Indian J Pediatr. 2025 Jan 24. doi: 10.1007/s12098-025-05428-7. Online ahead of print.

NO ABSTRACT

PMID:39853622 | DOI:10.1007/s12098-025-05428-7

Mol Biol Rep. 2025 Jan 24;52(1):155. doi: 10.1007/s11033-025-10258-z.

ABSTRACT

BACKGROUND: Pathogenic mutations in the CFTR gene disrupt the normal function of the chloride ion channel CFTR protein, resulting in Cystic Fibrosis (C.F.). Pakistan's situation regarding C.F. mutation is largely unknown, complicating the disease management and treatment. This study is designed to identify the disease-causing CFTR mutations in the Pakistani C.F. cohort and perform an in silico analysis of rare/novel variants.

METHODOLOGY: Ninety-five C.F. patients were recruited from pediatric healthcare facilities in different regions of Pakistan. Initially, we investigated ∆F508 mutation in all patients, followed by whole exome sequencing (W.E.S.) of nineteen patients and in silico analysis of identified rare/novel mutations.

RESULTS AND DISCUSSION: Initial screening revealed that ∆F508 mutation was absent in 73.74% of cases. W.E.S. identified three novel variants (c.3036del/Q1012Hfs*11, c.488 A > T/p.K163M, c.2384del/S795Yfs*8), one rare variant (c.489 + 2T > C) previously reported in two Pakistani residing in U.K. and one (c.164 + 1G > T/p.?) extremely rare in other populations. Additionally, c.1705T > G/p.Y569D, c.653T > A/p.L218X, c.2125 C > T/p.R709X, and c.3484 C > T/p.R1162X were also identified. Most variants in our cohort are either frameshift or nonsense, while only two are missense variants. Alarmingly, most of these variants, except ∆F508, are non-responsive to modulator drugs, while the responsiveness of c.488 A > T/p.K163M is yet to be determined. High consanguinity (73.40%) and homozygous status of all mutations, except c.3036del/Q1012Hfs*11, are indicative of a high ratio of C.F. carriers in Pakistan.

CONCLUSION: These findings represent the diverse pattern of CFTR mutations within the Pakistani population, highlighting the imperative need to improve earlier C.F. diagnostic and management facilities and to conduct research on treatment strategies other than modulator therapies.

PMID:39853500 | DOI:10.1007/s11033-025-10258-z

Microb Genom. 2025 Jan;11(1). doi: 10.1099/mgen.0.001332.

ABSTRACT

Bacteria from the Stenotrophomonas maltophilia complex (Smc) are important multidrug-resistant pathogens that cause a broad range of infections. Smc is genomically diverse and has been classified into 23 lineages. Lineage Sm6 is the most common among sequenced strains, but it is unclear why this lineage has evolved to be dominant. Antagonistic interactions can significantly affect the evolution of bacterial populations. These interactions may be mediated by secreted contact-dependent proteins, which allow inhibitor cells to intoxicate adjacent target bacteria. Contact-dependent inhibition (CDI) requires three proteins: CdiA, CdiB and CdiI. CdiA is a large, filamentous protein exported to the surface of inhibitor cells through the pore-like CdiB. The CdiA C-terminal domain (CdiA-CT) is toxic when delivered into target cells of the same species or genus. CdiI immunity proteins neutralize the toxicity of cognate CdiA-CT toxins. We found that all complete Smc genomes from the Sm6 lineage harbour at least one CDI locus. By contrast, less than a quarter of strains from other lineages have CDI genes. Smc CdiA-CT domains are diverse and have a broad range of predicted functions. Most Sm6 strains harbour non-cognate cdiI genes predicted to provide protection against foreign toxins from other strains. Finally, we demonstrated that an Smc CdiA-CT toxin has antibacterial properties and is neutralized by its cognate CdiI.

PMID:39853206 | DOI:10.1099/mgen.0.001332

BMC Health Serv Res. 2025 Jan 23;25(1):133. doi: 10.1186/s12913-025-12292-w.

ABSTRACT

BACKGROUND: Remote patient monitoring implies continuous follow-up of health-related parameters of patients outside healthcare facilities. Patients share health-related data with their healthcare unit and obtain feedback (which may be automatically generated if data are within a predefined range). The goals of remote patient monitoring are improvements for patients and reduced healthcare costs. The aim of this paper is to provide an overview of systematic reviews regarding remote patient monitoring for selected patient groups currently considered for the introduction of remote patient monitoring in Region Västra Götaland, Sweden. The selected sixteen patient groups were: patients with asthma, chronic obstructive pulmonary disease, children and adolescents with complex needs, children and adolescents with cystic fibrosis, children and adolescents with periodic fever, elderly patients with multiple diseases, patients with eye diseases, heart failure, haematological disease, hypertension, inflammatory bowel disease, neurorehabilitation, Parkinson's disease, psoriasis, sleep apnea, and specialist maternity care. Outcomes considered in this overview were patient-relevant clinical benefits as well as risks.

METHODS: A literature search for systematic reviews of clinical trials on remote patient monitoring in the selected patient groups was conducted by two information specialists, followed by assessment of relevance by a team of clinical and methodological experts in Region Västra Götaland, Sweden. The methodological rigour of identified systematic reviews was assessed using QUICKSTAR - a tool for stepwise appraisal of systematic reviews. In a QUICKSTAR assessment, a level of at least five is considered a prerequisite for reliable conclusions regarding the question at issue.

RESULTS: The literature search resulted in 4,049 hits, of which 84 SRs were considered relevant for the question at issue. A QUICKSTAR level of at least five was reached by 13 (15%) of the relevant systematic reviews. Some patient benefit of remote patient monitoring was reported for five patient groups (asthma, chronic obstructive lung disease, heart failure, hypertension, and elderly patients with multiple diseases). For four patient groups (children with complex needs, children with cystic fibrosis, specialist maternity care, and sleep apnea), systematic reviews of adequate quality concluded that scientific evidence on clinical patient benefits of remote monitoring is very limited. For seven patient groups, no systematic reviews of sufficient quality were identified.

CONCLUSION: Clinical benefits and risks of remote patient monitoring as a replacement for, or in addition to, standard of care compared to standard of care (face-to-face visits) are poorly studied for most of the selected patient groups based on systematic reviews of acceptable quality. Patient-relevant clinical benefits are limited or impossible to evaluate for most diagnoses based on currently available scientific information. Possible clinical risks and costs are poorly studied.

PMID:39849519 | DOI:10.1186/s12913-025-12292-w

J Cyst Fibros. 2025 Jan 22:S1569-1993(25)00006-2. doi: 10.1016/j.jcf.2025.01.007. Online ahead of print.

ABSTRACT

BACKGROUND: Reproductive life planning is key, now that people with cystic fibrosis (pwCF) may live into their 60s. This study explores contraceptive use, pregnancy trends, and whether concomitant cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy reduces contraceptive effectiveness.

METHODS: Females with CF aged 18-45 years from 10 U.S. CF centers completed a self-administered web-based questionnaire. Pregnancy rates were calculated by linear-mixed models with a logit link detected associations with contraception and modulator use.

RESULTS: A total of 561 pwCF (median age of 29 years [IQR 24.9-35.8] years) completed the survey. Most participants (n = 499, 89%) used modulators, and almost all (n = 555, 99%) used contraception. Condoms (n = 448, 80%) and oral contraceptive pills (n = 363, 65%) were the most prevalent methods used. One-third (n = 189, 34%) reported ever being pregnant. Of those reporting pregnancies (n = 319), about half (n = 151, 48%) were unintended. Pregnancy was significantly associated with age (20-29 years or 30-39 years), partner cohabitation (aOR 21.5, 95% CI 5.1 to 91.1), and non-hormonal contraceptive use (aOR 5.1, 95% CI 1.1 to23.0). Among pwCF cohabitating with a partner, modulator use was positively associated with pregnancy (OR 1.8, 95% CI 1.3 to 2.6) (p = 0.0008).

CONCLUSIONS: Despite almost universal contraceptive use, unintended pregnancy among pwCF is common. Likelihood of pregnancy is increased among CFTR modulator users who are partnered, although CFTR modulators themselves do not appear to decrease hormonal contraceptive effectiveness. Patient education about contraception is an increasingly critical aspect of CF care.

PMID:39848844 | DOI:10.1016/j.jcf.2025.01.007

Medicines (Basel). 2024 Dec 31;12(1):1. doi: 10.3390/medicines12010001.

ABSTRACT

Cystic fibrosis (CF) is a rare genetic disorder commonly affecting multiple organs such as the lungs, pancreas, liver, kidney, and intestine. Our search focuses on the pathophysiological changes that affect the drugs' absorption, distribution, metabolism, and excretion (ADME). This review aims to identify the ADME data that compares the pharmacokinetics (PK) of different drugs in CF and healthy subjects. The published data highlight multiple factors that affect absorption, such as the bile salt precipitation and the gastrointestinal pH. Changes in CF patients' protein binding and body composition affected the drug distribution. The paper also discusses the factors affecting metabolism and renal elimination, such as drug-protein binding and metabolizing enzyme capacity. The majority of CF patients are on multidrug therapy, which increases the risk of drug-drug interactions (DDI). This is particularly true for those receiving the newly developed transmembrane conductance regulator (CFTR), as they are at a higher risk for CYP-related DDI. Our research highlights the importance of meticulously evaluating PK variations and DDIs in drug development and the therapeutic management of CF patients.

PMID:39846711 | DOI:10.3390/medicines12010001

Noncoding RNA. 2025 Jan 12;11(1):3. doi: 10.3390/ncrna11010003.

ABSTRACT

The discovery of the involvement of microRNAs (miRNAs) in cystic fibrosis (CF) has generated increasing interest in the past years, due to their possible employment as a novel class of drugs to be studied in pre-clinical settings of therapeutic protocols for cystic fibrosis. In this narrative review article, consider and comparatively evaluate published laboratory information of possible interest for the development of miRNA-based therapeutic protocols for cystic fibrosis. We consider miRNAs involved in the upregulation of CFTR, miRNAs involved in the inhibition of inflammation and, finally, miRNAs exhibiting antibacterial activity. We suggest that antago-miRNAs and ago-miRNAs (miRNA mimics) can be proposed for possible validation of therapeutic protocols in pre-clinical settings.

PMID:39846681 | DOI:10.3390/ncrna11010003

NPJ Antimicrob Resist. 2024 Feb 20;2(1):4. doi: 10.1038/s44259-024-00022-x.

ABSTRACT

Antimicrobial peptides (AMPs) are key components of innate immunity across all domains of life. Natural and synthetic AMPs are receiving renewed attention in efforts to combat the antimicrobial resistance (AMR) crisis and the loss of antibiotic efficacy. The gram-negative pathogen Pseudomonas aeruginosa is one of the most concerning infecting bacteria in AMR, particularly in people with cystic fibrosis (CF) where respiratory infections are difficult to eradicate and associated with increased morbidity and mortality. Cationic AMPs exploit the negatively charged lipopolysaccharides (LPS) on P. aeruginosa to bind and disrupt bacterial membrane(s), causing lethal damage. P. aeruginosa modifies its LPS to evade AMP killing. Free-LPS is also a component of CF sputum and feeds pro-inflammatory cycles. Glatiramer acetate (GA) is a random peptide co-polymer-of glycine, lysine, alanine, tyrosine-used as a drug in treatment of multiple sclerosis (MS); we have previously shown GA to be an AMP which synergises with tobramycin against CF P. aeruginosa, functioning via bacterial membrane disruption. Here, we demonstrate GA's direct binding and sequestration/neutralisation of P. aeruginosa LPS, in keeping with GA's ability to disrupt the outer membrane. At CF-relevant LPS concentrations, however, membrane disruption by GA was not strongly inhibited. Furthermore, exposure to GA did not result in increased Lipid A modification of LPS or in increased gene expression of systems involved in AMP sensing and LPS modification. Therefore, despite the electrostatic targeting of LPS by GA as part of its activity, P. aeruginosa does not demonstrate LPS modification in its defence.

PMID:39843948 | DOI:10.1038/s44259-024-00022-x

NPJ Antimicrob Resist. 2024 Nov 14;2(1):38. doi: 10.1038/s44259-024-00060-5.

ABSTRACT

Polymicrobial communities inhabit the cystic fibrosis (CF) airway, whereby microbial interactions can occur. One prominent CF pathogen is Mycobacterium abscessus, whose treatment is largely unsuccessful. This creates a need to discover novel antimicrobial agents to treat M. abscessus, however the methods used within antibiotic discovery are typically monomicrobial. This review will discuss this pathogen whilst considering the CF polymicrobial environment, to highlight future perspectives to improve M. abscessus drug discovery.

PMID:39843836 | DOI:10.1038/s44259-024-00060-5

NPJ Antimicrob Resist. 2024 Nov 5;2(1):34. doi: 10.1038/s44259-024-00054-3.

ABSTRACT

Mycobacterium abscessus complex (MABSC) comprises a group of environmental microorganisms, which are a concerning cause of opportunistic respiratory infections in patients with cystic fibrosis or bronchiectasis. Only 45.6% of MABSC treatments are successful, and therefore this is a need to discover new antimicrobials that can treat these pathogens. However, the transferability of outcomes to the clinic is flawed by an inability to accurately represent the lung environment within the laboratory. Herein, we apply two preestablished formulations of sputum media (ACFS and SCFM1) to MABSC antibiotic susceptibility testing. Using conventional broth microdilution, we have observed strain and antibiotic dependent alterations in antimicrobial sensitivity in each sputum media compared standard laboratory media (7H9), with an overall reduction in susceptibility within the physiologically relevant conditions. We provide a timely contribution to the field of M. abscessus antibiotic discovery by emphasising the need for improved physiological relevance.

PMID:39843503 | DOI:10.1038/s44259-024-00054-3

Biomed Pharmacother. 2025 Jan 21;183:117819. doi: 10.1016/j.biopha.2025.117819. Online ahead of print.

ABSTRACT

A hypertonic solution of Ibuprofen (Ibu) was designed to nebulize, associating a low concentration of Ibu with L-Arginine (AR), to increase solubility and serve as a nitric oxide donor. To provide preclinical research human bronchial epithelial cells derived from a cystic fibrosis patient homozygous for the ΔF508 CFTR mutation (CFBE41o-) and mouse RAW 264.7 macrophages were pre-treated with Ibu (10-100 μM), AR (20 and 200 μM), or the combination Ibu-AR (10-100 μM). After Angiotensin II (AngII) or LPS/Interferon ϒ (IFN) stimulation, Reactive Oxygen Species (ROS) generation, Nitric Oxide (NO) formation, and the expression of inflammatory markers were determined. Ibu-AR (10/20 μM) significantly reduced ROS generation stimulated by AngII (p < 0.01) in CFBE41o- cells preserved the NO pathway and inhibited LPS-stimulated nitrite generation (p < 0.001). In macrophages, the combination Ibu-Ar, in a ratio of 1:2-1:6, efficiently scavenged excessive ROS generated by LPS, and significantly induced NO generation (p < 0.001), but inhibited nitrite formation. In LPS/IFNϒ-activated Raw, gene signature of M1polarization including tumor necrosis factor (TNF-α), NADPH Oxidase 2 (NOX-2), MCP-1, and inducible nitric oxide synthase (iNOS) were significantly downregulated by Ibu-AR, as well TNF-α, IL-6, and iNOS protein expressions. The inhibitory effect produced by Ibu-AR on M1 macrophages was associated with the inhibition of p-ERK1/2 and p-STAT3. Ibu-AR represents an effective therapeutic strategy for reducing oxidative stress, preserving NO bioavailability, and modulating inflammation in chronic inflammatory diseases.

PMID:39842270 | DOI:10.1016/j.biopha.2025.117819

Sleep Med. 2025 Jan 19;127:120-126. doi: 10.1016/j.sleep.2025.01.018. Online ahead of print.

ABSTRACT

AIM: This study aimed to assess the relationship between sleep quality, malnutrition risk, and nutritional status in adolescents with cystic fibrosis(CF).

MATERIAL AND METHOD: This cross-sectional study was conducted with 55 adolescents (aged 10-18 years) diagnosed with CF. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and malnutrition risk was evaluated based on disease-specific criteria. Nutritional status was assessed using body mass index (BMI), BMI percentiles, dietary energy intake, and food group consumption. Multiple linear regression analyses were used to determine the relationship between sleep quality, malnutrition risk, and nutritional status.

RESULTS: Among the participants, 50.9 % had poor sleep quality, and 29.1 % were classified as high-risk for malnutrition. Poor sleep quality was significantly associated with increased malnutrition risk (p < 0.05), independent of dietary energy intake and BMI percentiles. Lower BMI percentile was strongly associated with higher malnutrition risk (p < 0.001), identifying BMI as a critical predictor. Specifically, 27.3 % of participants had a BMI <10th percentile, which contributed to their classification as high-risk for malnutrition. However, dietary energy intake did not significantly predict malnutrition risk despite its relevance in dietary management.

CONCLUSION: This study emphasizes the crucial role of sleep quality in assessing malnutrition risk among adolescents with CF. Poor sleep quality was associated with higher malnutrition risk, suggesting that sleep disturbances may contribute to nutritional challenges. Sleep quality should be considered a key factor in assessing malnutrition risk among adolescents with CF and integrated into clinical practice to develop comprehensive management strategies addressing sleep disturbances and nutritional challenges, improving health outcomes.

PMID:39842132 | DOI:10.1016/j.sleep.2025.01.018

Sci Transl Med. 2025 Jan 22;17(782):eadk9145. doi: 10.1126/scitranslmed.adk9145. Epub 2025 Jan 22.

ABSTRACT

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, CFTR transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

PMID:39841805 | DOI:10.1126/scitranslmed.adk9145

J Bras Pneumol. 2025 Jan 20;50(6):e20240405. doi: 10.36416/1806-3756/e20240405.

NO ABSTRACT

PMID:39841779 | DOI:10.36416/1806-3756/e20240405

Dtsch Arztebl Int. 2024 Oct 18;121(21):712-713. doi: 10.3238/arztebl.m2024.0126.

NO ABSTRACT

PMID:39841500 | DOI:10.3238/arztebl.m2024.0126

J Clin Microbiol. 2025 Jan 22:e0148024. doi: 10.1128/jcm.01480-24. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (BCC) is a group of Gram-negative bacteria that cause opportunistic infections, most notably in people with cystic fibrosis (CF), and have been associated with outbreaks caused by contaminated medical products. Antimicrobial susceptibility testing (AST) is often used to guide treatment for BCC infections, perhaps most importantly in people with CF who are being considered for lung transplant. However, recent studies have highlighted problems with AST methods. Here, we address limitations from previous studies to further evaluate BCC AST methods. We assessed the performance of reference broth microdilution (BMD), disk diffusion (DD) using Mueller-Hinton agar (MHA) from three manufacturers, agar dilution (AD), and gradient diffusion (ETEST) for ceftazidime (CAZ), levofloxacin (LVX), meropenem (MEM), minocycline (MIN), and trimethoprim-sulfamethoxazole (TMP-SMX) on a set of 205 BCC isolates. The isolate set included 100 isolates from people with CF and 105 isolates from people without CF from a variety of sources, which enabled us to systematically evaluate whether specimen source impacts AST performance. For all BCC isolates, BMD reproducibility was 93%, 98%, 99%, 98%, and 96% for CAZ, LVX, MEM, MIN, and TMP-SMX, respectively. Using BMD as the comparator method, we show that DD, AD, and ETEST perform poorly, with neither MHA manufacturer nor specimen source significantly impacting method performance. Based on our data, we recommend that routine AST should not be performed for BCC isolates. If a provider requests AST, clinical microbiology laboratories should perform Clinical and Laboratory Standards Institute reference methodology for BMD (stored frozen) and report MIC only.IMPORTANCEAntimicrobial susceptibility testing for the Burkholderia cepacia complex (BCC) is often used to determine eligibility for lung transplant in people with cystic fibrosis. However, problems with method performance have been reported. Here, we systematically evaluate the performance of reference broth microdilution, disk diffusion, agar dilution, and gradient diffusion (ETEST) for BCC organisms isolated from people with and without cystic fibrosis. We show that broth microdilution reproducibility is acceptable for levofloxacin, meropenem, minocycline, and trimethoprim-sulfamethoxazole, while ceftazidime was just below the acceptability cut-off. Regardless of specimen source, the results from disk diffusion, agar dilution, and ETEST do not correlate with broth microdilution. Based on these findings, we recommend that antimicrobial susceptibility testing should not be routinely performed for BCC, and if requested by the provider, only broth microdilution following Clinical and Laboratory Standards Institute guidelines should be used. Providers should be aware of the significant limitations of antimicrobial susceptibility testing methods for BCC.

PMID:39840992 | DOI:10.1128/jcm.01480-24

Antimicrob Agents Chemother. 2025 Jan 22:e0116224. doi: 10.1128/aac.01162-24. Online ahead of print.

ABSTRACT

Stenotrophomonas maltophilia is an understudied, gram-negative, aerobic bacterium that is widespread in the environment and increasingly a cause of opportunistic infections. Treating S. maltophilia remains difficult, leading to an increase in disease severity and higher hospitalization rates in people with cystic fibrosis, cancer, and other immunocompromised health conditions. The lack of effective antibiotics has led to renewed interest in phage therapy; however, there remains a great need for well-characterized phages, especially against S. maltophilia. In response to an oncology patient with a sepsis infection, we collected 18 phages from Southern California wastewater influent that exhibit different plaque morphology against S. maltophilia host strain B28B. We hypothesized that, when combined into a cocktail, genetically diverse phages would give rise to distinct lytic infection kinetics that would enhance bacterial killing when compared to the individual phages alone. We identified three genetically distinct clusters of phages, and a representative from each group was further investigated and screened for potential therapeutic use. The results demonstrated that the three-phage cocktail significantly suppressed bacterial growth compared with individual phages when observed for 48 h. We also assessed the lytic impacts of our three-phage cocktail against a collection of 46 S. maltophilia strains to determine if a multi-phage cocktail has an expanded host range. Our phages remained strain-specific and infected >50% of tested strains. In six clinically relevant S. maltophilia strains, the multi-phage cocktail has enhanced suppression of bacterial growth. These findings suggest that specialized phage cocktails may be an effective avenue of treatment for recalcitrant S. maltophilia infections resistant to current antibiotics.

PMID:39840957 | DOI:10.1128/aac.01162-24

Front Immunol. 2025 Jan 7;15:1466802. doi: 10.3389/fimmu.2024.1466802. eCollection 2024.

ABSTRACT

BACKGROUND AND AIM: NK cells and NK-cell-derived cytokines were shown to regulate neutrophil activation in acute lung injury (ALI). However, the extent to which ALI regulates lung tissue-resident NK (trNK) activity and their molecular phenotypic alterations are not well defined. We aimed to assess the impact of 1,25-hydroxy-vitamin-D3 [1,125(OH)2D] on ALI clinical outcome in a mouse model and effects on lung trNK cell activations.

METHODS: Oleic acid (OA)-induced ALI in C57BL/6J mice and 1,25(OH)2D treatment 2×/2 weeks were performed. Lung tissue was harvested to assess alveolar I/II cell apoptosis and lung injury marker of Surfactant-Protein-D (SP-D). Pulmonary edema markers of epithelial sodium channel, cystic fibrosis transmembrane conductance regulator, and aquaporin 5 were assessed by RT-PCR. Lung trNK cells were assessed for activation markers of CD107a and NKp46, vitamin D receptor (VDR), and programmed cell death protein-1 (PD-1) via flow cytometry. The bronchoalveolar lavage fluid (BALF) obtained was investigated for soluble receptor for advanced glycation end products (sRAGE), inflammatory cytokines, soluble 1,25(OH)2D, and PDL-1. Naïve mice treated with DMSO (vehicle) were used as a control.

RESULTS: Flow cytometry analysis displayed a high apoptotic rate in alveolar I/II cells of threefold in ALI mice as compared to naïve mice. These findings were accompanied by elevated markers of pulmonary edema as well as lung injury markers of SP-D. Isolated lung trNK cells of the ALI mice exhibited reduced CD107a and NKp46 markers and cytotoxicity potentials and were correlated through significantly 2.1-fold higher levels of PD-1 and diminished VDR expressions as compared to naïve mice. BALF samples of ALI mice displayed high soluble PDL-1 and reduced soluble 1,25(OH)2D levels compared to naïve mice. 1,25(OH)2D treatment alongside OA led to a significant fourfold increase in the CD107a and NKp46 expressions to levels higher than the mice treated with the vehicle. Furthermore, 1,25(OH)2D ameliorates free radical scavengers of GSH, GPX, CAT, and GPx-1; decreased pro-inflammatory cytokines and soluble PDL-1; and increased soluble 1,25(OH)2D with amelioration in pulmonary edema markers and alveolar I/II apoptosis.

CONCLUSION: Our results indicate 1,25(OH)2D's potential therapeutic effect in preventing clinical outcomes associated with ALI via regulating NK cells through inhibiting inflammatory cytokines and alleviating levels of PDL-1 and 1,25(OH)2D released by lung tissue.

PMID:39840066 | PMC:PMC11746039 | DOI:10.3389/fimmu.2024.1466802

MDM Policy Pract. 2025 Jan 17;10(1):23814683241305106. doi: 10.1177/23814683241305106. eCollection 2025 Jan-Jun.

ABSTRACT

Introduction. Diminishing marginal lifespan utility (DMLU) implies that a particular lifespan increment (e.g., 1 life-year) confers lesser marginal utility if added to longer lifespans (e.g., 90 y to 91 y) than to shorter lifespans (e.g., 60 y to 61 y) if quality of life is unchanged. Because DMLU is difficult to disambiguate from discounting, risk attitude, and other elements of utility "curvature," it is poorly characterized. However, the imperative to consider equity in cost-effectiveness analysis (CEA) renders its characterization more important. Methods. I add certainty to the characterization of DMLU through literature review and illustrative example. The literature review synthesizes stated preference studies of utility curvature that exclude risk or probability. The example compares alternative valuations of approaches to reduce inequality in cystic fibrosis outcomes between US centers serving mostly White patients and centers serving mostly non-Black Hispanic patients, with versus without DMLU. Results. The existence of DMLU is likely, and empirical data support its relevance over typical CEA time horizons. The imperative to consider equity in CEA magnifies the importance of DMLU for several reasons. First, intergenerational CEAs require lower discount rates that are less likely to incidentally absorb DMLU. Second, DMLU is incompatible with the use of absolute measures of inequality aversion. Third, DMLU may bias the interpretation of relative measures of inequality aversion toward prioritarianism. Finally, not considering DMLU implicitly biases life-year-based metrics against equity. Conclusion. DMLU is likely to exist, can benefit from additional characterization, and may merit inclusion in CEA alongside discounting. Omitting consideration of DMLU will sometimes confer an antiequity bias and may affect the interpretation of CEAs incorporating inequality aversion.

HIGHLIGHTS: Diminishing marginal lifespan utility (DMLU) means that the value of extending lifespan may differ based on the duration of life already lived.DMLU is not typically considered in cost-effectiveness analyses.Not considering DMLU may bias cost-effectiveness analyses against equity.Not considering DMLU may reduce the accuracy of distributive cost-effectiveness analyses and other approaches to consider equity along with efficiency.

PMID:39839684 | PMC:PMC11748391 | DOI:10.1177/23814683241305106

Quant Imaging Med Surg. 2025 Jan 2;15(1):189-202. doi: 10.21037/qims-24-989. Epub 2024 Dec 30.

ABSTRACT

BACKGROUND: Clinical severity and progression of lung disease in cystic fibrosis (CF) are significantly influenced by the degree of lung inflammation. Non-invasive quantitative diagnostic tools are desirable to differentiate structural and inflammatory lung changes in order to help prevent chronic airway disease. This might also be helpful for the evaluation of longitudinal effects of novel therapeutics. Therefore, the present study assesses the quantification of inflammatory lung changes using positron emission tomography/magnetic resonance imaging (PET/MRI) of the lung in children and adolescents with CF and evaluates the possible impact of PET/MRI on individualized therapy management.

METHODS: This monocentric, retrospective cohort study included 19 PET/MRI of the lung performed between 2014 and 2021 in 11 patients (16±4.5 years, 8-22 years; 7 females). PET acquisition was performed at least 20 minutes after i.v. application of a weight-adjusted dose of fluor-18-fluorodeoxyglucose (18F-FDG) of 1 MBq/kgBW (mean effective dose, 1.3±0.4 mSv). Lesions of increased uptake were quantified based on standardized uptake values (SUV) and compared to background activity, liver and blood pool. Pulmonary changes were assessed using the established magnetic resonance imaging-CF (MR-CF) score and correlated to inflammatory lesions. Results were correlated to changes in therapy (initiation, modification or discontinuation of therapy after baseline-PET/MRI) based on the electronic medical records.

RESULTS: Uptake was highly increased in 5 cases, moderate in 4 cases, low in 7 cases, no uptake in 3 cases. Most MR-CF score points were assigned to peribronchitis (23%) and air trapping (23%). Metabolically increased lesions were mainly interpreted as consolidations (59%; P<0.001) and mucus plugging (19%, P=0.024). There was a decrease in mean number and volumes of inflammatory lesions (P=0.016 each) and MR-CF score (P=0.047) between baseline and follow-up. After PET/MRI, therapy changed in 18 cases (95%; new medication: 58%, n=11; termination of therapy: 16%, n=3; modification of therapy: 21%, n=4).

CONCLUSIONS: In selected cases, pulmonary FDG-PET/MRI can help guide therapeutic decision-making and provide complementary information on CF-related lung changes to conventional MRI at a low radiation exposure.

PMID:39838989 | PMC:PMC11744157 | DOI:10.21037/qims-24-989