The aim of this study was to determine the potential of early inflammatory markers to diagnose late-onset neonatal sepsis - procalcitonin (PCT), interleukin 6 (IL-6), interleukin 8 (IL-8) and endocan (ESM-1), and to compare them with routinely used markers. A prospective (January, 2022 – January, 2023) clinical-epidemiological study was conducted in a third level NICU in Pleven, Bulgaria. Patients with suspected nosocomial infection and healthy controls were tested. A sandwich ELISA method was used to measure the serum concentrations. Sixty newborns with an average gestational age of 29.75 ± 3.61 gestational weeks were included, of which 35 % were symptomatic and infected, 33.3 % were symptomatic but uninfected, and 31.7 % were asymptomatic controls. The mean values of PCT, IL-6, I:T index and PLT differ significantly in the three groups. For ESM-1, IL-8 and CRP, the difference was statistically insignificant. The best sensitivity (78%) and negative predictive value (84%) was found for IL-6. The combination of PCT + IL-6 + I:T+ PLT demonstrated high precision (78%) and best sensitivity (94%) and negative predictive value (95%). The introduction into routine practice of indicators such as PCT and IL-6 may provide an opportunity to promptly optimize the diagnostic and therapeutic approach to LOS.

Diagnosis of neonatal sepsis is difficult as signs and symptoms are nonspecific. Interleukin-6 (IL-6) is a promising marker for neonatal sepsis. We aimed to test the accuracy of IL-6 in term and preterm infants after 72 hours of life (late-onset sepsis-LOS). We searched for IL-6 diagnostic accuracy studies between 1990 and 2020 using the PubMed database. Study selection was performed. The range of reported IL-6 sensitivities and specificities was 68% to 100% and 28% to 100%, respectively, the median values were 85.7% and 82% from 15 studies including 1306 infants. Subgroup analysis was performed. Sensitivity (87% vs 82%), but not specificity (both 86%), was better in preterm infants than in preterm and term infants. Early sample collection had the highest sensitivity (84%), but the lowest specificity (86%). To assess quality we used a STARD checklist adapted for septic neonates. Limitation of this review include the heterogeneous group of studies on the one side and the small number of studies on the other side that analyzed different combinations of biomarker. We concluded that IL-6 had a good performance especially in the preterm infant population and best results are achieved by measurements at the time of LOS suspicion.

In dermatological practice, disturbances of the skin microbiome are found in various infectious and inflammatory dermatoses featuring one or more skin lesions with loss of tissue, directly exposing skin layers to microbial invasions. Literature data on the incidence of cutaneous-onset sepsis are, however, scarce. This retrospective observational study assessed hospital admissions for primary skin lesions with vs. without bacterial infections and sepsis during 2020-2022 in the largest emergency hospital in NE Romania. Of 509 patients 441 had infected lesions, 78 had sepsis caused by venous ulcers microbial eczema cellulitis, superinfected bullous dermatoses, erysipelas, erythroderma. Cultured samples revealed S. aureus, P. aeruginosa, E. coli, with K. pneumoniae, S. β-hemolytic associated with sepsis even if rarer. Clinical manifestations included ulcerations, erosions, fissures, excoriations, bullae, vesicles, pruritus, tumefaction, edema, fever, chills, pain, adenopathy, mildly altered mental status. Underlying chronic heart failure, atrial fibrillation, anemia, type-1 diabetes mellitus were comorbidities associated with infection and sepsis. Significant associations and risk factors, including their combined effects, are discussed to draw attention to the need for further research and adequate management to prevent sepsis in adult patients of any age presenting with infected skin lesions (especially cellulitis) and comorbidities (especially type 1 diabetes mellitus and anemia).

Sepsis is a life-threatening condition with high hospital mortality. Elevated mortality has also been observed in patients after hospital discharge due to post-sepsis syndrome (PSS). The etiology of PSS is still not entirely known, but it involves inflammation. Plasma extracellular vesicles (EVs) are recognized as a unique mechanism of intercellular communication in inflammatory processes. It has been reported that EV microRNA (miRNA) production during the acute sepsis phase may persist until after disease resolution and is associated with PSS. We employed mass spectrometry and qPCR analysis to determine the protein and miRNA composition of plasma-derived EVs of 36 patients during sepsis-related hospitalization, immediately after ICU discharge (post-sepsis), and three, six, twelve, and up to 36 months post-sepsis. We determined that patients’ immune system cells were the primary EV source. Fifteen differentially expressed EV miRNAs (DEmiRs) were identified in samples from septic patients compared to the control group. Predictive analyses revealed that these DEmiRs could influence inflammation by modulating pathways mediated by NF-κB, STAT3, and TLR4 signaling activation. Thirteen miRNAs (-15b-5p,-16-5p,-20a-5p,-25-3p,-27a-3p,-29a-3p,-30d-5p,-93-5p,-146a-5p,-148a-3p,-191-5p,-195-5p,-223-3p) were downregulated in the death group compared to the survivor group, making them candidate prognostic markers of ICU survival. One year after ICU discharge, the expression of miR-21-5p and miR-195-5p were decreased in the survivor group. The miRNAs identified in the present study represent potential biomarkers for the survival prognosis of post-sepsis patients.

Early onset neonatal sepsis is a significant contributor to neonatal morbidity and mortality. Although blood cultures remain the diagnostic gold standard, they detect pathogens in only a minority of suspected cases. This study compared the accuracy of blood cultures with a rapid multiplex PCR test. Newborns at risk for neonatal sepsis were prospectively screened as recommended per national guidelines. Evaluations included laboratory parameters (CrP, IL6, differential blood count), blood culture, and a molecular multiplex PCR test (ROCHE LightCycler SeptiFast) identifying 20 common microbial agents. Blood samples were taken simultaneously from umbilical cord or venous sources on the first day of life. Of 229 infants included, 69% were born preterm. Blood culture and multiplex PCR sensitivity were 7.4% and 11.1% respectively. Specificity, negative and positive predictive values between methods showed no significant variance, though multiplex PCR had more false positives due to contamination. The limited sensitivity of blood cultures for early onset neonatal sepsis is concerning. Despite quicker results, multiplex PCR does not enhance diagnostic accuracy or antibiotic therapy guidance, thus it can not be recommended for this indication.

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Anderson – Fabry disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to progressive accumulation of glycosphingolipids and structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who in most cases are heterozygous with delayed and variable clinical presentation caused by uneven X – chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke or unexplained cardiomyopathy. Here we describe a unique case of homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly including alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease has led to discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (N2015S) known to cause predominant cardiac involvement with late onset of the disease. The variant is amenable for an oral therapy by the small molecular chaperone migalastat which was started, then interrupted for recurrence of patient´s migraine and then re-initiated again after two years. During this period the patient received enzyme replacement therapy by agalsidase beta but developed a progressively worsening venous access. Our case illustrates the importance of systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom routine diagnostic process fails to discover Fabry disease, in particular variants with late onset cardiac manifestations. Many of the late onset variants are amenable for orally active therapy by migalastat which significantly improves the comfort of the treatment. Its long term results are analysed by a large international “Follow-me” registry which was designed to verify the validity of pivotal trials with migalastat in Fabry disease.

Late-onset Alzheimer’s disease (LOAD) is a dementia category disease that starts after the age of 65. Progressive problems in thinking, behaviour, learning etc. are its characteristics. Due to its progressive nature, early diagnosis is crucial. A complex pathway mechanism with different risk factors is involved in LOAD progression. A comprehensive study is done on factors causing LOAD, biomarkers used for diagnosis in clinical and preclinical stage of the disease, ML (Machine Learning) techniques to identify disease stage. We reviewed research papers on clinical and preclinical diagnosis of LOAD using ML techniques from biomarker data: MRI, PET image, MMSE, Genome / Gene expression, DNA / RNA binding sites with protein, Epigenetic expression /DNA, methylation, Speech and text. We have listed improvement scope after finding the gaps and scope of using Generative AI and SMOTE (Synthetic Minority Oversampling Technique) for data augmentation. At the end, we have elaborated current use of DL (Deep Learning) and CNN (‘Convolution Neural Network’) in Alzheimer’s disease (AD) diagnosis.

Background: Meniere disease (MD) is an inner ear disorder associated with comorbidities such as autoimmune diseases or migraine. This study describes clinical and cytokine profile in MD according to the age of onset of the condition. Methods: A cross-sectional study including 83 MD patients: 44 with early onset MD (EOMD, <35 years old), and 39 with late onset MD (LOMD, > 50 years old), 64 patients with migraine and 55 controls was carried out. Clinical variables and cytokines levels of CCL3, CCL4, CCL18, CCL22, CXCL1 and IL-1β were compared among the different groups. Results: CCL18 levels were higher in patients with migraine or MD than in controls. Elevated levels of IL-1β were observed in 11.4% EOMD and in 10.3% LOMD patients and these levels were not dependent on the age of individuals. EOMD had a longer duration of the disease (p=0.004) and a higher prevalence of migraine than LOMD (p=0.045). Conclusions: Patients with EOMD have a higher prevalence of migraine than LOMD, but migraine is not associated with any cytokine profile in patients with MD. The levels of CCL18, CCL3 and CXCL4 were different between patients with MD or migraine and controls.

Over the last decade, advances in our understanding about the genetic architecture of complex traits and common diseases, have increased our ability to perform susceptibility genetic testing for diseases in asymptomatic individuals. These technological developments raise complex ethical, legal and social considerations. Here we discuss a series of ethical issues associated with susceptibility genetic testing for Alzheimer's and Parkinson's disease. These include, amongst others, informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. As knowledge of the genetic basis of these diseases continues growing, and as genetic testing becomes more widespread, we anticipate that it will become increasingly important for scientists and clinicians to engage in the conversation about the ethical, social and policy implications of these technologies.

Carbon Quantum Dots (CQDs) have emerged as promising nanomaterials for enhancing the performance of supercapacitors, offering unique advantages such as high surface area, excellent electrical conductivity, and tunable surface chemistry. This review provides a comprehensive overview of recent advancements in the synthesis, characterization, and integration of CQDs into supercapacitor devices. Various synthesis methods, including chemical oxidation, hydrothermal/solvothermal methods, microwave-assisted synthesis, and pyrolysis, are discussed, highlighting their impact on the structural and electrochemical properties of CQDs. Characterization techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, and photoluminescence (PL) spectroscopy are elucidated for assessing the morphology, crystallinity, and optical properties of CQDs. The integration of CQDs into supercapacitors, including their utilization in composite electrodes, binder-free electrodes, and doping strategies, is explored to enhance specific capacitance, energy density, power density, and cycle stability of the devices. Challenges and future perspectives in the field are outlined, emphasizing the need for scalable synthesis methods, enhanced electrochemical performance, and sustainable device engineering to realize the full potential of CQD-based supercapacitors for various energy storage applications. This review aims to provide insights into the current state of research and guide future endeavors towards developing high-performance and environmentally sustainable energy storage technologies.

Coronavirus disease-19 (COVID-19) has disproportionately affected certain demographics in England, exacerbating existing health disparities. Effective therapeutics are a critical line of defence against COVID-19, particularly for patients at elevated risk for severe disease. Surveillance systems were established to monitor usage of COVID-19 therapeutics in hospital and community settings and inform stewardship. Three antiviral therapies: nirmatrelvir plus ritonavir (Paxlovid®), remdesivir (Veklury®), and molnupiravir (Lagevrio®); and two neutralising monoclonal antibody therapies (nMAbs): sotrovimab (Xevudy®) and casirivimab with imdevimab (Ronapreve®); were in use in England between July 2020 to April 2023. This paper aims to illuminate trends in the utilisation of COVID-19 therapeutics treatment in both hospital and community settings, stratified by the Index of Multiple Deprivation (IMD) in England. Chapter 3 of the English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR) report 2022 to 2023 also discusses the epidemiological surveillance of these five directly-acting antiviral COVID-19 therapeutics use in England between 2022 to 2023.

Late onset Pompe disease is a recessive lysosomal storage disease. Clinical features include skeletal muscles deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patents with chronic respiratory failure. M mode ultrasound and tissue Doppler imaging can be used to assess and to follow up diaphragm function.

Solar energy has emerged as a promising alternative to traditional fossil fuels due to its abundant availability and sustainability. Solar cells, the fundamental units of solar energy conversion, have undergone significant advancements in fabrication techniques to enhance their efficiency, durability, and cost-effectiveness. This review aims to provide a comprehensive overview of various methods employed in the preparation of solar cells, including thin-film, crystalline silicon, organic, and perovskite-based technologies. By analyzing recent research developments, challenges, and future prospects, this article sheds light on the evolving landscape of solar cell fabrication, contributing to the ongoing efforts in achieving widespread adoption of solar energy.

This comprehensive review explores the multifaceted landscape of supercapacitors, highlighting their pivotal role in meeting the global demand for efficient energy storage solutions. Supercapacitors, with their high power density, rapid charge-discharge cycles, and extended cycle life, offer a compelling alternative to conventional batteries and capacitors. The review delves into the fundamental mechanisms of energy storage in supercapacitors, categorizing them into Electrochemical Double-Layer Capacitors (EDLCs), pseudocapacitors, and hybrid capacitors. It discusses significant advancements in supercapacitor technology, including nanostructured materials, flexible and wearable supercapacitors, solid-state supercapacitors, and hybrid supercapacitors, highlighting their potential applications across industries such as transportation, renewable energy, consumer electronics, and industrial power management. Through continued research and development, supercapacitors are poised to play a pivotal role in driving the transition towards a greener and more efficient future.

The escalating global demand for clean water has propelled research into sustainable and cost-effective purification methods. Activated carbon (AC) derived from biowaste materials presents an environmentally friendly and economically viable solution for water treatment. This review article provides an extensive overview of the synthesis techniques, characterization methods, and applications of biowaste activated carbon (BAC) for water purification. It discusses the diverse sources of biowaste, such as agricultural residues, food waste, and biomass, and explores various activation methods including physical, chemical, and biological processes. Furthermore, the article examines the adsorption mechanisms, performance factors, regeneration strategies, and emerging trends in BAC synthesis and application. Insights from this review can guide future research endeavors and facilitate the development of sustainable water purification technologies.

The timely and accurate detection of HIV infection is pivotal in stemming the tide of this global pandemic and facilitating early treatment initiation. This review offers a comprehensive examination of the diverse array of methods employed for HIV detection, spanning traditional serological assays to cutting-edge technologies such as nucleic acid amplification, biosensor innovations, and artificial intelligence-driven diagnostics. Each method is scrutinized in terms of its principles, applications, strengths, and limitations. By integrating these complementary approaches and fostering collaboration across disciplines, researchers and clinicians gain a multifaceted understanding of HIV infection, enabling them to navigate the complexities of the virus with precision and insight. Through a multidisciplinary lens, encompassing immunology, molecular biology, engineering, and public health, this review aims to inform future directions in HIV detection, ultimately guiding efforts towards personalized, precise, and accessible diagnostics for all individuals affected by the HIV/AIDS epidemic.

Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are considered markers of premature cellular senescence. This is believed to contribute to age-related diseases, including Alzheimer's disease (AD) and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, which were all from Calabria, a region from south Italy. Following regression analysis, telomeres were found to be significantly shorter in LOAD cases than in controls (p<0.001 for both sporadic and familial cases). Interestingly, LTL were associated to disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the patho-genesis of LOAD.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

Medicinal plants have been a cornerstone of traditional medicine systems for centuries, offering a vast array of bioactive compounds with therapeutic potential. However, the identification, characterization, and elucidation of the pharmacological properties of these plants have often been challenging due to their complex chemical composition and diverse biological activities. Bioinformatics, with its interdisciplinary approach combining biology, computer science, and information technology, presents a powerful toolkit for the systematic study of medicinal plants. This review provides an overview of bioinformatics methodologies and resources that can facilitate the identification, phytochemical analysis, pharmacological investigation, and conservation of medicinal plants. It highlights the integration of omics technologies, computational algorithms, database resources, and molecular modeling techniques in advancing our understanding of medicinal plants' therapeutic potential and their applications in drug discovery and development.

DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-L-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the trans-sulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia – a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B₁₂ (methylcobalamin), vitamin B₉ (folic acid), vitamin B₆ (pyridoxine), and SAM to patients in early stages of LOAD.

The microvessel neurovascular unit with its brain endothelial cell (BEC) and blood-brain barrier remodeling is important in the development of impaired cognition in sporadic or late-onset Alzheimer’s disease (LOAD) and vascular dementia or vascular cognitive impairment and dementia including cerebral amyloid angiopathy in neurodegeneration. LOAD is considered to be the number one cause of dementia globally; however, when one considers the role of mixed dementia (MD) (the combination of both the amyloid cascade hypothesis and the vascular hypothesis of LOAD), it becomes apparent that MD is the number one cause. The microvessel BECs are the first cells in the brain to be exposed to the peripheral neurotoxins of the systemic circulation and are therefore the brain cells at the highest risk for early and chronic injury. Therefore, it is not surprising that microvessel BECs are the first cells to undergo injury and the response to injury wound healing mechanism and remodeling that is excessive and recurrent in the aging process plus other age-related diseases such as cerebro-cardiovascular disease, hypertension, type 2 diabetes mellitus, Parkinson’s disease, plus others. This narrative review explores the intricate relationship between microvessel remodeling, cerebral small vessel disease (SVD), and neurodegeneration as occurs in LOAD. Further, it discusses the current understanding of how microvessel dysfunction, disruption, and pathology contribute to the pathogenesis of LOAD and thus, highlights potential avenues for therapeutic interventions.

Blood cancers, including leukemia, lymphoma, and myeloma, pose significant diagnostic challenges due to their diverse and complex nature. Detecting these cancers early and accurately is crucial for timely intervention and improved patient outcomes. This review explores current and emerging detection methods for human blood cancers, focusing on their principles, advantages, limitations, and potential clinical applications.

Graphene quantum dots (GQDs) have garnered significant attention in recent years due to their unique properties and promising applications in various fields such as electronics, optoelectronics, bioimaging, and sensing. The synthesis of GQDs is a critical step in harnessing their potential, and numerous methods have been developed to produce GQDs with specific properties. This review provides an overview of the different techniques employed for synthesizing GQDs, including top-down and bottom-up approaches. Furthermore, it discusses the advantages, limitations, and potential applications of each method, offering insights into the future direction of GQD synthesis research.

Sepsis is a serious disease that can lead to mortality. The etiology of the disease is connected to how the body as a host reacts toward microbes such as bacteria, viruses, and fungi invasion. Current research shows that during sepsis, the reaction toward microbe attacks takes two main phases. The first is known as a cytokine storm, while the second is a vicious cycle of pro-inflammatory responses followed by a strict anti-inflammatory response led by CD4+ Tregs. Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials did not show promising results, indicating further research into the mechanism that Treg uses to inhibit proinflammatory reactions. We used next-generation sequencing (NGS) analysis of bulk RNA-seq and single-cell RNA-seq data to examine the exact molecular pathways used by Treg to inhibit the immune response in sepsis. Our approach identified ACOD1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells. We identified and validated CD36 as a downstream target of ACOD1. CD36 is a known metabolite regulator in Tregs. Taken together, our results indicate that targeting ACOD1 could prove valuable in regulating Treg function during sepsis.

A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn's disease attended Regional Hospital of Presidente Prudente and HC-FMUSP, São Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to failure of other treatments (phototherapy, oral acitretin) for psoriasis and Psoriasis Area Severity Index &lt;10. We evaluated the impact of ustekinumab, a potent immunosuppressor, on the risk of infectious diseases in this patient followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, culture of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation, absence of pathogenic variants in the genes analyzed and no clinically significant variants were detected in the whole exome. The main infections included chronic sinusitis, tonsillitis, fungal and bacterial otitis, gastroenteritis, and community-acquired pneumonia. The patient was infected with COVID-19, dengue (twice), and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence susceptibility to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn's disease in a patient with LOCID.

Abstract: Background: Neonatal sepsis continues to be one of the leading causes of mortality and morbidity, particularly in under development and underdeveloped countries. We aim to compare laboratory parameters between the early-onset sepsis (EOS) and non-EOS groups and to evaluate the association between TLR2- Arg753Gln, TLR4 -Asp299Gly, IL6-174G/C and IL10-1082G/A gene single nucleotide polymorphisms and EOS susceptibility in preterm newborns. Methods: Genotyping of the TLR2, TLR4, IL6 and IL10 polymorphisms was performed in 36 preterm neonates by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP). Logistic regression analysis was used to test the associations between the studied gene polymorphisms and EOS susceptibility. Results: Statistically significant differences in gestational age and birth weight were observed between the two groups, preterm neonates with EOS having a lower mean of gestational age (weeks, 29.4 ± 2.8 versus 32.6 ± 1.1, p = 0.00002) and lower mean of birth weight (gr., 1342.1 ± 446.5 vs. 1984 ± 376.9) than preterm neonates without EOS. C-reactive protein (CRP) values measured at first day significantly increased in EOS group compared with non-EOS group (median, 95% CI: 0.80 [0.40, 1.15] versus 0.30 [0.02, 0.50]). Mean of neutrophils significantly decreased in the EOS preterm neonates (mean difference: 17.3%, 95% CI: [4.0%, 30.5%], p = 0.0126) and non-EOS group (mean difference: 20.8%, 95% CI: [1.8%, 39.9%, p = 0.0354) between the first day and 7th hospitalization day. The minor IL10-A1082 allele frequency was higher in the EOS group than in the nonEOS group (50% versus 25%) with a marginal statistical significance (p=0.0550). In the dominant model, the A/G + A/A variant genotype of IL10- 1082G/A polymorphism significantly increased the odds of EOS compared with GG genotype (OR= 5.25, p = 0.0322). Conclusions: The results of the current study suggests the IL10- 1082G/A gene polymorphism as significant risk factor for early onset sepsis development in preterm neonates.

.Bacground: Sepsis remains a major health challenge worldwide, characterized by a dysre-gulated host response to infection, leading to high mortality and morbidity in intensive care units (ICUs). The Fibrosis 4 (FIB-4) index, originally developed to assess liver fibrosis in hepatitis C patients, has recently been explored for its potential prognostic value in sepsis patients. Method: This study retrospectively analyzed 309 sepsis patients admitted to the Internal Me-dicine and Anaesthesia ICUs between December 12, 2021, and December 15, 2023, to inves-tigate the relationship between FIB-4 levels, Acute Physiology and Chronic Health Evaluation (APACHE), and Sequential Organ Failure Assessment (SOFA) and clinical outcomes. Results: The study found that higher FIB-4 measurements were statistically significantly asso-ciated with increased 28-day mortality, with a cut-off value of 4.9 providing a sensitivity of 54.92% and specificity of 74.25%. Logistic regression analysis indicated that elevated Conclusion:FIB-4 levels were a significant predictor of early mortality, suggesting that the FIB-4 index could serve as a valuable prognostic tool in assessing the severity and prognosis of sepsis patients.

Objectives: To develop a multivariate model for risk factors specific to early onset preeclampsia (EOP) and late onset preeclampsia (LOP) in our entire population (singleton and twin pregnancies). Material and methods: 20 year-observational population-based historical cohort study (2001-2020). All consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion’s maternity. A standardized validated epidemiological perinatal data base. Results: During the 20-year period, there were 81,834 pregnancies and 83,555 infants born, 1232 dichorionic and 350 monochorionic twin pregnancies. There were 2120 cases of preeclampsia, of which 2001preeclamptic singleton pregnancies and 119 twin pregnancies (incidence 7.5% in twin pregnancies vs 2.5% singletons, OR 3.0, p<0.001). Independent risk factors for EOP and LOP in a multivariate model (controlling for the two major confounders: namely maternal ages -both risks for EOP and LOP- and maternal pre-pregnancy BMI – specific risk factor for LOP) were: history of preeclampsia (aOR 11.7 for EOP, 7.8 for LOP, p < 0.0001), chronic hypertension (aOR 7.3 for EOP, 3.9 for LOP, p < 0.0001), history of perinatal death (aOR 2.2 for EOP, p < 0.0001 and 1.48 for LOP, p= 0.007), primipaternity (aOR 3.0 for EOP and 3.6 for LOP, p = 0.001), dizygotic twin pregnancies (aOR 3.7 for EOP, p < 0.0001 and 2.1 for LOP, p = 0.003), monozygotic twin pregnancies (aOR 3.98 for EOP, p = 0.003 and NS for LOP), ovulation induction (aOR 5.6 for EOP, p = 0.004 and NS for LOP), and in vitro fertilization (aOR 2.8 for EOP, p = 0.05 and NS for LOP). Specific to LOP and NS for EOP: renal diseases (aOR for LOP 2.9, p= 0.007) and gestational diabetes mellitus (aOR 1.2, p= 0.04). Conclusions: Maternal ages over 35 years, chronic hypertension , history of preeclampsia, ovulation induction, in vitro fertilizations, history of perinatal deaths and twin pregnancy (in our experience, especially mono zygotic twin pregnancies) are significant risk factors for EOP. New paternity is an independent factor for both EOP and LOP.

The melanoma differentiation-associated protein 5 (MDA5; encoded by the IFIH1 gene) mediates the activation of the interferon pathway in response to viral infection. This protein is also upregulated in autoimmune diseases and psoriasis skin lesions. IFIH1 gene variants that increased the MDA5 activity have been associated with increased risk for immune mediated diseases, including psoriasis. Our aim was to determine the association between three IFIH1 variants (rs35337543, intron8 +1G>C; rs35744605, Glu627Stop; and rs1990760, Ala946Thr) and the main clinical findings in a cohort of Spanish patients with psoriatic disease (N=572; 77% early-onset). Early-onset psoriasis (EOPs) had a significant higher frequency of severe disease and Cw6+. Carriers of the 946Thr variant were more common in EOPs (p<0.001), and the effect was more pronounced among Cw6-negatives. This variant was also associated with an increased risk of psoriatic arthritis (PsA) independently of other factors (OR=1.62, 95%CI=1.11-2.37). The rs3533754 and rs35744605 have been reported as risk factors for viral infection and protective for autoimmune diseases, but we did not find significant differences between the two onset age or PsA groups. However, due to the reduced frequency of the two variants (<0.02) the size of our cohort was too low to conclude a significant effect. In conclusion, the common IFIH1 rs1990760 T allele that has been linked to increased gene expression was significantly more frequent in EOPs patients. This variant was also an independent risk factor for PsA in our cohort. This risk allele was in linkage disequilibrium with other variants previously associated with the risk of psoriasis and PsA. Our study reinforces the widely reported role of IFIH1 gene variants on psoriatic disease and other immune mediated diseases.

HIV early detection (CD4 counts ≥350 cells/μL) is correlated with higher life expectancy among people living with HIV (PLHIV). Several factors including physical, cultural, structural, and financial barriers have contributed to HIV late detection. This is the first-of-its-kind study on the regional differences in early detection of HIV within Tajikistan and any country in the Central Asia region. Utilizing Tajikistan Ministry of Health's national HIV data (N=10,700) spanning 2010 to 2023, we developed median regression models with median CD4 cell count as the outcome and as predictors: time (years), region, age, gender, and area (urban/rural status). Individuals younger than 19 years old are more likely to be detected early for HIV, whereas those older than 39 years are more prone to late detection. Given their active engagement in age-related and sexual activities, those older than 39 years face a higher risk of HIV transmission to others if diagnosed late. Therefore, they require further attention and targeted interventions. Females are detected earlier compared to their male counterparts, regardless of region of residence. Rural populations are detected earlier in most years compared to their urban counterparts. The COVID-19 pandemic accelerated HIV early detection in 2021 but most regions have returned to near pre-pandemic levels of detection in 2022 and 2023. These fluctuations in early detection may signify a shift in attention and resource allocation, potentially affecting efforts to address access gaps during the initial year of the COVID-19 pandemic. There are significant health inequities among different demographic and geographic groups which warrant further attention.

We presented unusual case of double left ventricular false aneurysm complicating late presentation AMI successfully treated with the combination of urgent surgical drainage of tamponade, staged PCI of non-culprit lesion, preventive implantation of ICD-DR, guideline directed heart failure medical therapy and delayed but effective reconstructive operation.

This research review explores the synthesis of graphene quantum dots (GQDs) from biowaste for supercapacitor applications, driven by the need for sustainable and efficient energy storage technologies. GQDs, with their unique properties like high surface area and excellent conductivity, hold promise for enhancing supercapacitor performance. Various synthesis methods, including hydrothermal/solvothermal processes, chemical exfoliation, carbonization/pyrolysis, and microwave-assisted synthesis, are discussed alongside characterization techniques to evaluate GQD properties. Biowaste-derived GQDs demonstrate significant potential by improving specific capacitance and cycling stability in supercapacitor electrodes. Challenges such as scalability and material purity are identified, with future directions focusing on enhancing energy density, cycle life, and cost-effectiveness to propel the adoption of biowaste-derived GQDs in commercial energy storage applications.

Graphene, a single layer of carbon atoms arranged in a two-dimensional honeycomb lattice, has attracted tremendous attention due to its exceptional properties and diverse applications. Synthesis methods play a crucial role in tailoring graphene's properties for specific applications. This review provides a comprehensive overview of recent advances in graphene synthesis techniques, including chemical vapor deposition (CVD), exfoliation, epitaxial growth, and chemical reduction. We discuss the principles, advantages, challenges, and applications associated with each method. Furthermore, emerging trends and future prospects in graphene synthesis are explored, with a focus on scalability, cost-effectiveness, and environmental sustainability.

Pediatric onset multiple sclerosis (POMS), characterized by the onset of multiple sclerosis before the age of 18, is gaining increased recognition. Approximately 5 percent of MS cases manifest before the age of 18, with less than 1 percent occurring before the age of 10. Despite its rarity, pediatric MS exhibits distinct characteristics, with an association between younger age at onset and a comparatively slower disease progression. Despite this slower progression, individuals with POMS historically reach disability milestones at earlier ages than those with adult-onset multiple sclerosis. While various immunomodulatory agents demonstrate significant benefits in MS treatment, such as reduced relapse rates and slower accumulation of brain lesions on magnetic resonance imaging (MRI), the majority of disease-modifying therapies (DMTs) commonly used in adult MS lack evaluation through pediatric clinical trials. Current evidence is predominantly derived from observational studies. This comprehensive review aims to consolidate existing knowledge on the mechanisms of action, efficacy, safety profiles, and recommended dosages of available DMTs specifically in the context of pediatric MS. Furthermore, the review outlines recent advancements and explores potential medications still in developmental stages, providing a thorough overview of the current landscape and future prospects for treating POMS.

Sepsis is a major health problem and accounts for 20 per cent of deaths worldwide. It is the most expensive condition treated in United States hospitals at $27 billion per year or about $20,000 per patient. Treatment consisting largely of fluid resuscitation and antibiotics has only marginal impact. Mortality is about 27 per cent for hospitalized patients and about 42 per cent for patients in intensive care.There are two phases of sepsis – a hyper inflammatory phase and a subsequent hypo inflammatory phase.During the hyper inflammatory phase the metabolic rate increases associated with an increase in body temperature and a rapid escalation of immune system functioning including increased numbers of leucocytes and migration of those leucocytes to infected and damaged tissues and an increased supply and consumption of glucose to fuel this immune system.During the subsequent hypo inflammatory phase the metabolic rate declines and this is associated with a decrease in body temperature and a generalized decrease in the physiological activity of many organs including the immune system akin to hibernation. The activated immune system has priority for the available glucose over most other organs and physiological functions during such potentially life threatening circumstances. Thus adenosine triphosphate (ATP) production by mitochondria (the source of energy at the cellular level for the organism as a whole) also has a lower priority for the available glucose relative to the activated immune system. If glucose availability is threatened then mitochondrial production of ATP is partially or substantially suppressed in favor of glycolysis because glycolysis can rapidly produce large quantities of ATP that are necessary for immune cell function in infected, anaerobic, ischemic, or damaged tissues.However, glycolysis is only a temporary fix as it cannot produce the quantities of ATP necessary on an ongoing basis for the normal functioning of the healthy animal. Mitochondrial production of ATP must be recommenced for full recovery.It appears that the partial or substantial suppression of mitochondrial production of ATP by activation of the immune response becomes relatively fixated in some patients leading to a substantial ATP deficit. This is the fundamental issue of sepsis.This paper reviews the metabolism of glucose and insulin during sepsis and concludes that high dose insulin with mild hyper glycaemia in conjunction with the intravenous administration of thiamine, an inhibitor of the pyruvate dehydrogenase kinase enzymes, to re-establish physiological ATP production by mitochondria, administered early in the hypo metabolic (hypo inflammatory) phase of sepsis should significantly improve survival.

Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological changes include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of plasma ammonia level at presentation and duration of hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days post natal with plasma ammonia and glutamine of 677 and 4024 micromol/L and had a missense mutation in Exon 4 (p.R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. He suffered recurrent acute hyperammonemic episodes despite compliance, triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI based disease biomarkers.

Sepsis is an inflammatory disorder caused by the host’s dysfunctional response to infection. Septic patients present diverse clinical characteristics, and in the recent years it has been the main cause of death in intensive care units (ICU). Aquaporins, membrane proteins with role in water transportation, have been reported to participate in numerous biological processes. Their role in sepsis progression has been studied extensively. This review aims to examine recent literature on aquaporin expression and regulation in clinical sepsis, as well as established experimental models of sepsis. We will present how sepsis affects aquaporin expression at the molecular and protein level. Moreover, we will delve into the importance of aquaporin regulation at the transcriptional, post-transcriptional, translational, and post-translational level in sepsis, by presenting data on aquaporin regulation by non-coding RNAs and selected chemical molecules. Finally, we will focus on the importance of aquaporin single nucleotide polymorphisms in the setting of sepsis.

The most prevalent musculoskeletal disorder of childhood with unclear aetiology is Growing Pains (GPs). Anatomic deformities and factors that change bone turnover are implicated in GPs pathophysiology. Perinatal risk factors alter the bone metabolism affecting the bone mineral density and content. The aim of our study was to analyze the relationship between GPs, knock knees and perinatal factors. The examined population consisted of 276 children aged 3-7 years. Among them 10 pairs of dizygotic twins were evaluated. The data were collected by using a combination of semi-structured questionnaires, clinical examinations and medical charts of the children and the obstetric history of the mothers. 78 children presented GPs meeting Peterson’s criteria. Genu valgum severity was a significant factor for GPs manifestation and for their increased frequency and intensity. Subsequently, perinatal factors regarding gestational age, Apgar score, head circumference (lower than 33cm) and birth length or weight (smaller than 50 cm and 3000gr, respectively) made a remarkable contribution to the development of GPs. Conversely, antenatal corticosteroid treatment, increased maternal age and maternal smoking during pregnancy were not predictive for the disorder. Our data are potentially supportive for the “bone strength” theory and for the contribution of anatomical disturbances in GPs appearance.

Sepsis still remains one of the most difficult conditions to diagnose as it presents unspecific clinical signs and symptoms, which makes early detection crucial. Our study aimed to enhance the accuracy of sepsis diagnosis by integrating multimodal monitoring technologies with traditional diagnostic methods. The research involved 121 newborns, comprising 39 cases of late-onset sepsis, 35 cases of early-onset sepsis, and 47 control subjects. Biosignals including pulse oximetry (PO), near-infrared spectroscopy (NIRS), and skin temperature (ST) were continuously monitored and an algorithm was developed using Python for identifying early signs of sepsis. The model demonstrated the ability to detect sepsis 6 to 48 hours in advance with an accuracy rate of 87.67% ± 7.42%. Sensitivity and specificity were recorded at 76% and 90%, respectively, with NIRS and ST having the most significant impact on predictive accuracy. Despite the promising results, limitations such as sample size, data variability, and potential biases were noted. The findings highlight the critical role of non-invasive biosensing methods in conjunction with traditional biomarkers and cultures, offering a robust framework for early sepsis detection and improved neonatal care. Further studies are recommended to validate these results across diverse clinical settings.

This article introduces a new interpretation to Socialism that approaches it via a heuristic study of Epochs. It is intended by this study that the intention of socialism (what it politically, socially, et cetera is proclaimed to be) is to be proposed to be indeterminate.The expectation of what Socialism is to be as a future entity is merely an interpretation that is predicated on Marx’s Capitalist Laws that have been since shown to be false. Its argument is suggested significantly by Engels’ discussions of human development and therein places an added focus on a historically based platform.

Due to the host immunological disease brought on by infection is sepsis, multiple organ dysfunction syndrome (MODS), which has a high morbidity and mortality rate, could be the result. With advances in pathogen detection technologies, breakthroughs in anti-infection drugs, and the creation of organ function support, the clinical diagnosis and treatment of sepsis have advanced significantly. Pathogen-induced abnormal immunological responses, which can range from excessive inflammation to immunosuppression, are recognized to play a significant role in the high death rate. Unfortunately, no medications that are specifically intended to treat sepsis have been licensed. In order to offer a theoretical foundation for the management of sepsis, we will now discuss current advancements in research on immunological responses in sepsis. The prognosis of sepsis patients may be improved by developing and optimizing a dynamic immune system treatment plan based on anti-infection therapy, fluid replacement, support for organ function, and timely application of immunomodulatory therapies

Evaluating genetic diversity in walnut (Juglans regia L.) populations is a rapid approach used by walnut breeding programs to distinguish superior genotypes. The present study identified the Hamedan province walnut population as one of the richest, most genetically diverse regions in Iran during 2019-2020. After initial screening, 47 genotypes were selected for further evaluation of pomological and phenological traits based on International Plant Genetic Resources Institute (IPGRI) descriptors. Nut and kernel weights among the selected genotypes ranged between 7.15-21.05 g and 3.0-10.8 g, respectively. Principal component analysis (PCA) categorized genotypes into three distinct groups while cluster analysis (CA) further categorized genotypes into one of four groups. Spearman correlation analysis showed a positive correlation (P <0.01) between nut weight (NWT), nut size, and kernel weight (KW) while a negative correlation (P <0.01) between shell thickness (STH) and packing tissue thickness (PTT) with kernel percentage (KP) was observed. Lastly, 10 of 47 genotypes (TAL8, TAL9, TAL10, TAL14, TAL19, TAL22, TB2, TB4, TB6, and RDGH5) were considered superior. Superior genotypes were late-leafing (25-40 days after the standard) and displayed a lateral bearing (LB) habit with heavy nuts (12.52–16.82 g) and kernels (6.53–8.15 g), thin-shells (1.06–1.25 mm), and lightly-colored kernels. Cuttings of superior genotypes were then grafted in the orchard. Detecting superior and late-leafing genotypes in this investigation suggests cultivars resistant to late-spring frost may soon be isolated.

Approximately 20% of patients with colorectal cancer (CRC) are diagnosed with a mucinous subtype of this tumor, have a worse prognosis, and often show resistance to available therapies. Molecules from the mucin family are involved in the regulation of epithelial-mesenchymal transition (EMT), which significantly determines the cancer aggressiveness. This study aimed to examine the diagnostic and prognostic significance of mucinous histology and EMT markers in patients with early-onset CRC and their association with disease severity and tumor characteristics. The study included tumor tissue samples from 106 patients diagnosed with CRC before the age of 45, 53 with mucinous and 53 with non-mucinous tumors. The EMT status was determined by immunohistochemical analysis of E-cadherin and Vimentin in tissue sections. Mucinous tumors had a significantly higher cytoplasmic E-cadherin score (P=0.043), they were significantly less differentiated (P=0.007), more advanced (P=0.005), and predominately affected right colon (P=0.030) in comparison to non-mucinous tumors. Epithelial tumors were significantly better differentiated (P=0.034) and with less prominent tumor budding (P < 0.001) than mesenchymal tumors. The process of EMT appears to be more prominent in tumors of younger patients regardless of mucinous histology. EMT status may represent a useful prognostic tool in early-onset CRC.

Abstract: Congenital hyperinsulinism (CHI) is a rare disorder of glucose metabolism and is the most common cause of severe and persistent hypoglycemia (hyperinsulinemic hypoglycemia, HH) in the neonatal period and childhood. Most cases are caused by mutations in the ABCC8 and KCNJ11 genes that encode the ATP-sensitive potassium channel (KATP). We present the correlation between genetic heterogeneity and the variable phenotype in patients with early-onset hyperinsulinemic hypoglycemia caused by ABCC8 gene mutations. In the first patients, which presented persistent severe hypoglycemia since the first day of life, molecular genetic testing revealed the presence of a homozygous mutation in the ABCC8 gene [deletion in the ABCC8 gene c.(2390+1_2391-1)_(3329+1_3330- 1)del] correlated with a diffuse form of hyperinsulinism (the parents being healthy heterozygous carriers). In the second patient, the onset was on the third day of life with severe hypoglycemia, and genetic testing identified a heterozygous mutation in the ABCC8 gene c.1792C&gt;T (p.Arg598*) inherited on the paternal line, which led to the diagnosis of focal form of hyperinsulinism. To locate the focal lesions, (18)F-DOPA (3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine) PET/CT was recommended (an investigation that cannot be carried out in the country), but the parents refused to carry out the investigation abroad. In this case, early surgical treatment could have been curative. In addition, the second child also presented secondary adrenal insufficiency requiring replacement therapy. At the same time, she developed early recurrent seizures that required antiepileptic treatment. We emphasize the importance and of molecular genetic testing for diagnosis, management and genetic counseling in patients with HH.

Keywords: Barriers; Facilitators; Sepsis; Sepsis Six Guidelines; Nurses.

Sepsis, a syndrome characterized by systemic inflammation during infection, continues to be one of the most common causes of patient mortality in hospitals across the United States. While standardized treatment protocols have been implemented, wide variability in clinical outcomes persist across racial groups. Specifically, Black and Hispanic populations are frequently associated with higher rates of morbidity and mortality in sepsis compared to the Caucasian population. While this is often attributed to systemic bias against minority groups, a growing body of literature has found patient, community, and hospital-based factors to be driving racial differences. In this article, we provide a focused review on some of the factors driving racial disparities in sepsis. We also suggest potential interventions aimed at reducing health disparities in the prevention, early identification, and clinical management of sepsis.

Sepsis is a pervasive condition that affects individuals of all ages, with significant social and economic consequences. Early diagnosis of sepsis is fundamental for establishing appropriate treatment and is based on warning scores and clinical characteristics, with positive microbiological cultures being the gold standard. Research has yet to identify a single biomarker to meet this diagnostic demand. Presepsin is a molecule that has the potential as a biomarker for diagnosing sepsis. In this paper, we present a narrative review of the diagnostic and prognostic performance of presepsin in different age groups. Given its particularities, it is identified that presepsin is a potential biomarker for sepsis at all stages of life.

Objectives: To investigate the etiology of amyotrophic lateral sclerosis (ALS) in an adult female patient. Methods: We conducted trio genome sequencing on a 35-year-old woman with progressive weakness in her left upper limb, as well as on her parents. Prior to sequencing, we performed a comprehensive neurological work-up on the patient, including neurological exam, electrophysiology, biomarker assessment, and brain and spinal cord MRI. Results : The propositus experienced weakness and atrophy in her left hand 6 months before the evaluation. This was associated with brisk reflexes and Hoffman sign in the same arm. Electroneuromyography revealed lower motor neuron involvement in three body regions. Neurofilament light chains were elevated in her cerebrospinal fluid. Brain imaging showed asymmetrical T2 hyperintensity of the corticospinal tracts and T2 linear hypointensity of the precentral gyri. Genome trio sequencing identified a likely pathogenic de novo variant in the propositus’s KIF1A gene (NM_001244008.2): c.574A&gt;G, p.(Ile192Val). Discussion: Pathogenic variants in the KIF1A gene have been associated with a wide range of neurological manifestations called KIF1A-associated neurological diseases (KAND). The present report describe a likely pathogenic de novo variant in KIF1A associated with ALS, expanding the phenotypic spectrum of KAND and our understanding of the pathophysiology of ALS.

Introduction: Lipoyl transferase 2 is involved in biosynthesis of the lipoate. Lipoate is the cofactor for the glycine cleavage system and four dehydrogenase enzymes. Biallelic variants in LIPT2 causing severe neonatal encephalopathy was first described in 2017. Methods: Clinical data was collected by retrospective chart review after obtaining consent from parents. The pathogenicity of these variants was further delineated using a yeast model. The YEp352-LIPT2 plasmid was used as a template to generate the two patient variants using QuickChange Lightning Site-Directed Mutagenesis Kit. Results: Patient was a 15-month-old female who presented at 1 month with dystonia, developmental delay and feeding difficulties. MR Brain showed cortical malformations including colpocephaly, polymicrogyria and heterotopia. Patient had elevations in lactate (6.1 mmol/L) and glycine. Exome sequencing showed 2 variants of uncertain significance in trans in the LIPT2 gene: c.346 G>T and c.418C>T. Patient was started on lipoic acid, thiamine and COQ10. Yeast complementation experiments indicate that both patient mutation variants result in diminished function versions of the LIPT2 protein. Conclusion: We report the fourth case of LIPT2-related disorder. Proband shared significant overlap with previous patients, however had a distinct movement disorder and brain malformations which have not been previously described. Unlike most neurometabolic disorders where dystonia develops later after metabolic stroke in basal ganglia, LIPT2- related disorder seems unique due to early onset of dystonia due to energy deficit in the developing brain. Lipoic acid supplementation has not led to significant clinical improvement. Analyses in yeast indicate that novel variants are deleterious but have retained some functionality.

New onset diabetes mellitus after transplantation (NODAT) is a common complication following solid organ transplantation, with varying incidence rates due to discrepancies in defining NODAT and follow-up duration, alongside modifiable and non-modifiable risk factors. NODAT adversely affects patient survival and graft longevity, warranting early detection, especially in countries experiencing a rise in kidney transplant cases, emphasizing the need for understanding diagnostic criteria, risk factors, pathogenic mechanisms, and post-transplant outcomes.

The paper presents a study of two novel visual motion onset stimulus-based brain–computer interfaces (vmoBCI). Two settings are compared with afferent and efferent to a computer screen center motion patterns. Online vmoBCI experiments are conducted in an oddball event–related potential (ERP) paradigm allowing for “aha–responses” decoding in EEG brainwaves. A subsequent stepwise linear discriminant analysis classification (swLDA) classification accuracy comparison is discussed based on two inter–stimulus–interval (ISI) settings of 700 and 150 ms in two online vmoBCI applications with six and eight command settings. A research hypothesis of classification accuracy non–significant differences with various ISIs is confirmed based on the two settings of 700 ms and 150 ms, as well as with various numbers of ERP response averaging scenarios.The efferent in respect to display center visual motion patterns allowed for a faster interfacing and thus they are recommended as more suitable for the no–eye–movements requiring visual BCIs.

Early diagnosis of paroxysmal atrial fibrillation (PAF) could suggest patients to receive timely interventions in clinical practice. Various PAF onset prediction algorithms might benefit from accurate heart rate variability (HRV) analysis and machine learning classification but to be challenged in real-time monitoring scenarios. The aim of this study is to present an end-to-end deep learning based PAFNet model that integrates a sliding window technique on raw R-R interval of electrocardiogram (ECG) segments to achieve a real-time prediction of PAF onsets. This integration enable the deep convolutional neural network (CNN) to be customized as a light-weight architecture that accommodates the size of sliding windows simply by altering the input layer, specifically its effectiveness in making a new prediction with each new heartbeat. Catering to potential influence of input sizes, three CNN models were trained using 50, 100, and 200 R-R intervals, respectively. For each model, the performance of automated algorithms was evaluated for PAF prediction using a ten-fold cross-validation. As a results, a total of 56,381 PAFN-type and 56,900 N-type R-R interval segments was collected from publicly accessible ECG databases, and a promising prediction performance of the automated algorithm with a 100 R-R intervals was achieved in terms of the sensitivity of 97.12%, the specificity of 97.77%, and the accuracy of 97.45%, respectively. Importantly, the automated algorithm with a sliding windows step of 1 could process one sample in only 23.1 milliseconds and identify the onset of PAF at least 45 minutes in advance. The present results suggest that the sliding window technique on raw R-R interval sequences along by deep learning based algorithms may offers the possibility of providing an accurate, real-time, and end-to-end clinical tool for mass monitoring of PAF.

Sepsis is a life-threatening condition caused by a dysregulated host response to an invading pathogen such as multidrug-resistant bacteria. Despite recent advancements, sepsis is a leading cause of morbidity and mortality, resulting in a significant global impact and burden. This condition affects all age groups, with clinical outcomes depending mainly on timely diagnosis and appropriate early therapeutic intervention. Because of the unique features of nanosized systems, there is a growing interest in developing and designing novel solutions. Nanoscale-engineered materials allow a targeted and controlled release of bioactive agents, resulting in improved efficacy with minimal side effects. Additionally, nanoparticle-based sensors provide a quicker and more reliable alternative to conventional diagnostic methods for identifying infection and organ dysfunction. Despite recent advancements, fundamental nanotechnology principles are often presented in technical formats that presuppose advanced chemistry, physics, and engineering knowledge. Consequently, clinicians may not grasp the underlying science, hindering interdisciplinary collaborations and successful translation from bench to bedside. In this review, we abridge some of the most recent and most promising nanotechnology-based solutions for sepsis diagnosis and management using an intelligible format to stimulate a seamless collaboration between engineers, scientists, and clinicians.

The growing concerns about floods have highlighted the need for accurate and detailed precipitation data as extreme precipitation occurrences can lead to catastrophic floods, resulting in significant economic losses and casualties. Integrated Multi-satellitE Retrievals for the Global Precipitation Measurement (GPM-IMERG) is a commonly used high-resolution gridded precipitation dataset and is recognized as trustworthy alternative sources of precipitation data. The aim of this study is to comprehensively evaluate the performance of GPM IMERG Early (IMERG-E), Late (IMERG-L), and Run Final (IMERG-F) in precipitation estimation and their capability in detecting extreme rainfall indices over southwestern Iran during 2001-2020. The Asfezari gridded precipitation data which are developed using a dense of ground-based observation were utilized as the reference dataset. The findings indicate that the IMERG-F performs reasonably well in capturing many extreme precipitation events (defined by various indices). All the three products showed a better performance in capturing fixed and non-threshold precipitation indices across the study region. The findings also revealed that both IMERG-E and IMERG-L have problems in rainfall estimation over elevated areas showing values of overestimations. Examining the effect of land cover type on the accuracy of the precipitation products suggest that both IMERG-E and IMERG-L show large and highly unrealistic overestimations over inland water bodies and permanent wetlands. The results of the current study highlight the potential of IMERG-F as a valuable source of data for precipitation monitoring in the region.

Recent epidemiologic studies have revealed an upward trend in young-onset colorectal cancer (YOCRC) overall, whereas specific data on young-onset colorectal neuroendocrine neoplasms (YONEN) remain limited. This study investigates demographic characteristics and survival trends in YONEN and compares these with those of young-onset colorectal adenocarcinoma (YOADC), the most common histologic subtype of YOCRC. A retrospective analysis was conducted from 2000 to 2019 using the Surveillance, Epidemiology, and End Results (SEER) database. Survival outcomes were assessed using univariate and multivariable Cox proportional models, with demographic differences evaluated via Wilcoxon Rank Sum and Chi-square tests. Out of 61,705 patients aged 20-49 with colorectal cancer, 8% had NEN, and 92% had adenocarcinoma. The YONEN cohort had a higher proportion of Black patients and a lower proportion of White patients than the YOADC cohort (21% vs. 13% and 44% vs. 57%, respectively). NEN was more commonly found in the rectum (79%), and adenocarcinoma was mostly colonic (57%) in origin. YONEN patients had better survival than YOADC patients. Multivariate analysis in YONEN patients revealed that Hispanic patients had better overall survival compared to White patients (HR 0.67, 95% CI 0.47-0.95, p=0.024). Racial disparities should be investigated further to aid in policymaking and targeted interventions.

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system which is crucial for memory, emotions, and learning. Though distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

There are limited proven therapies for the treatment of COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects, make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19, supporting anti-inflammatory treatment. This literature review focuses on vitamin C deficiency in respiratory infections including COVID-19; the mechanism of action in infectious disease and adrenal function supporting the anti-inflammatory actions of glucocorticosteroids: its role in preventing and treating colds and pneumonia and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8g/d) may reduce incidence and duration of respiratory infections and intravenous vitamin C (2-24g/d) has been shown to reduce mortality, Intensive Care Unit and hospital stays, time on mechanical ventilation in severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and frequency of vitamin C deficiency in respiratory infections it may be worthwhile testing patients’ vitamin C status and treating accordingly with intravenous use within ICUs and orally with doses between 2 and 8g/day in hospitalised and infected persons.

Background/Objectives: Obstructive Sleep Apnoea Syndrome (OSA) in children disrupts standard breathing patterns and sleep architecture, potentially leading to severe consequences. Early identification and intervention for OSA are crucial to prevent these issues. This study explored the relationships between waiting times for polysomnography (PSG), clinical history, age at the time of PSG, and PSG outcomes in children; Methods: Two hundred and fourteen children were prospectively enrolled. Data were extracted from medical records on the age at referral for PSG and at the time of its execution, the waiting time for PSG, diagnosis (primary snoring, mild, moderate, and severe OSA), history of snoring and apnoea, medications taken, surgical interventions, passive smoke exposure, and allergies. The records also included the Pediatric Sleep Questionnaire (PSQ); Results: The mean age at referral for PSG was 5.2 (2.8) years, the waiting time for PSG was 5.2 (5.0) months, and the age at the time of PSG was 5.6 (2.8) years. Children with a shorter history of OSA (≤12 months) underwent PSG at an earlier age (4.9 (2.7) years) compared to those with a more extended history (6.0 (2.7) years; p=0.006). A younger age at referral for PSG was associated with a lower PSQ score (r=0.167; p=0.015), a shorter history of apnoea (r=0.216; p=0.003) and snoring (r=0.187; p=0.023), but also with greater OSA severity, expressed as oxygen desaturation index (r=-0.152; p=0.026). In the correlation analysis, the waiting time for PSG, adjusted for age at referral, was longer in children with a prolonged history of apnoea (r=0.195; p=0.023) and snoring (r=0.259; p=0.002) but with a lower PSQ score (r=-0.172; p=0.045); Conclusions: Some children receive delayed treatment, increasing the risk of long-term complications. In evaluating children with suspected OSA, the duration of symptoms and the PSQ score at referral emerge as crucial factors that should be considered to optimise prioritisation for PSG access.

Paracetamol, also known as acetaminophen, is one of the most widely used over-the-counter analgesics and antipyretics globally. While generally considered safe when used as directed, excessive or prolonged use of paracetamol can lead to adverse effects on various organ systems within the human body. This comprehensive review explores the physiological mechanisms underlying paracetamol toxicity, its effects on different organs, risk factors for overdose, diagnostic methods, and potential management strategies.

In chronic myeloid leukemia (CML), a clonal proliferative disorder of granulocytic lineage, the 90%‐95% of cases are characterized by t(9;22) (q34.1;q11.2) translocation, leading to the Philadelphia chromosome (1). Rarely, CML patients directly present a blast crisis, mostly of myeloid origin (2, 3). Herein, we describe one rare CML case, showing an unusual early T lymphoid blastic crisis.

Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which ranks among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients “mimics bacterial sepsis”. Furthermore, the immune response to SARS-CoV-2 was described by others as “mirror image of sepsis”. Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection was frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. These data indicate similarity and interdependences of both syndromes, but also significant differences which will be discussed in the present review.

Background and Objectives: Uveitis, a prevalent eye disorder characterized by inflammatory processes, often leads to cataract formation and significant visual impairment. This study aimed to evaluate preoperative conditions and postoperative outcomes following cataract surgery in uveitis patients. Materials and Methods: A retrospective study was conducted at the University Hospital Center Rebro Zagreb, Croatia, involving uveitis patients who underwent cataract surgery between 2013 and 2022. Eligible patients had uveitic cataracts affecting visual acuity or posterior segment visualization in a "quiet eye" and were disease-inactive for at least three months. Patients with certain preexisting ocular conditions were excluded. Data collected included patient demographics, uveitis type, preoperative therapy, preexisting lesions, and postoperative outcomes such as visual acuity, intraocular pressure, central macular thickness, and complications. Statistical analysis was performed to identify risk factors associated with complications. Results: The study included 105 patients. After cataract surgery, there was a significant improvement in visual acuity at various time points, with 90% of eyes showing improvement. Intraocular pressure decreased over time. Central macular thickness increased at three months post-surgery but remained stable thereafter. Early and late complications were observed in 52.4% and 63.8% of eyes, respectively. The most common complications were posterior capsular opacification, macular edema, and epiretinal membrane. Factors associated with complications varied between early and late stages but included age, age at onset of uveitis, and uveitis type. Conclusion: Cataract surgery in uveitis patients presents challenges but can lead to significant visual improvement. This study highlights the importance of careful patient selection, preoperative and postoperative inflammation management, and precise surgical techniques. Although complications were common, they were manageable, and most patients experienced improved vision, emphasizing the benefits of cataract surgery in this population. However, future investigations should address the study's limitations and further refine perioperative strategies.

Background: Neonatal sepsis associated with severe morbidity and mortality defines the systemic condition arising from the bacterial, viral, fungal origin associated with hemodynamic and clinical alterations. Symptomatology can be different, from subclinical to severe, focal or systemic disease. The causal agent comes from maternal flora or can be of community/hospital origin. Material and method: Our retrospective study evaluated 121 newborns (both preterm and term), divided into three groups: early onset sepsis (35), late onset sepsis (39), and control group (47), from 0 to 28 days old. Blood samples and cultures were collected at admission, after 24 hours, and 72 hours. Results: The two-sample Wilcoxon signed rank test revealed a statistically significant difference between the initial and final measures of lactate dehydrogenase (LDH) and ferritin within the early onset sepsis (EOS) and late onset sepsis (LOS) groups. No significant differences were observed for those two variables within the control group. There were significant differences for first and last measurements of C-Reactive Protein (CRP) (p = 0.029), leukocyte count (p = 0.002), and platelets (TR) (p = 0.00001). Conclusions: Ferritin is a potential biomarker that can be associated with systemic response and sepsis in both cases of early and late onset sepsis.

This article focuses on the description of the other view of Valencia in the fifteenth century, that of social marginalization, which could be manifested by the fact of exercising various trades considered immoral. In the following pages, a description is offered of two female collectives that are particularly treated as vile and despicable: that of healers, sorceresses and witches, whose strength was considered to stem from a demonic origin, and that of prostitutes, dedicated to covering a "lesser evil" in society but seen as unworthy by society because of the practical exercise of their trade.

We measure the accelerated cosmic expansion rate of the late-time Universe and derive constraints on cosmological parameters from the final baryon acoustic oscillation (BAO) uncorrelated measurements of different surveys after two decades of dedicated spectroscopic observation combined with the Pantheon sample of Type Ia supernovae, the Hubble diagram of gamma-ray bursts &amp; quasars data, the Cosmic Chronometers data, and the recent Hubble constant value measurement from the Hubble Space Telescope and the SH0ES Team as an additional prior. In Λ cold dark matter (ΛCDM) scenario, the model fit yields Ωm=0.313±0.034 and ΩΛ=0.672±0.025. Combining BAO with CC+Pantheon+QSR+GRB data sets we get H0=69.21±1.22 km s−1 Mpc−1, rd=133.46±2.49 Mpc. For the a flat wCDM model, we get w=−1.111±0.030. For a dynamical evolution of dark energy in a flat w0waCDM cosmology, we get wa=−0.292±0.167. We apply the Akaike information criteria probe to compare the three models, and see that all models are favored and cannot be discarded from the current data.

Using a joint statistical analysis, we test a four-dimensional FLWR model embedded in a five-dimensional bulk based on the Nash-Greene embedding theorem. Performing a Markov Chain Monte Carlo (MCMC) modelling, we combine observational data sets as those of the recent Pantheon type Ia supernovae, Baryon Acoustic Oscillations (BAO) and the angular acoustic scale of the Cosmic Microwave Background (CMB) to impose restrictions on the model and correlating the model parameters to mimick an equation of state. From statistical classifiers as the Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), we use the Jeffreys' scale and find a strong evidence favoring a statistically consistence with a dynamical Dark energy (CPL parameterization) and a relative consistence with both ΛCDM and ωCDM models. Moreover, we find that the transition redshift used as a cosmic discriminator with the best fit z_t=0.634 ± 0.014 at 1-σ C.L. with a range scenario for late time sharp transitions.

Sepsis-induced cardiomyopathy (SICM) may be defined as a non-ischemic cardiac dysfunction associated with sepsis. SICM is characterized by a decrease in left ventricular contractility, ultimately associated with left ventricular dilation, with or without right ventricular dysfunction. Echocardiography stands as the current gold standard in diagnosis of SICM. Left ventricular ejection fraction (LVEF) is the most frequently utilized parameter for evaluating left ventricular systolic function, but some traditional parameters, including LVEF, are dependent on cardiac preload and afterload, limiting their clinical application. Advanced echocardiography techniques, such as speckle-tracking analysis, have the potential to diagnose and evaluate myocardial dysfunction even in the early phases of sepsis, facilitating risk stratification for proactive personalized treatment of patients. This article reviews the progress in the application of various echocardiographic parameters in SICM.

Sepsis is a serious and life-threatening medical emergency associated with dysregulated host immune responses to infection. Like cerebral vascular or acute cardiovascular incidents, sepsis is considered a time-dependent condition having severe and long-term consequences on human health. Apart from organ support, prompt administration of appropriate antimicrobial therapy is crucial to limit the burden of complications related to sepsis in ICU patients. The management of septic patients requires comprehensive and multi-disciplinary strategies for an adequate diagnosis. Most of the ICU population receives empirical antibiotic therapy without having a confirmed diagnosis. The misuse of antibiotics in intensive care units may increase the possibility of developing multidrug resistance along with considerable ecological side effects. The first doses of empirical anti-microbial therapy are slightly higher, regardless of the presence or absence of organ dysfunction, which may upregulate the production of circulating pro-and-anti-inflammatory mediators, having negative effects on the general well-being of the patients. This notion supports the introduction of individualized antimicrobial approaches based on local patterns of resistance to ensure the appropriate dosage of empirical therapy, as well as to limit the emergence of multidrug resistance in advanced-care patients. The adequacy and treatment duration must be viewed at regular intervals for effective de-escalation, and novel diagnostic approaches must be introduced to improve the quality of care in the ICU population.

For decades, sepsis research has been motivated by the idea of a dangerous overreaction of the immune system in sepsis. But is it true that the response to sepsis is dysregulated? This review surveys the history of sepsis trials and found that evidence for dysregulation does not exist in many of the physiologic mechanisms of sepsis. It is time to consider the alternative hypothesis, that sepsis traits are often functional, and do more harm than good. This review discusses the implications of this perspective for the future of sepsis research

Sepsis is a life-threatening syndrome triggered by infection and accompanied by high mortality, with antimicrobial resistances (AMRs) further escalating clinical challenges. Rapid and reliable detection of causative pathogens and AMRs are key factors for fast and appropriate treatment, in order to improve outcome in septic patients. However, current sepsis diagnostics based on blood culture is limited by low sensitivity and specificity while current molecular approaches fail to enter clinical routine. Therefore, we developed a Suppression PCR-based selective enrichment sequencing approach (SUPSETS), providing a molecular method combining multiplex suppression PCR with Nanopore sequencing to identify most common sepsis-causative pathogens and AMRs using plasma cell-free DNA. Applying only 1 mL of plasma, we target eight pathogens across three kingdoms and ten AMRs in a proof-of-concept study. SUPSETS was successfully tested on first ten clinical samples and revealed comparable results to clinical metagenomics while clearly outperforming blood culture. Several clinically relevant AMRs could be detected additionally. Furthermore, SUPSETS provided first pathogen and AMR-specific sequencing reads within minutes of starting sequencing, thereby potentially decreasing time to results to 11 - 13 hours and suggesting diagnostic potential in sepsis.

Inflammatory allergic and nonallergic respiratory pathologies often co-exist. The root cause is not clear. This paper demonstrates that it is ascribable to protons (H⁺) released into cells by exogenous and endogenous acids. The hypothesis of acids as the common cause stems from two considerations: a) it has long been known that exogenous acids present in air pollutants can induce the irritation of epithelial surfaces, particularly the airways, inflammation and bronchospasm; b) according to recent articles, endogenous acids, generated in cells by phospholipases, play a key role in the biochemical mechanisms of initiation and progression of allergic responses. Therefore, the intracellular acidification and consequent Ca²⁺ increase, induced by protons generated by either acid pollutants or endogenous phospholipases, may be the causal mechanism of the multimorbidity of these diseases, and environmental acidity may contribute to their spread.

We investigate the evolution of gravitational waves through discontinuous evolution (transition) of the Hubble expansion rate H(z) at a sudden cosmological singularity which may be due to a transition of the value of the gravitational constant. We find the evolution of the scale factor and the gravitational wave waveform through the singularity by imposing the proper boundary conditions. We also use existing cosmological data and mock data of future gravitational wave experiments (the ET) to impose current and anticipated constraints on the magnitude of such a transition. We show that mock data of the Einstein Telescope can reduce the uncertainties by up to a factor of 3 depending on the cosmological parameter considered.

Introduction: Third molar surgery can cause post-operative complications to the patient due to the presence of wound from the incision. The study aimed to compare marginal flap with para-marginal flap on postoperative complications by the measurements on pre and post-surgical plaque index (PI), bleeding on probing (BoP), maximum opening of the mouth (MOM), pain perception (PP) and post-surgical tumefaction (PT). Methods: In this double-blind randomized clinical trial, 40 patients were recruited and randomly allocated in two groups. In Group 1, third molar extraction was carried out after a marginal flap design was performed, while in group 2 a para-marginal flap was per-formed. Plaque Index, Bleeding on Probing, Maximum Mouth Opening, and Distal Probing were assessed right before and one week after surgery, while Post-operative Pain Perception and Post-operative Swelling were accounted one week following sur-gery. Results: Statistically significant difference are reported between treatment groups, as the para-marginal flap led to better outcomes for all the measured indexes. Conclusion: The para-marginal flap design may decrease the occurrence of post-operative compli-cations and discomforts after mandibular third molar surgery, compared to marginal flap design.

Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics, Colistin and Fosfomycin, for the empirical treatment of neonatal sepsis. Based on current knowledge, Colistin and Fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile.

Objectives: To investigate the value of early lactate dynamic monitoring index in predicting prognosis of patients with sepsis and septic shock. Methods: We performed our test on 50 patients. Out of 50 patients, 28 are male, and 22 are female. Prospectively studied pediatric patients with septic shock were performed. Vital signs, Lactate clearance, were obtained at presentation 6 h, 12 h, 24 h over the first 48 h of hospitalization. The therapy received, outcome parameters of mortality and duration of hospitalization were recorded. Results: The statistical data and comparative analysis showed that an average of 16.88 days after admission, 5 patients have died, 17 patients are poorly prognosis leaves the hospital, and the remaining 28 are recovered and discharged. The primary outcome variable of mean 16 days hospitalization mortality rate was 10%. Poor prognosis 34% and fully recovery 56 % were observed. In this retrospective cohort study, a lactate level of more than 2.5mmol/L was the best threshold to predict 28-day mortality among severe sepsis and septic shock patients. In our research, we found mean LC 6 h 3.08mmol/L, and after 48 h mean it is 1.79mmol/L. Significant LC 6 h found, which is 8.08mmol/L in the death group patient where 48 h mmol/L shows significant high. Poor prognosis also presents a clinical increase of lactate level high in the LC 6 h analysis, which is 3.32mmol/L. Recovered patients showed a significant improvement after administering treatment depending on the patient organ involvement and good decrease of lactate reports achieved, which is 1.20mmol/L, where admission reports show it was 1.91mmol/L in LC 6 h. Mean Heart rate 94/51mmhg, pulse 119, temperature 39℃, respiratory rate 32.26, and urine output 456 ml recorded during our study. Death patient shows a remarkable detonation of those reports but has a significant clinical report with the recovered patients. Conclusion: The early lactate dynamic monitoring index has a high value in predicting sepsis and septic shock patients' prognosis, thus worth popularizing.

Severe COVID-19 disease is characterised by an exaggerated inflammatory response, called cytokine storm, accompanied by a condition of immune depression. Even sepsis is characterised by an exaggerated inflammatory response, called SIRS (Systemic Inflammatory Response Syndrome), accompanied by a condition of immune depression called CARS (compensatory anti-inflammatory response syndrome). Clinical studies reveal that most sepsis patients who did not die during the hyper inflammatory response (SIRS) subsequently succumbed to the condition of immune depression (CARS). Severe acute pancreatitis begins with local inflammation that induces systemic inflammatory response syndrome (SIRS), accompanied and followed by a compensatory anti-inflammatory response (CARS). In COVID-19 disease, the male response to SARS CoV-2 virus is typically characterised by a robust inflammatory response. Instead, a cell-mediated immune response is dominant in women. This means that the male sex tends to have a more robust hyper inflammatory response than the female one. Furthermore, in women the condition of immune depression is less represented, therefore they are more protected. Sepsis, severe acute pancreatitis and COVID-19 disease evolve between two fundamental aspects: hyper inflammation and immunodepression. The experience gained over years of studies of sepsis and severe acute pancreatitis suggests that therapies should be differentiated according to the evolutionary stage of the disease. The goal is to save the lives of most patients with COVID-19 disease. The identification of critical points, suitable for designing the windows of therapeutic opportunity, may allow the use of therapeutic interventions, in the COVID-19 disease, which are effective (there are no approved drugs yet), safe (without significant side effects), targeted (based on the evolutionary phase of the disease) personalized, (based on sex, co-morbidities, age, etc.) and timely (based on signs, symptoms, laboratory parameters and instrumental investigations).

Extensive genomic analyses of Enterococcus cecorum isolates from sepsis outbreaks in broilers suggests a polyphyletic origin likely arising from core genome mutations rather than gene acquisition. This species is normal intestinal flora in avian species with particular isolates associated with osteomyelitis. More recently, the species has been associated with sepsis outbreaks affecting broilers during the first 3 weeks post hatch. Understanding the genetic and management basis of this new phenotype is critical for developing strategies to mitigate this emerging problem. Phylogenomic analyses of 227 genomes suggest that sepsis isolates are polyphyletic and closely related to both commensal and osteomyelitis isolate genomes. Pangenome analyses detect no gene acquisitions that distinguish all sepsis isolates. Core genome SNP analyses identify a number of mutations, affecting protein coding sequence, that are enriched in sepsis isolates. Analysis of the protein substitutions supports mutational origins of sepsis isolates.

Background： Sepsis-induced acute lung injury (ALI) is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. This study aimed to discover potential diagnostic molecular biomarkers based on bioinformatics, which will benefit the diagnosis and treatment of sepsis-induced ALI. Methods: GSE10474 was analyzed for differentially expressed genes (DEGs) in sepsis patients with ALI (sepsis + ALI) compared with sepsis patients without ALI. Functional enrichment analysis and protein-protein interaction (PPI) network were performed. on the DEGs via R package “clusterProfiler”, and visualized via Cytoscape. Prediction analysis of microarrays (PAM) was performed to identify diagnostic biomarkers and the diagnostic ability of diagnostic biomarkers was accessed via receiver operating characteristic (ROC) curves. Moreover, interactions among diagnostic biomarkers were analyzed via GeneMANIA. We also analyzed the function of diagnostic biomarkers and predicted their corresponding drugs via Cytoscape plugin BiNGO and web tool DGIdb. At last, we analyzed the transcriptional regulation of the diagnostic biomarkers via the web tool miRNet. Results: 71 genes were found to be differentially expressed in the sepsis + ALI group, mainly involved in immune-related biological processes and pathways. STRING database indicated 31 DEGs have protein-protein interactions. In addition, the PAM identified 6 diagnostic biomarkers, including HIST1H4H, CDKN1A, HMOX1, NQO2, RHOB, and TREM1, from these 31 DEGs. Conclusion: In conclusion, through bioinformatics analyses, we identified 6 potential diagnostic biomarkers and targets for sepsis-induced ALI.

We show that the accelerating expansion phase of the universe can emerge from the group field theory formalism, a candidate theory of quantum gravity. The cosmological evolution can be extracted from condensate states using mean field approximation, in a form of modified FLRW equations. By introducing an effective equation of state w, we can reveal the relevant features of the evolution, and show that with proper choice of parameters, w will approach to −1, corresponds to the behaviour of cosmological constant, results in a late time acceleration and leads to de Sitter spacetime asymptotically.

Cardiovascular diseases (CVDs) remain the leading cause of mortality. Traditional approaches to diagnosing and treating CVDs often involve interpretation, which can lead to errors. The emergence of Artificial Intelligence (AI) and Machine Learning aids the management of CVDs. AI examines amounts of data and identifies patterns offering solutions for disease detection, risk prediction, and patient care. The American Heart Association's 2023 Scientific Sessions (AHA23) showcased studies that highlight AIs potential to revolutionize cardiac healthcare. This article presents a review of these cutting-edge studies exploring how AI is applied in health, the outcomes of these applications, and their implications for clinical practice. The insights gained from this review will contribute to the discussion on AI's role in healthcare and its capacity to enhance outcomes.

Background: Little is known about risk and prognostic factors in very old patients developing sepsis secondary to community-acquired pneumonia (CAP). Methods: We conducted a retrospective observational study of data prospectively collected at the Hospital Clinic of Barcelona over a 13-year period. Consecutive patients hospitalized with CAP were included if they were very old (≥80 years) and divided into those with and without sepsis for comparison. Sepsis was diagnosed based on the Sepsis-3 criteria. The main clinical outcome was 30-day mortality. Results: Among the 4,219 patients hospitalized with CAP during the study period, 1,238 (29%) were very old. The prevalence of sepsis in this aged group was 71%. Male sex, chronic renal disease, and diabetes mellitus were independent risk factors for sepsis, while antibiotic therapy before admission was independently associated with a lower risk of sepsis. Thirty-day and intensive care unit (ICU) mortality did not differ between patients with and without sepsis. In CAP-sepsis group, chronic renal disease and neurological disease were independent risk factors for 30-day mortality. Conclusion: In very old patients hospitalized with CAP, in-hospital and 1-year mortality rates were increased if they developed sepsis. Antibiotic therapy before hospital admission was associated with a lower risk of sepsis.

This article presents a narrative review of neonatal and paediatric complications in post-dated pregnancy and covers scientific views on the aetiology, pathology, risk factors, symptoms and complications of post-dated pregnancy. A pregnancy extending beyond 42 weeks of gestation is termed as a post term pregnancy. There are multiple complications that can occur in the perinatal period, some of the most common ones are stillbirth, asphyxia, meconium aspiration syndrome, fetal distress syndrome, etc which are found to be greater in post-dated pregnancy and hence ultimately leads to increased mortality and morbidity of the new born. Studies have shown that post-term pregnancy also causes increased risk of developing behavioural and emotional problems in children of paediatric age group. It is surprising not much importance has been given to the maternal and neonatal consequences of post- term pregnancies. It is not well understood why some women experience post-dated pregnancies. It is found that factors such as hormones and genetic build up, are responsible for causing post-term pregnancy in an obese female. The treatment and management of a post-term pregnancy still poses a challenge to clinicians in determining the right choice and right time for a particular intervention so that both mother and fetus can be prevented from having complications.

(1) Background: Although resistance to pathogens and pests has been researched in many potato cultivars and breeding lines with DNA markers, there is scarce evidence as to the efficiency of the marker-assisted selection (MAS) for these traits when applied at the early stages of breeding. A goal of this study was to estimate the potential of affordable DNA markers to track Rpi disease resistance genes, that are effective against the pathogen Phytophthora infestans, as a practical breeding tool on a progeny of 68 clones derived from a cross between the cultivar Sudarynya and 13/11-09. (2) Methods: this population was studied for four years to elucidate the distribution of LB resistance and other agronomical desirable or simple to phenotype traits such as tuber and flower pigmentation, capacity and structure of yield. LB resistance was phenotypically determined through natural and artificial infection and the presence/absence of nine Rpi genes was assessed via 11 sequence-characterized amplified region (SCAR) markers. To aid this analysis, the profile of Rpi genes in the 13/11-09 parent was established using diagnostic resistance gene enrichment sequencing (dRenSeq) as a gold standard. (3) Results: at the early stages of a breeding program, MAS can halve the workload when screening the segregation of F1 offspring and selected SCAR markers for Rpi-genes provide useful tools.

One of the challenges in Content-Based Image Retrieval (CBIR) is to reduce the semantic gaps between low-level features and high-level semantic concepts. In CBIR, the images are represented in the feature space and the performance of CBIR depends on the type of selected feature representation. Late fusion also known as visual words integration is applied to enhance the performance of image retrieval. The recent advances in image retrieval diverted the focus of research towards the use of binary descriptors as they are reported computationally efficient. In this paper, we aim to investigate the late fusion of Fast Retina Keypoint (FREAK) and Scale Invariant Feature Transform (SIFT). The late fusion of binary and local descriptor is selected because among binary descriptors, FREAK has shown good results in classification-based problems while SIFT is robust to translation, scaling, rotation and small distortions. The late fusion of FREAK and SIFT integrates the performance of both feature descriptors for an effective image retrieval. Experimental results and comparisons show that the proposed late fusion enhances the performances of image retrieval.

Volunteering has many social, emotional and health benefits and could be an option for people with younger/early onset dementia to engage in stage and age-appropriate, personally meaningful activities within their local communities. This study explored how people with young onset dementia volunteer in the UK, the benefits and barriers, and how we can improve access to volunteering opportunities. Audio data of people with young onset dementia discussing their experiences of volunteering were taken from the Dementia Diaries audio and video diary project (https://dementiadiaries.org/). The data were co-analysed by a co-production team, (X), made up of six researchers living with young onset dementia and two facilitators. The findings suggest that stigma is the overarching concept (or net) which influences people’s experiences of volunteering with dementia. Within the stigma net, three themes were developed that employed a lifespan approach to challenging said stigma: 1) Valuing the past, 2) Valuing the present and 3) Valuing the future, each with additional subthemes. This research contributes to the limited pool of literature that highlights the clear benefits of volunteering for people with young onset dementia, while also considering how dementia stigma can create practical and institutional barriers to accessing volunteering. Guidance is provided for how to deliver meaningful and accessible volunteering opportunities.

Introduction: Type 1 diabetes mellitus is a chronic disease of autoimmune etiology that is highly prevalent in childhood. In the last decade, the possibility of using the Bacillus Calmette-Guérin vaccine for the treatment of this disease has been studied thanks to its immunomodulatory action . Objectives: The objective of this work is to carry out a systematic review of the available scientific evidence on the relationship between the tuberculosis vaccine and the treatment of diabetes in childhood. Secondarily, the aim is to study the incidence of Type 1 Diabetes Mellitus in a cohort of children from the Basque Country according to whether or not they have received the vaccine. Methods: An exhaustive bibliographic search has been carried out on the evidence available to date. For the epidemiological study in Euskadi, a comparison of accumulated incidences between vaccinated and unvaccinated population groups was made. Results: According to the literature analyzed, There is more and more evidence about the possible use of the tuberculosis vaccine in Type 1 Diabetes Mellitus. The results of our study were not conclusive, but we believe that it is necessary to continue with long-term studies to eliminate biases. Conclusions: The Bacillus Calmette-Guérin vaccine could be used for the treatment of autoimmune, allergic, infectious or oncological processes, although more studies are still necessary in this regard.

We present the case of a 28-year-old male with a history of alcohol dependency and smoking, who presented with chest pain, shortness of breath, and altered sensorium. He exhibited severe metabolic acidosis, low platelet count, and acute kidney injury. Alcoholic ketoacidosis (AKA) was suspected due to ketonuria, metabolic acidosis, and ketonemia, compounded by electrolyte abnormalities and radiographic findings of pneumonia.Prompt intervention included electrolyte correction, thiamine supplementation, broad-spectrum antibiotics, and diuretics. Thiamine played a pivotal role in the patient's recovery, with significant improvement in consciousness observed within a day. After six days, the patient was discharged in stable condition, showing normal renal and hepatic function during follow-up.This case emphasizes the need for early recognition and comprehensive management in AKA, highlighting thiamine's crucial role in treatment success.

This is growing recognition of early onset gastrointestinal (GI) malignancies in young adults

In this paper, the ductile fracture mechanism is discussed. The results of the numerical and experimental analyses are used to estimate of the onset of the crack front growth . It is assumed that the ductile fracture in front of the crack starts at the location along the crack front where the accumulated effective plastic strain reaches a critical value. It is also assumed that the critical effective plastic strain depends on the stress triaxiality and the Lode angle. The experimental programme was performed using five different specimen geometries, three different materials and three different temperatures of +20°C, -20°C and -50°C. Using the experimental data and the results of the finite element computations, the critical effective plastic strains are determined for each material and each temperature. However, before the critical effective plastic strain is determined, a careful calibration of the stress–strain curves was performed after modification of the Bai–Wierzbicki procedure. Finally, by analysing the experimental results recorded during the interrupted fracture tests and scanning microscopy observations, the research hypothesis is verified.

Ebstein anomaly, a congenital heart condition, can manifest across a broad age spectrum, including adulthood. We present a unique case of a 67-year-old woman with no significant medical history who sought medical attention for severe headaches, vomiting, and respiratory distress, accompanied by elevated blood pressure and rapid pulse. Initial investigations, including troponin T levels, yielded unremarkable results. However, an electrocardiogram unveiled a right bundle branch block (RBBB) pattern, prompting further assessment. A subsequent chest X-ray disclosed an enlarged heart, indicating cardiomegaly, prompting echocardiography. The echocardiogram confirmed the diagnosis of Ebstein anomaly, revealing a 26 mm apical displacement of the tricuspid valve (TV). The patient was managed conservatively with supplemental oxygen and exhibited gradual improvement. This case underscores the infrequent occurrence of Ebstein anomaly in adulthood and underscores the necessity for thorough evaluation in cases of unexplained cardiopulmonary symptoms.

Cell death by apoptosis is a major cellular response, in the control of tissue homeostasis and as a defense mechanism in case of cellular aggression like an infection. Cell self-destruction is part of antiviral responses, aimed at limiting the spread of a virus. Although it may contribute to the deleterious effects in infectious pathology, apoptosis remains a key mechanism for viral clearance and resolution of infection. The control mechanisms of cell death processes by viruses have been extensively studied. Apoptosis can be triggered by different viral determinants, through different pathways, as a result of virally induced cell stresses and innate immune responses. Zika virus (ZIKV) induces Zika disease in humans which has caused severe neurological forms, birth defects and microcephaly in newborns during the last epidemics. ZIKV also surprised by revealing an ability to persist in the genital tract and in semen, thus being sexually transmitted. Mechanisms of diverting antiviral responses such as the interferon response, the role of cytopathic effects and apoptosis in the etiology of the disease have been widely studied and debated. In this review, we examined the interplay between ZIKV infection of different cell types and apoptosis and how the virus deals with this cellular response. We illustrate a duality in the effects of ZIKV-controlled apoptosis, depending on whether it occurs too early or too late, respectively in neuropathogenesis, or in long-term viral persistence. We further discuss a prospective role for apoptosis in ZIKV-related therapies, and the use of ZIKV as an oncolytic agent.

The Hubble parameter H(z), as a function of redshift, is modified by the presence of a new term originated from the extrinsic curvature in an embedded space-time. Assuming an asymptotic expansion factor $a\sim 0$ or, equivalently $z\rightarrow \infty$, it is obtained a nearly resemblance of the present model ($\beta$-model) with quintessence $w$CDM model with $H(z)\sim H_{wCDM}(z)$ at background level. In conjunction with $\Lambda$CDM, we test the models using a pack of recent datasets like that of the ``Gold 2018'' growth data, the best-fit Planck2018/$\Lambda$CDM parameters on the Cosmic Microwave Background (CMB), the Baryon Acoustic Oscillations (BAO) measurements, the Pantheon Supernovae type Ia and the Hubble parameter data with redshift ranging from $0.01 < z < 2.3$. Performing the Akaike Information Criterion (AIC) to ascertain the statistical viability of the model from Jeffreys' scale, we apply a joint likelihood analysis to the data with the Markov Chain Monte Carlo (MCMC) method. We find that the present model is in very good agreement with observations with a close statistical equivalence with the $\Lambda$CDM and $w$CDM cosmologies at 1-$\sigma$ level. We also show that a mild alleviation of the $\sigma$ tension between the growth amplitude factor and the matter content $(\sigma_8$-$\Omega_m)$ of the observations from CMB and Large Scale Structure (LSS) probes. A comparison of the aforementioned full pack of data in MCMC chains is made with the resulting MCMC from Pantheon SNIa+$H(z)$ in order to analyse the sensitivity of the models and how they respond to a cosmography analysis on the evolution of $H(z)$ and the deceleration parameter $q(z)$. In this sense, we find that only the $\beta$-model can be unaffected to the variations of the previous datasets due to its several minima in the likelihood (degeneracies) of the related parameters with an overall percentage relative difference only up to 4$\%$.

Background: Recent reports on the national temporal trends of sepsis-related mortality in the United States (US) suggested outcome improvement in several race and ethnicity groups. However, it is unknown whether national data reflect state-level trajectories. Methods: We used the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death dataset to identify all decedents with sepsis in the US during 2010-2019. Negative binomial regression models were fit to estimate national and state-level trends of age-adjusted sepsis-related mortality rates within race and ethnicity groups. Results: There were 1,852,610 sepsis-related deaths in the US during 2010-2019. Nationally, sepsis-related mortality rates decreased among Blacks and Asians, were unchanged among Hispanics and Native Americans, and rose among Whites. The percent of states with similar trends were 30.0% among Blacks, 32.1% among Asians, 74.3% among Hispanics, 75.0% among Native Americans, and 66.7%% among Whites, while trending in opposite direction from 3.6% among Asians to 15.0% among Blacks. Conclusions: National trends in sepsis-related mortality in the US did not represent state-level trajectories in race and ethnicity groups. Gains in sepsis outcomes among race and ethnicity groups at the national level were not shared equitably at the state level.

Background The Delta Neutrophil Index (DNI), a prodiagnostic marker for sepsis, utilizes leukocyte count. Platelet activation, similar to leukocytes, plays a crucial role in host defence against pathogens and may serve as a predictor of sepsis outcome. However, the combined evaluation of Mean Platelet Component (MPC) and DNI in assessing sepsis has been rarely used. Methods To assess the prodiagnostic validity of simultaneous utilization of DNI and MPC in cases of human febrile sepsis, we conducted measurements of cellular indices, including DNI and MPC, as well as molecular biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP). This study was carried out on patients admitted to the emergency department with suspected sepsis. Results Using a cutoff value of 2.65%, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DNI in sepsis were found to be 69%, 73.9%, 77.9%, and 64.1%, respectively. Furthermore, significant differences in DNI and MPC levels were observed between the sepsis and non-sepsis groups (6.7±7.8% versus 2.1±2.2%, P=0.000 and 26.0±1.9 g/dl versus 26.8±1.4 g/dl, P=0.002), respectively. Notably, there was a negative correlation between DNI and MPC, with the strength of the correlation varying based on the cause of sepsis. By setting the cutoff value for DNI at 6.2%, the sensitivity, specificity, and NPV improved to 100%, 80.3%, and 100%, respectively, although the PPV remained at 10.6%. Importantly, the DNI≥6.2 group exhibited a higher incidence of death (10.9%, 5/46) and multiorgan failure (19.6%, 9/46) compared to the DNI<6.2 group (0.0%, 0/46 and 0.0%, 0/167, respectively) (P=0.000 and P=0.000, respectively). Conclusions In our study, DNI demonstrates superior effectiveness compared to other molecular biomarkers such as CRP and procalcitonin in distinguishing febrile septic patients from febrile nonseptic patients and predicting prognosis. Additionally, there exists a negative correlation between MPC and DNI, making MPC a valuable marker for differentiating the etiology of sepsis. These findings hold significant clinical implications as DNI/MPC is a cost-effective and readily applicable approach in various impending sepsis scenarios. Notably, this study represents the first examination of the prodiagnostic validity of simultaneously employing DNI and MPC in human cases of febrile sepsis.

Early diagnosis and appropriate treatments are crucial to reducing mortality risk in septic patients. Low SOFA scores and current biomarkers may not discern adequately patients that could develop severe organ dysfunction or have an elevated mortality risk. The aim of this prospective observational study is to evaluate the predictive value of the biomarkers midregional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-Reactive Protein (CRP), and lactate for 28-day mortality in patients with sepsis and a SOFA score ≤ 6. 284 patients were included, with a 28-day all-cause mortality of 8.45 % (N=24). Non-survivors were older (p=0.003), required mechanical ventilation (p=0.04) and were ventilated for longer (p=0.02), had a higher APACHE II (p=0.015) and SOFA (p=0.027) scores. Lactate showed the highest predictive ability for all-cause 28-day mortality with an area under the receiver-operating characteristic curve (AUROC) of 0.67 (0.55–0.79). The AUROC for all-cause 28-day mortality in patients with community-acquired infection was 0.69 (0.57–0.84) for SOFA, and 0.70 (0.58–0.82) for MR-proADM. A 2.1 nmol/L cut-off point for this biomarker in this subgroup of patients discerned with 100% sensibility survivors from non-survivors at 28 days. In patients with community acquired sepsis and initial SOFA score ≤ 6, MR-proADM could help identify patients at risk of 28-day mortality.

Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents which targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents which target multiple components of the host’s response to an infectious agent will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.

Background. This study aimed to establish a prognostic nomogram for predicting overall survival (OS) and cancer-specific survival (CSS) of patients with early-onset endometrial cancer (EOEC). Methods. Patients diagnosed with EOEC during 2004-2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox regression analyses were performed to ascertain the independent factors impacting the prognosis of EOEC patients, while a prognostic nomogram was established. Its performance was verified by the receiver operating characteristic (ROC) curves, and calibration plots. The prediction accuracy and clinical net benefit between the model, TNM stage and SEER stage were further compared by the concordance index (C-index) and decision curve analysis (DCA). Results. A total of 4415 eligible patients with EOEC were identified and enrolled in this study. Independent prognostic factors for OS and CSS were confirmed by multivariate Cox regression, which were further incorporated to constructed a nomogram. ROC curves and calibration curves indicated an optimal accuracy of the nomogram. Meanwhile, the C-index and DCA showed the predictive capability and the clinical applicability of the nomogram was superior over the TNM stage and SEER stage. Conclusions. Nomogram based on risk factors was developed as an individualized tool to predict OS and CSS for EOEC patients. The novel tool will assist in patient counseling and selection of appropriate therapeutic regimens.

This study evaluated the exogenous application of PGRs substitute chemical fertilization without compromising the growth and yield of tomato in fluctuated day-night temperature and humidity stressed late winter. Two-factor experiment comprising chemical fertilizers at 100, 110, 90 and 80 % of recommended doses besides control and PGRs of GA3; NAA, 4-CPA and SA @ 50 ppm including control was conducted where treatments were assigned in triplicates. Results revealed no significant variation among the fertilizer doses (80% to 110% of recommendation) regarding growth and yield contributing traits while among the PGRs, GA3 @ 50 ppm produced maximum number of flower clusters plant-1 (16.85), flowers (8.80) and fruits (5.79) cluster-1, single fruit weight (67.83 g) and fruit yield (6.61 kg plant-1) of tomato that was statistically identical with the findings of SA. But significant reduction in yield was noted in NAA and 4-CPA (1.20 kg and 1.21 kg plant-1, respectively). Interestingly, GA3 and SA in combination with any doses of the studied fertilizers maximize the tomato morphological and reproductive traits while fertilizer plus NAA and 4-CPA interaction gave the inferior results. Further, correlation matrix and PCA findings revealed that five fertilizer doses have no distinctiveness whereas GA3 and SA has distinct position than other PGRs with the maximum dependent variables those were contributed positively in the total variations. The study findings suggested that 20% fertilizer requirement could be reduced with the substitution of GA3 and SA @ 50 ppm for successful cultivation of tomato in late winter having the extreme environmental issues.