J Cyst Fibros. 2025 Mar 10:S1569-1993(25)00061-X. doi: 10.1016/j.jcf.2025.02.013. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies revealed that some people with cystic fibrosis (pwCF) receiving the full dose of Elexacaftor/Tezacaftor/Ivacaftor (ETI) experience adverse events (AEs), leading to discontinuation or dose adjustments of their modulator treatment. We aimed to investigate if pwCF who experienced AEs had high exposure to ETI, and to what extent dose reduction resulted in changes in exposure, side effects and efficacy.

METHOD: This retrospective case series presents ETI exposure in pwCF who required ETI dose reduction due to AEs. ETI exposure was measured by minimal concentration (Cmin) levels, while sweat chloride concentration (SCC) was used to assess efficacy. AEs were graded using the common terminology criteria for AEs. Ten pwCF who experienced AEs during ETI treatment were included in the study.

RESULTS: The mean Cmin levels at the full ETI dose were 10.1 mg/L for elexacaftor, 4.2 mg/L for tezacaftor, and 1.2 mg/L for ivacaftor. These values exceed the mean Cmin values from the registration studies, which are 5.5 mg/L for elexacaftor, 2.1 mg/L for tezacaftor, and 0.8 mg/L for ivacaftor. The most frequently reported AEs were psychiatric and nervous system disorders. In all ten pwCF, an improvement of AEs was noted after dose reduction. The mean SCC measured on the full ETI dose was 38 mmol/L. Post dose reduction, the mean SCC was 44 mmol/L.

CONCLUSION: This study suggest that AEs of ETI in most cases could be related to elevated exposure levels. Dose reduction decreases ETI exposure and AEs while maintaining efficacy as determined with sweat chloride levels.

PMID:40069050 | DOI:10.1016/j.jcf.2025.02.013

Neonatal Netw. 2025 Mar 1;44(1):20-32. doi: 10.1891/NN-2024-0033.

ABSTRACT

Meconium ileus (MI) is the result of the accumulation of thick, dry, inspissated meconium that creates a bowel blockage, most commonly in the terminal ileum. These pockets of meconium prevent passage of stool beyond the point of obstruction, which leads to distention of the proximal bowel, bowel wall thickening, and distal microcolon. Occurring most commonly (90%) in conjunction with cystic fibrosis (CF), the occurrence of MI without CF is rare. The literature describes the incidence of MI associated with CF occurring in as many as 24.9% of those who have a pair (homozygous) of the most common CF gene mutation, Delta F508. The incidence of MI decreases with other CF mutations, of which there are over 2,000. The morbidity and mortality risks are related to whether the MI is simple or complex. Simple MI can be managed clinically with contrast enemas to relieve the obstruction and restore bowel function, while complex MI requires surgical intervention for possible bowel necrosis, perforation, peritonitis, strictures, and/or volvulus that can occur in utero or after birth. This article presents a case report of a 32-week-gestation female infant with gross abdominal distention beginning on day of life 1. The differential diagnosis, necessary testing, and required treatment that led to the final diagnosis will be presented. Additionally, radiographic modalities used to confirm the diagnosis are discussed. Finally, nursing management of the infant with simple or complex MI and short- and long-term challenges for infants and their families will be addressed.

PMID:40068907 | DOI:10.1891/NN-2024-0033

Cancer Cell. 2025 Mar 10;43(3):361-379.e10. doi: 10.1016/j.ccell.2025.02.010.

ABSTRACT

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

PMID:40068595 | DOI:10.1016/j.ccell.2025.02.010

Pediatr Pulmonol. 2025 Mar;60(3):e71038. doi: 10.1002/ppul.71038.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease characterized by persistent lung infection. Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) improves respiratory-related quality of life and reduces rates of infection and antibiotic treatments. Reduced antibiotic use may alter bacterial drug resistance patterns.

METHODS: This was a single center, retrospective, observational study analyzing respiratory cultures obtained from people with CF (pwCF) before and after starting ETI therapy. Antibiotic courses and culture data, including susceptibilities, were obtained from the electronic medical record.

RESULTS: There were 312 pwCF on ETI included, with an average age at ETI initiation of 20.9 ± 12.0 years and an average length of time on ETI 2.48 ± 0.69 years. Compared to the pre-ETI period, pwCF post-ETI had reductions in the number of antibiotic courses per year (2.5 to 0.7, p < 0.001), antibiotics utilized per course (1.4 to 1.0, p < 0.001), and percentage of courses including intravenous antibiotics (59% to 38%, p < 0.001). The fraction of pwCF with at least one culture positive for Pseudomonas aeruginosa, Burkholderia species, or Stenotrophomonas maltophilia decreased after ETI initiation, though changes were not significant for Staphylococcus aureus. Antibacterial resistance patterns were similar for most antibiotics in pre- and post-ETI periods, with P. aeruginosa exhibiting more resistance to fluoroquinolones post-ETI. Individuals with resistant organisms pre-ETI were less likely to clear the pathogen post-ETI.

CONCLUSION: Treatment with ETI significantly decreased antibiotic utilization and the prevalence of gram-negative organisms. Although fewer antibiotics were used, antibiotic resistance remained unchanged or even increased post-ETI due largely to the greater persistence of resistant organisms.

PMID:40067072 | DOI:10.1002/ppul.71038

Ann Am Thorac Soc. 2025 Mar 11. doi: 10.1513/AnnalsATS.202406-625OC. Online ahead of print.

ABSTRACT

Background The epidemiology of adult interstitial lung disease (ILD) is uncertain, given heterogeneous estimates from prior studies. The objective of this study was to define the incidence, prevalence, and mortality of ILD over a 10-year period using population-based data. Methods We created an administrative ILD cohort in Alberta, Canada between 2010-2019 using population-based administrative data (inpatient, ambulatory, and outpatient physician billing databases) for a repeat cross-sectional study. Case definitions were developed from an established ILD cohort and applied to the general population, with performance characteristics tested using a nested case-control design. Age-and sex-standardized annual incidence and point prevalence rates were estimated for ILD overall and within diagnostic sub-groups, with trends over time, per 100,000 at-risk adults and to permit comparisons with other studies, per 100,000 total population. Cox models estimated risk of death or lung transplantation. Results Between 2010-2019, 31,492 incident and 42,549 prevalent adult ILD cases were identified. The case definition for ILD performed well with 96.8% sensitivity, 98.5% specificity, and positive predictive value 94.3% in the population cohort. Mean age-standardized ILD incidence was 107.9/100,000 at-risk adults, 90.9/100,000 for females and 129.1/100,000 for males. Age-standardized ILD point prevalence increased from 416.5/100,000 at-risk adults in 2010 to 789.7/100,000 in 2019, higher in males vs females, and in rural vs urban areas. Age-standardized mean idiopathic pulmonary fibrosis (IPF) incidence was 36.9/100,000 at-risk and point prevalence was 205.3/100,000 at-risk in 2019. Mean age-standardized ILD incidence and prevalence was 84 and 516.9/100,000 total population, respectively. One-year all-cause mortality for ILD patients decreased from 14.5% in 2011 to 11.7% in 2018 (adjusted rate ratio (RR) for 2018 vs 2011, 0.76; 95%CI 0.67-0.86). One-year all-cause mortality for IPF similarly decreased from 20.9% in 2011 to 14.7% in 2018 (adjusted RR for 2018 vs 2011, 0.71; 95%CI 0.59-0.85), representing improved survival. Conclusions In this population-based cohort, claims-based case definitions derived from a established ILD cohort performed well to develop an administrative cohort. Incidence remained stable over time, while prevalence increased and mortality decreased, for ILD overall and within the IPF subgroup. These estimates are higher than most prior reports, suggesting an overall underestimate of ILD burden.

PMID:40068156 | DOI:10.1513/AnnalsATS.202406-625OC

Life Sci. 2025 Mar 10:123550. doi: 10.1016/j.lfs.2025.123550. Online ahead of print.

NO ABSTRACT

PMID:40069054 | DOI:10.1016/j.lfs.2025.123550

Structure. 2025 Mar 5:S0969-2126(25)00057-7. doi: 10.1016/j.str.2025.02.004. Online ahead of print.

ABSTRACT

Cryogenic electron microscopy (cryo-EM) has the potential to capture snapshots of proteins in motion and generate hypotheses linking conformational states to biological function. This potential has been increasingly realized by the advent of machine learning models that allow 100s-1,000s of 3D density maps to be generated from a single dataset. How to identify distinct structural states within these volume ensembles and quantify their relative occupancies remain open questions. Here, we present an approach to inferring variable regions directly from a volume ensemble based on the statistical co-occupancy of voxels, as well as a 3D convolutional neural network that predicts binarization thresholds for volumes in an unbiased and automated manner. We show that these tools recapitulate known heterogeneity in a variety of simulated and real cryo-EM datasets and highlight how integrating these tools with existing data processing pipelines enables improved particle curation.

PMID:40068687 | DOI:10.1016/j.str.2025.02.004

Cell. 2025 Mar 6:S0092-8674(25)00196-5. doi: 10.1016/j.cell.2025.02.011. Online ahead of print.

ABSTRACT

Brassinosteroid hormones are positive regulators of plant organ growth, yet their function in proliferating tissues remains unclear. Here, through integrating single-cell RNA sequencing with long-term live-cell imaging of the Arabidopsis root, we reveal that brassinosteroid activity fluctuates throughout the cell cycle, decreasing during mitotic divisions and increasing during the G1 phase. The post-mitotic recovery of brassinosteroid activity is driven by the intrinsic polarity of the mother cell, resulting in one daughter cell with enhanced brassinosteroid signaling, while the other supports brassinosteroid biosynthesis. The coexistence of these distinct daughter cell states during the G1 phase circumvents a negative feedback loop to facilitate brassinosteroid production while signaling increases. Our findings uncover polarity-guided, uneven mitotic divisions in the meristem, which control brassinosteroid hormone activity to ensure optimal root growth.

PMID:40068682 | DOI:10.1016/j.cell.2025.02.011

Cell. 2025 Mar 7:S0092-8674(25)00195-3. doi: 10.1016/j.cell.2025.02.010. Online ahead of print.

ABSTRACT

Bifidobacteria represent a dominant constituent of human gut microbiomes during infancy, influencing nutrition, immune development, and resistance to infection. Despite interest in bifidobacteria as a live biotic therapy, our understanding of colonization, host-microbe interactions, and the health-promoting effects of bifidobacteria is limited. To address these major knowledge gaps, we used a large-scale genetic approach to create a mutant fitness compendium in Bifidobacterium breve. First, we generated a high-density randomly barcoded transposon insertion pool and used it to determine fitness requirements during colonization of germ-free mice and chickens with multiple diets and in response to hundreds of in vitro perturbations. Second, to enable mechanistic investigation, we constructed an ordered collection of insertion strains covering 1,462 genes. We leveraged these tools to reveal community- and diet-specific requirements for colonization and to connect the production of immunomodulatory molecules to growth benefits. These resources will catalyze future investigations of this important beneficial microbe.

PMID:40068681 | DOI:10.1016/j.cell.2025.02.010

Cell. 2025 Mar 5:S0092-8674(25)00194-1. doi: 10.1016/j.cell.2025.02.009. Online ahead of print.

ABSTRACT

Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.

PMID:40068680 | DOI:10.1016/j.cell.2025.02.009

Physiol Rep. 2025 Mar;13(5):e70142. doi: 10.14814/phy2.70142.

ABSTRACT

The respiratory control system can exhibit neuronal plasticity following exposures to repetitive respiratory challenges. For example, repeated obstructive apneas can trigger a form of respiratory plasticity that results in the enhancement of inspiratory hypoglossal (XII) motoneuron activity. This increase in respiratory motor output is known as hypoglossal long-term facilitation (hLTF). In adult male Sprague-Dawley rats, we demonstrate that hLTF can also be triggered in the absence of repeated apneas by intermittent optogenetic stimulation of locus coeruleus (LC) neurons, or through pharmacological activation of adenosine-A2a-receptors at the level of brainstem XII motor pool. Both our pharmacological and optogenetic approaches that trigger hLTF require noradrenergic signaling through activation of α1-noradrenergic receptors on hypoglossal motoneurons. We also use optical LC inhibition to reaffirm the importance of the LC in mediating apnea-induced hLTF. These results demonstrate that hLTF can be triggered by multiple hypoxia-independent stimuli, and for the first time, identify the LC as a key brainstem source for noradrenaline necessary for the expression of hLTF.

PMID:40067835 | DOI:10.14814/phy2.70142

JMIR Cancer. 2025 Mar 11;11:e69663. doi: 10.2196/69663.

ABSTRACT

BACKGROUND: Androgen receptor axis-targeting reagents (ARATs) have become key drugs for patients with castration-resistant prostate cancer (CRPC). ARATs are taken long term in outpatient settings, and effective adverse event (AE) monitoring can help prolong treatment duration for patients with CRPC. Despite the importance of monitoring, few studies have identified which AEs can be captured and assessed in community pharmacies, where pharmacists in Japan dispense medications, provide counseling, and monitor potential AEs for outpatients prescribed ARATs. Therefore, we anticipated that a named entity recognition (NER) system might be used to extract AEs recorded in pharmaceutical care records generated by community pharmacists.

OBJECTIVE: This study aimed to evaluate whether an NER system can effectively and systematically identify AEs in outpatients undergoing ARAT therapy by reviewing pharmaceutical care records generated by community pharmacists, focusing on assessment notes, which often contain detailed records of AEs. Additionally, the study sought to determine whether outpatient pharmacotherapy monitoring can be enhanced by using NER to systematically collect AEs from pharmaceutical care records.

METHODS: We used an NER system based on the widely used Japanese medical term extraction system MedNER-CR-JA, which uses Bidirectional Encoder Representations from Transformers (BERT). To evaluate its performance for pharmaceutical care records by community pharmacists, the NER system was first applied to 1008 assessment notes in records related to anticancer drug prescriptions. Three pharmaceutically proficient researchers compared the results with the annotated notes assigned symptom tags according to annotation guidelines and evaluated the performance of the NER system on the assessment notes in the pharmaceutical care records. The system was then applied to 2193 assessment notes for patients prescribed ARATs.

RESULTS: The F1-score for exact matches of all symptom tags between the NER system and annotators was 0.72, confirming the NER system has sufficient performance for application to pharmaceutical care records. The NER system automatically assigned 1900 symptom tags for the 2193 assessment notes from patients prescribed ARATs; 623 tags (32.8%) were positive symptom tags (symptoms present), while 1067 tags (56.2%) were negative symptom tags (symptoms absent). Positive symptom tags included ARAT-related AEs such as "pain," "skin disorders," "fatigue," and "gastrointestinal symptoms." Many other symptoms were classified as serious AEs. Furthermore, differences in symptom tag profiles reflecting pharmacists' AE monitoring were observed between androgen synthesis inhibition and androgen receptor signaling inhibition.

CONCLUSIONS: The NER system successfully extracted AEs from pharmaceutical care records of patients prescribed ARATs, demonstrating its potential to systematically track the presence and absence of AEs in outpatients. Based on the analysis of a large volume of pharmaceutical medical records using the NER system, community pharmacists not only detect potential AEs but also actively monitor the absence of severe AEs, offering valuable insights for the continuous improvement of patient safety management.

PMID:40068144 | DOI:10.2196/69663

JAMA Netw Open. 2025 Mar 3;8(3):e250814. doi: 10.1001/jamanetworkopen.2025.0814.

ABSTRACT

IMPORTANCE: Given that older adults are at high risk for adverse drug events (ADEs), many geriatric medication programs have aimed to optimize safe ordering, prescribing, and deprescribing practices.

OBJECTIVE: To identify emergency department (ED)-based geriatric medication programs that are associated with reductions in potentially inappropriate medications (PIMs) and ADEs.

DATA SOURCES: A systematic search of Scopus, Embase, PubMed, PsycInfo, ProQuest Central, CINAHL, AgeLine, and Cochrane Library was conducted on February 14, 2024, with no date limits applied.

STUDY SELECTION: Randomized clinical trials or observational studies focused on ED-based geriatric (aged ≥65 years) medication programs that provide ED clinician support to avoid PIMs and reduce ADEs.

DATA EXTRACTION AND SYNTHESIS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for abstracting data and the Cochrane risk-of-bias tool were used to assess data quality and validity. Abstract screening and full-text review were independently conducted by 2 reviewers, with a third reviewer acting as an adjudicator.

MAIN OUTCOMES AND MEASURES: Process (ordering, prescribing, and deprescribing PIM rates) and clinical (ADE, health care utilization, and falls) outcomes.

RESULTS: The search strategy identified 3665 unique studies, 98 were assessed for eligibility in full-text review, and 25 studies, with 44 640 participants, were included: 9 clinical pharmacist reviews (with 28 360 participants), 1 geriatrician teleconsultation (with 50 participants), 8 clinician educational interventions (with 5888 participants), 4 computerized clinical decision support systems (CDSS; with 9462 participants), and 3 fall risk-increasing drug (FRID) reviews (with 880 participants). Clinical pharmacist review was not associated with decreased hospital admission or length of stay, but 2 studies showed a 32% reduction in PIMs from deprescribing (odds ratio [OR], 0.68 [95% CI, 0.50-0.92]; P = .01). One study also found that ED geriatrician teleconsultation was associated with enhanced deprescribing of PIMs. Three clinician educational intervention studies showed a 19% reduction in PIM prescribing (OR, 0.81 [95% CI, 0.68-0.96]; P = .02). Two computerized CDSS studies showed a 40% reduction in PIM ordering (OR, 0.60 [95% CI, 0.48-0.74]; P < .001). FRID reviews were not associated with reduced time to first fall or fall recurrence at 12 months.

CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of ED-based geriatric medication safety programs, a multidisciplinary team, including clinical pharmacists and/or geriatricians, was associated with improved PIM deprescribing. Furthermore, computerized CDSS, alone or in combination with ED clinician education, was associated with enhanced geriatric ordering and prescribing practices. These findings will inform the Geriatric ED Guidelines version 2.0 update.

PMID:40067297 | DOI:10.1001/jamanetworkopen.2025.0814

Chem Biodivers. 2025 Mar 11:e202402883. doi: 10.1002/cbdv.202402883. Online ahead of print.

ABSTRACT

Zinc (Zn) ions play a crucial role in cancer therapy due to their ability to induce reactive oxygen species (ROS) generation, oxidative stress, and ferroptosis. Combining Zn ions with other therapeutic agents can significantly enhance their efficacy through synergistic mechanisms. This study explores the synergistic mechanism of Zn ions form pH-responsive ZIF-8 and repurposed drug Pimozide in tumor microenvironment mimic conditions. The synthesized ZIF-8 exhibited an average size distribution of 36 nm with 52.21 ± 1.86 % of encapsulation efficiency for Pimozide. Notably, the maximum drug release of 84.13% was observed at pH 6. Further, in-vitro cytotoxicity investigations revealed heightened efficacy of Pimozide-ZIF-8 formulations after 48 h of treatment. In addition, Pimozide-ZIF-8 concomitantly induced ferroptosis and apoptosis in MCF-7 cells at pH 6, underscoring the pharmacological potency of the composite structure. Complementary to these experimental findings, an in-silico network analysis was performed to uncover protein interaction networks of Zn ions and Pimozide, highlighting their multi-targeted action in cancer-related pathways. Altogether, this dual-action approach activates both ferroptosis and apoptosis, presenting a promising therapeutic strategy for breast cancer that offers enhanced efficacy and targeting through the combined effects of Zn ions and Pimozide.

PMID:40065747 | DOI:10.1002/cbdv.202402883

Orphanet J Rare Dis. 2025 Mar 10;20(1):112. doi: 10.1186/s13023-024-03435-z.

ABSTRACT

BACKGROUND: Rare and complex diseases can have a significant impact on family life, and managing the reproductive aspects of patients of childbearing age with rare diseases is often difficult and complex. A European Reference Network (ERN) Transversal Working Group (WG) on Pregnancy and Family Planning was created to join forces to promote and address issues on these topics in rare and low-prevalence diseases.

OBJECTIVE: To outline the challenges and the good practices related to pregnancy and family planning in rare and complex diseases for healthcare professionals (HCPs).

METHODS: A survey on state of the art and unmet needs was created by a co-design group of both clinicians and patients' representatives from 20 ERNs. The survey was uploaded in English on the online platform "EU Survey" and disseminated by respective ERNs and learned societies. Seven transversal domains were explored in the survey by using closed and open-ended questions: fertility preservation, pre-conceptional counselling, family planning counselling, pre-implantation diagnosis, prenatal diagnosis, pregnancy monitoring and post pregnancy monitoring, lactation monitoring/counselling and newborn management. The questions investigated for each topic were the following: level of importance, activities performed by the centre, clinical challenges, good practice and educational activities.

RESULTS: A total of 197 answers were collected from 24 different countries. Unmet needs for HCPs included: the need to improve communication between different HCPs, the lack of predefined organizational pathways, the lack of availability of expert HCPs for some pregnancy-related issues and the need to streamline the care provided among different countries. In addition, the survey underlined the need to improve the educational activities provided to rare disease patients.

CONCLUSIONS: Physicians and patients need to be educated on the emerged unmet needs in order to standardize the information for both HCPs and patients with rare diseases. Educational activities should be considered to help to disseminate information.

PMID:40065363 | DOI:10.1186/s13023-024-03435-z

Drug Des Devel Ther. 2025 Mar 4;19:1527-1541. doi: 10.2147/DDDT.S495647. eCollection 2025.

ABSTRACT

BACKGROUND: Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.

METHODS: We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).

RESULTS: The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.

CONCLUSION: The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.

PMID:40066084 | PMC:PMC11891766 | DOI:10.2147/DDDT.S495647

Pharmacogenomics J. 2025 Mar 10;25(1-2):6. doi: 10.1038/s41397-025-00365-2.

ABSTRACT

Tacrolimus (TAC) is one of the most widely prescribed maintenance immunosuppressant drugs in solid organ transplantation. Kidney transplantation is often the preferred treatment for patients with the kidney failure and is complemented with TAC treatment. TAC treatment is often associated with adverse drug events, which can be reduced by pharmacogenomic (PGx)-guided prescription. We conducted a cost-utility analysis to assess the cost-effectiveness of PGx-guided TAC treatment versus the conventional scheme in patients who recently underwent kidney transplantation in Slovenia. Clinical data were collected from the PREPARE study. The effectiveness of the treatment was determined by mean survival and utility values and Incremental Cost-Effectiveness Ratio was also calculated. Costs of PGx-guided treatment was comparable to conventional treatment but shared reduced risk for severe ADEs and 43% improved quality of life. PGx-guided arm showed a mean of 0.956 Quality-Adjusted Life Years (QALYs) (95% CI: 0.900-1.014) compared to 0.862 QALYs (95%CI: 0.801-0.918) in the other arm. Probabilistic sensitivity analyses confirmed the results' robustness. In conclusion, PGx-guided treatment represents a cost-effective option for the TAC treatment of kidney-transplanted patients in the Slovenian healthcare setting.

PMID:40064851 | DOI:10.1038/s41397-025-00365-2

Front Pharmacol. 2025 Feb 24;16:1537095. doi: 10.3389/fphar.2025.1537095. eCollection 2025.

ABSTRACT

OBJECTIVE: Intestinal current measurement (ICM) provides a sensitive bioassay for assessment of cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies ex vivo and is used as a diagnostic tool for cystic fibrosis (CF). Furthermore, ICM was shown to be sensitive to detect pharmacological rescue of CFTR function by CFTR modulators in people with CF carrying responsive CFTR mutations. Results from clinical trials of CFTR modulators across age groups indicate that CFTR function in the sweat duct may be age-dependent with children reaching higher levels than adults. However, little is known about age dependency of CFTR function in the intestinal epithelium.

METHODS: We investigated CFTR-mediated chloride secretion in rectal biopsies from 258 people without CF and 72 people with pancreatic-insufficient CF from 1 month to 68 years of age. Change in transepithelial short-circuit current in response to cyclic adenosine monophosphate (cAMP)-mediated (100 μM IBMX, 1 µM forskolin, basolateral) and cholinergic (100 μM carbachol, basolateral) stimulation was assessed as a readout for CFTR function using perfused micro-Ussing chambers. Furthermore, quantitative real-time PCR of CFTR and morphometric analysis of epithelial cells lining the crypts and surface of the rectal mucosa were performed to assess regulation at the levels of gene expression and epithelial cell densities.

RESULTS: We found that CFTR-mediated chloride secretion across rectal tissues, as determined from cAMP-mediated as well as cholinergic chloride-secretory responses was highest during infancy and early childhood and declined with age in people without CF (both P < 0.001). Although, there was no difference in cAMP-mediated currents in people with CF, potassium-secretory responses induced by cholinergic stimulation were also reduced with increasing age. Transcript analyses showed that CFTR mRNA expression was slightly increased with increasing age in people without CF (P < 0.05). Morphometric analyses demonstrated that CFTR expressing colonocytes at the crypt base were decreased with age (P < 0.05). A secondary analysis of the ICM data of our previous studies on the effects of lumacaftor/ivacaftor on CFTR function in F508del -homozygous people with CF aged 12 years and older and 2-11 year old children showed correlations of the change in cAMP-mediated and cholinergic chloride secretory response with the age of people with CF (P < 0.01 and P < 0.05, respectively).

CONCLUSION: These results demonstrate that CFTR function in the rectal epithelium is reduced with increasing age and indicate that this change is likely due to a decline in the number of secretory colonocytes at the crypt base. These findings suggest that differences in CFTR expressing cells may explain increased functional responses to CFTR modulator therapies in children compared to adult people with CF.

PMID:40066329 | PMC:PMC11891205 | DOI:10.3389/fphar.2025.1537095

Gastroenterol Rep (Oxf). 2025 Mar 10;13:goaf019. doi: 10.1093/gastro/goaf019. eCollection 2025.

ABSTRACT

Exocrine pancreatic insufficiency (EPI) is a major cause of maldigestion and malnutrition, resulting from primary pancreatic diseases or other conditions. As the prevalence of EPI continues to rise, accurate identification of its etiology has become critical for the diagnosis and treatment of pancreatic secretory insufficiency. EPI can result from both pancreatic and non-pancreatic disorders. Pancreatic disorders include acute and chronic pancreatitis, pancreatic tumors, cystic fibrosis, procedures that involve pancreatic resection, and other rare causes. Non-pancreatic disorders of EPI include diabetes mellitus, celiac disease, inflammatory bowel disease, gastrointestinal and esophagectomy surgery, as well as advanced patient age. This review aims to provide a comprehensive analysis of the literature on EPI etiology, with a thorough overview to support its consideration as a potential diagnosis.

PMID:40066317 | PMC:PMC11893156 | DOI:10.1093/gastro/goaf019

Biofilm. 2025 Feb 22;9:100265. doi: 10.1016/j.bioflm.2025.100265. eCollection 2025 Jun.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that produces a biofilm containing the polysaccharides, alginate, Psl, and Pel, and causes chronic lung infection in cystic fibrosis patients. Others and we have previously explored the use of alginate lyases in inhibiting P. aeruginosa biofilm formation on plastic and lung epithelial cell monolayers. We now employ a more physiologically representative model system, i.e., three-dimensional aggregates of A549 lung epithelial cells cultured under conditions of microgravity in a rotary cell culture system to mimic the natural lung environment, and a previously isolated clinical strain, Pseudomonas aeruginosa CF2843 that we engineered by transposon-mediated integration to express Green Fluorescent Protein and for which we also report the complete genome sequence. Immunostaining and lectin binding studies indicated that the three-dimensional cell aggregates harbored sialylated and fucosylated epitopes as well as Muc1, Muc5Ac, and β-catenin on their surfaces, suggestive of mucin secretion and the presence of tight junctions, hallmark features of lung epithelial tissue. Using this validated model system with confocal microscopy and viable bacterial counts as readouts, we demonstrated that Cellulophaga algicola alginate lyase and Pseudomonas aeruginosa Psl glycoside hydrolase, but not Pseudomonas aeruginosa Pel glycoside hydrolase, inhibit biofilm formation by Pseudomonas aeruginosa on three-dimensional lung epithelial cell aggregates.

PMID:40066315 | PMC:PMC11891150 | DOI:10.1016/j.bioflm.2025.100265