Background/Objectives: Intravascular large B-cell lymphoma (IVLBCL) is a rare and diagnostically challenging disease, often presenting as fever of unknown origin (FUO). This study aimed to develop and validate diagnostic predictive models and scoring systems to distinguish IVLBCL from other causes of FUO in hospitalized patients. Methods: A retrospective analysis was conducted in patients with IVLBCL or other causes of FUO who were treated between February 2015 and October 2023. Two multivariable logistic regression models and corresponding integer-based scoring systems were developed in a training cohort comprising 42 patients with IVLBCL and 45 FUO controls. Internal validation was performed using leave-one-out cross-validation and bootstrap resampling, followed by temporal validation in an independent cohort of 18 patients with IVLBCL and 21 FUO controls. Model 1 was additionally evaluated for sensitivity in an external case-only cohort comprising 40 patients with IVLBCL from eight hospitals. Results: Model 1 incorporated peripheral edema, hypoxemia, neurological symptoms, hemophagocytic lymphohistiocytosis, and interstitial lung abnormalities on computed tomography and achieved an area under the receiver operating characteristic curve (AUC) of 0.916 in the training cohort. Model 2 combined the interleukin-10/interleukin-6 (IL-10/IL-6) ratio with peripheral edema, hypoxemia, and neurological symptoms and demonstrated significantly improved discrimination (AUC = 0.982, p = 0.021 vs. Model 1). In the temporal validation cohort, the AUCs of Models 1 and 2 were 0.975 and 0.997, respectively. The corresponding integer-based scoring systems achieved AUCs of 0.903 and 0.952 in the training cohort and 0.926 and 0.992 in the temporal validation cohort. In the external case-only cohort, both Model 1 and its integer-based score identified 32 of 40 patients, yielding a sensitivity of 80.0%. Random skin biopsy provided the histological diagnosis in 58% of cases, with a positivity rate of 79.5%. Conclusions: Two diagnostic models and their simplified scoring systems were developed and internally and temporally validated to aid the diagnosis of IVLBCL in hospitalized patients with FUO. These models may assist in the diagnostic workup of hospitalized FUO patients, especially when IL-10/IL-6 testing is unavailable. Their performance in outpatient or community settings remains uncertain, and prospective multicenter validation with appropriate FUO controls is warranted.

Tick-borne diseases pose significant public health threats. Non-specific symptoms and co-infections present diagnostic challenges for conventional methods. To address this, we developed the tick-borne pathogen (TBP) Panel, utilizing eight separate multiplex qPCR assays to simultaneously detect 25 TBPs (7 bacteria, 14 viruses, 4 parasites). Optimal Quantification Cycle (Cq) cut-offs were established using nested/semi-nested PCR amplicon sequencing, and digital PCR as reference standards. The Panel was then deployed for screening 2,333 ticks, 59 rodents, and 553 febrile patients. The Panel demonstrated robust analytical performance, achieving limits of detection (LOD99%) being 3.5-131 copies/reaction of plasmid, 10[2]-10[3] copies/mL of blood and 10[3]-10[4] copies/tick pool. This study established a tiered determination framework (Cq ≤ 36.6 as positive; Cq 36.6-39.6 requiring dual-replicate confirmation), yielding an overall AUC of 0.979, with 96.5% sensitivity and 96.5% specificity. Screening revealed a diverse pathogen landscape, identifying a total of 14 pathogens in 16.9% of the ticks (395/2,333), revealing a diverse geographical distribution. Five pathogens were identified in 7.9% of AFI patients (25/317), including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) and Ehrlichia spp., which were found circulating in local ticks. In the FUO cohort, a single case of Rickettsia spp. was identified. Rodent surveillance identified four pathogens, predominantly Bartonella spp. (67.8%). In conclusion , the rigorously validated TBP Panel enables rapid etiological identification of undifferentiated febrile illnesses, serving as a high-throughput tool that bridges large-scale surveillance with clinical diagnostics to close critical gaps in tick-borne disease management.

Ovotransferrin (OvoTf) is an iron-binding glycoprotein of avian innate immunity with antimicrobial activity, but its antifungal mechanism remains incompletely understood. We examined the candidacidal activity of OvoTf and two derived γ-core-containing peptides, kaliocin-3 (Kal-3) and kaliocin-4 (Kal-4), against Candida albicans. All three agents reduced fungal viability in a concentration-dependent manner, with minimal propidium iodide uptake, indicating a predominantly non-permeabilizing mechanism. Their activity was attenuated by extracellular Na[+] and K[+], whereas isoosmotic sorbitol did not confer protection. OvoTf induced partial K[+] release, and tetraethylammonium increased cell survival. Inhibition of mitochondrial complex I or ATP synthase also reduced susceptibility, although none of the agents detectably suppressed oxygen consumption under the conditions tested. OvoTf, Kal-3, and Kal-4 caused plasma membrane depolarization, ATP accumulation, and impaired glucose-induced proton extrusion. This phenotype is consistent with disruption of Pma1-dependent proton and ion homeostasis, with mitochondrial bioenergetic activity contributing as a downstream requirement rather than constituting the primary target. Neither peptide caused detectable hemolysis; Kal-4 had minimal effects on mammalian cell metabolic viability, whereas Kal-3 reduced MCF-7 metabolic viability at higher concentrations. The activity of γ-core regions in both OvoTf lobes supports their further study as templates for mechanism-guided antifungal design.

Background/Objectives: The objective of this study is to evaluate the efficacy and safety of maintaining antimicrobial (AM) therapy or adjusting AM therapy during episodes of febrile neutropenia (FN) catalogued as a fever of unknown origin (FUO) in children with cancer. Methods: This is a prospective, multicenter, noninferiority, randomized study, approved by ethics committee, in children with episodes of FN in eight hospitals in Chile. Microbiological and molecular samples were drawn at admission. Patients with FUO (negative bacterial and viral study with no clinical focus suggesting infection) and favorable evolution during the first 48-72 h of AM therapy were randomized 1:1 to maintain or adjust treatment, reducing the number and spectrum of AMs. The primary endpoint was the percentage of episodes with an uneventful resolution; the secondary endpoints were the re-adjustment of AM therapy, days of fever/hospitalization/AM therapy, days of vancomycin and meropenem per 1000 days of neutropenia, number of AMs after randomization, pediatric intensive care unit (PICU) admission, sepsis, and death. Results: A total of 266 of 939 FN episodes recruited between March 2021 and January 2024 were catalogued as FUO, of which 231 had a favorable evolution at 48-72 h and were randomized, 111 to maintain and 120 to adjust AM therapy. Both groups presented the same percentage of uneventful resolution, with 106 (96%) in the group that maintain AM therapy and 114 (95%) in the adjusted group (p = 1.00); relative risk 1.01, (95%CI 0.95-1.06); absolute risk difference 0.01, (95%CI -0.05-0.06). Conclusions: The main finding of this study demonstrates that adjusting antimicrobial therapy appears safe in carefully selected FUO cases with a favorable early evolution, during episodes of FN catalogued as FUO in children with cancer. These findings open an opportunity to new AM stewardship strategies in this population, with a possible future impact on AM resistance.

A clinical observation of a previously asymptomatic native knee developing a relevant coronal alignment change after total hip arthroplasty (THA) motivated this research. This raised the question of whether the native knee morphology could influence the response to biomechanical changes elsewhere in the lower limb. First, we developed a simplified finite element model incorporating the Coronal Plane Alignment of the Knee (CPAK) classification. We developed a simplified model of the knee, where we represented the lateral distal femoral angle (LDFA) by physically rotating the femur, and to avoid remodeling the tibia coronal plane for each simulation, we represented the medial proximal tibial angle (MPTA) by adjusting the neutral angle of the joint (the angle at which the joint generates no reaction force). This allowed for quick parametric iteration over the CPAK input space, showing which type of knees were more vulnerable to extreme valgus (CPAK III) and varus (CPAK VII) due to their morphology. The simplicity of this model will also enable users with less technical expertise to quickly obtain insights into specific knee morphologies, without requiring deep knowledge about finite element modeling. This existing model lays the foundation for later work, with a deeper look into how changes to hip morphology build on the pre-existing tendencies to varus and valgus.

Fever of unknown origin (FUO) poses significant challenges for clinicians due to the myriad of possible etiologies, exhaustive evaluation requirements, diagnostic delays, patient and family frustration, and prolonged hospital stays. Defined as a fever lasting more than three weeks without a diagnosis despite one week of inpatient evaluation, this clinical phenomenon could result from infectious, autoimmune, neoplastic, or miscellaneous etiologies. We report the case of an elderly woman with FUO who was diagnosed with oncocytic carcinoma of thyroid origin on cervical lymph node biopsy. Interestingly, the biopsy was taken from a cervical node that was detected incidentally on neuroimaging. Oncocytic thyroid cancers, also known as Hürthle cell carcinomas, are differentiated but aggressive thyroid neoplasia. These rare tumors often present as thyroid nodules, detected incidentally during imaging or as palpable thyroid swellings. This case report highlights the clinical and diagnostic challenges in patients with FUO and reports an exceedingly rare presentation of oncocytic thyroid cancer as FUO. Additionally, it emphasizes the diagnostic utility of imaging and the need to follow even subtle diagnostic clues when evaluating patients with FUO.

Background: Fever of unknown origin (FUO) remains a major diagnostic challenge due to its heterogeneous etiologies and nonspecific clinical manifestations. Although metagenomic next-generation sequencing (mNGS) represents a promising diagnostic tool, its clinical utility in adult patients with FUO remains incompletely characterized. Methods: In this study, we retrospectively analyzed adult FUO patients who underwent mNGS testing at Peking Union Medical College Hospital between March 2022 and April 2024. Clinically meaningful diagnostic contribution was determined according to the final clinical diagnosis following multidisciplinary adjudication. Diagnostic performance, pathogen spectrum, therapeutic impact, specimen type, and predictors of clinically meaningful mNGS results were evaluated. Results: A total of 127 FUO patients were included in the study. Infectious diseases accounted for 53.5% of final diagnoses, followed by noninfectious inflammatory diseases (11.0%), malignancies (10.2%), and undiagnosed conditions (19.7%). mNGS made a clinically meaningful diagnostic contribution in 31.5% (40/127) of patients, despite an overall positivity rate of 56.7% (72/127), and showed a higher sensitivity than conventional culture for infectious etiologies (69.1% vs. 16.9%), though with a lower specificity (57.6% vs. 96.0%). Diagnostic contribution varied significantly by specimen type, with drainage fluid/abscess samples showing the highest diagnostic yield (90.9%). Lower white blood cell count was independently associated with clinically meaningful mNGS results (OR 0.87, 95% CI 0.77-0.98). Conclusions: mNGS provides clinically meaningful diagnostic value in adult patients with FUO, particularly for identifying occult infectious etiologies. Lesion-directed sampling, whenever feasible, and careful interpretation of sequencing results in the clinical context are essential to maximize the diagnostic utility of this approach. A lower white blood cell count was independently associated with clinically meaningful mNGS results, although this finding requires validation in larger prospective studies.

Persistent fever as an initial manifestation of polycythemia vera (PV) is uncommon and may lead to diagnostic delay. We report a 72-year-old woman with recurrent low-grade fever for 1 month, with a maximum temperature not exceeding 38.0 °C. Although this presentation did not meet the classic fever-of-unknown-origin temperature threshold, it prompted an FUO-like diagnostic evaluation because routine infectious and autoimmune investigations were unrevealing and empirical antimicrobial therapy was ineffective. Laboratory evaluation revealed elevated hemoglobin and hematocrit levels, accompanied by leukocytosis and initially high-normal platelet counts that later progressed to thrombocytosis. Chest CT/PET-CT showed diffuse ground-glass/interstitial pulmonary changes; active bacterial pneumonia was considered unlikely based on the absence of respiratory symptoms, procalcitonin at the upper limit of the normal range, negative cultures and sputum smears, and absence of FDG-avid pulmonary consolidation, although a concomitant viral or noninfectious inflammatory pulmonary process could not be completely excluded. Bone marrow biopsy showed hypercellular marrow with panmyelosis and megakaryocytic proliferation, and molecular testing identified a JAK2 V617F mutation with a high allele burden. The diagnosis of PV was established based on the 5th edition of the World Health Organization (WHO) diagnostic criteria. The patient was treated with hydroxyurea and aspirin, resulting in gradual resolution of fever and improvement in hematological parameters. This case highlights that PV should be considered in the differential diagnosis of persistent unexplained low-grade fever when erythrocytosis and other myeloproliferative features are present, while alternative pulmonary causes should be assessed carefully.

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder that should be considered in patients presenting with fever of unknown origin (FUO). Diagnosis is challenging due to overlapping features with infectious, autoimmune, and hematological conditions. We report the case of a 19-year-old female presenting with a six-day history of persistent fever, later developing an evanescent rash and migratory polyarthralgia. Laboratory findings included cytopenias, elevated inflammatory markers, and markedly elevated ferritin levels. After ruling out infectious, autoimmune, and neoplastic etiologies, AOSD was diagnosed based on the Yamaguchi classification criteria. Initial treatment with corticosteroids led to partial clinical improvement, but persistent articular symptoms required escalation to anakinra, resulting in complete remission. This case reinforces that AOSD should be considered in the differential diagnosis of FUO, particularly in the presence of quotidian fever, rash, polyarthralgia, and marked hyperferritinemia. Early recognition and appropriate treatment, including biological therapy, are essential to control disease activity and prevent complications.

This case highlights the diagnostic challenges of managing a patient who initially presented with a fever of unknown source and subsequently met the criteria for fever of unknown origin (FUO) after more than 3 weeks of persistent fever despite an extensive diagnostic workup in a resource-limited tertiary hospital within Brazil's public health system. A man in his sixth decade presented with prolonged high-grade fever and severe lower-limb myalgia, initially raising suspicion for leptospirosis due to rural exposure and occupational history. Extensive evaluation-including blood cultures, serologies, and imaging screening-revealed no infectious or malignant cause. Persistent neutrophilic leukocytosis, marked hyperferritinemia, and elevated inflammatory markers suggested a systemic autoinflammatory disorder. A trial of low-dose prednisone produced partial improvement, and rheumatology consultation supported the diagnosis of adult-onset Still disease (AOSD) based on Yamaguchi criteria. Corticosteroid escalation resulted in the rapid resolution of fever and myalgia. This case underscores the importance of structured reasoning, systematic exclusion of common causes, and careful attention to laboratory patterns for timely diagnosis in resource-limited settings.