Asthma is a heterogeneous condition characterized by chronic airway inflammation, airway hyperresponsiveness, and mucin hypersecretion. Obesity-related asthma is one phenotype of asthma with significant metabolic dysregulation. A complete understanding of obesity-related asthma remains elusive, but it is most often characterized by the absence of hallmark features of Type-2 (T2) high asthma, such as eosinophilia or elevated exhaled nitric oxide (NO) levels. Patients with obesity-related and T2 low asthma with or without type 2 diabetes mellitus (T2DM) experience worse clinical outcomes, including more severe acute exacerbations. Among the Food and Drug Administration (FDA) approved drug classes for T2DM, there is a growing interest in glucagon-like peptide 1 receptor agonists' (GLP-1RAs) ability to potentially exert effects in the airway. Previous studies found that individuals with T2DM and asthma who were prescribed GLP-1RAs, had decreased asthma exacerbations and improved lung function. However, there remains a gap in understanding GLP-1RAs mechanism of action in the lung and airways to improve pulmonary function. In this review we discuss the potential mechanisms by which GLP-1RAs may impact T2 low asthma and offer a therapeutic option for this highly prevalent disorder.

The 2007 US Food and Drug Administration (FDA) Amendments Act (FDAAA) expanded its safety-related regulatory authorities, including enhanced postmarketing safety surveillance and new clinical study requirements. However, whether FDAAA has been associated with differences in the frequency and timing of postmarket safety-related actions remains poorly understood. To assess whether FDAAA was associated with differences in time to first FDA postmarket drug safety-related action, and to assess whether therapeutic and regulatory characteristics were associated with differences in time to these actions post-FDAAA implementation. This was a cross-sectional study of all novel therapeutics approved by FDA between January 1, 2001, and December 31, 2019, and followed up through December 31, 2024. Approvals were categorized as pre- or post-FDAAA (before or after March 25, 2008). Post-FDAAA therapeutic and regulatory characteristics included drug class, therapeutic area, orphan status, special regulatory pathway, and presence of a boxed warning or FDAAA-mandated postmarket study requirement at approval. Time to first FDA postmarket drug safety-related action, a composite of withdrawals due to safety concerns, incremental boxed warnings, and safety-related communications. Of the 560 novel therapeutics approved, FDA took postmarket safety-related actions for 130 (23.2%) during a median (IQR) follow-up of 12.1 (7.8-18.2) years. These comprised actions within 5 years of approval for 34 of 164 therapeutics (20.7%) approved pre-FDAAA, and 57 of 396 (14.4%) approved post-FDAAA (rate ratio, 0.69; 95% CI, 0.47-1.02; P = .06). Compared to pre-FDAAA approvals, after accounting for therapeutic and regulatory characteristics, there was no statistically significant difference in time to first postmarket safety-related action for post-FDAAA approvals (time ratio, 0.40; 95% CI, 0.15-1.07; P = .07). However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA (median [IQR], 3.1 (2.0-4.2) years for pre-FDAAA vs 1.8 [1.3-2.5] years post-FDAAA; P = .004). Among 260 novel therapeutics approved post-FDAAA, after the October 2013 enactment of breakthrough therapy designation, the following therapeutic and regulatory characteristics were associated with time to first postmarket safety-related action: small molecule type (time ratio, 0.24; 95% CI, 0.07-0.81; P = .02), orphan designation (time ratio, 8.29; 95% CI, 2.43-28.27; P < .001), fast track (time ratio, 0.22; 95% CI, 0.08-0.64; P = .005), breakthrough therapy designation (time ratio, 0.10; 95% CI, 0.03-0.32; P < .001), prolonged regulatory review time (>400 days; time ratio, 0.16; 95% CI, 0.03-0.73; P = .02), and FDAAA-mandated postmarket study requirements at approval (time ratio, 0.35; 95% CI, 0.15-0.80; P = .01). This cross-sectional analysis found that the enhanced safety-related regulatory authorities of FDAAA were not associated with differences in time to first postmarket safety-related action. However, among therapeutics with postmarket safety-related actions within 5 years of approval, median time to first action was shorter post-FDAAA implementation.

SmartTots and the Power of Scientific Public-Private Partnerships With the US Food and Drug Administration.

The increasing reliance on accelerated approvals and surrogate endpoints for Food and Drug Administration (FDA) approvals of gastrointestinal (GI) cancer therapies raises concerns about their clinical benefit and long-term patient outcomes. The shift toward single-arm trials in regulatory decisions further complicates treatment evaluation. This retrospective observational study evaluated all FDA approvals for GI cancer therapies from January 2006 through January 2025. Data were extracted from FDA archives, ClinicalTrials.gov, and PubMed. Approvals were categorized by regulatory pathway (accelerated vs. regular), trial design (single-arm vs. randomized), and primary endpoint (surrogate vs. overall survival [OS]). Clinical benefit was assessed based on OS improvement and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The primary outcome was the proportion of approvals based on surrogate versus OS endpoints. Secondary outcomes included use of single-arm designs, frequency of accelerated approvals, OS gain, and the proportion meeting ESMO-MCBS substantial benefit (score ≥4). The FDA granted 60 GI cancer drug approvals from 67 trials. Approvals rose from 15 (25%) in 2006-2014 to 45 (75%) in 2015-2025. Single-arm trials increased to 24%, and surrogate endpoints were used in 41.8% (ORR 20.9%, PFS 19.4%). Median OS improvement was 2.1 months (IQR: 1.6-2.65). Only 24.3% of trials met ESMO-MCBS substantial benefit. Of 15 accelerated approvals, 66.7% remained pending, 13.3% received full approval, and 20% were withdrawn. Expedited approvals have improved drug access in GI oncology, but modest benefits highlight the need to balance speed with outcomes that truly matter to patients.

Alzheimer's disease (AD) remains one of the most challenging neurodegenerative disorders, with limited therapeutic options and high failure rates in clinical trials. This work developed a drug repurposing pipeline powered by a machine learning (ML) model to find possible glycogen synthase kinase-3 beta (GSK-3β) inhibitors, a crucial target in AD pathogenesis. We selected, pre-processed, and optimized a dataset of 4,087 experimentally verified GSK-3β inhibitors using dimensionality reduction and descriptor creation. The most excellent prediction performance was obtained by Random Forest (100 descriptors) out of six supervised ML algorithms that were studied (R2 = 0.8178, RMSE = 0.8118, MAE = 0.6084). Following the virtual screening of 1,616 Food and Drug Administration (FDA)-approved drugs using this refined model, many compounds with projected IC₅₀ < 500 nM were found. Docking experiments showed insightful interactions and high binding affinities with the active-site residues of GSK-3β. With the best docking score (-9.3kcal/mol), stable molecular dynamics (Average RMSD values (1000 ns): protein, 2.23 ± 0.93 Å; protein-ligand complex, 1.40 ± 0.43 Å) and long-lasting contacts with crucial residues, dolutegravir stood out among the top choices. ADMET profiling validated good pharmacokinetics and safety characteristics; however, possible hepatotoxicity needs more research. A HOMO-LUMO gap of 3.07eV was found by density functional theory (DFT) analysis, indicating robust electron transport characteristics and balanced reactivity that are favorable for protein-ligand interaction. Together, these findings show that dolutegravir is a potential repurposable option against AD and how integrative ML, docking, MD, ADMET, and quantum chemistry techniques may speed up the identification of new drugs.

To understand the utility and limitations of using the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database to evaluate rates of adverse events (AEs) for devices used in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) procedures. A systematic literature review was performed in Embase, MEDLINE, and Google Scholar to identify literature published between 1991 and August 2024 using the MAUDE database to analyze complications reported for BPH and PCa procedures. A total of 11 full text articles (6 BPH articles and 5 PCa articles) met the inclusion criteria, citing use of a variety of BPH and PCa devices. The majority of articles (9 out of 11) used the number of AEs, events, or device failures/malfunctions as the denominator for determining incidence rates. Top author-reported advantages of MAUDE were anonymity of the system and ability to detect more unusual AEs. Top author-reported disadvantages of MAUDE were inability to determine AE rate/incidence and under-reporting. The MAUDE database is useful in identifying previously unknown AEs occurring in BPH and PCa medical device procedures. However, the database should not be used to calculate adverse event/malfunction rates. Safety signals found via MAUDE should be further studied prior to reporting AE rates.

Real-world evidence on pregnancy-related thromboembolic events (PTEs) following drug exposure before or during pregnancy remains limited, with most studies based on small-scale retrospective analyses. To assess this association, we conducted a pharmacovigilance study. We analyzed reports from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Disproportionality analysis was performed to identify drugs associated with PTEs. Multivariate logistic regression was used to explore factors associated with designated serious outcomes, including disability, life-threatening events, and death. A total of 4,122 reports were included. Disproportionality analysis identified 40 drugs with positive risk signals. The three most prominent were ethinylestradiol-etonogestrel (n=843; reporting odds ratio [ROR]=20.12), drospirenone-ethinylestradiol (n=351; ROR=19.35), and rofecoxib (n=121; ROR=20.62). Multivariate logistic regression showed that ethinylestradiol-etonogestrel (odds ratio [OR]=2.059; 95% confidence interval [CI]: 1.450-2.923; P < 0.001), rofecoxib (OR=4.154; 95% CI: 2.693-6.407; P < 0.001), and dinoprostone (OR=33.375; 95% CI: 9.987-111.534; P < 0.001) were significantly associated with serious outcomes, while drospirenone-ethinylestradiol showed a protective effect (OR=0.401; 95% CI: 0.286-0.563; P < 0.001). Drawing on the FAERS database, we have provided a list of drugs with risk signals for PTEs in this exploratory study. Our findings highlight the importance of considering both before and during-pregnancy drug exposures when assessing thromboembolism risk. More well-designed studies are warranted for drugs whose association with PTEs is not fully understood.

T-cell engaging immunotherapies have transformed the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). First revolutionizing outcomes for relapsed and refractory disease, these therapies are now being incorporated and studied in the frontline setting. With the US Food and Drug Administration (FDA) approval of the CD19-directed bispecific T-cell engager (BiTE) blinatumomab for remission consolidation, the majority of patients with B-ALL receive blinatumomab in frontline therapy. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is FDA approved for pediatric patients with B-ALL that is refractory or in second or greater relapse. With the same target, similar mechanisms of action, and some overlap in indications, the optimal placement and sequence of these immunotherapies remain unclear. Here we review the recent data and expanded use of blinatumomab and CAR T-cell therapy and discuss the role of CAR T-cell therapy in the current pediatric B-ALL treatment landscape, including in populations with relapsed/refractory disease and at very high risk of relapse.

Low- and intermediate-risk myelodysplastic syndromes (LR-MDS and Int-MDS, respectively) are characterized by ineffective hematopoiesis, along with the presence of at least 10% dysplasia in one cell line, accompanied by a low number and depth of peripheral blood cytopenias, a low bone marrow blast percentage, and a score of ≤0 on the Molecular International Prognostic Scoring System (IPSS-M). The information gleaned from mutational profiles at the time of myelodysplastic syndrome (MDS) diagnosis and over subsequent time points help with classification and prognosis, guiding therapeutic decisions. In LR-MDS, these decisions are initially focused on improving symptom control and optimizing hematologic parameters. New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits. Patients can derive years of benefit from these approaches in LR-MDS, but despite these therapies, ultimately MDS will evolve into higher-risk MDS (HR-MDS)/acute myeloid leukemia. Even though most LR-MDS patients present with anemia, patients can have isolated thrombocytopenia for which thrombopoietin receptor analogues can be used if blasts are low. Immunosuppressive therapy such as antithymocyte globulin is favored in the hypocellular MDS setting. Dose-modified hypomethylating agent use can be considered for LR-MDS, although neither overall survival (OS) nor progression-free survival (PFS) has been shown to improve with this approach. Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1.

Objective.Histotripsy is a non-invasive, non-thermal, and non-ionizing tissue ablation method based on high-amplitude pulses of focused ultrasound that has been approved by the federal Food and Drug Administration for the treatment of liver tumors. However, histotripsy currently cannot treat all locations in the liver due to attenuation of the pressure amplitude at the focus by sound-blocking ribs and air pockets and by phase aberration, or de-focusing of the ultrasound pulses by heterogeneous bodily tissues. Previous work suggests that correcting for phase aberration could increase the focal pressure to expand the treatment envelope (the treatable region) for histotripsy in the liver. The objective of this study was to investigate the effect of aberration correction on the treatment envelope.Approach. Acoustic propagation was simulated in the human body using a linear model (k-Wave) for a histotripsy phased array of similar dimensions to the current Histosonics Edison® clinical device and anatomical data from 10 subjects of varying body size.Main results. We find that aberration correction increases the focal pressure throughout the liver to substantially expand the treatment envelope (from 67% to 81% of the liver volume, on average, by linear estimations).Significance. The study suggests that aberration correction could help enable non-invasive, non-thermal histotripsy treatments for a broader patient population.

Neglected tropical diseases (NTDs) are a diverse group of more than twenty diseases caused by parasitic, bacterial, and viral infections, affecting more than one billion individuals worldwide. Economic evidence can help guide the investment in Community Health Workers (CHWs) who can help expand access to preventive and curative NTD services in low- and middle-income countries (LMICs). A scoping review was conducted across ten databases and grey literature, covering studies published between August 2015 and July 2024. Search terms related to “Community Health Workers” and “Economic Evaluations” were used. Studies were screened via Covidence software based on inclusion and exclusion criteria. Data on study methodology, costs, and outcomes were extracted, tabulated in Microsoft Excel, and analysed. Of the 29 included scenarios (n = 10 studies), 7 were about community mass drug administration and 22 focused on other topics - such as disease-specific prevention and treatment (e.g., dengue). Across scenarios, the most commonly reported outcomes were cost per service delivered (ranging from $0.13-$5.33) and cost per capita (ranging from $10.24-$21.09). Five scenarios reported on cost-effectiveness, with varied results (40–50% of scenarios were reported as cost effective). One study found that interventions were more likely to be cost-effective when they leveraged integrated care as opposed to vertical approaches. The evidence base for economic evaluations regarding CHW involvement in NTD programs is highly limited. From the 10 studies identified there was no clear conclusion with regards to cost-effectiveness or affordability of CHWs in NTD programs in LMICs. To better understand the critical role CHWs can play in both prevention- and treatment-focused NTD programs, further evidence of the cost-effectiveness and affordability of such interventions is needed.

The US Food and Drug Administration (FDA) has recommended, but not required, age ranges for pediatric age labeling in devices, despite regulation existing for drugs, and this policy perpetuates off-label use of devices and creates several issues in practice for safety and monitoring. Proper device labeling is an important regulatory component that impacts risk stratification, clinical use, marketing, and reimbursement. To evaluate the variability in pediatric medical device age labeling among all pediatric class III devices approved by the FDA from 2008 to 2017 and their adherence to nonbinding FDA age range recommendations, and to review the device type, clinical use, and whether the pediatric population was included in clinical trials. This retrospective cross-sectional study reviewed data from public databases to understand pediatric age labeling practices. Data included in the 2008 to 2017 Reports to Congress: Premarket Approval of Pediatric Uses of Devices were reviewed in 2022. Additional data were extracted from the FDA Databases. Two physicians independently reviewed the data and assigned clinical descriptors to each device. Descriptive analysis was performed. Device approval by the FDA from 2008 to 2017. The primary outcomes were whether approved devices had age labeling, whether they described the approved pediatric population, and whether pediatric populations were included in clinical studies of the devices. Pairwise comparison was done with Student t test and P < .05 to indicate statistically significant differences. Of 101 unique devices, 26 (25.7%) did not include any specific age ranges and among the remaining 75 devices, 51 (50.5%) were not indicated for patients younger than 18 years. There was significant variation in age labeling, with only 4 devices using fully structured age ranges (eg, 2 to 17 years). Only 8 (7.9%) devices used the FDA recommended pediatric age ranges. The review of clinical trials evaluating device safety and efficacy revealed that 60 (59.4%) included pediatric patients (aged 0 to <22 years); however, only 33 (32.7%) included patients younger than 18 years. In contrast, the Indications For Use statements for the same devices indicate 52 (51.5%) did not include any specific age ranges and 29 (28.7%) were indicated for adults 18 years or older. In this cross-sectional analysis of devices included the 2008 to 2017 Reports to Congress, most high-risk devices were not evaluated or specifically indicated for children younger than 18 years. This poses substantial problems for clinical use, reimbursement, research, and policy evaluation. To address this gap, the FDA should establish pediatric labeling requirements that consider age and other relevant factors.

This study measured serum biomarkers at baseline and during an ovariohysterectomy in healthy female Spanish greyhounds, aiming to enhance the objectivity of current methods for assessing acute postoperative pain in dogs. Blood samples from 20 Spanish greyhounds were collected before drug administration (T0-baseline). Premedication included dexmedetomidine and methadone, followed by propofol and isoflurane. Four additional samples were taken: post-second ovariectomy (T1-PostOvary), 4hours post-premedication (T2-PreRescue), 30minutes post-rescue methadone (T3-PostRescue) and 24hours post-extubation (T4-24H). Biomarkers were quantified via ELISA, and postoperative pain was assessed using the short-form Glasgow scale (Glasgow-SF). Data analysis included ANOVA, Friedman test and Spearman's correlation. Glutamate (p = 0.007; Kendall's W = 0.186) and calcitonin gene-related peptide (CGRP) (p = 0.001; = 0.324) peaked at T0-baseline. Cortisol peaked at T3-PostRescue (p = 0.041; = 0.099). Glasgow-SF scores increased postoperatively compared with T0-baseline (p = 0.001; Kendall's W = 0.612), without significant biomarker correlation. Sample homogeneity may limit result generalisability and lack of acclimatisation may introduce bias, as initial stress could affect the synthesis of stress-related biomarkers. Although glutamate, CGRP and cortisol levels fluctuated over time-with glutamate and CGRP peaking at T0-baseline-none proved useful for assessing postoperative pain compared with conventional clinical parameters.

Background Despite substantial efforts to eliminate onchocerciasis, the disease remains a significant public health problem in endemic communities in Ghana. We investigated the suitability of an educational intervention as an effective tool to strengthen onchocerciasis knowledge, attitudes, and prevention (KAP) among residents in endemic communities in southern Ghana. Methods The intervention consisting of a pre-test, a PowerPoint presentation covering the agent, vector, symptoms, groups at risk, treatment, prevention practices, and misconceptions of onchocerciasis, and a post-test was conducted in nine communities of three districts from June to August 2024. Results Four hundred and eighty residents participated in the study. Comparison of pre-test with post-test scores showed significant improvement in KAP for 17 of the 21 questions. Scores related to the organism and vector for onchocerciasis increased from 11.0% and 35.2%, respectively, on the pre-test to over 95.0% for both on the post-test. Regarding symptoms, while 69.4% reported itching of the skin, only 6.3% knew that eye disease and blindness was a major symptom; these responses increased to 97.0% and 86.6%, respectively, on the post-test. No respondent knew the correct breeding places of blackflies on the pre-test compared to 92.0% on the post-test. Participants’ scores also improved significantly regarding attitude and prevention questions, such as whether they would try to prevent onchocerciasis, methods to prevent blackfly bites, and willingness to participate in the next mass drug administration (MDA) of ivermectin. On the post-test, the majority of participants felt they were better prepared in preventing onchocerciasis (99.1%), and in educating others (98.5%). Conclusion This educational intervention improved the KAP of residents and seems to be an effective tool for strengthening onchocerciasis literacy and prevention practices in vulnerable communities. Follow-up of the intervention along with timely MDA of ivermectin should lead to a decrease in onchocerciasis transmission and eventual elimination of the disease.

Association of Aggression and Anti-seizure Medications in Pediatric Patients: Disproportionality Analysis Using the FDA Adverse Event Reporting System.

This update expands the 2020 American Cancer Society (ACS) cervical cancer screening guideline for average‐risk women and individuals with a cervix who are at average risk, to include self‐collection for human papillomavirus (HPV) testing and revised guidance for exiting cervical cancer screening. Self‐collected vaginal specimens, a method of primary HPV testing, align with the ACS cervical cancer screening guideline. When clinician‐collected cervical specimens are used for HPV testing, repeat screening is recommended every 5 years for those with a negative test. For self‐collected vaginal specimens, the ACS endorses the following recommendations of the Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee (of which it is a member): (1) primary HPV screening using clinician‐collected cervical specimens is preferred, and self‐collected vaginal specimens are acceptable for average‐risk individuals aged 25–65 years; and (2) repeat testing in 3 years is recommended after a negative result on a self‐collected HPV screening test. These recommendations apply only to combinations of collection devices and HPV assays approved by the US Food and Drug Administration for HPV testing in a clinical setting or at home. The rationale notes that the use of self‐collected vaginal specimens can overcome barriers to screening for many patients, but most patients who test HPV‐positive will require extra follow‐up steps, and data on long‐term, real‐world effectiveness are limited. For certain high‐risk individuals, clinician‐collected samples are still recommended. Furthermore, in response to high rates of cervical cancer among individuals older than 65 years and with poor implementation of current exiting screening criteria, ACS has amended the 2020 guideline to recommend HPV testing at ages 60 and 65 years, with the last HPV test at an age no younger than 65 years as a requisite to exiting screening. The revised recommendation states: To qualify for discontinuation of screening, the ACS recommends an average‐risk woman or an individual with a cervix at average risk have negative primary HPV tests (preferred) or negative co‐testing using HPV tests and cytology (acceptable) at ages 60 and 65 years. If primary HPV tests or co‐testing are not available, three consecutive negative cytology (Papanicolaou) tests at the recommended screening interval with the last test at age 65 years are acceptable. If self‐collected vaginal specimens are used for HPV testing, the 3‐year testing interval should be followed. Additional screening exit stipulations relate to women at higher risk because of prior abnormal test results or current immune suppression.

The US Food and Drug Administration (FDA) has the authority to prohibit companies from making unauthorised harm reduction claims about tobacco products. The 2018 Farm Bill removed hemp products containing no more than 0.3% delta-9-tetrahydrocannabinol (THC) from regulation as Schedule I controlled substances. Hemp cigarettes that contain no tobacco or nicotine and less than 0.3% THC fall into a loophole in federal law and may evade federal tobacco and drug regulation despite potential health harms. In August-September 2024, we analysed TAAT's consumer website to determine whether the manufacturer made 12 marketing claims related to harm reduction or therapeutics that may lead customers to believe that TAATs are safe, safer than other cigarettes, or useful for cessation. We found 307 (36.1%) of 851 sentences on TAAT's website included one or more harm reduction or therapeutic claims. Of the 519 claims identified, the most frequent were for cessation/tobacco/smoking alternative (35.3%), no nicotine (10.2%), no tobacco (8.5%), hemp/CBD/reduced THC (7.3%) and less harmful/better/wellness (6.2%). The website did not provide independent verification to support claims. TAAT's website contains hundreds of unsubstantiated harm reduction and therapeutic claims. While TAAT hemp cigarettes have evaded FDA regulations that apply to tobacco and drug products, the FDA can enforce laws prohibiting TAAT from making unauthorised therapeutic claims for unapproved products and the Federal Trade Commission can take action for deceptive health claims. States and localities can also prohibit TAAT from marketing cigarettes with unsubstantiated claims.

This study systematically evaluated the safety profile of tumor necrosis factor-alpha (TNF-α) inhibitors in pediatric patients using data from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from Q1 2004 to Q3 2024.Through disproportionality analysis of adverse event (AE) reports for infliximab, etanercept, adalimumab, golimumab and certolizumab, we identified 852 significant safety signals spanning 27 system organ classes (SOCs). The most frequently reported SOCs included General Disorders and Administration Site Conditions (12,940 cases), Injury, Poisoning, and Procedural Complications (5,503 cases), and Gastrointestinal Disorders (4,346 cases).Key findings revealed that infection-related AEs and injection-site reactions were the predominant safety concerns. The median onset time of AEs was 235 days (IQR: 46–832 days), with 19.8% of cases occurring within the first month of treatment. Notably, 25.5% of reported AEs required hospitalization, while fatal and life-threatening outcomes accounted for 0.9% and 1.4% of cases, respectively. This comprehensive analysis confirms the multisystemic involvement and prolonged latency of TNF-α inhibitors-associated AEs in pediatric populations. While these agents remain vital for managing chronic inflammatory diseases, the findings advocate for enhanced clinical vigilance. We propose a tiered monitoring protocol prioritizing infection surveillance (e.g., serial inflammatory markers), systematic injection-site evaluations, and longitudinal organ function assessments, particularly during the initial treatment phase, to optimize therapeutic risk-benefit ratios.

Despite the progressive extension of CFTR variant eligibility to the triple combination of elexacaftor/tezacaftor/ivacaftor (ETI), most rare CFTR pathogenic variants remain ineligible for CFTR modulators. It is crucial to determine whether unexplored variants are rescuable by clinical modulators and to identify innovative therapeutic strategies for rescuing non-responder variants. The approach known as “theratyping” (in vitro testing of genotypes) has been accepted by the Food and Drug Administration (FDA) for the extension of clinical modulators’ approval for in vitro responding genotypes. We used one of the most advanced models for theratyping: organoids derived from nasal epithelia of people with cystic fibrosis (pwCF). We optimized the forskolin-induced swelling (FIS) of organoids to assess CFTR basal or modulator-restored function. Nasal organoids mimicked the original epithelial tissue, CFTR residual activity, and modulator response. We set up the FIS assay using nasal organoids with reference genotypes and theratyped 38 rare (non-F508del) CFTR genotypes, either eligible or non-eligible for FDA approval, for treatment with ETI or ivacaftor. We found strong correspondence between the in vitro response of CFTR variants to modulators and their FDA approval status. Additionally, some previously uncharacterized CFTR variants have proven responsive to clinical modulators, with significant therapeutic implications. These results suggest that the nasal organoid FIS assay, pending confirmation of the prediction in the corresponding pwCF, might be considered as a powerful in vitro tool to predict modulator efficacy in each pwCF, guiding out-of-label prescription in CF, and to identify uncharacterized variants responsive to modulators. This approach may allow comparison of the efficacy of different therapeutics or the identification of innovative strategies for non-responding genotypes, improving personalized therapy and quality of life for pwCF.

Design strategies of biomaterial-based intra-articular drug delivery system for osteoarthritis therapy.