Respir Res. 2025 Feb 28;26(1):77. doi: 10.1186/s12931-025-03140-w.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis is associated with frequent and diverse microbial infections, yet an overall understanding of microbial presence across different disease stages is lacking.

METHODS: A meta-analysis assessed lung microbes in adults with non-CF bronchiectasis, collecting data using both culture-based and sequencing approaches through three international databases and three Chinese databases. Subgroups were categorized by disease stage: the stable group (S), the exacerbation group (E), and unclassified data consolidated into the undetermined group (U). Culture data were analysed in random-effects meta-analyses while sequencing data were processed using QIIME 2.

RESULTS: A total of 98 studies were included with data from 54,384 participants worldwide. Pseudomonas aeruginosa was the most frequently isolated bacterium (S: 26[19-34]%, E: 23[20-25]%, U: 20[16-25]%), while not specified Mycobacterium avium complex exhibited the highest mycobacterial prevalence (S: 3[1-5]%, E: 4[2-5]%, U: 15[3-27]%). Aspergillus spp. (S: 15[-10-39]%, E: 2[1-3]%, U: 10[5-15]%) and Candida spp. (S: not applicable, E: 11[2-20]%, U: 10[-8-27]%) were predominant in fungi culture with variable distributions among groups. Rhinovirus was the most commonly detected virus with varying prevalence across airway sample types rather than disease stages (S-sputum: 18[-16-53]%, S-nasopharyngeal: 4[-1-9]%, E-sputum: 22[16-29]%, E-nasopharyngeal: 6[4-8]%). Sequencing results revealed notable antibiotic persistence of Pseudomonas in 16S, and significant domination of Candida in ITS.

CONCLUSION: Our findings indicate consistent bacterial patterns throughout bronchiectasis stages in both culture and sequencing results. Viruses are extensively detected in stable patients but vary across different airway sample types. Lower bacterial diversity and higher fungal diversity may be associated with exacerbation risks.

PMID:40022075 | DOI:10.1186/s12931-025-03140-w

Mol Med. 2025 Feb 28;31(1):81. doi: 10.1186/s10020-025-01133-5.

ABSTRACT

BACKGROUND AND PURPOSE: Shwachman-Diamond Syndrome (SDS) is an autosomal recessive disease belonging to the inherited bone marrow failure syndromes and characterized by hypocellular bone marrow, exocrine pancreatic insufficiency, and skeletal abnormalities. SDS is associated with increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). Although SDS is not primarily considered an inflammatory disorder, some of the associated conditions (e.g., neutropenia, pancreatitis and bone marrow dysfunction) may involve inflammation or immune system dysfunctions. We have already demonstrated that signal transducer and activator of transcription (STAT)-3 and mammalian target of rapamycin (mTOR) were hyperactivated and associated with elevated IL-6 levels in SDS leukocytes. In this study, we analyzed the level of phosphoproteins involved in STAT3 and mTOR pathways in SDS lymphoblastoid cells (LCLs) and the secretomic profile of soluble pro-inflammatory mediators in SDS plasma and LCLs in order to investigate the systemic inflammation in these patients and relative pathways.

METHODS: Twenty-six SDS patients and seven healthy donors of comparable age were recruited during the programmed follow-up visits for clinical evaluation at the Verona Cystic Fibrosis Center Human. The obtained samples (plasma and/or LCLs) were analyzed for: phosphoproteins, cytokines, chemokines and growth factors levels by Bio-plex technology; microRNAs profiling by next generation sequencing (NGS) and microRNAs expression validation by Real Time-PCR (RT-PCR) and droplet digital PCR (ddPCR) .

RESULTS: We demonstrated dysregulation of ERK1/2 and AKT phosphoproteins in SDS, as their involvement in the hyperactivation of the STAT3 and mTOR pathways confirmed the interplay of these pathways in SDS pathophysiology. However, both these signaling pathways are strongly influenced by the inflammatory environment. Here, we reported that SDS is characterized by elevated plasma levels of several soluble proinflammatory mediators. In vitro experiments show that these pro-inflammatory genes are closely correlated with STAT3/mTOR pathway activation. In addition, we found that miR-181a-3p is down-regulated in SDS. Since this miRNA acts as a regulator of several pro-inflammatory pathways such as STAT3 and ERK1/2, its down-regulation may be a driver of the constitutive inflammation observed in SDS patients.

CONCLUSIONS: The results obtained in this study shed light on the complex pathogenetic mechanism underlying bone marrow failure and leukemogenesis in SDS, suggesting the need for anti-inflammatory therapies for SDS patients.

PMID:40021961 | DOI:10.1186/s10020-025-01133-5

NPJ Antimicrob Resist. 2025 Feb 28;3(1):17. doi: 10.1038/s44259-025-00088-1.

ABSTRACT

R-pyocins, bacteriocin-like proteins produced by Pseudomonas aeruginosa, present a promising alternative to phage therapy and/or adjunct to currently used antimicrobials in treating bacterial infections due to their targeted specificity, lack of replication, and stability. This review explores the structural, mechanistic, and therapeutic aspects of R-pyocins, including their potential for chronic infection management, and discusses recent advances in delivery methods, paving the way for novel antimicrobial applications in clinical settings.

PMID:40021925 | DOI:10.1038/s44259-025-00088-1

Transplant Proc. 2025 Feb 27:S0041-1345(25)00102-2. doi: 10.1016/j.transproceed.2025.02.020. Online ahead of print.

ABSTRACT

Although active malignancy is a contraindication to lung transplantation, there is increasing uncertainty as to what constitutes "active" malignancy given the rapidly changing therapeutic armamentarium and overall survival of patients with malignancy. Chronic myeloid leukemia (CML) is an example of a previously fatal malignancy that has been transformed into a chronic disease with close-to-normal life expectancy since the advent of tyrosine kinase inhibitor (TKI) therapy. However, it remains relatively unknown if lung transplantation could successfully be performed in patients with CML. We describe the course of a 34-year-old woman with cystic fibrosis and advanced lung disease who was diagnosed with CML while undergoing lung transplant evaluation. She was initiated on imatinib with optimal treatment response; she achieved major molecular response (MMR) and deep molecular response (DMR) at 8 and 10 months of treatment, respectively. She developed progressive respiratory failure and underwent bilateral lung transplantation at close to 3 years after achieving MMR. At 6 years post-transplant, she has excellent graft function and remains in DMR on imatinib. Treated CML in DMR should be regarded as inactive malignancy and should not preclude patients from life-saving transplant consideration. Our case also demonstrates the feasibility of long-term immunosuppression on TKI therapy.

PMID:40021434 | DOI:10.1016/j.transproceed.2025.02.020

Sci Adv. 2025 Feb 28;11(9):eads1568. doi: 10.1126/sciadv.ads1568. Epub 2025 Feb 28.

ABSTRACT

A reduced sense of smell is a common condition in people with cystic fibrosis (CF) that negatively affects their quality of life. While often attributed to nasal mucosa inflammation, the underlying causes of the olfactory loss remain unknown. Here, we characterized gene expression in olfactory epithelium cells from patients with CF using single-nuclei RNA sequencing and found altered expression of olfactory receptors (ORs) and genes related to progenitor cell proliferation. We confirmed these findings in newborn, inflammation-free samples of a CF animal model and further identified ultrastructural alterations in the olfactory epithelium and bulbs of these animals. We established that CFTR, the anion channel whose dysfunction causes CF, is dispensable for odor-evoked signaling in sensory neurons, yet CF animals displayed defective odor-guided behaviors consistent with the morphological and molecular alterations. Our study highlights CF's major role in modulating epithelial structure and OR expression, shedding light on the mechanisms contributing to olfactory loss in CF.

PMID:40020072 | DOI:10.1126/sciadv.ads1568

Pediatr Pulmonol. 2025 Mar;60(3):e71021. doi: 10.1002/ppul.71021.

ABSTRACT

BACKGROUND: People with CF (pwCF) frequently have gastrointestinal symptoms (GI), including abdominal pain and irregular bowel movements. These are often embarrassing, difficult to report, and frequently missed. Thus, a GI Symptom Tracker was created and validated in the USA and translated and validated in Dutch. This questionnaire consists of four subscales: Eating Challenges, Stools, Adherence Challenges, and Abdominal Symptoms. The aim of this study was to investigate the relationship between GI symptoms, anxiety/depression, and health-related quality of life (HRQoL) in Dutch pwCF.

METHODS: In this prospective, cross-sectional single-center pilot study, pwCF completed the Dutch GI Symptom Tracker, GAD-7 (anxiety), PHQ-9 (depression), and CFQ-R (HRQoL) from September 2021 to June 2022. Regression analyses were used to analyze the univariable associations between GI symptoms, anxiety/depression, and HRQoL.

RESULTS: A total of 51 pwCF were enrolled consecutively (n = 41 adults, 66% female, mean age (y) [range] = 32.7 [19-71] and n = 10 adolescents, 70% female, mean age (y) [range] = 14.2 [12-17]). Elevated levels of anxiety (scores ≥ 10 on GAD-7) were found in 17% of adults and 0% of adolescents. Elevated depression scores (≥ 10 on PHQ-9) were found in 9% of adults and 20% of adolescents. GI scales "Abdominal Symptoms" and "Stools" were significantly, positively associated with elevated symptoms of anxiety and depression. Most GI scales were associated with lower HRQoL.

CONCLUSION: This is the first study investigating the link between GI symptoms assessed by the Dutch GI Symptom Tracker and anxiety/depression and HRQoL in Dutch pwCF. More GI symptoms were associated with higher anxiety and depression scores and worse HRQoL. Additional research is needed to better understand how mental and physical health are linked in GI symptoms in CF.

PMID:40019138 | DOI:10.1002/ppul.71021

Pediatr Pulmonol. 2025 Mar;60(3):e71017. doi: 10.1002/ppul.71017.

ABSTRACT

BACKGROUND: Substance use has increased among people with CF (pwCF), yet communication about use remains understudied between pwCF and their healthcare providers.

OBJECTIVE: Investigate pwCF's perceptions regarding their healthcare team's discussions surrounding substance use, comfort level discussing such usage, and barriers encountered during these discussions.

METHODS: This cross-sectional study used a one-time electronic survey to assess communication regarding substance use between pwCF aged 13 years and older and their CF healthcare team.

RESULTS: Of 226 participants, 74% (n = 167) reported being asked about marijuana, 57% (n = 128) about CBD, 70% (n = 150) about e-cigarettes, and 88% (n = 189) about cigarettes by their CF healthcare team. Fewer providers discussed the risks and benefits of each substance: 47% (n = 107) for marijuana, 40% (n = 90) for CBD, 44% (n = 99) for e-cigarettes, and 61% (n = 138) for cigarettes. Provider knowledge was rated higher for cigarettes and e-cigarettes compared to marijuana and CBD. Most participants felt comfortable discussing substance use, though a minority expressed discomfort, mainly due to concerns about documentation in medical records and perceived lack of support.

CONCLUSION: This study highlights variability in communication between pwCF and their healthcare teams regarding substance use, particularly when it comes to marijuana and CBD. The findings suggest a need for standardized guidelines and educational resources to improve recreational substance screening and discussion in CF clinical care, especially given the changing landscape of marijuana regulations and increasing use among pwCF.

PMID:40019020 | DOI:10.1002/ppul.71017

Pediatr Pulmonol. 2025 Mar;60(3):e71019. doi: 10.1002/ppul.71019.

ABSTRACT

RATIONALE: The introduction of elexacaftor/tezacaftor/ivacaftor (ETI), a highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, to younger ages and the COVID-19 pandemic have significantly reduced pulmonary exacerbations requiring hospitalization among children with CF.

OBJECTIVE: To assess demographic and clinical characteristics of children and young adults with CF hospitalized for pulmonary exacerbations before and after pediatric ETI approval.

METHODS: A retrospective chart review was conducted at five United States CF Foundation-accredited care centers. Hospitalization data from children and young adults with CF in 2018 and 2022 were analyzed.

RESULTS: Hospitalizations decreased from 471 cases (241 individuals) in 2018 to 163 cases (110 individuals) in 2022. The racial distribution shifted, with more hospitalized patients identifying as people of color in 2022 (28% vs. 14%; p = 0.018). A greater proportion of hospitalized children in 2022 had two non-F508del mutations compared with children hospitalized in 2018 (38% vs. 19%) and were less likely to be infected with methicillin-resistant Staphylococcus aureus (MRSA). Comparing 2022-2018, children on CFTR modulator therapy, including ETI (76%), showed reduced infections with Pseudomonas aeruginosa and Achromobacter xylosoxidans.

CONCLUSIONS: The decline in hospitalizations for pulmonary exacerbations likely reflects the benefits of ETI therapy, as a higher proportion of children and young adults hospitalized in 2022 had two non-F508del mutations and were not eligible for ETI. A greater percentage of those hospitalized in 2022 identified as belonging to minority racial groups, highlighting ongoing health disparities in the ETI era. Additionally, there were notable changes in the microbiological characteristics between 2018 and 2022.

PMID:40018992 | DOI:10.1002/ppul.71019

Front Biosci (Landmark Ed). 2025 Jan 24;30(2):25765. doi: 10.31083/FBL25765.

ABSTRACT

BACKGROUND: A number of association studies have linked ribosomal DNA gene copy number (rDNA CN) to aging and pathology. Data from these studies are contradictory and depend on the quantitative method.

METHODS: The hybridization technique was used for rDNA quantification in human cells. We determined the rDNA CN from healthy controls (HCs) and patients with schizophrenia (SZ) or cystic fibrosis (CF) (total number of subjects N = 1124). For the first time, rDNA CN was quantified in 105 long livers (90-101 years old). In addition, we conducted a joint analysis of the data obtained in this work and previously published by our group (total, N = 3264).

RESULTS: We found increased rDNA CN in the SZ group (534 ± 108, N = 1489) and CF group (567 ± 100, N = 322) and reduced rDNA CN in patients with mild cognitive impairment (330 ± 60, N = 93) compared with the HC group (422 ± 104, N = 1360). For the SZ, CF, and HC groups, there was a decreased range of rDNA CN variation in older age subgroups compared to child subgroups. For 311 patients with SZ or CF, rDNA CN was determined two or three times, with an interval of months to several years. Only 1.2% of patients demonstrated a decrease in rDNA CN over time. We did not find significant rDNA CN variation in eight different organs of the same patient or in cells of the same fibroblast population.

CONCLUSIONS: The results suggest that rDNA CN is a relatively stable quantitative genetic trait statistically associated with some diseases, which however, can change in rare cases under conditions of chronic oxidative stress. We believe that age- and disease-related differences between the groups in mean rDNA CN and its variance are caused by the biased elimination of carriers of marginal (predominantly low) rDNA CN values.

PMID:40018927 | DOI:10.31083/FBL25765

BMJ Public Health. 2024 Nov 27;2(2):e001459. doi: 10.1136/bmjph-2024-001459. eCollection 2024 Dec.

ABSTRACT

INTRODUCTION: Newborn screening (NBS) is an essential public health initiative for early diagnosis of inborn errors of metabolism (IEM), where timely intervention can reduce morbidity and mortality. While routine in developed countries, NBS is not widely practised in India. This study aimed to implement NBS programme in a tertiary care hospital in South India and validate predetermined cut-off values tailored to the regional population.

METHODS: Between 2020 and 2022, 5157 neonates were screened for congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDD), phenylketonuria (PKU), galactosemia and biotinidase deficiency. Screening was performed using dissociation-enhanced lanthanide fluorescent immunoassay technology on Victor2D platform (Revvity). Markers assessed included 17-α-OH progesterone, neonatal thyroid stimulating hormone, total galactose, immunoreactive trypsinogen, G6PD enzyme, biotinidase enzyme and phenylalanine levels. Data analysis was conducted using R V.4.1.1 software.

RESULTS: Of the 5157 neonates, the recall rates were consistent with those reported in similar studies. However, only 26.7% of screen-positive newborns returned for retesting, indicating a significant gap in awareness about IEMs and the importance of follow-up. Of these, none were diagnosed with CAH; however, four were found to have CH, two had galactosemia, three had G6PDD, one had CF, one had PKU and none had biotinidase deficiency. The confirmed cases were promptly treated and monitored regularly. The distribution of each marker's values fell within 2.5th-97.5th percentiles suggesting consistency.

CONCLUSION: The reference ranges provided by the manufacturer appear valid in the Indian context. A key challenge identified was low follow-up compliance for screen-positive infants, highlighting the need for enhanced public education on IEM and NBS. Future research will focus on determining the incidence of IEMs and improving parental awareness and follow-up rates.

PMID:40018536 | PMC:PMC11816103 | DOI:10.1136/bmjph-2024-001459

J Family Community Med. 2025 Jan-Mar;32(1):74-77. doi: 10.4103/jfcm.jfcm_217_24. Epub 2025 Jan 17.

ABSTRACT

Aquagenic wrinkling of the palms (AWP) is a rare transient dermatological disorder, characterized by an extreme and early wrinkling and pruning of the palms that occurs within a few minutes of exposure to water. Greater awareness of AWP is needed since the vast majority of AWP cases are linked with cystic fibrosis (CF) and CF carrier state. Initial assessment of AWP cases can be done in a primary care setting. A comprehensive medical history and physical examination should be done upon the diagnosis of AWP with additional investigations based on patients' presentation. We report two cases of AWP diagnosed at a family medicine center in Dammam, Saudi Arabia. The first case was related to the use of ibuprofen and discounting this medication led to a marked improvement in the patient's symptoms. The second case was related to primary palmar hyperhidrosis that was managed successfully with topical 20% aluminum chloride.

PMID:40018333 | PMC:PMC11864362 | DOI:10.4103/jfcm.jfcm_217_24

Mol Ther Methods Clin Dev. 2024 Jun 24;32(3):101292. doi: 10.1016/j.omtm.2024.101292. eCollection 2024 Sep 12.

ABSTRACT

Lung cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to a dysfunctional CFTR protein. Gene therapy offers promise for the treatment of lung CF. However, the development and clinical application of CF gene therapy have long been hampered by the absence of safe and highly efficient delivery vectors. In this work, a novel polymer-based gene replacement treatment approach was developed. A series of poly (β-amino esters) (PAEs) with various topological structures and chemical compositions were screened to create non-viral therapeutic systems for CFTR restoration in lung CF disease. A nanoparticle, formed by the selected highly branched PAE (HPAE) with a CpG-depleted CFTR plasmid, demonstrated CFTR gene expression and biocompatibility in lung epithelial cells, outperforming leading commercial gene transfection reagents such as Lipofectamine 3000 and Xfect. The newly developed gene therapy system successfully restored functional CFTR protein production in lung CF epithelial monolayers. This therapeutic approach holds great potential for use as an efficient and safe non-viral treatment for CF patients.

PMID:40017666 | PMC:PMC11866167 | DOI:10.1016/j.omtm.2024.101292

Intensive Care Med Exp. 2025 Feb 27;13(1):27. doi: 10.1186/s40635-025-00731-1.

ABSTRACT

BACKGROUND: Streptococcus pneumoniae, a primary cause of community-acquired pneumonia (CAP), is typically treated with β-lactams and macrolides or quinolones. Corticosteroids are now recommended as adjunctive therapy in severe CAP to improve outcomes. In this prospective randomized animal study, we evaluated the bactericidal efficacy of various antibiotic regimens combined with corticosteroids using a porcine pneumococcal pneumonia model.

RESULTS: In 30 White-Landrace female pigs, pneumonia was induced by intrabronchial inoculation of macrolide-resistant S. pneumoniae 19A isolate. Animals were randomized to receive saline, ceftriaxone (CRO) with levofloxacin (LVX), CRO with azithromycin (AZM), or combinations of these with methylprednisolone (MP). The primary outcome, S. pneumoniae concentrations in lung tissue after 48 h of treatment, showed that the CRO + LVX, CRO + AZM, CRO + LVX + MP, and CRO + AZM + MP groups were equally effective in reducing bacterial load. However, complete bacterial eradication from lung tissue was achieved only in the CRO + AZM + MP group. Secondary outcomes, including bacterial burden in tracheal aspirates and bronchoalveolar lavage (BAL) samples, showed similar bactericidal activity across all treatment groups. The CRO + AZM + MP group demonstrated the most controlled inflammatory response, achieving baseline levels of inflammation, while other groups exhibited elevated inflammatory markers.

CONCLUSIONS: Despite using a macrolide-resistant S. pneumoniae isolate, the combination of CRO, AZM, and MP achieves similar or even superior results compared to other antibiotic combinations. This regimen provides both bactericidal and immunomodulatory benefits, suggesting its effectiveness in treating macrolide-resistant S. pneumoniae pneumonia.

PMID:40016489 | DOI:10.1186/s40635-025-00731-1

Methods Mol Biol. 2025;2903:97-111. doi: 10.1007/978-1-0716-4410-2_9.

ABSTRACT

Rhinovirus primarily infects airway epithelial cells lining the conductive airways. Mucociliary-differentiated airway epithelial cell cultures, established from airway basal cells, are relevant in vitro model systems to examine the rhinovirus-stimulated innate immune responses and changes in barrier function. The airway epithelium in patients with chronic respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease often shows remodeling, such as goblet cell metaplasia, squamous metaplasia, and basal cell hyperplasia. Such changes profoundly affect the airway epithelial responses to rhinovirus infection. Previously, we have demonstrated that mucociliary-differentiated cell cultures, established from airway basal cells isolated from COPD patients, show goblet cell and basal cell hyperplasia similar to that observed in patients. These cultures also show a pro-inflammatory phenotype and abnormal innate immune responses to rhinovirus infection. We describe a culturing method that maintains these in vivo features.

PMID:40016461 | DOI:10.1007/978-1-0716-4410-2_9

Transplant Proc. 2025 Feb 26:S0041-1345(25)00084-3. doi: 10.1016/j.transproceed.2025.01.007. Online ahead of print.

ABSTRACT

Genetic mutations are increasingly recognized as significant contributors to post-transplant complications. Common genetic conditions, such as short telomere syndrome (STS), lymphangioleiomyomatosis, cystic fibrosis (CF), and alpha-1 antitrypsin deficiency (AAT), have been documented to influence outcomes in lung transplant recipients. Here, we present a case of hereditary transthyretin (ATTR) cardiac amyloidosis leading to heart failure in a 71-year-old female, six years after undergoing a single-lung transplantation (LTx) for interstitial lung disease. This case report highlights the need for awareness of genetic predispositions, including rare conditions such as hereditary ATTR amyloidosis, among individuals being considered for solid organ transplantation.

PMID:40016044 | DOI:10.1016/j.transproceed.2025.01.007

J Biol Chem. 2025 Feb 25:108355. doi: 10.1016/j.jbc.2025.108355. Online ahead of print.

ABSTRACT

The 2-methylcitrate cycle (2-MCC) and the glyoxylate cycle are central metabolic pathways in Pseudomonas aeruginosa, enabling the organism to utilize organic acids such as propionate and acetate during infection. Here, we show that these cycles are linked through enzymatic redundancy, with isocitrate lyase (AceA) exhibiting secondary 2-methylisocitrate lyase (2-MICL) activity. Furthermore, we use a combination of structural analyses, enzyme kinetics, metabolomics, and targeted mutation of PrpBPa to demonstrate that whereas loss of PrpB function impairs growth on propionate, the promiscuous 2-MICL activity of AceA compensates for this by mitigating the accumulation of toxic 2-MCC intermediates. Our findings suggest that simultaneous inhibition of PrpB and AceA could present a robust antimicrobial strategy to target P. aeruginosa in propionate-rich environments, such as the cystic fibrosis airways. Our results emphasize the importance of understanding pathway interconnections in the development of novel antimicrobial agents.

PMID:40015638 | DOI:10.1016/j.jbc.2025.108355

Lancet Infect Dis. 2025 Feb 24:S1473-3099(24)00804-1. doi: 10.1016/S1473-3099(24)00804-1. Online ahead of print.

ABSTRACT

BACKGROUND: Sipavibart is an anti-spike monoclonal antibody that neutralises SARS-CoV-2 with exceptions, including Phe456Leu-containing variants (eg, KP.2* and KP.3*). This trial assessed sipavibart efficacy and safety for prevention of symptomatic COVID-19 in participants who are immunocompromised.

METHODS: In this ongoing, double-blind, international, phase 3 trial, we enrolled participants who were immunocompromised and aged 12 years or older at 197 hospitals, university health centres, and clinical trial units in 18 countries. Participants were randomly allocated 1:1 to a sipavibart group (intramuscular sipavibart 300 mg on days 1 and 181) or a comparator group (tixagevimab 300 mg-cilgavimab 300 mg on day 1 and placebo on day 181 or placebo on days 1 and 181), stratified by previous COVID-19 vaccination and infection status and use of tixagevimab-cilgavimab. The primary efficacy outcomes were symptomatic COVID-19 caused by any variant or symptomatic COVID-19 caused by non-Phe456Leu-containing variants within 181 days of dosing, assessed in the SARS-CoV-2-negative set, comprising all participants without a positive RT-PCR test for SARS-CoV-2 at baseline and who received at least one trial intervention dose. Safety outcomes for adverse events were assessed 90 days following the first dose and for serious adverse events throughout the study in the safety analysis set (ie, all participants who received at least one injection of sipavibart or comparator). This study is registered with ClinicalTrials.gov, NCT05648110.

FINDINGS: Participants were screened from March 31 to Oct 27, 2023; 3349 participants (56·8% female) were randomly assigned: 1674 to the sipavibart group (five no first dose; 1669 sipavibart) and 1675 to the comparator group (nine no first dose; 1105 tixagevimab-cilgavimab and 561 placebo). Within 181 days of dosing, 122 (7·4%) of 1649 participants in the sipavibart group and 178 (10·9%) of 1631 participants in the comparator group had symptomatic COVID-19 due to any variant (relative risk reduction [RRR] 34·9% [97·5% CI 15·0 to 50·1]; p=0·0006), 54 (3·3%) participants in the sipavibart group and 90 (5·5%) participants in the comparator group had symptomatic COVID-19 due to non-Phe456Leu-containing variants (RRR 42·9% [95% CI 19·9 to 59·3]; p=0·0012), and 47 (2·9%) participants in the sipavibart group and 64 (3·9%) participants in the comparator group had symptomatic COVID-19 due to Phe456Leu-containing variants (30·4% [-1·8 to 52·5]). Adverse events occurred in 833 (49·9%) of 1671 participants in the sipavibart group and 857 (51·5%) of 1663 participants in the comparator group within 3 months of the first dose. One COVID-19-related death occurred in the comparator group. Serious adverse events considered related to trial intervention occurred in two (0·1%) of 1671 participants in the sipavibart group and seven (0·4%) of 1663 participants in the comparator group (none fatal). No serious cardiovascular or thrombotic events were considered to be related to sipavibart.

INTERPRETATION: The primary analysis showed efficacy and safety of sipavibart in preventing symptomatic COVID-19 in participants who are immunocompromised when susceptible (ie, non-Phe456Leu-containing) variants dominated, although no efficacy was shown against resistant (ie, Phe456Leu-containing) variants that dominate as of November, 2024.

FUNDING: AstraZeneca.

PMID:40015292 | DOI:10.1016/S1473-3099(24)00804-1

Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2425526122. doi: 10.1073/pnas.2425526122. Epub 2025 Feb 27.

ABSTRACT

Mimicking metabolic pathways on electrodes enables in vivo metabolite monitoring for decoding metabolism. Conventional in vivo sensors cannot accommodate underlying complex reactions involving multiple enzymes and cofactors, addressing only a fraction of enzymatic reactions for few metabolites. We devised a single-wall-carbon-nanotube-electrode architecture supporting tandem metabolic pathway-like reactions linkable to oxidoreductase-based electrochemical analysis, making a vast majority of metabolites detectable in vivo. This architecture robustly integrates cofactors, self-mediates reactions at maximum enzyme capacity, and facilitates metabolite intermediation/detection and interference inactivation through multifunctional enzymatic use. Accordingly, we developed sensors targeting 12 metabolites, with 100-fold-enhanced signal-to-noise ratio and days-long stability. Leveraging these sensors, we monitored trace endogenous metabolites in sweat/saliva for noninvasive health monitoring, and a bacterial metabolite in the brain, marking a key milestone for unraveling gut microbiota-brain axis dynamics.

PMID:40014569 | DOI:10.1073/pnas.2425526122

ACS Sens. 2025 Feb 27. doi: 10.1021/acssensors.4c03366. Online ahead of print.

ABSTRACT

Flexible wearable potentiometric ion sensors for continuous monitoring of electrolyte cations have made significant advances in bioanalysis for personal healthcare and diagnostics. However, less attention is paid to the most abundant extracellular anion, chloride ion (Cl-) as a mark of electrolyte imbalance and an important diagnostic indicator of cystic fibrosis, which has important significance for accurate monitoring in complex biological fluids. An all-solid-state Cl--selective electrode is constructed utilizing oxygen vacancies reinforced vanadium oxide with a nitrogen-doped carbon shield as the solid contact (V2O3-x@NC/Cl--ISE). The prepared V2O3-x@NC/Cl--ISE exhibits a low detection limit of 10-5.45 M without an interfacial water layer and shows a highly stable potential with 7.24 μV/h during 24 h, which is attributed to the rapid interfacial electron transfer of the conductive carbon layers and the valence state transition of the polyvalent vanadium center in charge storage processes. Additionally, the custom flexible sensing patch presents an excellent sensitivity retention rate under bending (95%) and twisting (93%) strains and possesses good anti-interference performance (ΔE < 8 mV) against common interfering ions and organic substances in sweat. Real-time monitoring of the Cl- concentration in sweat aligns with ion chromatography analysis results. This study presents a compact wearable Cl- monitoring platform for the easy tracking of exercise-induced dehydration and cystic fibrosis screening with promising applications in smart healthcare.

PMID:40014548 | DOI:10.1021/acssensors.4c03366

Pediatr Nephrol. 2025 Feb 27. doi: 10.1007/s00467-025-06728-y. Online ahead of print.

ABSTRACT

BACKGROUND: Pediatric palliative care (PPC) aims to improve the quality of life for children with life-limiting conditions, such as advanced chronic kidney disease (CKD), from the time of diagnosis. However, PPC is not commonly integrated into routine pediatric nephrology care. This study explores the perspectives and experiences of healthcare providers (HCPs) to better understand the experiences and specific barriers related to PPC integration for children and adolescents with advanced CKD.

METHODS: We conducted a qualitative study with 23 HCPs, including nurses, psychologists, social workers, and physicians from seven German pediatric nephrology centers, analyzing semi-structured focus groups and individual interviews using structured content analysis.

RESULTS: Five main categories emerged from the analysis, revealing HCPs' perceptions of CKD as a life-limiting condition, HCPs' moral distress in addressing end-of-life issues, and barriers to PPC integration. Although HCPs reported comprehensive multidisciplinary support for end-of-life situations, a lack of interprofessional communication occasionally hindered coordinated care. HCPs rarely addressed CKD's life-limiting nature proactively. A fear of diminishing hope led HCPs to avoid conversations about prognosis unless in response to a therapeutic crisis. PPC was mostly reserved for end-of-life cases, as HCPs associated PPC with terminal care and expressed concerns over distressing families.

CONCLUSIONS: This study highlights the gap between guidelines recommending early integration of PPC and daily nephrology practice, which tends to introduce PPC late in the course of the disease. Training for nephrology teams could improve the quality of life for children with advanced CKD and their families by promoting early integration of primary PPC principles.

PMID:40014135 | DOI:10.1007/s00467-025-06728-y