J Cyst Fibros. 2025 Feb 15:S1569-1993(25)00060-8. doi: 10.1016/j.jcf.2025.02.007. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Cystic fibrosis hepatobiliary involvement is a heterogeneous and systemic entity. The primary objective was to determine the prevalence of steatosis, by magnetic resonance-proton density fat fraction (MR-PDFF), and liver fibrosis, by magnetic resonance elastography (MRE), in a cohort of adults with cystic fibrosis. The secondary objective was to determine the diagnostic yield of widely available non-invasive liver markers for steatosis and fibrosis, and vibration controlled transitional elastography (VCTE) releasing Control Attenuation Parameter (CAP) (dB/m) and stiffness (kPa), with the aim of proposing a diagnostic algorithm.

METHODS: We conducted a cross-sectional study including 101 adult patients with cystic fibrosis seen in a multidisciplinary unit. The study encompassed a clinical evaluation, morpho-functional assessment, VCTE, non-invasive liver markers and MR-PDFF and MRE. Diagnostic accuracy was assessed using ROC curves and 2 × 2 tables.

RESULTS: MR-PDFF detected hepatic steatosis in 18 of 101 (17.8 %) patients, while MRE detected significant liver fibrosis in 15 of 101 (14.9 %). The VCTE cut-off with the best diagnostic yield, determined by the Youden index, was 222 dB/m for the presence of steatosis (AUC 0.864 (95 % CI 0.768-0.961; p < 0.001) and the VCTE cut-off was 6.65 kPa for liver fibrosis (AUC 0.951(95 % CI 0.81-1; p = 0.053). A screening algorithm for hepatic steatosis was developed using the fatty liver index (FLI) and CAP, with a negative predictive value of 83.3 %. For liver fibrosis, it was outperformed by the Hepamet Fibrosis Score (HFS) and VCTE, with a negative predictive value of 100 %.

CONCLUSIONS: The prevalence of hepatic steatosis and liver fibrosis was 17.8 % and 14.9 %, respectively. VCTE alone or in combination with FLI for steatosis or HFS for fibrosis demonstrated high diagnostic accuracy. This approach effectively allows for the exclusion of steatosis and fibrosis, thereby reducing the need for MR-PDFF and MRE studies.

PMID:39956714 | DOI:10.1016/j.jcf.2025.02.007

Lancet Respir Med. 2025 Feb 12:S2213-2600(25)00017-7. doi: 10.1016/S2213-2600(25)00017-7. Online ahead of print.

NO ABSTRACT

PMID:39954705 | DOI:10.1016/S2213-2600(25)00017-7

BMC Gastroenterol. 2025 Feb 14;25(1):80. doi: 10.1186/s12876-025-03682-9.

ABSTRACT

BACKGROUND: Intestinal failure (IF) is a broad term encompassing various conditions that hinder the body's ability to absorb nutrients for growth and maintenance. These conditions can significantly affect child's well-being, leading to physical limitations, psychological distress, and social isolation. We aimed to evaluate the available data on health-related quality of life (HRQoL) in pediatric patients with IF and without neurodevelopmental delay.

METHODS: For this systematic review and meta-analysis, we searched CINAHL, EMBASE, PsycINFO, PubMed, and Web of Science. All observational studies of pediatric patients (< 18 years) with IF which measured HRQOL and with evidence of absence of neurodevelopmental delay were included, without language or date restrictions, up to June 2024. We did separate random-effects meta-analyses for overall HRQOL and subgroup domains. Evidence from observational studies was synthesised as differences between standardised mean differences (SMDs) for all subgroup domains. Heterogeneity was assessed using the I² statistic and the Cochran Q test. The quality of the evidence was assessed with the Newcastle-Ottawa scale. This study is registered on PROSPERO, number CRD42024561812.

RESULTS: Of 491 records identified, 14 were eligible and data were available for 12 studies, all of which had a fair/good quality. The included studies involved a pooled sample of 510 participants (mean age = 7.0 ± 3.6 years). The analysis disclosed that compared to healthy children, pediatric patients with IF had lower overall quality of life in both child- and parent-report (Standardized Mean Difference [SMD]= -0.62; 95% CI [-0.80, -0.43]; p < 0.001, and SMD= -0.70; 95% CI [-1.11, -0.28]; p < 0.001, respectively), except for emotional and social domains (SMD[child] = -0.23; 95% CI [ -0.38, -0.08]; p = 0.001 Vs SMD[parent]= -0.23; 95% CI [ -0.60, 0.14]; p = 0.21, and SMD[child] = -0.40; 95% CI [ -0.70, -0.10]; p = 0.007 Vs SMD[parent]= -0.24; 95% CI [ -0.62, 0.14]; p = 0.21, respectively), where parents overestimate emotional and social HRQOL of their children.

CONCLUSIONS: This study highlights the significant impact of IF on well-being of pediatric patients. Targeted interventions addressing both physical and psychosocial needs are crucial to improve HRQOL in this population.

PMID:39953378 | DOI:10.1186/s12876-025-03682-9

Adv Med Sci. 2025 Feb 12:S1896-1126(25)00009-4. doi: 10.1016/j.advms.2025.01.009. Online ahead of print.

NO ABSTRACT

PMID:39952431 | DOI:10.1016/j.advms.2025.01.009

PLoS One. 2025 Feb 14;20(2):e0316721. doi: 10.1371/journal.pone.0316721. eCollection 2025.

ABSTRACT

BACKGROUND: Non-cystic fibrosis bronchiectasis (NCFBE) is a disease that exhibits dilatation of airways, airflow obstruction, persistent cough, excessive sputum production, and refractory respiratory infections. NCFBE exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically ≥60 mEq/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings.

OBJECTIVE: Based on a considerable body of evidence, we believe many patients with NCFBE have disease likely to benefit from drugs such as elexacaftor/tezacaftor/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF and has not been adequately tested or proposed for patients with NCFBE, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFBE.

METHODS: Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers-which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV1 (forced expiratory volume in one second), sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFBE to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit.

TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (Identifier: NCT05743946. Date: 02/23/2023).

PMID:39951444 | DOI:10.1371/journal.pone.0316721

JAMA Netw Open. 2025 Feb 3;8(2):e2459557. doi: 10.1001/jamanetworkopen.2024.59557.

ABSTRACT

IMPORTANCE: Textbooks attribute 80% of meconium-related small bowel obstructions to cystic fibrosis and 15% of colonic obstructions to Hirschsprung disease. It is unknown whether these estimates are accurate, particularly among preterm infants, whose immature bowel predisposes them to meconium-related obstruction (MRO).

OBJECTIVE: To estimate the incidence of MRO by type and to assess its association with clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study of live-born infants included in the National Inpatient Sample from January 1, 2016, to December 31, 2020, used survey weighting methods to estimate the national incidence of MRO by etiology. Data were analyzed from November 27, 2023, to November 12, 2024.

EXPOSURE: MRO.

MAIN OUTCOMES AND MEASURES: The primary outcome was diagnosis with MRO. Secondary outcomes included mortality, need for abdominal surgery, hospitalization duration, and cost. Multivariable regression models were developed to evaluate characteristics associated with MRO and to assess the association of MRO of prematurity with clinical outcomes after adjusting for demographic and clinical covariates.

RESULTS: Of 3 550 796 infants, 51.2% were male and 46.7% were privately insured. Overall, 9.1% (n = 322 499) were born preterm. Of 1844 (0.1%) infants treated for MRO, 41 (2.2%) had cystic fibrosis, 60 (3.3%) had Hirschsprung disease, and 1743 (94.5%) had neither predisposing condition. Preterm infants were at highest risk for MRO, with 4.7 MRO cases per 100 000 births associated with cystic fibrosis, 4.7 MRO cases per 100 000 births associated with Hirschsprung disease, and 187.3 MRO cases per 100 000 births associated with neither predisposing condition. Among infants with neither cystic fibrosis nor Hirschsprung disease, those with gestational ages from 28 weeks to 31 weeks 6 days were most likely to develop MRO compared with term infants (adjusted odds ratio, 6.08 [95% CI, 4.27-8.67]). Among preterm infants, having an MRO was associated with a 4.2 percentage point increase in the probability of abdominal surgery (95% CI, 3.1-5.4 percentage points), a 7.3-day increase in length of stay (95% CI, 5.8-8.8 days), and a $23 215 increase in hospitalization costs (95% CI, $17 739-$28 690) compared with infants who did not have an obstruction, with no change in mortality rate (0.1 percentage point change [95% CI, -0.6 to 0.8 percentage points]).

CONCLUSIONS AND RELEVANCE: In this cohort study of over 3.5 million infants, MRO was most likely to occur among preterm infants without cystic fibrosis or Hirschsprung disease. These infants more frequently required surgery and had longer and more costly hospitalizations, indicating a need for dedicated prevention and treatment pathways for this understudied disease.

PMID:39951267 | DOI:10.1001/jamanetworkopen.2024.59557

J Bacteriol. 2025 Feb 14:e0053124. doi: 10.1128/jb.00531-24. Online ahead of print.

ABSTRACT

Phenotypic diversity in bacteria often results from adaptation to changing environmental conditions, exemplified by variable colony morphotypes. In Burkholderia pseudomallei, discrete genomic alterations and modulation of gene expression facilitate adaptation. Adapted variants of species within the Burkholderia cepacia complex (Bcc) often lose the pC3 virulence megaplasmid, impacting their colony morphology and their production of virulence factors. In this study, we characterize variants arising in Burkholderia ambifaria clinical isolates using proteomics and phenotypic tests and show that some of them have retained the pC3, indicating a distinct phase variation mechanism at play in this Bcc species. Interestingly, variants of B. ambifaria strains CEP0996 (pC3-null) and HSJ1 (pC3-positive) still share similarities in phenotypes controlled by the Cep quorum-sensing (QS) system. We further investigated the role of QS in B. ambifaria HSJ1 phase variation and confirmed that the Cep QS system is important for the emergence of variants. Given that DNA methylation is a key epigenetic factor regulating virulence factors in Burkholderia cenocepacia, we hypothesized that adenosine DNA methylation also governs phase variation in B. ambifaria HSJ1. By deleting the genes encoding putative adenosine DNA methyltransferases, we discovered that an orphan type II DNA methyltransferase inhibits the emergence of phase variants. This study is the first to demonstrate that quorum sensing and adenosine DNA methylation are two antagonistic systems independently controlling phase variation in B. ambifaria.IMPORTANCESome Burkholderia species are pathogenic to plants, animals, or humans. In immunocompromised individuals, and people suffering from cystic fibrosis, infection from the Burkholderia cepacia complex (Bcc) can lead to "cepacia syndrome." In northern Australia and southeast Asia, melioidosis caused by Burkholderia pseudomallei is prevalent among native population, particularly among people with diabetes, chronic lung or kidney disease or alcoholism. Burkholderia's phenotypic plasticity, including colony morphotype variation (CMV), enables rapid adaptation to diverse environments, enhancing its survival and pathogenicity. This study reveals phase variation as a new CMV mechanism within the Bcc group and is the first to report that quorum sensing and DNA methylation are involved in phase variation. Understanding the underlying mechanisms of CMV could lead to the development of targeted therapies against these highly antibiotic-tolerant bacteria.

PMID:39950805 | DOI:10.1128/jb.00531-24

Front Tuberc. 2024;2:1473341. doi: 10.3389/ftubr.2024.1473341. Epub 2024 Oct 30.

ABSTRACT

INTRODUCTION: Chronic pulmonary infection with Mycobacterium abscessus (M. abscessus) is a significant cause of morbidity and mortality in people with cystic fibrosis (CF). Developing an animal model of M. abscessus pulmonary infection, especially under CF conditions, is essential to understanding clinical pulmonary M. abscessus infection. βENaC transgenic mice are known to develop spontaneous CF-like disease characterized by airway mucus obstruction and inflammation. The aim of this study was to evaluate the suitability of βENaC mice as a preclinical model and characterize their respiratory function during M. abscessus lung infection.

METHODS: Mice received an intrapulmonary aerosol of M. abscessus using a high-pressure syringe device (Penn-Century) for subsequent characterization of disease progression and respiratory function. Whole body unrestrained plethysmography (WBP) data was collected to monitor lung function and endpoints determined organ bacterial burden and associated pathology.

RESULTS: Endpoint CFU data in the lung and spleen showed that there was no significant difference in bacterial clearance between βENaC and WT mice. WBP data showed an impairment in overall respiratory function during and after M. abscessus infection in both strains of mice. Interestingly, even in wildtype control mice, lung dysfunction persisted after bacterial clearance.

DISCUSSION: Even with CF-like features, the βENaC transgenic mice cleared M. abscessus at a similar rate than WT mice, however, the associated respiratory monitoring revealed that there are long-term implications of M. abscessus lung exposure. The clear decline in respiratory function, even after M. abscessus clearance, suggests that WBP coupled animal modeling provides important insight that is relevant to disease burden and treatment efficacy. The M. abscessus clearance in the βENaC mice may help improve the fields understanding of CF-modulated immune deficiencies in M. abscessus pulmonary infection.

PMID:39950136 | PMC:PMC11822858 | DOI:10.3389/ftubr.2024.1473341

Med Pharm Rep. 2025 Jan;98(1):29-35. doi: 10.15386/mpr-2806. Epub 2025 Jan 31.

ABSTRACT

BACKGROUND: Patients with cystic fibrosis (CF) frequently require modulatory therapies such as Lumacaftor/Ivacaftor (LI) and Elexacaftor/Tezacaftor/Ivacaftor (ETI) to manage their condition. Given the potential hepatic complications associated with CF, it is critical to understand the impact of these therapies on liver function and fibrosis indices. This study aimed to evaluate the changes in liver function markers and fibrosis indices in CF patients undergoing LI and ETI therapies, with a specific focus on the influence of underlying hepatic disease.

METHODS: In this retrospective analysis, liver function markers and fibrosis indices were assessed in CF patients receiving ETI (n=24), LI (n=4), or LI transitioned to ETI (LI/ETI, n=8). Key liver function markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, platelet count, and fibrosis indices (APRI and FIB-4), were measured at baseline and at various time points up to 12 months.

RESULTS: In patients receiving LI therapy, ALT and AST levels demonstrated a slight but non-significant decrease over six months, accompanied by significant fluctuations in total bilirubin levels. Among those receiving ETI therapy, ALT and AST levels initially increased but stabilized over time, while total bilirubin levels significantly increased from baseline to 12 months. No significant differences were observed in liver function markers between patients with and without hepatic disease under ETI therapy. Trends in fibrosis indices (APRI and FIB-4) were modest and largely non-significant across both therapies.

CONCLUSIONS: ETI therapy appears to be safe for CF patients, including those with pre-existing hepatic disease, with no significant deterioration in liver function over a 12-month period. However, the observed fluctuations in bilirubin levels underscore the necessity for ongoing monitoring. Further research is warranted to investigate the long-term hepatic effects of LI and ETI therapies.

PMID:39949910 | PMC:PMC11817584 | DOI:10.15386/mpr-2806

Cureus. 2025 Jan 13;17(1):e77407. doi: 10.7759/cureus.77407. eCollection 2025 Jan.

ABSTRACT

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a complex and often underdiagnosed disorder characterized by impaired water homeostasis, leading to hyponatremia and associated complications. This comprehensive review explores the intersection of SIADH with chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), pulmonary tuberculosis, cystic fibrosis, and interstitial lung disease. The review looks at current evidence on pathophysiology, diagnostic challenges, and treatment approaches, highlighting the need for specialized management strategies to improve patient outcomes. Through an analysis of clinical and observational studies, this review highlights the significant impact of SIADH on morbidity and mortality among patients with respiratory diseases. It illustrates the necessity for further research to refine diagnostic and therapeutic modalities.

PMID:39949461 | PMC:PMC11822327 | DOI:10.7759/cureus.77407

Cancers (Basel). 2025 Jan 24;17(3):394. doi: 10.3390/cancers17030394.

ABSTRACT

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by aggressive and heterogeneous tumors originating from B-cells. Especially in patients with relapsed or refractory (R/R) disease, DLBCL remains a challenging cancer to treat. Metabolic reprogramming is a hallmark of malignant cells. Our research focuses on developing strategies to enhance clinical outcomes for R/R DLBCL patients by targeting metabolic vulnerabilities. Methods: We investigated the effects of combining metformin and L-asparaginase, two FDA-approved antimetabolic drugs, on DLBCL cell metabolism and survival. Nuclear magnetic resonance (NMR) spectroscopy was employed to assess metabolic disturbances induced by the drug combination. The impact on lipid metabolism, glycolysis, glutaminolysis, the tricarboxylic acid (TCA) cycle, and antioxidant responses was examined. Induction of apoptosis was evaluated by FACS analysis. Results: The combination of metformin and L-asparaginase strongly sensitized DLBCL cells to apoptosis, independently of their oxidative phosphorylation (OxPhos) or BCR/glycolytic status. NMR spectroscopy revealed that this combination induces broader metabolic disturbances than either drug alone. It disrupts lipid metabolism by altering levels of phospholipids, cholesterol, and fatty acids. Additionally, it counteracts the pro-glycolytic effect of metformin, decreases glycolysis, and reduces glutaminolysis. It also affects the TCA cycle and antioxidant responses, critical for cellular energy production and redox balance. Furthermore, this combination interferes with two key cancer survival pathways, mTORC1 and MAPK signaling. Importantly, proof of principle for its beneficial effect was demonstrated in DLBCL patients. Conclusions: Combining metformin and L-asparaginase affects DLBCL cell survival by targeting multiple metabolic pathways and may represent a novel therapeutic approach for R/R DLBCL patients.

PMID:39941763 | PMC:PMC11816127 | DOI:10.3390/cancers17030394

Pulm Ther. 2025 Feb 13. doi: 10.1007/s41030-025-00287-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to substantially improve clinical outcomes among people living with cystic fibrosis (pwCF). The impact of ETI on health care resource utilization in the context of universal health care is largely unknown. We aimed to assess the impact of ETI on hospital and non-hospital health care resource utilization in a national cohort of pwCF up to 2 years after ETI initiation.

METHODS: We included all pwCF aged 12 years or older in the Danish Cystic Fibrosis Cohort initiating ETI therapy between 1 September 2020 and 31 December 2022. The following health care contacts were reported: acute and elective hospitalizations, acute and elective outpatient contacts, general practitioner (GP) visits, other specialist visits, physiotherapist/chiropractor visits, pharmacy visits, and blood sampling appointments. Pre- and post-ETI data were analyzed using logistic and linear regression models estimating number of visits, days in hospital, and odds ratios (ORs) for one monthly contact.

RESULTS: A total of 283 pwCF initiated ETI in the study period. At 24 months post-ETI, utilization of the following health care resources was reduced: elective hospitalizations [OR 0.20 (95% CI: 0.08; 0.50)], elective outpatient hospital contacts [0.70 (0.57; 0.86)], pharmacy visits [0.56 (0.45; 0.71)], and blood sampling appointments [0.61 (0.49; 0.77)]. Number of contacts per month was reduced for the aforementioned outcomes, as well as number of days in hospital for elective hospitalizations. A downward but not statistically significant trend was observed for acute hospitalizations. No significant change was observed for acute outpatient visits, GP visits, other specialist visits, or visits to a physiotherapist/chiropractor.

CONCLUSION: In a national cohort of pwCF, ETI was associated with substantial reductions in elective hospitalizations, elective outpatient contacts, duration of elective hospitalizations, pharmacy visits, and blood sampling appointments, sustained 2 years post-ETI initiation. These findings highlight the real-world effectiveness of ETI in the context of a universal health care system.

PMID:39948204 | DOI:10.1007/s41030-025-00287-1

J Cyst Fibros. 2025 Feb 12:S1569-1993(25)00049-9. doi: 10.1016/j.jcf.2025.01.016. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic pulmonary inflammation strongly contributes to respiratory failure and mortality in patients with cystic fibrosis (pwCF). Effective anti-microbial immunity and maintaining lung homeostasis require continuous structural-immune cell communication. Whether and how this crosstalk is altered in CF remains poorly understood, obscuring potential new angles for therapy development to restore airway homeostasis in pwCF.

METHODS: We performed droplet-based single cell RNA-sequencing on bronchial biopsies from pwCF to investigate structural-immune cell crosstalk. Computational analyses were used to compare these data to samples obtained from healthy controls.

RESULTS: CF airway wall biopsies showed lower proportions and altered transcriptomes of basal cells, submucosal gland cells and endothelial cells, and a higher abundance of ciliated cells, monocytes, macrophages and T cells. Both B and T lymphocytes displayed aberrantly activated phenotypes with transcriptional changes linked to hypoxia and vascular endothelial growth factor signaling, indicative of crosstalk with endothelial cells. The CF lung displayed unique changes in intercellular communication potential involving ionocytes, macrophages, endothelial cells and lymphocytes. This included interactions between HLA-E on structural cells and the druggable CD94/NKG2A immune checkpoint on CD8+T cells.

CONCLUSIONS: We report the first single cell transcriptome atlas of the CF lung containing the full spectrum of structural and immune cells, providing a valuable resource for investigating changes to cellular composition, phenotypes and crosstalk linked to CF. Our analyses highlight dysregulated basal cell function and adaptive immunity in pwCF - despite favorable responses to CFTR modulator therapy. We identify novel aspects of CF pathophysiology and potential entry points for therapeutic strategies.

PMID:39947933 | DOI:10.1016/j.jcf.2025.01.016

J Cyst Fibros. 2025 Feb 12:S1569-1993(25)00050-5. doi: 10.1016/j.jcf.2025.01.017. Online ahead of print.

NO ABSTRACT

PMID:39947932 | DOI:10.1016/j.jcf.2025.01.017

Int J Epidemiol. 2024 Dec 16;54(1):dyaf006. doi: 10.1093/ije/dyaf006.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic, mortality from some chronic diseases increased. In this study, we evaluated monthly excess mortality from all causes, cancer, cardiovascular diseases (CVD) and diabetes during the months of 2020 and 2021, examining its relationship with COVID-19 cases.

METHODS: Monthly cause-specific mortality data were downloaded from public repositories of national statistics offices or directly requested from them, and population data were obtained from the United Nations archives. Excess deaths were estimated as the difference between observed and expected deaths. Monthly expected deaths for 2020 and 2021 were calculated using a quasi-Poisson regression model trained on 2010-19 data (or a shorter timespan if the full decade of data was not available). To quantify the correlation between COVID-19 cases and monthly excess mortality, we used the Spearman's correlation coefficient (rs).

RESULTS: The study included 16 countries that provided monthly national data on causes of death (Argentina, Austria, Brazil, Switzerland, Chile, the Czech Republic, Germany, Georgia, Hungary, Italy, Lithuania, Latvia, Mexico, Serbia, Slovakia and the USA). A positive correlation was found between COVID-19 cases and monthly excess mortality from all causes in all countries (rs ranging from 0.61 to 0.91), from CVD in 11 countries (rs ranging from 0.45 to 0.85) and for diabetes in 13 countries (rs ranging from 0.42 to 0.79). Excess mortality above 5% was estimated from all causes in 14 countries for both 2020 and 2021, from CVD in seven countries for 2020 and in nine countries for 2021, and from diabetes in 11 countries for 2020 and in 12 countries for 2021. No excess above 5% was estimated for cancer mortality in any of the countries considered.

CONCLUSIONS: Excess mortality from CVD and diabetes persisted in several countries throughout 2021. These increases coincide with COVID-19 peaks, supporting a short-term impact of the COVID-19 pandemic on mortality from these causes.

PMID:39947655 | DOI:10.1093/ije/dyaf006

PLoS Pathog. 2025 Feb 13;21(2):e1012922. doi: 10.1371/journal.ppat.1012922. eCollection 2025 Feb.

ABSTRACT

Persistent bacterial infections evade host immunity and resist antibiotic treatments through various mechanisms that are difficult to evaluate in a living host. Pseudomonas aeruginosa is a main cause of chronic infections in patients with cystic fibrosis (CF) and wounds. Here, by immersing wounded zebrafish embryos in a suspension of P. aeruginosa isolates from CF patients, we established a model of persistent infection that mimics a murine chronic skin infection model. Live and electron microscopy revealed persisting aggregated P. aeruginosa inside zebrafish cells, including macrophages, at unprecedented resolution. Persistent P. aeruginosa exhibited adaptive resistance to several antibiotics, host cell permeable drugs being the most efficient. Moreover, persistent bacteria could be partly re-sensitized to antibiotics upon addition of anti-biofilm molecules that dispersed the bacterial aggregates in vivo. Collectively, this study demonstrates that an intracellular location protects persistent P. aeruginosa in vivo in wounded zebrafish embryos from host innate immunity and antibiotics, and provides new insights into efficient treatments against chronic infections.

PMID:39946497 | DOI:10.1371/journal.ppat.1012922

Cytotherapy. 2025 Jan 20:S1465-3249(25)00034-9. doi: 10.1016/j.jcyt.2025.01.006. Online ahead of print.

ABSTRACT

The acute respiratory distress syndrome (ARDS) inflammatory environment alters mesenchymal stromal cell (MSC) gene and protein expression but effects on microRNA (miRNA) content of MSC-extracellular vesicle (EVs) remain unknown. To assess this, sequencing analysis of EV-miRNAs prepared from human bone marrow-derived MSCs (hMSCs) exposed ex vivo to bronchoalveolar lavage fluid (BALF) from ARDS patients or healthy volunteers (HV) identified a number of differentially expressed miRNAs. Discriminant, differential expression, and functional enrichment analyses identified 14 miRNAs significantly changed following ARDS versus HV BALF exposure. Network analysis showed 4 (miR-760, miR-3175, miR-885-3p, and miR-766-3p) of the 14 EV-miRNAs formed a regulatory "hub", suggesting co-targeting of specific gene pathways. In silico prediction identified a number of pathways important in lung injury. Two miRNAs involved in regulation of the cystic fibrosis transmembrane conductance regulator (CFTR), miRNA-145-5p and miRNA-138-5p, were also significantly increased in ARDS BALF-exposed hMSCs EVs. Functionally, EVs from hMSCs exposed to either ARDS or HV BALF had differential effects on CFTR Cl- secretion by cultured primary human bronchial epithelial cells, an effect predicted to reduce mucociliary clearance. The potential clinical impact of these finding highlights the need for further studies assessing the role of hMSC-EV miRNAs in regulating lung inflammation and mucociliary clearance.

PMID:39945694 | DOI:10.1016/j.jcyt.2025.01.006

Pediatr Crit Care Med. 2025 Feb 13. doi: 10.1097/PCC.0000000000003695. Online ahead of print.

ABSTRACT

OBJECTIVE: To develop consensus statements that clinicians can apply to standardize and optimize endotracheal aspirate culture (EAC) practices in hospitalized children with artificial airways who are being evaluated for a bacterial lower respiratory tract infection (LRTI).

DESIGN: A modified Delphi consensus process with expert panelists. Panelists conducted a "pre-survey" to itemize respiratory signs of bacterial LRTI. Round 1 included a literature summary and electronic survey of 50 potential statements sent to all panelists. We surveyed panelist opinions using a 5-point Likert scale. We grouped the responses "agree" and "strongly agree" as agreement. Consensus was defined as statements reaching greater than 75% agreement. Round 2 was moderated by an independent expert in consensus methodology. Panelists convened in person in November 2023, discussed any statements not reaching consensus or statements with disagreement, were resurveyed, and finalized statements in real time.

SETTING: Electronic surveys and in-person meetings in Baltimore, MD.

SUBJECTS: The BrighT STAR (Testing STewardship for Antibiotic Reduction) collaborative along with U.S.-based pediatric experts in critical care, cardiac critical care, infectious diseases, hospital medicine, otolaryngology, pulmonology, and clinical microbiology.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Thirty-eight of 40 invited panelists completed round 1. Of 50 initial statements, 28 reached greater than 90% agreement, 16 had 75-89% agreement, and 6 had less than 75% agreement. Twenty-eight statements were finalized. Round 2 involved 37 panelists: 23 statements were discussed, of which 17 reached an agreement and 6 did not reach consensus. We concluded with 30 statements and 15 sub-statements, 37 of which had greater than 90% agreement. Final statements informed a clinical decision support algorithm.

CONCLUSIONS: The BrighT STAR collaborative group achieved consensus for 45 clinical practice statements that can standardize EAC practices, including indications to consider for testing, reasons to defer, optimal specimen collection, and result interpretation. These statements offer a starting point for clinical decision support tools and diagnostic stewardship programs for EAC practices in patients with artificial airways.

PMID:39945582 | DOI:10.1097/PCC.0000000000003695

mBio. 2025 Feb 13:e0342024. doi: 10.1128/mbio.03420-24. Online ahead of print.

ABSTRACT

The healthy human infant gut microbiome undergoes stereotypical changes in taxonomic composition between birth and maturation to an adult-like stable state. During this time, extensive communication between microbiota and the host immune system contributes to health status later in life. Although there are many reported associations between microbiota compositional alterations and disease in adults, less is known about how microbiome development is altered in pediatric diseases. One pediatric disease linked to altered gut microbiota composition is cystic fibrosis (CF), a multi-organ genetic disease involving impaired chloride secretion across epithelia and heightened inflammation both in the gut and at other body sites. Here, we use shotgun metagenomics to profile the strain-level composition and developmental dynamics of the infant fecal microbiota from several CF and non-CF longitudinal cohorts spanning from birth to greater than 36 months of life. We identify a set of keystone species that define microbiota development in early life in non-CF infants but are missing or decreased in relative abundance in infants with CF, resulting in a delayed pattern of microbiota maturation, persistent entrenchment in a transitional developmental phase, and subsequent failure to attain an adult-like stable microbiota. Delayed maturation is strongly associated with cumulative antibiotic treatments, and we also detect the increased relative abundance of oral-derived bacteria and higher levels of fungi in infants with CF, features that are associated with decreased gut bacterial density. These findings suggest the potential for future directed therapies targeted at overcoming developmental delays in microbiota maturation for infants with CF.IMPORTANCEThe human gastrointestinal tract harbors a diversity of microbes that colonize upon birth and collectively contribute to host health throughout life. Infants with the disease cystic fibrosis (CF) harbor altered gut microbiota compared to non-CF counterparts, with lower levels of beneficial bacteria. How this altered population is established in infants with CF and how it develops over the first years of life is not well understood. By leveraging multiple large non-CF infant fecal metagenomic data sets and samples from a CF cohort collected prior to highly effective modulator therapy, we define microbiome maturation in infants up to 3 years of age. Our findings identify conserved age-diagnostic species in the non-CF infant microbiome that are diminished in abundance in CF counterparts that instead exhibit an enrichment of oral-derived bacteria and fungi associated with antibiotic exposure. Together, our study builds toward microbiota-targeted therapy to restore healthy microbiota dynamics in infants with CF.

PMID:39945545 | DOI:10.1128/mbio.03420-24

mSphere. 2025 Feb 13:e0090424. doi: 10.1128/msphere.00904-24. Online ahead of print.

ABSTRACT

Lysogenic bacteriophages can integrate their genome into the bacterial chromosome in the form of a prophage and can promote genetic transfer between bacterial strains in vitro. However, the contribution of lysogenic bacteriophages to the incidence of antimicrobial resistance (AMR) in clinical settings is poorly understood. Here, in a set of 186 clinical isolates of Pseudomonas aeruginosa collected from respiratory cultures from 82 patients with cystic fibrosis, we evaluate the links between prophage counts and both genomic and phenotypic resistance to six anti-pseudomonal antibiotics: tobramycin, colistin, ciprofloxacin, meropenem, aztreonam, and piperacillin-tazobactam. We identified 239 different prophages in total. We find that P. aeruginosa isolates contain on average 3.06 ± 1.84 (SD) predicted prophages. We find no significant association between the number of prophages per isolate and the minimum inhibitory concentration for any of these antibiotics. We then investigate the relationship between particular prophages and AMR. We identify a single lysogenic phage associated with phenotypic resistance to the antibiotic tobramycin and, consistent with this association, we observe that AMR genes associated with resistance to tobramycin are more likely to be found when this prophage is present. However, we find that they are not encoded directly on prophage sequences. Additionally, we identify a single prophage statistically associated with ciprofloxacin resistance but do not identify any genes associated with ciprofloxacin phenotypic resistance. These findings suggest that prophages are only infrequently associated with the AMR genes in clinical isolates of P. aeruginosa.IMPORTANCEAntibiotic-resistant infections of Pseudomonas aeruginosa (Pa), a leading pathogen in patients with cystic fibrosis (CF), are a global health threat. While lysogenic bacteriophages are known to facilitate horizontal gene transfer, their role in promoting antibiotic resistance in clinical settings remains poorly understood. In our analysis of 186 clinical isolates of P. aeruginosa from CF patients, we find that prophage abundance does not predict phenotypic resistance to key antibiotics but that specific prophages are infrequently associated with tobramycin resistance genes. In addition, we do not find antimicrobial resistance (AMR) genes encoded directly on prophages. These results highlight that while phages can be associated with AMR, phage-mediated AMR transfer may be rare in clinical isolates and difficult to identify. This work is important for future efforts on mitigating AMR in CFCF and other vulnerable populations affected by Pa infections and advances our understanding of bacterial-phage dynamics in clinical infections.

PMID:39945525 | DOI:10.1128/msphere.00904-24