning and racial inequality) and internal processes (what they believe and understand about Covid-19 vaccines). We may be able to support knowledge accumulation through the provision of reliable and accessible information, particularly through primary and community care. But we recommend a number of changes to research, policy and practice which address structural inequalities. These include working with communities to improve ethnicity data collection, increasing funding allocation to health conditions where ethnic minority communities experience poorer outcomes, greater transparency and public engagement in the vaccine development process, and culturally adapted research recruitment processes.

The Indian educational system grapples with deep-rooted structural and systemic challenges that have hindered equitable access to quality education across all levels. Central issues include outdated curricula that fail to equip students with contemporary skills, significant socio-economic disparities limiting access and outcomes, and inadequate teacher training alongside deficient infrastructure, particularly in rural and economically disadvantaged areas. These challenges contribute to unequal educational opportunities and outcomes, with a stark divide between urban and rural, and between private and public institutions. This review delves into these pervasive issues, analyzing how they manifest from primary through tertiary education. In primary education, the focus often remains on rote learning, overlooking critical thinking and problem-solving skills. At the secondary and tertiary levels, curriculum relevance remains a concern, as courses frequently do not align with modern industry demands or technological advancements, creating a skills gap among graduates. Addressing these challenges, this review proposes a series of reforms aimed at building a more inclusive and effective system. Key reforms include curriculum modernization to incorporate skills for the 21st century, integrating digital learning tools to expand access and facilitate adaptive learning, and comprehensive teacher development programs that emphasize continuous professional growth. Together, these initiatives aim to create an educational environment that is not only inclusive but also adaptive to the evolving demands of a globalized world, thereby enhancing the quality and reach of education across India.

One of the main problems for managing global crises is to clarify and reduces drivers of systemic weaknesses to face complex emergencies. This study here analyzes the relation between public debt, healthcare expenditures and fatality rates in the presence of pandemic crises, such as COVID-19. Statistical evidence, based on a sample of European countries, here shows that high public debt over time reduces health expenditures and increases the vulnerability of countries to face emergencies, such as COVID-19 pandemic crisis. Regression analysis with a log-log model suggests that when European countries experience a 1% increase in healthcare expenditure per capita, in general they have a 1.2% reduction in the COVID-19 fatality rate. Main implications of this study to reduce the systemic risk and vulnerability to environmental threats are that countries must reduce public debt with good governance and institutions without reducing the allocation of economic resources to the healthcare sector in order to improve the preparedness to unforeseen emergencies and crises, such as pandemics, natural disasters, conflicts, and other environmental threats.

In an age of unprecedented global complexity, interconnectedness, and urgency, the inadequacy of traditional, reductionist models of knowledge production has become glaringly apparent. This pioneering, landmark article offers a sweeping, paradigm-shifting exploration of the revolutionary emergence of "Mode 4" knowledge production - a fundamental reconceptualization of the epistemological, organizational, and methodological foundations of the research enterprise. Drawing on cutting-edge theoretical frameworks and a vast corpus of rigorous empirical evidence, this work argues that Mode 4 represents a transformative leap towards a more collaborative, transdisciplinary, and adaptive approach to knowledge creation - one that holds the potential to catalyze a profound and lasting transformation in the way we conceive of, organize, and mobilize research to address the complex, interconnected challenges facing our world. At the heart of this paradigm shift lies the groundbreaking "decuple helix" framework, which expands the scope of stakeholder engagement and knowledge co-creation to incorporate a comprehensive range of actors, from academia and industry to marginalized communities, the natural environment, and international organizations. This article delves deeply into the multifaceted roles and invaluable contributions of this diverse array of stakeholders, demonstrating how their active integration can unlock the transformative power of collaborative, values-oriented research and innovation. Furthermore, the paper provides a comprehensive example of how Mode 4 knowledge production concepts could be implemented using cutting edge innovationology research. By drawing on a rich tapestry of theoretical foundations, including complexity theory, quantum physics, humanities, social sciences, spirituality, and the arts, innovationology exemplifies the transdisciplinary ethos at the core of this paradigm shift. The article delves deeply into the collaborative co-creation, iterative and adaptive methodologies, and holistic, values-driven vision that define this groundbreaking transdisciplinary science. However, this work also candidly explores the significant institutional, methodological, equity-related, and scalability challenges that continue to hinder the widespread adoption and implementation of the Mode 4 and decuple helix frameworks. In doing so, it charts a course forward, outlining a comprehensive set of practical implications and recommendations to address these barriers and unlock the transformative potential of these emerging paradigms. Ultimately, this article offers a sweeping, cohesive, and visionary analysis of the revolutionary emergence of Mode 4 knowledge production and the decuple helix framework - positioning itself as a landmark contribution that has the potential to catalyze a profound transformation in the way we conceive of, organize, and mobilize research for a sustainable and equitable future. With its groundbreaking insights, bold vision, and rigorous interdisciplinary foundation, this work stands as a clarion call for a new era of collaborative, transdisciplinary knowledge production that can truly address the complex, interconnected crises facing our world.

The Estimation of systemic risk in India is still in its infancy stage. There are several methods which are available but none of the methods are fully compatible to forecast the systemic risk since under different circumstances the factors responsible for the risk differs. In this paper the systemic risk estimation in India being carried out based on spread in daily stock market price(Difference between the bid and ask price of a share) of the top 100 firms in India according to market capitalization for the period of July2007 to March 2016. The results were compared with the Financial Stability Report published by Reserve Bank Of India for the period of March 2010 to June 2016.The results clearly indicates that there exits relationship between market illiquidity represented by spread and risks associated with the Financial System. In most of the cases the Z score (deviation from the mean/Standard Deviation) of the spread has become negative which provides the spread which is farther from the mean, also a good indicator of volatility in market and risk to financial system. It is also seen that the Systemic Risk Survey conducted by Reserve Bank of India which started during October 2011 has supported the results.

The use of chimeric antigen receptors (CAR-T cells) for the treatment of patients with malignant haematological diseases has become a well-established application, for conditions such as refractory or relapsed B cell acute lymphoblastic leukaemia (B-ALL), B cell lymphomas (BCL), and multiple myeloma (MM). Nearly 35,000 patients have received autologous CAR-T cells for the treatment of these conditions only in the USA. Since their approval by the Food and Drug Administration (FDA) in 2017, over 1200 clinical trials have been initiated globally and there are at least 10 different CAR-T cells with approval by different regulatory agencies around the globe. In the USA the Food and Drug Administration (FDA) has approved 6 commercial CAR-T cells that are widely distributed worldwide. At the time of this writing, several clinical trials have been performed in patients with solid tumours such as glioblastoma, renal and pancreatic cancer, as well as in patients with autoimmune conditions such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SS). There are also several studies showing the potential benefit of CAR-T cells for other non-malignant diseases such as asthma and even fungal infections. In this review, without pretending to cover all the current areas of treatments with CAR-T cells, we offer a brief summary of some of the most relevant aspects of the use of CAR-T cells for some of these conditions.