The HIV epidemic remains a major public health challenge, specifically for women living with HIV who face vulnerabilities during pregnancy and motherhood. Furthermore, high vulnerability is closely linked to a lower quality of life. It is essential to address the determinants that influence quality of life within this population in order to enhance health outcomes and inform the development of evidence-based care protocols. An observational, cross-sectional study was conducted from 2020 to 2022 to assess the quality of life of Mexican postpartum women living with HIV (n = 75). The WHOQoL-HIV-Bref instrument was used. Quality of life results were analysed statistically in relation to sociodemographic and clinical factors to evaluate their associations and their predictive power through multinomial logistic regression analysis. Nearly half of postpartum WLWH experienced a lower quality of life (49%). Psychological health, Environment, Spirituality, religion and personal beliefs domains scores were below the median. There were multiple associations with socio-demographic and clinical factors. Highlights the use of ART during pregnancy and postpartum, HIV symptoms, sexual behavior, marital and educational status, mainly. Physical health, Independence level, and Spirituality, religion and personal beliefs domains were identified as potential predictors of a perception of high quality of life of this population. There are clinical and socio-demographic factors that influence the perception of quality of life in Mexican women living with HIV during postpartum. It is important to identify and mitigate these factors for the well-being of these women and their children. Further research is needed to evaluate the impact of interventions on Physical health, Independence level, and Spirituality, religion and personal beliefs domains to improve perception of high quality of life in WLWH. These findings ultimately underscore the need to integrate quality of life assessment as the fourth '95' target in World Health Organization strategies for people living with HIV.
Cough is one of the most common and distressing symptoms in pediatric practice and represents a major cause of medical consultation, parental anxiety, and inappropriate medication use. Although most acute cough episodes are benign and self-limiting, they can significantly affect child's sleep, school performance, and quality of life. The COVID-19 pandemic and subsequent changes in infection patterns and immune responses have further highlighted the need to update the existing clinical guidance. This joint position paper by the Italian Society of Pediatric Allergy and Immunology (SIAIP) aims to provide a pragmatic, evidence-based update on the management of acute and post-viral cough in children and adolescents, integrating recent scientific advances and real-world clinical experiences. A multidisciplinary board of experts from SIAIP critically reviewed the literature published from 2019 to 2025 and updated the previous 2019 SIAIP document. The group achieved consensus on diagnostic and therapeutic recommendations through structured discussion and iterative revision. The document emphasizes a stepwise approach to pediatric acute cough, starting with careful history-taking, clinical evaluation, and reassurance. Non-pharmacological measures-hydration, nasal saline irrigation, and avoidance of irritants-remain the first-line management. Pharmacological therapy may be considered in selected cases where cough is particularly distressing or significantly interferes with sleep; peripherally acting, nonsedative antitussives represent a reasonable option in terms of efficacy and safety. Centrally acting antitussives and unnecessary antibiotics should be avoided. Standardized, high-quality natural medical devices-with appropriate supporting evidence-represent a valid option. Honey-based preparations can be considered as complementary options. The paper also discusses new insights into cough pathophysiology, particularly the role of airway sensory hypersensitivity and neurogenic inflammation, which are paving the way for mechanism-based treatments. This position paper provides an updated, pragmatic framework for the management of acute and post-viral cough in children and adolescents. It promotes rational drug use, integration of non-pharmacological and complementary measures, and awareness of emerging therapeutic targets. A mechanism-driven, individualized, and family-centered approach is advocated to improve clinical outcomes and quality of life for pediatric patients.
To evaluate the predictive value of the systemic immune-inflammation index (SII) for clinical efficacy of acupuncture combined with exercise rehabilitation in patients with knee osteoarthritis (KOA). In this retrospective observational study, 151 patients with radiographically confirmed Kellgren-Lawrence Grade II or III KOA who completed an 8-week standardized protocol of acupuncture and exercise rehabilitation were enrolled. Clinical efficacy was defined as the attainment of minimal clinically important improvement (MCII) in both the 11-point Numeric Rating Scale (NRS) for pain (≥ 2-point reduction) and the 68-point WOMAC function subscale (≥ 6-point improvement, Likert version 3.1). Baseline demographic, clinical, and hematological data were collected, and SII was subsequently calculated from baseline hematological parameters. Uni- and multivariate logistic regression analyses were used to identify independent predictors of treatment response. Receiver operating characteristic (ROC) curves were constructed to assess the discriminative ability of SII, body mass index (BMI), and lymphocyte count, individually and in combination. Of the 151 patients, 73 were classified as responders and 78 as nonresponders. Baseline BMI and SII were significantly lower, while lymphocyte count was higher in the effective group (all p < 0.001). Multivariate logistic regression identified BMI (OR = 0.596, 95% CI: 0.472-0.753), lymphocyte count (OR = 34.597, 95% CI: 3.234-370.131), and SII (OR = 0.912, 95% CI: 0.873-0.953) as independent predictors of treatment response. ROC analysis showed that SII demonstrated only moderate predictive power (AUC = 0.749, 95% CI: 0.670-0.828), with improved but still moderate accuracy when combined with BMI and lymphocyte count (AUC = 0.858, 95% CI: 0.799-0.917). Although SII is an independent and accessible biomarker for predicting clinical efficacy, its discriminative ability is moderate. A combined model incorporating SII, BMI, and lymphocyte count may provide better, though not strong, predictive performance and could support clinical decision-making and individualized treatment planning. However, the retrospective single-center design may introduce selection bias and limit generalizability. Residual confounding from unmeasured variables cannot be excluded, and the absence of longitudinal SII measurements limits evaluation of temporal changes. Future multicenter prospective studies are warranted to validate these findings.
Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications. Deficiency of adenosine deaminase 2 (DADA2) is a rare genetic condition that causes inflammation and can affect multiple organs. We studied how often the liver is involved in DADA2 and whether simple, noninvasive tests can help detect liver involvement and track response to treatment. We found that DADA2 can cause problems with tiny blood vessels inside the liver called porto‐sinusoidal vascular disease (PSVD). PSVD can increase pressure in the portal vein system (portal hypertension), which may cause enlargement of the spleen, low platelet counts, development of enlarged veins in the oesophagus (varices), and fluid accumulation in the abdomen (ascites). In our cohort, clinical signs of portal hypertension were documented in 14% of patients, and 5% developed complications such as bleeding from varices or ascites. Because liver disease was largely silent, we evaluated practical ways to identify it early. More than half of patients had an enlarged spleen at baseline, and spleen size adjusted for height (the spleen‐to‐height ratio) emerged as a sensitive marker of liver involvement. Treatment with anti‐tumour necrosis factor medications led to a reduction in the spleen‐to‐height ratio in most treated patients, suggesting improvement in liver disease. We recommend routine screening for liver involvement in DADA2, with SH ratio and platelet counts, selective liver biopsy and endoscopy for suspected portal hypertension, and baseline hepatology evaluation prior to stem cell transplantation.
Following the COVID-19 pandemic, the clinical patterns of pediatric respiratory infections have undergone significant changes, with increasing attention on the immunological imprint left by Post-Acute Sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID. A perplexing clinical phenomenon has been observed: some children with a history of Long COVID exhibit a disproportionately severe inflammatory response and extensive lung injury when encountering common community-acquired pneumonia, such as that caused by Mycoplasma pneumoniae or Streptococcus pneumoniae, inconsistent with their pathogen load. This review aims to dissect this phenomenon and proposes the "Immune Priming and Two-Hit" model as its core pathophysiological framework. This model posits that the Long COVID state constitutes the "first hit," establishing a "primed" or "hyper-reactive" immune baseline through viral persistence, trained immunity-induced monocyte reprogramming, and sustained endothelial dysfunction. Upon the "second hit" of a bacterial infection, this primed immune system triggers a dysregulated, synergistically amplified inflammatory cascade. The mechanisms involve the exponential release of cytokines such as Interleukin-6 (IL-6), IL-1β, and Tumor Necrosis Factor-α (TNF-α), inflammation-mediated immunothrombosis, and excessive activation of Neutrophil Extracellular Trap formation (NETosis), ultimately leading to severe outcomes like Acute Respiratory Distress Syndrome (ARDS) and necrotizing pneumonia. Consequently, identifying and defining this "Hyper-inflammatory endotype" is of critical clinical importance. We define it as an "endotype" to emphasize the distinct, host-determined pathophysiological mechanisms underlying it, rather than merely a collection of clinical manifestations. By monitoring biomarkers such as ferritin, D-dimer, lactate dehydrogenase (LDH), and lymphocyte counts, clinicians may be able to perform early risk stratification of these children. This approach not only facilitates a shift in therapeutic strategy from purely antimicrobial therapy to "host-directed therapy"-emphasizing the necessity of early, adequate corticosteroid use and consideration of anticoagulation-but also provides a new theoretical basis and intervention window for preventing long-term sequelae such as pulmonary fibrosis.
Atopic dermatitis (AD), a chronic, immune-mediated inflammatory disease, is characterized by intense itch, eczematous rash, and skin pain, which can have negative impacts to quality-of-life (QoL), sleep, and mental health (especially anxiety and depression). Evaluation of the impacts of AD on the patient's lived experience are most accurately assessed by the patient, making measures of patient-reported outcomes (PROs) indispensable. The objective of the current study was to assess the long-term impact of upadacitinib, a once-daily oral selective Janus kinase inhibitor approved for the treatment of moderate-to-severe AD, on patient-reported outcomes, providing a comprehensive in-depth evaluation of results of patient experience across multiple domains. Using integrated data from the Measure Up 1 & 2 trials, the current study characterizes the efficacy of upadacitinib on several measures that assess the impact of AD on patients' lives, including patient-reported disease and symptom severity, sleep, emotional well-being, daily activities, QoL, and treatment satisfaction. Results demonstrated that rapid improvements in PRO measures of itch, sleep, daily activities, QoL, and emotional well-being reported at week 16 and week 52 were sustained or further improved at week 140 for patients with moderate-to-severe AD continuing upadacitinib 15 mg or 30 mg therapy, with no new safety signals observed. These findings support upadacitinib as a long-term treatment option to improve patient-reported burdensome symptoms of AD across 140 weeks of exposure.
Despite advances in acute care, stroke remains a leading cause of death and long-term disability worldwide, with limited treatment options to improve recovery after stroke. Traditionally, the management of ischemic stroke has mostly focused on early reperfusion, yet growing evidence highlights a central role for inflammation in both acute and long-term pathophysiology of stroke. The inflammatory response post-stroke is complex and dynamic, beginning with early intravascular activation of platelets and neutrophils (thrombo-inflammation), followed by microglial activation and the subsequent infiltration of peripheral immune cells, which together paradoxically contribute to tissue repair but can also worsen tissue injury. Importantly, this evolving understanding opens new therapeutic opportunities. However, efforts to target inflammation in stroke have yielded limited clinical success, as many strategies that showed promise in preclinical studies have failed to translate into beneficial outcomes. Here, we systematically review the role of inflammatory responses in stroke, integrating insights from both experimental and clinical studies. We highlight the roles of key immune cell populations and signaling pathways in mediating tissue injury and repair, also discussing the progress and limitations of inflammation-targeting clinical trials. We further address translational challenges, including optimal timing of intervention, mechanistic target validity, and the relevance of preclinical models. Finally, we explore emerging approaches, including targeting thrombo-inflammation, modulation of the gut-brain axis, reverse translation, and adaptive data-driven trial designs as potential strategies to refine therapy development to improve stroke outcomes. These insights provide a foundation for advancing the long-elusive goal of clinically translating immune therapy into effective stroke recovery treatments.
To comprehensively evaluate the efficacy and safety of three-dimensional (3D)-printed template-assisted CT-guided 125I seed implantation for refractory bone metastases in a multicenter cohort, to explore its impact on systemic immune function and to identify potential mechanisms. This retrospective analysis was conducted on 253 patients with refractory bone metastases who were continuously admitted to Affiliated Zhongshan Hospital of Dalian University, Linyi Cancer Hospital, The Affiliated Hospital of Xuzhou Medical University, Dalian Public Health Clinical Center, and The Second Hospital of Dalian Medical University. The onset time and the duration of pain relief were recorded. The therapeutic efficacy was evaluated by comparing pre- and postoperative Daily Oral Morphine Equivalent Consumption (OMEC), Numerical Rating Scale (NRS) for pain, Quality of Life (QOL) scores, and Karnofsky Performance Status (KPS) scores, as well as by measuring the quantitative changes in target lesion volume and Hounsfield unit (HU) values on imaging before and after the procedure. According to Response Evaluation Criteria in Solid Tumors version 1.1, the objective response rate (ORR) and disease control rate (DCR) were calculated to evaluate tumor response. Flow cytometry was used to detect and compare pre- and postoperative proportions of CD3+CD16+/CD56+ natural killer-like T (NKT) cells and CD3-CD16+/CD56+ NK cells, interleukin (IL)-17A level, and CD4+/CD8+ T-cell ratio, to assess the changes in host immune function after treatment. Local progression-free survival (LPFS) and overall survival (OS) were calculated, and adverse events were documented. All patients completed 3D-printed template-assisted CT-guided 125I seed implantation, with a procedural success rate of 100%. The clinical symptoms improved after treatment; the median onset time to pain relief was 3.5 days, and the median duration of relief was 10.7 months. The OMEC values and the NRS scores were significantly lower than those before procedure (P < 0.05), whereas QOL and KPS scores were significantly higher (P < 0.05). The radiologic evaluation showed that ORR and DCR were 42.29% and 69.56%, and 79.05% and 88.93%, respectively, at 1 and 6 months after implantation. The target lesion volumes reduced significantly (P < 0.05), whereas the HU value increased significantly (P < 0.05), indicating tumor necrosis and osteoblastic repair. The median LPFS was 14.1 months, and the median OS was 19.5 months. The immune function analysis revealed enhanced antitumor immune response, reflected by significant increases in the proportions of NKT cells, NK cells, and CD8+ T cells, a decrease in IL-17A level, and a trend toward normalization of the CD4+/CD8+ ratio (P < 0.05). Adverse events mainly consisted of transient local pain of Common Terminology Criteria for Adverse Events grades 1-2. No uncontrollable major bleeding, needle-track seeding, or other severe complication, and no treatment-related death occurred. The 3D-printed template-assisted CT-guided 125I seed implantation was a safe and effective treatment for refractory bone metastases. It provided durable local tumor control and pain relief, and was accompanied by systemic immunological changes. These changes correlated with clinical improvements, suggesting a potential immunological component to the therapeutic effect. This therapy therefore provided a promising treatment strategy for refractory bone metastases.
Dedicator of cytokinesis protein 8 (DOCK8) is a crucial regulator for the formation of immune synapses, allowing for a proper function of innate and adaptive immune systems. DOCK8 deficiency is a primary immunodeficiency, currently known as Inborn Errors of Immunity (IEI) affecting both cellular and humoral immunity, thus leading to various clinical presentations ranging from infections, autoimmunity, inflammations and malignancies. We aimed to identify unique molecular signatures in the adaptive immune repertoire of DOCK8-deficient patients through comprehensive sequencing and analysis of the T-cell receptor (TCR) and B-cell receptor (BCR) repertoires, correlating these signatures with clinical features of the patients, ultimately providing a "fingerprint" of both individual's immunological status and disease conditions. We characterized the TCR repertoires of αβ T- and γδ T-cells, together with BCR repertoires of B-cells, in peripheral blood of 13 patients and age matched healthy donor controls using next generation sequencing. TCR repertoire in patients with DOCK8 deficiency demonstrated restricted diversity and clonal expansions, favorable use of specific gene in the V-D-J recombination process, and a unique finding of longer complementarity-determining-region-3 (CDR3) length, revealing an impaired T-cell development and activation. Furthermore, BCR repertoire demonstrated high diversity without clonal expansions, portraying an abnormal B-cell development leading to a possible mechanism for atopy and autoimmunity, alongside inadequate activation in DOCK8 deficiency. Lastly, various DOCK8 mutations demonstrated a more profound defects in immune repertoire. These findings expand our knowledge on the role DOCK8 plays in shaping the TCR and BCR repertoires in DOCK8 deficiency.
To develop and evaluate a combined model integrating musculoskeletal ultrasound (MSK US) with a machine learning (ML) algorithm for assessing disease activity in rheumatoid arthritis (RA). A total of 203 patients with clinically confirmed RA were prospectively enrolled from December 2023 to September 2025. A cohort of 142 patients from the First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology served as the training cohort, while 61 patients from Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University (Fourth Clinical Medical College, Xinjiang Medical University) constituted the independent external test cohort. Three predictive models were developed: (1) an MSK US model incorporating two-dimensional grayscale ultrasound, power Doppler ultrasound (PDUS), and superb micro-vascular imaging (SMI); (2) a radiomics model based on two-dimensional grayscale images using the extremely randomized trees (ExtraTrees) algorithm; and (3) a combined model integrating the first two. Model performance in assessing RA disease activity was evaluated and compared using receiver operating characteristic (ROC) curve analysis. Calibration curves and decision curve analysis (DCA) were subsequently used to validate the overall performance of the optimal model. Multivariate logistic regression analysis identified erythrocyte sedimentation rate (ESR)>54 mm/h, C-reactive protein (CRP)>32.83 mg/L, and SMI synovial blood flow grade III as independent predictors of clinically active RA. The area under the ROC curve (AUC) values for the MSK US model, radiomics model, and combined model were 0.935 (95% confidence interval [CI]: 0.893-0.978), 0.976 (95% CI: 0.955-0.997), and 0.998 (95% CI: 0.998-1.000), respectively, in the training cohort; in the independent external test cohort, the AUC values for the three models were 0.904 (95% CI: 0.825-0.983), 0.823 (95%CI:0.714-0.933), and 0.929 (95%CI:0.866-0.992),respectively. The discriminative performance of the combined model was significantly superior to that of either the MSK US model or the radiomics model alone. Calibration curves demonstrated good agreement between the observed risk levels and the predicted risk probabilities. Decision curve analysis indicated that the model provided significant net benefit across threshold probability ranges of 0.02-0.80 in the training cohort and 0.12-0.78 in the test cohort. The combined model developed based on MSK US and radiomics demonstrated satisfactory performance for assessing disease activity in RA, enabling clinicians to dynamically monitor RA disease activity and evaluate treatment response, thereby providing a reliable imaging basis for the selection of routine medical treatment strategies.
Studies evaluating viral pathogenicity in small mammalian models often quantify disease severity using the magnitudes of temperature rise and weight loss post-challenge. However, no rigorous assessment on the transformation of serially collected data into features suitable for predictive models has been conducted. Using data aggregated from ferrets inoculated with a diverse panel of influenza A viruses (IAV) spanning a broad range of clinical outcomes, we assessed statistical correlations and predictive performance of temperature and weight loss, summarized by conventional and novel approaches. Conventional summary metrics (peak values or area under the curve) were weak and inconsistent correlates of overall disease severity and viral titers. Novel dynamic weight metrics capturing onset, duration, slope, and volatility over 14 days showed lower coefficients of variation than conventional summary approaches. However, inclusion of novel metrics did not meaningfully improve the predictive performance of machine learning models for disease severity outcomes in IAV-inoculated ferrets. Mixed-effects models indicated that weight loss post-IAV infection is driven by time and viral burden, with temperature contributing little additional information. Collectively, these findings support that derived metrics are at least comparable, if not enhanced, to conventional summaries for data science analyses of serially generated clinical data from in vivo pathogen studies. However, because pathogen disease severity in mammals is multifactorial, models that rely solely on weight and temperature metrics without additional quantitative measures of clinical perturbation within-host are unlikely to achieve strong predictive performance.
Timely access to early infant diagnosis (EID) is crucial for newborns with HIV, as late diagnosis can delay lifesaving antiretroviral treatment (ART). We assessed the comparative cost and cost-effectiveness of integrating point-of-care EID at birth into routine care in primary healthcare settings. This pre-specified secondary analysis was nested in the cluster-randomized LIFE study conducted at 28 primary healthcare facilities in Mozambique and Tanzania from October 2019 to September 2021. We estimated the health system cost of point-of-care birth plus 4-8-week HIV testing (very early infant diagnosis; VEID) compared to standard-of-care (SoC) testing at 4-8 weeks only, both with immediate ART initiation. We assessed the cost-effectiveness of VEID relative to SoC with respect to ART initiation within one week of life using Bayesian hierarchical models. As this is an intermediate outcome, incremental cost-effectiveness ratios (ICERs) cannot be directly compared to available life-year-based cost-effectiveness thresholds. To contextualize results, we derived the minimum life-years gained per early ART initiation required for VEID to meet standard thresholds in a break-even analysis. VEID was associated with a higher cost and resulted in earlier ART initiation than SoC in both countries. In Mozambique, VEID increased the proportion of infants initiating ART within one week of life by 90.0 (95% CrI [67.5, 98.5]) percentage points at an incremental cost of $2,632 (95% CrI [$2,249, $3,062]) per infant with HIV. In Tanzania, VEID increased early ART initiation by 59.9 (95% CrI [20.9, 89.5]) percentage points at an incremental cost of $6,263 (95% CrI [$5,394, $7,243]) per infant with HIV. The ICER was $2,924 and $10,458 in Mozambique and Tanzania, respectively and was sensitive to intrauterine transmission rate. These findings were limited by the lack of long-term health outcome data and reliance on an intermediate outcome. Based on the break-even analysis, we estimated that VEID would need to yield 6-32 life-years gained per additional early ART initiation to meet standard thresholds. Adding birth testing improved early ART initiation but was unlikely to be cost-effective relative to standard thresholds given current prices, vertical transmission rates, and knowledge of long-term health benefits. Cost-effectiveness could be achieved at current costs if early ART translates to substantial long-term health benefits or if targeted to infants at high risk of vertical transmission.
In recent years, the feasibility of immunotherapy targeting activated fibroblasts in pulmonary fibrosis has received further support. Recent studies have shown that transient FAP-targeted immunotherapy can alleviate pulmonary fibrosis by eliminating excessively activated fibroblasts, improving the aberrant extracellular matrix environment, and promoting alveolar cell lineage remodeling, suggesting that FAP-associated pathological stromal cells are amenable to therapeutic intervention. Based on this, research on FAP-centered engineered cell therapies is being gradually extended from settings such as myocardial fibrosis to pulmonary fibrosis. In this context, primary human NK cells represent a promising effector cell platform, as they are generally associated with a lower risk of severe treatment-related toxicities and relatively limited in vivo persistence, which may confer a more controllable therapeutic window. This feature is particularly important in fibrotic diseases, because long-term and continuous depletion of fibroblast populations may disrupt tissue homeostasis and injury repair. In addition, current studies of FAP-targeted CAR-NK therapy have mainly relied on NK cell lines such as NK-92, but these systems may not fully reflect the functional characteristics, receptor signaling, or clinical potential of primary human NK cells. Based on these considerations, it is necessary to develop a FAP-targeted cell therapy platform with greater clinical relevance for pulmonary fibrosis. In this study, we established a primary human FAP-CAR-NK-cell platform and conducted a proof-of-concept evaluation in pulmonary fibrosis-related models, including in vitro systems, a human pulmonary fibrosis-like organoid model, and an acute in vivo observation model. The main novelty of this study lies in the use of primary human NK cells for FAP-targeted intervention in pulmonary fibrosis-related models. We focused on whether these engineered cells could selectively target and eliminate FAP-positive activated fibroblasts, retain effector function in a fibrotic microenvironment, and show short-term feasibility after adoptive transfer. The study was not intended to assess long-term therapeutic efficacy or systemic safety, but rather to examine the feasibility of FAP-directed fibroblast targeting by primary human CAR-NK cells in pulmonary fibrosis and to provide a basis for further preclinical investigation.
Bullous pemphigoid (BP) is the most common autoimmune blistering disease in the elderly, for whom conventional systemic corticosteroids and immunosuppressants pose significant safety risks due to age-related comorbidities, leading to infections, osteoporosis, and metabolic disorders. While stapokibart, a novel IL-4Rα inhibitor, holds promise for type 2 inflammatory diseases, clinical evidence regarding its efficacy in BP is currently lacking. Therefore, this study aims to observe the clinical efficacy and long-term safety of stapokibart in the treatment of moderate-to-severe BP in the elderly. This single-center, retrospective, uncontrolled case series included 15 elderly patients with moderate-to-severe BP. In addition to conventional topical glucocorticoids or combined systemic therapy, patients received an initial dose of 600 mg stapokibart, followed by 300 mg every 2 weeks. Dosage adjustments were made based on patients' clinical responses after 16 weeks. The core treatment period was 24 weeks, with a subsequent post-treatment follow-up duration ranging from 4 to 34 weeks (mean 18.78 ± 11.54 weeks). The primary outcome was explicitly defined as the achievement of disease control at 4 weeks. Secondary outcomes included the BP disease area index (BPDAI), dermatology life quality index (DLQI), itch numerical rating scale (NRS), absolute eosinophil count (EO), anti-BP180 antibody levels, relapse rate, and safety profiles, which were assessed at baseline and weeks 2, 4, 8, 16, and 24. The primary outcome of disease control was achieved in 100.00% (15/15) of the patients within 4 weeks, with a mean time to control of 10.18 ± 3.06 days. Secondary outcomes including BPDAI, DLQI, itch NRS scores, EOs, and anti-BP180 antibody levels were all significantly reduced at week 24 compared to baseline (all P < 0.05). During the study and a subsequent mean follow-up duration of 18.78 ± 11.54 weeks, the disease recurrence rate was 26.67% (4/15). Regarding safety, injection site reactions occurred in 13.3% (2/15) of the patients, these were mild and self-limiting, with no patients discontinuing treatment due to adverse events. Stapokibart may serve as an effective and well-tolerated adjunctive option for alleviating skin lesions and pruritus in elderly patients with moderate-to-severe BP. However, given the small sample size and uncontrolled retrospective design, larger, prospective randomized controlled trials are required to definitively confirm its long-term efficacy and safety.
Traditional radical cystectomy has a high recurrence rate, a high probability of metastasis, and a reduced quality of life for patients. This study aimed to explore the efficacy of combining immunotherapy and surgical resection for high-risk muscle-invasive bladder cancer. In a retrospective study, 231 patients with high-risk muscle-invasive bladder cancer admitted to Yueyang People's Hospital between January 2019 and May 2024 were selected. After exclusions, 200 cases were analyzed and divided into two groups according to the treatment modality: the control group (surgical resection alone, n=100) and the intervention group (combination of immunotherapy and surgical resection, n=100). The cellular immune function indexes (CD3+, CD4+/CD8+, and natural killer cell levels), tumor markers (carcinoembryonic antigen, carbohydrate antigen 125, cytokeratin 21-1, and neuron-specific enolase), serum cytokines (basic fibroblast growth factor, vascular endothelial growth factor, and tumor necrosis factor-α), pathological complete remission (pCR), 1-year survival, and Functional Assessment of Cancer Therapy-Bladder (FACT-BL) quality-of-life scores were assessed in the two groups. After 1 year of treatment, the indicators of the two groups of patients were statistically significant in comparison with each other. Patients in the intervention group had substantial improvements in immune function indexes, pCR, 1-year survival rate, and FACT-BL scores in comparison with the control group. Tumor markers and serum cytokines were lower than those in the control group. The combination of immunotherapy and surgical resection can enhance clinical efficacy, providing a scientific basis for optimizing the clinical treatment plan.
Refractory or unexplained chronic cough (RUCC) represents an unmet clinical need. This study aimed to explore the components constituting the disease burden in patients with RUCC by comparing clinical features, healthcare use, and patient-reported outcomes with those of chronic cough (CC) of recent onset (< 1 year). A total of 200 individuals were prospectively enrolled from seven referral clinics in South Korea, including 100 with RUCC and 100 with CC of recent onset (< 1 year). Data were obtained through structured interviews and medical record reviews. Measures included general and cough-specific quality-of-life, mood, cough hypersensitivity symptoms, work productivity, and healthcare utilization. Individuals with RUCC were significantly older than those with CC (57.5 ± 15.1 vs. 48.9 ± 17.6 years) and had markedly longer cough duration (median 80 vs. 4 months). The RUCC group demonstrated higher out-of-pocket costs, more healthcare facility visits, and greater numbers of diagnostic tests and prescribed medications. However, cough-specific and general health-related quality of life scores showed no significant differences. Correlation analysis revealed comparable but stronger associations between cough-specific quality-of-life and general health outcomes in RUCC than in CC. RUCC imposes a substantial and multidimensional burden that extends beyond symptom severity. Chronicity, healthcare complexity, and psychosocial impact appear to be central features. Future evaluation tools should incorporate time and lived experience to more accurately capture the true burden of chronic cough.
The therapeutic strategy for late-onset multiple sclerosis (LOMS) with a relapsing-remitting onset remains unclear, potentially leading to underexposure to disease-modifying therapies (DMTs) compared with adult-onset multiple sclerosis (AOMS). We investigated the differences in DMT use between LOMS and AOMS within the French MS registry at comparable levels of disease severity. This retrospective cohort study used data extracted in December 2024 from the French MS registry on patients with relapsing-remitting onset MS between 1997 and 2023. The primary outcome was the annual probability of receiving a DMT according to age at MS onset, adjusted for disease severity. Secondary outcomes included the annual probability of receiving a highly effective DMT (HEDMT), each DMT separately, having ≥1 EDSS measurement, having ≥1 brain MRI, and DMT initiations and discontinuations. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. A total of 36,148 were included patients; 26,540 (73.4%) were female, mean age was 33.5 years (SD, 9.7), and 2,308 (6.4%) were aged ≥50 at disease onset. Median follow-up was 10.8 years (interquartile range, 5.6-17.0). Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with AOMS (73.7% vs 83.1%; odds ratio [OR], 0.57 [95% CI 0.52-0.62]). The difference was greater for HEDMT (24.6% vs 44.4%; OR, 0.41 [95% CI 0.36-0.46]). Patients with LOMS were more likely to receive teriflunomide and less likely to receive fumarates, S1PR modulators, natalizumab, or anti-CD20. Clinical and radiologic follow-up did not differ significantly between patients with LOMS and AOMS. The rate of DMT initiation was lower in patients with LOMS (0.13 vs 0.17 initiation per patient-year). Although the proportions of DMT discontinuation were similar (59.7% vs 60.4%, excluding pregnancy-related discontinuations), these discontinuations were more often attributed to a complete discontinuation strategy (27.9% vs 22.3%) and less often to an escalation strategy (9.2% vs 13.8%) in patients with LOMS. At comparable levels of disease severity, patients with LOMS were less likely to be treated with DMTs, particularly HEDMT, than patients with AOMS. This gap was driven both by fewer DMT initiations and more frequent complete discontinuations.
T helper 1 (TH1) and T helper 2 (TH2) cells can secrete various proinflammatory and anti-inflammatory factors, which can serve as indicators for predicting the severity of pneumonia. However, they are rarely used in combination with procalcitonin (PCT) and high-sensitivity C-reactive protein (hsCRP) detection to predict the severity of pneumonia. The purpose of this study is to investigate the combination of serum TH1/TH2 cytokines, PCT, and hsCRP for predicting the severity of community-acquired pneumonia (CAP). This study observed 58 inpatients with CAP. Analyses were conducted on the serum levels of TH1/TH2 cytokines, PCT, and hsCRP; imaging examination results; underlying diseases; pathogens; and the pneumonia severity index (PSI). The severe pneumonia group showed significantly higher PSI scores, age, and complication rates. Serum IL-2 was notably elevated in severe cases, while a combination of PCT, IL-4, TNF-α, and IFN-γ effectively predicted severe pneumonia, with an AUC of 0.712. Specific alterations in cytokines and biomarkers were identified as risk factors for higher PSI, complications, and prolonged hospitalization. The combined detection of PCT, IL-4, TNF-α, and IFN-γ provides a potential tool for predicting severe CAP, and distinct biomarker profiles are associated with different clinical outcomes.
Asthma is a heterogeneous disease, making uniform diagnosis challenging, resulting in both under- and overdiagnosis. We conducted a systematic review and meta-analysis to summarise the data on diagnostic accuracy of a cold air bronchial challenge test (CACh) in exercise-induced bronchoconstriction and asthma. Databases (PubMed, Embase, Web of Science core collection, Cochrane Library and the Cumulative Index to Nursing and Allied Health Literature via EBSCO) were systematically screened for articles evaluating the use of CACh as a diagnostic tool in exercise-induced bronchoconstriction and asthma. A random-effects model was used to calculate the effect on the reduction in forced expiratory volume in 1 s (FEV1) by CACh in healthy controls compared to patients with asthma. Risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-Comparative. This study is registered with PROSPERO (www.crd.york.ac.uk/PROSPERO/ identifier number CRD42021290350). After screening and removal of duplicates, 39 studies were included. Aggregate sensitivity and specificity of a FEV1 decrease ≥10% after CACh were 0.808 and 0.959, respectively. The weighted mean difference in percentage FEV1 decrease after CACh for patients with asthma compared to healthy controls was -17.58. High heterogeneity (I2=99) was mainly explained by differences in reference tests to diagnose asthma. Application of the trim-and-fill method to account for publication bias imputed eight studies, resulting in a notable reduction in heterogeneity. The overall effect (a significant decrease in FEV1 in patients with asthma) remained statistically significant (-8.18, p<0.001). Our study shows the high sensitivity and specificity and possible clinical implications of a CACh in the diagnosis of asthma. Further research is needed to confirm this.
COVID-19 mRNA vaccines have been reported to reduce severe COVID-19 outcomes in high-risk populations. In Japan, booster vaccinations up to the seventh dose are publicly funded; however, evidence regarding the safety and potential benefits of repeated booster doses in younger adults remains limited. This exploratory observational study aimed to describe age-specific patterns of all-cause mortality according to the number of COVID-19 vaccine doses using municipal administrative registry data. Municipal registry data obtained through information disclosure requests from Hamamatsu City (2021-2024) and Matsudo City (2021-2025) were analyzed. The dataset included age group or year of birth (5-year increments), sex, date of residence, COVID-19 vaccination records (date and lot number), and date of death. Individuals aged 20-89 years were categorized into three age groups (20-49, 50-64, and 65-89 years). All-cause mortality rates were calculated per 100,000 person-years according to the number of vaccine doses. Exploratory comparisons between dose groups were conducted using Poisson tests. Because the registry dataset lacked information on comorbidities, healthcare utilization, socioeconomic status, and cause of death, multivariable adjustment and causal inference were not feasible. Age-specific differences in all-cause mortality rates were observed across vaccine dose groups. Among individuals aged 65-89 years, higher numbers of vaccine doses were associated with lower all-cause mortality rates. In contrast, among those aged 20-49 years, all-cause mortality rates were higher among individuals who had received ≥5 doses than among those who had received fewer doses. Among individuals aged 50-64 years, the all-cause mortality rate was higher among those who had received six doses than among those who had received 1, 3, or 4 doses. This exploratory analysis identified age-specific differences in all-cause mortality across COVID-19 vaccine dose groups. However, the dataset available so far lacked important clinical covariates and information on causes of death, limiting causal interpretation. These findings highlight the need for constructing in Japan nationally linked datasets that allow adjustment for comorbidities, healthcare utilization, and other potential confounders.