Immunity, Inflammation and Disease

Incidence of ventilator-associated pneumonia (VAP) is increased in patients admitted for brain injury. Staphylococcus aureus appears to be a particularly common pathogen in these respiratory infections. Our aim was to confirm the extent of S. aureus involvement in VAP among patients with neurological injuries. We conducted a retrospective, multicenter study including patients with and without neurological injuries who developed VAP during their ICU stay. Among 15 702 patients admitted in the participant centers during the study period. 407 were finally included in the study. S. aureus was involved in 122 (61.6%) VAP in brain-injured patients and 63 (30.1%) of non-brain-injured patients. In brain-injured patients, multivariate analysis identified age (0.97 [0.95; 0.98]), antibioprophylaxis (0.31 [0.18; 0.53]; p < 0.0001), subarachnoid hemorrhage (2.18 [1.01; 4.68]; p=0.0461), lower Glasgow coma score (0.92 [0.87; 0.97]; p= 0.004) and SAPS II (0.98 [0.97; 1]; p=0.0174) as critical factors associated with the risk of S. aureus in VAP. In the non-brain-injured population, multivariate analysis identified antibioprophylaxis (0.38 [0.22; 0.65]; p=0.0006), age (0.96 [0.95; 0.98]; p<0.0001), SAPS II (0.98 [0.97; 1]; p=0.0265), thoracic surgery (0.21 [0.09; 0.48]; p=0.0002) and peripheral neurosurgery (1.95 [1.2; 3.19]; p=0.0076) as critical factors. A total of 172 patients (42.3%) died during their ICU stay and 90-days mortality was 194 (47.7%). No difference of mortality was noticed function of VAP-associated pathogen.

BackgroundReactive oxygen species (ROS) overproduction, inflammatory cytokines, and plasma mediators disrupt alveolar tight junction integrity and perpetuate oxidative injury in acute respiratory distress syndrome (ARDS). Biological heterogeneity of ARDS, reflected by hyper- and hypoinflammatory subphenotypes with distinct plasma mediator profiles, may contribute to heterogeneity of treatment effect. Stem cell-derived EVs have been shown to exert regenerative and immunomodulatory effects by horizontal transfer of proteins, lipids and genetic material to injured target cells. This study investigated whether extracellular vesicles derived from bone marrow (MSC-EVs) and adipose tissue (ASC-EVs) mesenchymal stem cells restore barrier integrity and redox homeostasis, and whether efficacy differs across subphenotypes. MethodsBronchial epithelial cells (BEAS-2B), microvascular endothelial cells (HMEC-1), and small airway epithelial cells (SAEC) were challenged with plasma from patients with hyperinflammatory or hypoinflammatory ARDS subphenotypes, including those treated with venovenous ECMO. MSC-EVs or ASC-EVs were added concomitantly with plasma exposure or six hours later, at a dose of 5,000 particles/cell. After 24 h, the expression of actin and tight junction proteins, zonula occludens (ZO)-1, occludin, and vascular endothelial (VE)-cadherin, was evaluated by immunofluorescence. Oxidative stress parameters, antioxidant defenses, and antioxidant enzyme activities, were measured. ResultsPlasma from patients with the hyperinflammatory ARDS subphenotype induced marked disruption of ZO-1, occludin, and VE-cadherin expression, together with actin cytoskeletal rearrangement, across BEAS-2B, HMEC-1, and SAEC cells. Barrier disruption was accompanied by increased oxidative stress markers and altered antioxidant enzyme activity. Both MSC-EVs and ASC-EVs restored tight junction protein expression and cytoskeletal organization when administered either concurrently with ARDS plasma or 6 hours after exposure, and both effectively modulated redox parameters. Delayed administration 6 hours after injury produced greater effects for several oxidative stress endpoints, particularly in cells challenged with hypoinflammatory plasma. ConclusionARDS-associated plasma mediators induce subphenotype-dependent impairment of epithelial-endothelial barrier integrity through oxidative mechanisms. Both MSC-EVs and ASC-EVs mitigate this injury, with efficacy that varies according to ARDS subphenotype and timing of administration.

Sepsis is a global health problem. Patients in the Intensive Care Unit (ICU) are at risk of having sepsis because of their vulnerability and use of invasive medical devices. Emerging antimicrobial-resistance complicates treatment. Understanding bacterial profiles and antibiotic sensitivity patterns in the ICU plays an important role in managing sepsis, optimizing antimicrobial use, and improving patient outcomes. The aim of this study was to show bacterial profiles and antibiotic sensitivity patterns among patients who were admitted to the ICU at Mbeya Zonal Referral Hospital for 12 months. This was a prospective cross-sectional study among 187 sepsis-suspected patients. Data analysis was performed using SPSS Version 27. Categorical data were summarized by frequency and percentage. Fishers exact test, chi-square test, and modified Poisson regression were used to show the association between patients clinical variables and culture positivity at a 95% CI. Statistical significance was set at a p-value < 0.05. Out of 187 samples, 41.7% were culture positive. Gram-negative bacteria were commonly isolated (65.4%, with Klebsiella pneumoniae and Escherichia coli being commonly isolated. Commonly isolated Gram-positive bacteria were Coagulase-negative Staphylococcus species (19%). 100% of gram-positive bacteria and 96% of gram-negative bacteria were Multi-Drug Resistant (MDR), respectively. In multivariable analysis, patients who were intubated and mechanically ventilated (aPR = 2.208, 95% CI: 1.133-4.305, p = 0.020) and post-laparotomy patients (aPR = 3.241,95% CI: 1.320-7.958, p = 0.010) independently had a higher proportion of Gram-negative bacteria. The study reveals a high level of resistance to commonly used antimicrobials in our setting, necessitating strengthening of the antimicrobial stewardship program and routine surveillance of antimicrobial resistance patterns.

The human host defence peptide LL-37 mediates pleiotropic immunomodulatory functions that can be both pro- and anti-inflammatory. Under inflammatory conditions in the lungs, LL-37 is susceptible to the post-translational modification (PTM) citrullination. The impact of this PTM on LL-37's immunomodulatory functions is not fully understood. Therefore, we characterized the transcriptome and cytokine profile in response to LL-37 and citrullinated-LL-37 (citLL-37), in human bronchial epithelial cells (HBEC). Cells were stimulated with either LL-37 or citLL-37 (0.5 M), or a scrambled peptide (sLL-37). RNA after 4 hours (h) was analyzed with NanoString nCounter Host Response Panel, and 96 cytokines were examined (after 24 h) in tissue culture supernatants (Luminex platform). Genes and cytokines with a Log2 fold-change [&ge;]0.5 with p<0.05 compared to unstimulated cells were considered differentially expressed (DE). These studies revealed overlapping and distinct biosignatures. There were 118 DE genes with LL-37 and 71 with citLL-37, of which magnitude of change was significantly different for 32 genes. 16 out of 17 DE genes altered by both peptides were directly related to inflammation, and these were significantly less (by ~45%) with citLL-37 compared to LL-37. Similarly, inflammatory cytokines enhanced in response to LL-37 were significantly less (by 37-94%) with citLL-37. Overall, our findings indicate that citrullination of LL-37 does not abrogate cellular response in HBEC, instead dampens the inflammatory biosignature induced by LL-37.

Background: Recurrent ocular herpetic disease is a leading infectious cause of corneal blindness and is associated with psychological distress, anxiety, and social withdrawal. No ocular herpes vaccine or immunotherapy currently exists. Hypothesis: A prime/pull/keep (PPK) T-cell immunotherapy, built on HSV-1 epitopes preferentially recognized by CD8+/CD4+ T cells from naturally protected asymptomatic (ASYMP) individuals, would reduce viral reactivation, shedding, recurrent corneal disease, and associated neurobehavioral deficits. Methods: Immunodominant HLA-restricted CD8+/CD4+ epitopes from HSV-1 gD/gB, tegument proteins VP11/12/VP13/14, and helicase UL9 were delivered via topical ocular AAV8 vector (prime) to latently infected HLA-A*0201/DRB1 mice, combined with chemokine CXCL11 (pull) and IL-2/IL-15 cytokines to sustain TRM cells (keep), then UVB-exposed to trigger reactivation and recurrent corneal disease. Results: PPK immunotherapy conferred robust, near-complete protection against recurrent HSV-1 disease and improved survival after UVB-induced reactivation, unlike its individual components. This protection was associated with site-specific accumulation of HSV-1-specific CD8+/CD4+ TRM cells in the cornea and trigeminal ganglia (TG), but not in the spleen, with peak retention from combined IL-2/IL-15, alongside durable central/effector memory populations. PPK-induced T cells showed enhanced polyfunctionality (cytokine production, cytotoxicity, proliferation), reduced exhaustion markers, and a TCF-1+ self-renewing phenotype. PPK also elicited robust, Th1-biased HSV-1-specific IgG responses complementing mucosal immunity, and restored spatial memory, reduced depression-like behavior, and reversed social withdrawal in mice with recurrent ocular herpes. Conclusion: PPK immunotherapy induces potent, durable antiviral TRM cells at primary sites of HSV-1 latency and reactivation, protecting against recurrent ocular herpetic disease and alleviating associated neurobehavioral deficits, supporting its translational potential in humans.

Dendritic cells (DCs) are central orchestrators of antiviral immunity but can be exploited by HIV-1 to facilitate systemic dissemination. HIV-1 recognition by CD169 triggers massive endocytosis (MEND)-related internalization of viral particles into sac-like compartments in monocyte-derived dendritic cells (MDDCs), thereby promoting trans-infection of CD4+ T cells. However, MDDCS represent only one DC subpopulation, and whether other physiologically relevant DC subsets exhibit similar behavior remains unclear. Moreover, endogenous CD169 expression and viral capture have not been fully characterized in cDC1, DC2, or pDCs, while remain unknown in DC3. We therefore investigated the contribution of these DC subsets to CD169-mediated HIV-1 capture and subsequent viral dissemination. We used flow cytometry to assess CD169 expression and viral capture across DC subsets differentiated from CD34 hematopoietic stem and progenitor cells (HSPC) obtained from bone marrow (BM) and cord blood (CB), two sources that differ in cellular maturity. Confocal microscopy was used to evaluate sac-like compartment formation following immune activation with IFN- or LPS and treatment with MEND inhibitors. Trans-infection capacity was quantified by measuring luciferase activity in TZM-bl reporter cells. We identified cDC1, DC2, DC3, moDC (similar to MDDCs), and pDC subsets following the differentiation of CD34 HSPC from both CB and BM. Among these populations, DC2, DC3, and moDC displayed high CD169 expression, which was significantly upregulated by IFN- or LPS stimulation. BM-derived DCs exhibited higher basal CD169 expression than CB-derived DCs, whereas stimulation induced greater CD169 upregulation in CB-derived DCs. DC2, DC3, and moDC efficiently captured HIV-1 particles in cultures derived from both sources, and viral uptake was further enhanced by immune activation. Viral internalization into sac-like compartments depended on CD169 binding and MEND-related mechanisms, ultimately facilitating HIV-1 transfer to target cells. DC2 and DC3 are key dendritic cell subsets that support CD169 dependent HIV-1 capture and are associated with MEND-driven internalization into sac-like compartments and subsequent viral transfer to target cells, as was previously described for moDCs. We further observed distinct basal and inducible CD169 expression profiles in BM- and CB-derived DCs, consistent with source-dependent maturation states. These results identify DC2 and DC3 as key cellular contributors to HIV-1 dissemination.

Introduction: Thyroid diseases are major health problems and among the most common endocrine disorders worldwide, including in Ethiopia. They are characterized by alterations in hormone secretion, enlargement of the thyroid gland, or both. Fine needle aspiration cytology is an important initial screening tool, and histopathologic examination is essential for the definitive diagnosis of thyroid disease. This study aimed to compare the diagnostic accuracy of fine needle aspiration cytology with histopathology in identifying thyroid diseases. Methods: A cross-sectional study was conducted at three health facilities in Hawassa City, Ethiopia, involving 304 patients who underwent both thyroid fine needle aspiration cytology and histopathologic examination of the same site between 30th October 2024 and 29th October 2025. FNAC results were classified using the Bethesda system, with histopathology as the gold standard. Data were entered into Kobo Toolbox, exported to SPSS version 27, and analyzed using cross-tabulation and chi-square ({chi}{superscript 2}) tests to determine diagnostic accuracy. Result: 304 patient records were included in the study. The fine needle aspiration cytology was determinate/diagnostic in 81.6% of cases. The study revealed the sensitivity and specificity of fine needle aspiration cytology to be 88.2% (CI 77.6-95.1%) and 94.4% (CI 90.6-97.1%), respectively. The false negative and false positive rates in this study were 2.4% and 4.4%, respectively. The positive predictive value was 80.3% (CI 68.7-89.3%), and the negative predictive value was 96.8% (CI 93.8-98.7%). The accuracy of fine needle aspiration cytology in differentiating benign from malignant thyroid lesions was 93.1%. Conclusion: FNAC demonstrated strong agreement with histopathology and remains a reliable, cost-effective first-line diagnostic tool for thyroid disease, particularly in resource-limited settings. Strengthening sample handling, ultrasound guidance, and adherence to Bethesda criteria may further improve diagnostic precision

Background Vitiligo is an acquired depigmenting disorder characterised by melanocyte loss. While immune responses against melanocytes are implicated in its pathogenesis, melanocyte detachment, melanocyte senescence and aberrant epidermal differentiation are increasingly characterised as additional pathological features. Granzyme B (GzmB), classically recognised as an intracellular effector of perforin-dependent cytotoxicity, is increased in vitiligo lesions; however, its extracellular contribution to vitiligo pathology remains unclear. Objectives To determine whether extracellular GzmB contributes to depigmentation and epidermal pathological features relevant to vitiligo, and to define its cellular source and underlying mechanisms. Methods Human vitiligo skin samples, murine depigmentation models and cultured human epidermal cells were analysed. The functional effects of extracellular GzmB were examined by subcutaneous administration of recombinant GzmB in mice. A rhododendrol (RD)-induced leukoderma model was used to evaluate the disease relevance of GzmB and the therapeutic effect of topical GzmB inhibition with VTI-1002. Results GzmB-positive cells were markedly increased in active vitiligo lesions and were predominantly associated with tryptase-positive cells, with limited co-distribution with CD8 or perforin. Vitiligo lesions also showed melanocyte detachment, increased p16INK4A-positive melanocytes and aberrant keratinocyte differentiation. These pathological features were recapitulated in vivo by extracellular GzmB administration, accompanied by focal depigmentation. In cultured melanocytes, GzmB exerted no cytotoxic effects but reduced attachment strength and induced a senescence-associated phenotype characterised by decreased extracellular matrix- and adhesion-related gene expression, increased p16INK4A level, elevated senescence-associated {beta}-galactosidase activity and activation of transforming growth factor-{beta}/SMAD signalling. In keratinocytes, extracellular GzmB promoted aberrant differentiation associated with activation of p53 signalling. Topical inhibition of GzmB in RD-induced leukoderma attenuated depigmentation progression, melanocyte detachment, melanocyte senescence and abnormal epidermal differentiation. Conclusions Extracellular GzmB promotes depigmentation associated with inducing melanocyte detachment, melanocyte senescence and aberrant keratinocyte differentiation. These findings identify extracellular GzmB as a previously underrecognised pathogenic mediator and potential therapeutic target in vitiligo-associated depigmentation.

Abstract Background: Chronic subdural hematoma (cSDH) remains a significant and increasingly prevalent cause of morbidity in older adults. Disease progression is sustained by de novo formed highly vascularized pseudomembranes and a persistent cycle of fluid accumulation and hematoma expansion. Although inflammatory and angiogenic pathways have been implicated in cSDH pathogenesis, the endothelial mechanisms underlying persistent vascular leak remain poorly understood. We investigated the cSDH vascular microenvironment in human patients and examined the role of vascular endothelial cadherin (VECAD) remodeling in cSDH endothelial dysfunction. Methods: Human cSDH membranes and fluid were evaluated by multiplex profiling, histology, immunofluorescence, immunoprecipitation, western blotting and exploratory bulk RNA sequencing. A human brain endothelial cell (HBEC) line was exposed to patient-derived cSDH fluid to assess VECAD remodeling, endothelial barrier permeability, and proliferation. Results: Multiplex profiling of patient-derived cSDH fluid detected mediators associated with endothelial cell (EC) activation, extracellular matrix remodeling, inflammation, and angiogenesis. In patient pseudomembranes, discontinuous VECAD coincided with erythrocyte extravasation. Two hyperdense (high-risk) specimens showed more extensive disruption than the hypodense (low-risk) specimen while vessel counts appeared similar. Bulk RNA sequencing identified an angiogenic environment and enrichment in cadherin regulation. A soluble VECAD (sVECAD) isoform was detected in cSDH fluid. Exposure of HBECs to patient-derived cSDH fluid increased EC proliferation, cytoplasmic VECAD (cVECAD) accumulation, and EC barrier permeability. Concurrent dexamethasone or minocycline treatment attenuated VECAD cleavage. Conclusions: VECAD disruption is a prominent feature of cSDH and is associated with EC barrier dysfunction. These findings support further evaluation of soluble VECAD as a candidate biomarker and of junction-preserving pathways as potential therapeutic targets.

Stem cell-derived (SC) islets hold promise as a transformative therapy for type 1 diabetes (T1D). To enhance graft uniformity, SC-islet organoids are often dissociated and reaggregated into standardized sizes. However, how endocrine cell composition varies with islet size in native human islets remains largely unknown. Defining this relationship is essential for establishing physiological benchmarks for islet engineering for transplantation. In this study, we examined the relationships among islet size, endocrine cell composition, and spatial distribution throughout whole pancreata from 10 age-matched, non-diabetic male subjects. Insulin-, glucagon-, and somatostatin-positive endocrine cells were identified as single-, double-, and triple-hormone populations ranging from non-islet single endocrine cells and small clusters (niSSCs) to large islets. Approximately 80% of the total endocrine area was contained in islets positive for all three hormones. Islet size strongly correlated with endocrine composition. Specifically, larger islets had increased alpha-cell fractions and reduced beta-cell fractions, while delta-cell fractions were consistent across sizes. Spatial analysis revealed that niSSCs, mono-, and tri-hormone islets frequently exhibit a clustered distribution. Additionally, tri-hormone islets were positioned near the core of the pancreas, whereas mono-somatostatin islets were often localized in the periphery. These findings were consistent across all three pancreatic regions (head, body and tail).

Objective: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) frequently present as overlap syndromes, characterized by shared sexual dimorphism and elevated intestinal Veillonella dispar (V. dispar) abundance, yet exhibiting distinct hallmark pathological manifestations. This study aimed to elucidate the shared pathogenesis, phenotypic differentiation mechanisms and sex-specific predisposition of AIH and PBC induced by V. dispar. Methods: Clean-grade and germ-free (GF) mice were employed to establish AIH and PBC models. Model induction involved oral gavage of V. dispar and intraperitoneal injection of either liver-specific antigen S100 (for AIH) or a pyruvate dehydrogenase complex E2 subunit (PDC-E2) mimetic peptide (for PBC). Single-cell RNA sequencing, metabolomics, transmission electron microscopy, western blotting, and flow cytometry were utilized to elucidate the underlying mechanisms. Results: V. dispar successfully induced autoimmune liver disease-like features in mice, characterized by significant intrahepatic B cell infiltration. Mechanistically, V. dispar caused systemic arginine reduction, leading to intrinsic apoptosis of gonadal stromal cells and a subsequent reduction in testosterone. This decreased testosterone weakened its inhibitory effect on B cell activating factor (BAFF) secretion, thereby amplifying B cell-mediated immune responses. Furthermore, in the presence of S100 or PDC-E2 mimetic peptide, V. dispar also facilitated Th17 cell activation, which guided the phenotypic differentiation into AIH or PBC, respectively. Consistent with these findings, our clinical observations revealed that patients with AIH and PBC tended to harbor enriched V. dispar, along with lower serum arginine and testosterone. In addition, elevated serum levels of BAFF and IL-17 were also observed in these patients. Conclusion: V. dispar induces reduced testosterone levels and upregulation of BAFF, leading to intrahepatic B cell expansion, which serves as the common pathogenic basis for AIH and PBC. The presence of S100 and PDC-E2 subsequently drives further maturation of these expanded B cells and promotes Th17 cell activation, thereby determining the phenotypic divergence between AIH and PBC.

Background: Neutrophils migrate to the respiratory epithelium during rhinovirus (RV) infection, but whether RV directly activates neutrophils or whether activation arises from epithelial responses remains unclear. Objective: To determine whether RV directly activates human neutrophils or indirectly activates them through RV infected airway epithelial cells. Methods: Human neutrophils were exposed to purified RV, and activation was assessed by myeloperoxidase activity, CD11b/CD66b expression, and reactive oxygen species (ROS) production. Neutrophils were co-cultured with RV-infected air liquid interface (ALI) bronchial epithelium evaluated for effects on epithelial integrity. At 48 to 72 hours post-infection, we used live-cell imaging to measure ROS responses and neutrophil-tracking assays to measure migration velocity and ROS responses to basolateral supernatants, clarified apical washes, and apical debris from RV-infected epithelial cells. Plaque assays were used to assess for RV infectivity after incubation with apical neutrophils. Results: RV did not directly activate neutrophils. Adding neutrophils to the apical surface of airway epithelial cells increased neutrophil ROS production at 48 to 72 hrs post-infection but did not alter epithelial cytotoxicity. Conversely, basolateral supernatants from infected cells enhanced neutrophil migration but not ROS, consistent with cytokine-mediated priming. Clarified apical washes had no effect on migration or ROS. By contrast, apical debris from infected cultures triggered a robust ROS response. Basolateral fractions from medium control or RV infected cultures did not induce ROS. Infectivity is not impacted by apical neutrophil presence. Conclusion: RV does not directly activate neutrophils. Instead, RV infected epithelial cells release basolateral factors that enhance neutrophil migration, while apical debris from infected cells drives ROS activation. These findings indicate that epithelial injury, not RV itself, is the dominant trigger of neutrophil activation during infection.

The honey bee ectoparasitic mite Tropilaelaps mercedesae is an emerging threat to Western beekeeping, as it is expanding its range from native Asia. In this study, the first record of the presence of Tropilaelaps mercedesae in Turkiye, in the Artvin province, in the north-east of the country is documented. Following reports of weakening colonies, eight apiaries were inspected using the rapid brood decapping method. All apiaries were found positive, and infestation was detected in 22 of 24 examined colonies. Mite samples were analysed with morphometry and barcoding and were confirmed as T. mercedesae. In the paper, we discuss the impact of imports and migration practices on the mites occurrence in Turkiye. In addition, we forecast the potential corridors and means of further invasion and address the implications for European and global apiculture.

Epidermodysplasia verruciformis (EV) is characterized by susceptibility to cutaneous {beta}-human papillomaviruses, persistent viral lesions and an increased risk of cutaneous squamous cell carcinoma (cSCC). We investigated whether expression of Toll-like receptors 3, 4, 5 and 9 (TLR3, TLR4, TLR5 and TLR9) differs across histological states within EV. Immunoreactivity was quantified by digital H-score using QuPath in 97 specimens from 28 patients, comprising 13 lesion-free skin samples, 15 flat warts and 69 cSCCs. Prespecified comparisons evaluated flat wart versus lesion-free skin, cSCC versus non-neoplastic tissue and invasive versus in situ cSCC, with invasive tumour differentiation assessed secondarily. Patient-clustered generalized estimating equations and false-discovery-rate (FDR) correction were used for inference. After correction for multiple testing, TLR9 H-scores were higher in flat warts than in lesion-free skin ({beta}=60.58; q=0.0332). Compared with non-neoplastic tissue, cSCC showed lower TLR3 ({beta}=-81.40; q=0.00745), higher TLR4 ({beta}=55.59; q=0.04793) and lower TLR9 expression ({beta}=-34.80; q=0.03412). TLR5 showed a nominal increase in cSCC that did not meet the FDR threshold. None of the four receptors differed significantly between invasive and in situ cSCC, and no differentiation trend remained significant after FDR correction. These findings show receptor-specific differences in TLR expression across histological states of EV, particularly involving TLR3, TLR4 and TLR9, although the diagnostic and prognostic significance of these tissue patterns remains to be established.

Objective: To test the hypothesis that selected SIRS and SOFA criteria measured at ICU admission have divergent associations with (1) the development of new culture-confirmed infections and (2) early empiric broad-spectrum antibiotic receipt in critically ill patients with cirrhosis. Design: Retrospective, observational study using electronic health record (EHR) data. Setting: Both community and academic ICUs within a five-hospital health system between July 2017 and December 2025. Subjects: Adult patients >18 years of age diagnosed with cirrhosis admitted to the ICU within 96 hours of hospital admission. Patients transferred from outside facilities and those with positive cultures collected >24 hours before ICU admission were excluded. Interventions: None. Measurements: Multivariable logistic regression tested the association of the most aberrant values in nine SIRS/SOFA vital sign and laboratory parameters measured during the 24 hours prior to ICU admission with (1) the development a newly positive culture collected during the 24 hours before through the 96 hours after ICU admission and (2) receipt of broad-spectrum antibiotics during the 24 hours before through the 24 hours after ICU admission. Main Results: The presence of hyperthermia, hypothermia, hypoxia, or hypotension at ICU admission was associated with both culture positivity and antibiotic receipt. The presence of leukocytosis was associated with antibiotic receipt but not culture positivity. Among patients in the 21.6% of encounters with newly positive cultures, normothermia and normal WBC were common (respectively present in 97.2% and 77.5% of encounters) and associated with antibiotic omission at ICU admission despite the subsequent development culture positivity. Conclusions: Traditional physiologic markers of infection are often absent in critically ill patients with cirrhosis who develop new culture-confirmed infections at ICU admission, possibly contributing to delayed antibiotics. There may be opportunities to improve antibiotic delivery and stewardship at ICU admission in this high-risk population.

Introduction: Mast cells are central effectors of IgE-mediated allergic responses and reside in barrier tissues, where they encounter diverse environmental compounds. How naturally occurring bioactive compounds influence mast cell function under resting versus allergic conditions remains poorly defined. Methods: We compared the effects of cholera toxin, aconitine, and sennoside A on viability, degranulation, and cytokine production in murine bone marrow-derived mast cells. We then examined the acute physiological effects of oral sennoside A in an ovalbumin-induced mouse model of food allergy. Results: None of the compounds reduced mast cell viability at the concentrations tested. Sennoside A, but not cholera toxin or aconitine, induced modest degranulation in resting mast cells without increasing TNF- or IL-6 secretion. In contrast, sennoside A markedly suppressed IgE-dependent antigen-induced degranulation, TNF- and IL-6 secretion, and Il1b expression. Acute oral sennoside A induced dose-dependent diarrhea and hypothermia and increased colonic Tnfa, Il1b, Il33, and Hdc expression. In allergic mice, sennoside A attenuated allergen-induced hypothermia, reduced duodenal Tpsab1 expression, and decreased circulating total IgE, OVA-specific IgE, and OVA-specific IgG1, while increasing Il5 expression. Conclusion: Sennoside A differentially regulates mast cell responses according to activation state and attenuates features of experimental food allergy. These findings identify a previously unrecognized immunomodulatory effect of sennoside A on IgE-driven mast cell activation. However, the mechanisms and the contribution of mast cells to the in vivo phenotype remain to be defined.

Sepsis mimics resemble sepsis clinically but may require different treatments. We evaluated whether inflammatory protein profiles could distinguish these conditions in a retrospective case-control study using 4 prospective Japanese cohorts. The study included 34 adults with sepsis and 46 with sepsis mimics. We measured 92 proteins using Olink, assessed between-group differences with false discovery rate (FDR) adjustment, and evaluated 3 prediction models using repeated nested cross-validation. No protein met the FDR threshold; the lowest FDR-adjusted P value was 0.345. The primary elastic-net model had an area under the receiver operating characteristic curve of 0.442 (95% confidence interval, 0.315-0.574), based on cross-validation predictions averaged for each participant. Random forest and gradient boosting also showed no clear evidence of discrimination above chance. Confidence intervals included chance performance in both the all-serum and quality-control-Pass sensitivity analyses. In this cohort, a single measurement of an inflammation-focused protein panel showed limited discrimination between sepsis and sepsis mimics. Integration with clinical information and longitudinal measurements warrants further investigation.

Objective: Hyperthyroidism and hypothyroidism related to iodine deficiency are major public health concerns in Afghanistan. This study aimed to assess the frequency of thyroid dysfunction among male patients referred for thyroid testing and its association with age, and to examine monthly trends in thyroid dysfunction at Asia Med Laboratory in Herat, Afghanistan, from July 2021 to January 2022. Methods: A retrospective analysis was conducted on 250 male patients aged 0-69 years. We measured Serum TSH, total T4, and total T3 levels, and thyroid status was classified using age specific reference ranges. In addition, the frequency of thyroid dysfunction was analyzed across age groups with monthly trends of thyroid state. Results: Overall, the euthyroid state consisted of 69.2% of participants, 24.8% with overt hypothyroidism, 3.2% with overt hyperthyroidism, and 2.8% with subclinical hyperthyroidism. Thyroid status differed significantly by age (p = 0.0135), with hypothyroidism increasing in older age groups and reaching its highest proportion among men aged 60-69 years (55.6%). Euthyroidism predominated in patients aged 10-39 years, while hyperthyroidism across age groups remained relatively infrequent. After September 2021, a threefold increase was observed in the total number of male patients referred for thyroid testing. During this period, the proportion of hyperthyroidism increased slightly, whereas hypothyroidism cases declined. Conclusion: In conclusion, hypothyroidism was more frequent with older age. The rise in absolute case numbers after September 2021 likely reflects increased patient referrals, underscoring the need for ongoing monitoring of thyroid function. The study may assist in the early management of thyroid disorders and in reducing their complications.

Background/Aims: In medical practice, the rising prevalence of infections in kidney transplant recipients (KTRs) is a notable concern. However, understanding the incidence and risk factors associated with infections in KTRs remains limited. This study aims to assess the incidence and factors associated infection among KTRs. Additionally, we also investigate the median time of each infection among KTRs. Methods: A retrospective cohort study was conducted from 1 January 2018- 31 December 2022 at Thailand's tertiary hospital. We performed univariable and multivariable logistic regression analyses to identify potential risk factors related infection and investigated for the incidence and median time of each infection among KTRs. Results: A total of 179 participants were included in this study. Our findings reveal the kidney from living donor was protective factor for infection among KTRs (aOR 0.063, 95% CI 0.005-0.792; p = 0.032). Urinary tract infections (UTIs)showed as the predominant pathogenic manifestation among KTRs (43%). The median time of UTIs, cytomegalovirus (CMV) infection and pneumocystis pneumonia (PCP) were 16, 57 and 94.5 days, respectively. Conclusions: Our study establishes that receiving a kidney from a living donor is a protective factor against post-kidney transplant infections. Particularly urinary tract infections were most common of infection. Monitoring urinary tract infections post-transplantation is recommended. Moreover, awareness of UTI, CMV infection and PCP should be concerned during 2-3 months after transplantation. However, due to a small sample size; we recommend to increase the number of particular participants in further investigations.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy associated with a poor prognosis and an unmet need for more effective treatment options, particularly after relapse. One potential approach to address this need, which has been used successfully in solid tumors, is adoptive transfer of T cells engineered to express specific T cell receptors (TCRs). Particularly attractive are TCRs that can target epitopes derived from oncogenes on which cancer cells depend while sparing normal cells that do not harbor the mutation. One promising oncogenic target in AML is mutated nucleophosmin 1 (mtNPM1), present in up to 30% of AML cases. Most NPM1 mutations result in a common frameshifted sequence that generates peptides presented by several class I human leukocyte antigens (HLAs), such as HLA-A*11:01. In this study, we vaccinated HLA-A*11:01-transgenic mice with the mtNPM1 peptide AVEEVSLRK and isolated six functional TCRs from mtNPM1-reactive lymphocytes. When engineered into human T cells, two of these TCRs consistently mediated robust and specific lysis of an AML cell line and primary AML cells co-expressing HLA-A*11:01 and mtNPM1. Neither TCR recognized related human peptides, HLA-A*11:01-expressing normal peripheral blood mononuclear cells or stem/progenitor cells, or cells expressing diverse allogeneic HLAs, suggesting a low risk of cross-reactivity and alloreactivity. In an AML xenograft model, both TCRs controlled AML in hematopoietic organs, although extramedullary tumors emerged during treatment, potentially reflecting the aggressive behavior of the model that may not be representative of AML in patients. Together, these data suggest that the two TCRs represent strong candidates for further preclinical development in adoptive T cell therapy for NPM1-mutated, HLA-A*11:01-positive AML. These results also support the use of HLA-transgenic mice as a platform for generating TCRs targeting oncogene-derived epitopes in hematologic malignancies.