Notice NOT-OD-25-064 from the NIH Guide for Grants and Contracts

Notice NOT-EY-25-005 from the NIH Guide for Grants and Contracts

Notice NOT-AG-24-032 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-AI-25-006 from the NIH Guide for Grants and Contracts. The purpose of this notice of funding opportunity (NOFO) is to support research studies of two or more vaccine adjuvants (combination adjuvants) in order to understand the mechanisms by which they work in concert. All adjuvants considered must have previously demonstrated immune modulating activity. The long-term goal of this research program is to improve the rational design of vaccines by predicting the immune profile elicited by combination adjuvants.

Funding Opportunity PAR-25-342 from the NIH Guide for Grants and Contracts. The purpose of this Notice of Funding Opportunity (NOFO) is to support innovative and interdisciplinary research teams focused on clinical, health services, and/or community-based interventions that address health and healthcare disparities related to non-communicable and chronic diseases (NCDs) with the highest burden and mortality in Latin America and among U.S. Hispanics/Latinos. Multidisciplinary research teams would be expected to meaningfully collaborate with key partners that must include at least one PI or MPI from institutions in Latin America.

Notice NOT-AG-24-089 from the NIH Guide for Grants and Contracts

Notice NOT-OD-25-059 from the NIH Guide for Grants and Contracts

JAMA Pediatr. 2025 Feb 1;179(2):197-202. doi: 10.1001/jamapediatrics.2024.5100.

ABSTRACT

IMPORTANCE: Cell and gene therapies are revolutionizing the treatment landscape for children and adults with rare diseases and can be life-changing for patients and their families. Successful implementation of these new therapies into clinical practice depends on their accessibility and affordability, particularly through publicly funded Medicaid agencies, which cover many children and adults with rare diseases.

OBJECTIVE: To provide a framework to broadly assess cell and gene therapies, evaluate payment options, and ensure equitable access through the lens of publicly funded Medicaid programs.

EVIDENCE REVIEW: This review draws on peer-reviewed articles, federal reports, and other relevant publications as well as the expertise of chief medical officers and medical directors of state Medicaid agencies across 5 diverse states.

FINDINGS: Twenty-nine articles and other references provide the foundation for this review. The recommendations presented focus on thoughtful implementation of cell and gene therapies, including policy recommendations in the domains of safety, effectiveness, population health, access, and budget.

CONCLUSIONS AND RELEVANCE: Proposed health care policy changes are intended to balance innovation, affordability, and equitable access for children and adults with rare diseases.

PMID:39804636 | DOI:10.1001/jamapediatrics.2024.5100

medRxiv [Preprint]. 2024 Oct 4:2024.10.04.24313542. doi: 10.1101/2024.10.04.24313542.

ABSTRACT

INTRODUCTION: Structural variants (SVs) of the nebulin gene (NEB), including intragenic duplications, deletions, and copy number variation of the triplicate region, are an established cause of recessively inherited nemaline myopathies and related neuromuscular disorders. Large deletions have been shown to cause dominantly inherited distal myopathies. Here we provide an overview of 35 families with muscle disorders caused by such SVs in NEB.

METHODS: Using custom Comparative Genomic Hybridization arrays, exome sequencing, short-read genome sequencing, custom Droplet Digital PCR, or Sanger sequencing, we identified pathogenic SVs in 35 families with NEB-related myopathies.

RESULTS: In 23 families, recessive intragenic deletions and duplications or pathogenic gains of the triplicate region segregating with the disease in compound heterozygous form, together with a small variant in trans, were identified. In two families the SV was, however, homozygous. Eight families have not been described previously. In 12 families with a distal myopathy phenotype, eight unique, large deletions encompassing 52 to 97 exons in either heterozygous (n = 10) or mosaic (n = 2) state were identified.In the families where inheritance was recessive, no correlation could be made between the types of variants and the severity of the disease. In contrast, all patients with large dominant deletions in NEB had milder, predominantly distal muscle weakness.

DISCUSSION: For the first time, we establish a clear and statistically significant association between large NEB deletions and a form of distal myopathy. In addition, we provide the hitherto largest overview of the spectrum of SVs in NEB.

PMID:39802796 | PMC:PMC11722492 | DOI:10.1101/2024.10.04.24313542

Sci Rep. 2025 Jan 13;15(1):1836. doi: 10.1038/s41598-024-83767-9.

ABSTRACT

Tyrosine-protein kinase Src plays a key role in cell proliferation and growth under favorable conditions, but its overexpression and genetic mutations can lead to the progression of various inflammatory diseases. Due to the specificity and selectivity problems of previously discovered inhibitors like dasatinib and bosutinib, we employed an integrated machine learning and structure-based drug repurposing strategy to find novel, targeted, and non-toxic Src kinase inhibitors. Different machine learning models including random forest (RF), k-nearest neighbors (K-NN), decision tree, and support vector machine (SVM), were trained using already available bioactivity data of Src kinase targeting compounds. The performance evaluation of these models demonstrated SVM as the best model, which was further utilized to shortlist 51 highly potent compounds by screening an FDA-approved library of 1040 drugs. Molecular docking and molecular dynamic simulation were subsequently employed to evaluate the binding affinity and stability of the proposed compounds. Orlistat, acarbose and afatinib were identified as the potent leads, demonstrating stable conformations and stronger interactions, validated by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (RoG), and hydrogen bond analyses. Molecular Mechanics/Generalized Born Surface Area (MMGBSA) analysis validated their binding affinities by providing comparably lower binding free energies for orlistat (- 33.4743 ± 3.8908), acarbose (- 19.5455 ± 5.4702), and afatinib (- 36.4944 ± 5.4929) than the control, dasatinib (- 13.7785 ± 5.8058). Finally, toxicity analysis revealed orlistat and acarbose as the possible safer therapeutics by eliminating afatinib as it showed significant toxicity concerns. Our investigation supports the advance computational methods utilization in the field of drug discovery and suggest further experimental validation of proposed inhibitors of Src kinase for their safer use against inflammatory diseases. The ultimate aim of this study is to advance the development of effective treatments for inflammatory diseases, linked with Src overexpression.

PMID:39805859 | DOI:10.1038/s41598-024-83767-9

BMC Med Educ. 2025 Jan 14;25(1):63. doi: 10.1186/s12909-025-06651-8.

ABSTRACT

BACKGROUND: Individuals often respond differently to medications, giving rise to the field of precision medicine (PM), which focuses on tailoring treatments to individual genetic, environmental, and lifestyle factors. This study examined the level of comfort healthcare professional students have with their knowledge of precision medicine, alongside their attitudes and perceptions toward precision medicine, at a tertiary institution in Nigeria.

METHODS: A cross-sectional questionnaire-based study was conducted among healthcare professional students (400-600 level) at the University of Nigeria Nsukka between January and March 2024. The data were analyzed via IBM Statistical Product and Service Solutions (SPSS) for Windows version 27. Descriptive analyses (frequency, percentage, mean, and standard deviation) and chi-square tests were used to summarize and compare the variables. Statistical significance was set at p < 0.05.

RESULTS: A total of 431 healthcare professional students participated in this study. Fewer than half (n = 200, 46.4%) were pharmacy students, and the majority were within the age range of 21-25 years (n = 288, 66.8%). Nearly half (n = 206, 47.8%) reported having information about precision medicine from the internet, and the majority (n = 341, 79.1%) expressed having an interest in a career involving research in precision medicine. More than half of the students (n = 240, 55.7%) were comfortable with their knowledge of precision medicine and had favourable attitudes (n = 236, 54.8%). Additionally, more than half had positive perceptions of ethical concerns (n = 216, 50.1%) and education in precision medicine (n = 239, 55.5%). Gender, age, department, level of study, awareness of PM, and interest in a career involving research were significantly associated with students' knowledge, attitudes, and perceptions of precision medicine (p < 0.001).

CONCLUSION: Healthcare professional students were comfortable with their knowledge of PM and, in addition, had favourable attitudes and positive perceptions toward the use of precision medicine.

PMID:39806360 | DOI:10.1186/s12909-025-06651-8

Sci Rep. 2025 Jan 13;15(1):1824. doi: 10.1038/s41598-024-84744-y.

ABSTRACT

This study was designed to assess the effect of brentuximab vedotin on several breast cancer cell lines in terms of promoting apoptosis and managing cancer progression. Additionally, the study investigated the potential of repurposing this drug for new therapeutic reasons, beyond its original indications. The study evaluates the cytotoxic effects of Brentuximab vedotin across five cell lines: normal human skin fibroblasts (HSF), three breast cancer cell lines (MCF-7, MDA-MB-231, and T-47D), and histiocytic lymphoma (U-937). Brentuximab treatment was administered at four time points (0, 24, 48, and 72 h), with cell viability assessed at each interval. HSF cells, serving as controls, exhibited minimal viability loss (above 70%), indicating limited toxicity in normal fibroblasts. In contrast, MCF-7 and MDA-MB-231 cells demonstrated time-dependent reductions in viability, with a pronounced decline by 72 h, suggesting Brentuximab's efficacy in both ER-positive and triple-negative breast cancer. T-47D cells also showed decreased viability, though at a slower rate. U-937 cells exhibited the most substantial reduction, highlighting Brentuximab's potent activity against hematologic malignancies. Wound healing assays further revealed that Brentuximab significantly impaired the migration and healing capacity of cancer cells compared to untreated controls. Additionally, cell cycle analysis indicated G2/M phase arrest in cancer cells, particularly in MCF-7 and MDA-MB-231, while HSF cells remained largely unaffected. Apoptosis detection confirmed Brentuximab-induced cell death, with significant increases in late apoptosis in cancer lines, especially by 72 h. Gene expression analysis revealed upregulation of pro-apoptotic genes (BAX, Caspase 3, and Caspase 9) in cancer cells, alongside a decrease in anti-apoptotic BCL-2 expression. These findings suggest Brentuximab's selective cytotoxicity against cancer cells and its potential as an effective therapeutic agent, particularly in breast cancer and histiocytic lymphoma.

PMID:39805861 | DOI:10.1038/s41598-024-84744-y

BMJ Support Palliat Care. 2025 Jan 13:spcare-2024-005205. doi: 10.1136/spcare-2024-005205. Online ahead of print.

ABSTRACT

CONTEXT: Pharmacogenomics (PGx) is an area of expanding research, which could indicate whether an individual is likely to benefit from a symptom control medication. Palliative and supportive care (PSC) could be an area that benefits from PGx, however, little is known about the current evidence base for this.

OBJECTIVE: To determine how PGx can be applied in PSC, whether there is any evidence of benefit, and to understand the extent and type of evidence that supports the use of PGx in PSC.

METHODS: A search of six databases up to July 2024. Reference snowballing from review articles and screened papers was used to identify any missed articles.

RESULTS: 11 articles were reviewed. A total of 550 patients had a PGx test across 8/11 studies. Up to half of the patients had an actionable PGx result, and in one study there were 4.6 drug-gene interactions per patient. Implementation of PGx was found to be feasible. Clinician adherence to advice given was under-reported. No studies reported health economics analysis, or was designed to definitively answer whether PGx was better than standard care.

CONCLUSIONS: It is both feasible and acceptable to conduct PGx testing in a supportive and palliative care setting. Many supportive care medications are amenable to PGx. Clinician adherence to recommendations is variable and there is no clear evidence that PGx enhances palliative/supportive care patient outcomes. Prospective, clinical trials are needed to establish whether PGx can improve symptom management for people receiving PSC.

PMID:39805678 | DOI:10.1136/spcare-2024-005205

Nat Rev Drug Discov. 2025 Jan 13. doi: 10.1038/d41573-025-00008-y. Online ahead of print.

NO ABSTRACT

PMID:39806010 | DOI:10.1038/d41573-025-00008-y

Sci Rep. 2025 Jan 13;15(1):1849. doi: 10.1038/s41598-025-85948-6.

ABSTRACT

Approaches to mitigate the severity of infections and of immune responses are still needed for the treatment of cystic fibrosis (CF) even with the success of highly effective modulator therapies. Previous studies identified reduced levels of melatonin in a CF mouse model related to circadian rhythm dysregulation. Melatonin is known to have immunomodulatory properties and it was hypothesized that treatment with melatonin would improve responses to bacterial infection in CF mice. Data demonstrate that CF mice (G542X/G542X) treated with melatonin (10 µg/mL) in drinking water for 10 weeks had improved responses to airway infection with a clinical isolate of Pseudomonas aeruginosa. Melatonin-treated mice exhibited improved bacterial clearance, reduced inflammatory markers. Mice treated in drinking water for 1 week had improved bacterial clearance but no improvement in inflammation. Wild type (WT) control mice showed no response to melatonin treatment suggesting melatonin is eliciting a CF-specific response in this model. The efficacy of direct melatonin (1 µM) treatment to the airways was also tested and found to be ineffective. In conclusion, long-term systemic treatment with melatonin is an effective therapy in a CF mouse model that normalizes the response to airway infection to a WT pattern.

PMID:39805903 | DOI:10.1038/s41598-025-85948-6

NPJ Biofilms Microbiomes. 2025 Jan 13;11(1):14. doi: 10.1038/s41522-024-00644-z.

ABSTRACT

Biofilms are critical in the persistence of Pseudomonas aeruginosa infections, particularly in cystic fibrosis patients. This study explores the adaptive mechanisms behind the phenotypic switching between Small Colony Variants (SCVs) and revertant states in P. aeruginosa biofilms, emphasizing hypermutability due to Mismatch Repair System (MRS) deficiencies. Through experimental evolution and whole-genome sequencing, we show that both wild-type and mutator strains undergo parallel evolution by accumulating compensatory mutations in factors regulating intracellular c-di-GMP levels, particularly in the Wsp and Yfi systems. While wild-type strains face genetic constraints, mutator strains bypass these by accessing alternative genetic pathways regulating c-di-GMP and biofilm formation. This increased genetic accessibility, driven by higher mutation rates and specific mutational biases, supports sustained cycles of SCV conversion and reversion. Our findings underscore the crucial role of hypermutability in P. aeruginosa adaptation, with significant implications for managing persistent infections in clinical settings.

PMID:39805827 | DOI:10.1038/s41522-024-00644-z

Arch Dis Child Educ Pract Ed. 2025 Jan 13:edpract-2024-328203. doi: 10.1136/archdischild-2024-328203. Online ahead of print.

ABSTRACT

Transformative changes in the health of children with cystic fibrosis (CF) mean that more sensitive outcome measures are needed to monitor paediatric CF lung disease. Multiple breath washout (MBW) and its primary readout lung clearance index are gaining increasing traction as an endpoint for clinical trials in the CF space and show promise as a clinical investigation. In this article, we use four clinically based questions to explore what MBW can and cannot (yet) do and highlight some of its strengths and weaknesses as an investigation. We end by discussing how we can increase the utility of MBW as an investigation in children with CF.

PMID:39805677 | DOI:10.1136/archdischild-2024-328203

Lancet Respir Med. 2025 Jan 10:S2213-2600(24)00364-3. doi: 10.1016/S2213-2600(24)00364-3. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis is a disease with a global impact, but most published data come from high-income countries. We aimed to describe the clinical characteristics of patients with bronchiectasis in China.

METHODS: The Chinese Bronchiectasis Registry (BE-China) is a prospective, observational cohort enrolling patients from 111 hospitals in China. Data on demographics, comorbidities, and aetiological testing results were collected from adult patients with bronchiectasis at baseline and annual follow-up. Patients who met the inclusion criteria (age ≥18 years; received chest high-resolution CT in the past year showing bronchiectasis affecting one or more lung lobes; and clinical history consistent with bronchiectasis, including chronic cough, daily sputum production, and history of exacerbations) were included. Patients with known cystic fibrosis were excluded. To investigate variations according to different economic regions, two groups were compared based on whether per capita disposable income of residents was greater than US$5553. Clinical characteristics were compared with the European (EMBARC) registry and other national registries.

FINDINGS: Between Jan 10, 2020, and March 31, 2024, 10 324 patients from 97 centres were included in the study. Among 9501 participants with available data, the most common cause of bronchiectasis was post-infective disease (4101 [43·2%] patients), followed by idiopathic (2809 [29·6%] patients). 6676 (70·0%) of 9541 patients with available data had at least one exacerbation in the year before enrolment and 5427 (57·2%) of 9489 patients with available data were hospitalised at least once due to exacerbations. Treatments commonly used in high-income countries, such as inhaled antibiotics and macrolides, were infrequently used in China. Implementation of airway clearance in China was scarce, with only 1177 (12·2%) of 9647 patients having used at least one method of airway clearance. Compared with upper-middle-income regions, patients from lower-middle-income regions were younger (61·0 years [SD 14·0] vs 63·9 years [14·2]) with a higher proportion of pulmonary comorbidities (521 [17·8%] of 2922 patients vs 639 [8·6%] of 7402 with chronic obstructive pulmonary disease and 194 [6·6%] of 2922 patients vs 364 [4·9%] of 7402 patients with asthma), a higher tuberculosis burden (442 [16·0%] of 2768 patients vs 715 [10·6%] of 6733 patients), more severe radiological involvement (1160 [42·4%] of 2736 patients vs 2415 [35·4%] of 6816 patients with cystic bronchiectasis), more exacerbations (median 1·4 [IQR 0-2] in both groups; mean 1·4 [SD 1·6] vs 1·2 [1·4] in the previous year) and hospitalisations (1662 [60·6%] of 2743 patients vs 3765 [55·8%] of 6746 patients hospitalised at least once in the previous year), and poorer quality of life (median 57·4 [IQR 53·5-63·1] vs 58·7 [54·8-64·8] assessed by the Bronchiectasis Health Questionnaire).

INTERPRETATION: The clinical characteristics of patients with bronchiectasis in China show differences compared with cohorts in Europe and India. Bronchiectasis is more severe with a higher burden of exacerbations in lower-income regions. The management of patients with bronchiectasis in China urgently needs standardisation and improvement.

FUNDING: National Natural Science Foundation of China, Innovation Program of the Shanghai Municipal Education Commission, Program of the Shanghai Municipal Science and Technology Commission, and Program of the Shanghai Shenkang Development Center.

TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PMID:39805296 | DOI:10.1016/S2213-2600(24)00364-3

Lancet Respir Med. 2025 Jan 10:S2213-2600(24)00427-2. doi: 10.1016/S2213-2600(24)00427-2. Online ahead of print.

NO ABSTRACT

PMID:39805295 | DOI:10.1016/S2213-2600(24)00427-2

Semin Thromb Hemost. 2025 Jan 13. doi: 10.1055/s-0044-1801825. Online ahead of print.

ABSTRACT

The purpose of this study is to (1) estimate and compare the prevalence of venous thromboembolism (VTE) in children (age 0 to ≤21) with versus without cystic fibrosis (CF); (2) investigate putative associations between specific gastrointestinal (GI) manifestations and the development of VTE among children with CF. This was a multicenter case-control analysis among patients aged 0 to ≤ 21 years between 2010 and 2020, using the TriNetX Research Network. Data queries included ICD-9/10 (International Classification of Diseases-9th/10th Revision) diagnosis codes. Bivariate associations with VTE among CF patients were compared using Chi-square testing for categorical variables and Student's t-test for continuous variables. We used multivariable logistic regression to test for independent associations of GI manifestations with VTE among children with CF, with adjustment for other salient covariates. There was a total of 7,689 children with and 22,327,660 without CF. The frequency of occurrence of VTE was increased nearly 20-fold among those with, as compared with without CF (130 vs. 7 per 10,000 patients). Acute pancreatitis (adjusted odd ratio [aOR] = 3.80, [95% confidence interval, CI: 2.00-7.22]), biliary disease (aOR = 2.17 [95% CI: 1.17-4.03]), gastrostomy status (aOR = 2.01 [95% CI: 1.27-3.18]), and malabsorption/malnutrition (aOR = 2.41 [95% CI: 1.52-3.82]) were each associated with a higher likelihood of VTE among children with CF. In conclusion, we found a significantly increased frequency of VTE occurrence and association of specific GI diseases as independent risk factors for VTE among children with CF compared with those without.

PMID:39805291 | DOI:10.1055/s-0044-1801825