Ann Allergy Asthma Immunol. 2024 Nov 28:S1081-1206(24)01711-3. doi: 10.1016/j.anai.2024.11.021. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma in children is a leading cause of missed school days, emergency department visits, and hospitalizations. Approximately 40% of children with asthma experience uncontrolled disease and annual exacerbations. There is a need for a validated composite tool for children like the Asthma Impairment and Risk Questionnaire (AIRQ®), which was developed to assess current control and predict exacerbations in adolescents and adults with asthma.

OBJECTIVE: To obtain feedback from children with asthma and their parents/caregivers to inform development of a version of the AIRQ for pediatric use (Peds-AIRQ).

METHODS: Children with asthma aged 5-11 years and their parents/caregivers participated in cognitive interviews to elicit language describing asthma symptoms and exacerbations and to assess understanding and relevance of draft Peds-AIRQ questions. Physicians and parents/caregivers provided clinical information and performed assessments relative to the children's asthma morbidity.

RESULTS: Sixty dyads participated: children's mean (SD) age=7.9 (1.9) years; 68% male, 45% non-White, 32% Hispanic, and 40% with public health insurance. Overall, 53% had well-controlled, 30% partly controlled, and 17% uncontrolled asthma based on the Global Initiative for Asthma symptom control questions. Oral or injected corticosteroids were used for asthma by 53% of the children in the prior year. Participants found draft Peds-AIRQ items understandable and relevant. Seven impairment and three risk questions were retained for validation, along with five additional items containing wording or control threshold variations.

CONCLUSION: This study supports the need for developing a composite (impairment and risk) control tool to assess children aged 5-11 years with asthma and identified suitable questions for the validation of a Peds-AIRQ.

PMID:39615584 | DOI:10.1016/j.anai.2024.11.021

Lung. 2024 Nov 30;203(1):9. doi: 10.1007/s00408-024-00768-1.

ABSTRACT

PURPOSE: In people with cystic fibrosis (pwCF), elexacaftor/tezacaftor/ivacaftor (ETI) therapy is associated with an average improvement in FEV1 of 10-14%. However, a subset of individuals fails to achieve a clinically meaningful increase in spirometric indicators. In this study, we aimed to assess whether the lung clearance index (LCI2.5), a more sensitive indicator of lung involvement, improves following ETI initiation in this population.

METHODS: We conducted a prospective observational study in a specialized CF center in Italy. PwCF performed a spirometry and a multiple breath nitrogen washout test the day they initiated ETI therapy and after 6 and 12 months. They were grouped according to the 12-month change in FEV1 into two groups: Individuals who experienced a change in FEV1 ≥ a minimal clinically important difference (MCID) of 3% and those who did not. Mean changes in LCI2.5 were estimated using generalized estimating equations.

RESULTS: The study included 129 pwCF who initiated ETI at our center (Age Range: 12-36 years). In 20 subjects (15.5%), the FEV1 change was < MCID. These individuals had better baseline pulmonary function than those with FEV1 changes ≥ MCID (Median FEV1: 102.5 vs 87.0%), with the majority (90%) having FEV1 values ≥ 90%. Mean changes in LCI2.5 at 12-month follow-up visit were - 1.44 units (95% CI: - 2.12; - 0.75) in individuals with changes in FEV1 < MCID and - 2.64 units (95% CI: -3.05; -2.23) in those with values ≥ MCID.

CONCLUSION: LCI2.5 is a useful measure to monitor the effectiveness of ETI in pwCF with normal spirometry and limited FEV1 change following treatment initiation.

PMID:39614886 | DOI:10.1007/s00408-024-00768-1

Ann Clin Microbiol Antimicrob. 2024 Nov 29;23(1):104. doi: 10.1186/s12941-024-00763-7.

ABSTRACT

BACKGROUND: During prolonged FDC therapy, the emergence of FDC non-susceptibility in CRAB has been reported. Here, we report a transmission cluster of FDC-non-susceptible CRAB in four patients, all naïve to FDC treatment, characterized by a premature stop codon and amino acid deletion in the PirA protein.

METHODS: CRAB strains obtained from patients admitted in a single medicine ward of the IRCCS Fondazione Ospedale Maggiore Policlinico between March and July 2024 were analyzed by WGS and antimicrobial susceptibility testing. Phylogenetic analysis was used to assess their genetic relatedness.

RESULTS: Between March and July 2024, an outbreak of 33 CRAB was observed among hospitalized patients in a single ward at IRCCS. Genomic analysis, available in 29 cases, revealed that 24 isolates belonged to ST208/1806, 4 to ST369, and one to ST195/1816 (according to the Oxford scheme). FDC susceptibility was affected only in the four ST369 isolates (Kirby-Bauer disk diffusion diameter: 13 mm; UMIC® method MIC: 4 mg/L), all characterized by a premature stop codon followed by a 52 amino acid deletion located between the amino acids 377 and 428 of the siderophore-drug receptor PirA. No other relevant mutations were detected in the iron-uptake genes. Core-genome ML tree including ST369 reference strains revealed that the four ST369 isolates were highly related and formed a distinct cluster (SNP distance: 3 [IQR: 1-6]). Of note, the four isolates were collected from four FDC-naïve individuals, two experiencing a CRAB-mediated infection.

CONCLUSIONS: Our findings alert about the circulation of clones carrying modified siderophore-drug receptors without evidence of previous FDC treatment and support the importance of testing FDC susceptibility appropriately before its administration.

PMID:39614286 | DOI:10.1186/s12941-024-00763-7

Sci Rep. 2024 Nov 29;14(1):29727. doi: 10.1038/s41598-024-80326-0.

ABSTRACT

Phase contrast x-ray imaging (PCXI) provides high-contrast images of weakly-attenuating structures like the lungs. PCXI, when paired with 4D X-ray Velocimetry (XV), can measure regional lung function and non-invasively assess the efficacy of emerging therapeutics. Bacteriophage therapy is an emerging antimicrobial treatment option for lung diseases such as cystic fibrosis (CF), particularly with increasing rates of multi-drug-resistant infections. Current efficacy assessment in animal models is highly invasive, typically requiring histological assessment. We aim to use XV techniques as non-invasive alternatives to demonstrate efficacy of bacteriophage therapy for treating Pseudomonas aeruginosa CF lung infections, measuring functional changes post-treatment. Time-resolved in vivo PCXI-CT scans of control, Pseudomonas-infected, and phage-treated mouse lungs were taken at the Australian Synchrotron Imaging and Medical Beamline. Using XV we measured local lung expansion and ventilation throughout the breath cycle, analysing the skew of the lung expansion distribution. CT images allowed visualisation of the projected air volume in the lungs, assessing structural lung damage. XV analysis demonstrated changes in lung expansion between infection and control groups, however there were no statistically significant differences between treated and placebo groups. In some cases where structural changes were not evident in the CT scans, XV successfully detected changes in lung function.

PMID:39614107 | DOI:10.1038/s41598-024-80326-0

Cell Death Dis. 2024 Nov 29;15(11):864. doi: 10.1038/s41419-024-07255-8.

ABSTRACT

Ezrin, an actin-binding protein, orchestrates the organization of the cortical cytoskeleton and plasma membrane during cell migration, adhesion, and proliferation. Its role in monocytes/macrophages (MΦs) is less understood. Here, we used a monocyte/MΦ-specific ezrin knock-out mouse model to investigate the contribution of ezrin to monocyte recruitment and adaptation to the lung extracellular matrix (ECM) in response to lipopolysaccharide (LPS). Our study revealed that LPS induces ezrin expression in monocytes/MΦs and is essential for monocytes to adhere to lung ECM, proliferate, and differentiate into tissue-resident interstitial MΦs. Mechanistically, the loss of ezrin in monocytes disrupts activation of focal adhesion kinase and AKT serine-threonine protein kinase signaling, essential for lung-recruited monocytes and monocyte-derived MΦs to adhere to the ECM, proliferate, and survive. In summary, our data show that ezrin plays a role beyond structural cellular support, influencing diverse monocytes/MΦ processes and signaling pathways during inflammation, facilitating their differentiation into tissue-resident macrophages.

PMID:39613751 | DOI:10.1038/s41419-024-07255-8

J Cyst Fibros. 2024 Nov 28:S1569-1993(24)01815-0. doi: 10.1016/j.jcf.2024.11.007. Online ahead of print.

ABSTRACT

BACKGROUND: Parents play a major role in shaping their children's physical activity (PA) behaviour. This study aimed to investigate the association between PA of youth with Cystic Fibrosis (YwCF) and their parents.

METHODS: PA was measured by an ActiGraph GT3x-BT for seven consecutive days. Data were processed by GGIR and PA intensities were based on the age-specific Hildebrand equations. Moderate-to-vigorous PA was chosen as primary outcome.

RESULTS: 26 YwCF-parent dyads participated. A significant positive association was found between parental PA behaviour and YwCF's PA behaviour for both moderate-to-vigorous PA and total PA (R2 = 0.60; p = 0.001; R2 = 0.64; p < 0.001). Furthermore, YwCF with less active parents perform 16 min/day less moderate-to-vigorous PA compared to YwCF with more active parents (p = 0.004).

CONCLUSION: Higher parental PA levels are strongly associated with higher YwCF's PA levels. This association needs to be confirmed in a larger cohort to explore whether parental behaviour is an effective strategy to improve YwCF's PA levels.

PMID:39613539 | DOI:10.1016/j.jcf.2024.11.007

Biomed Pharmacother. 2024 Nov 28;181:117724. doi: 10.1016/j.biopha.2024.117724. Online ahead of print.

ABSTRACT

Although the discovery of antibiotics has made significant positive contributions to public health and medicine, it now poses a serious threat due to the increasing antibiotic resistance in various bacteria. Carbapenem-resistant and multidrug-resistant (MDR) Acinetobacter baumannii is spreading globally, exacerbating respiratory diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Antimicrobial peptides (AMPs), with broad antibacterial activity, have emerged as promising alternatives for treating MDR A. baumannii infections. The AMP P5 exhibits strong antibacterial and anti-biofilm activities against MDR A. baumannii strains isolated from patients. Compared to colistin, a commonly used antibiotic for MDR A. baumannii infections, P5 has a lower potential for inducing drug resistance. Additionally, P5 displays stability in human serum and minimal cytotoxicity in human cell lines. P5 not only suppressed the overexpression of pro-inflammatory cytokines and inflammatory transcription factors in lung epithelial cells (A549) and in a mouse model of respiratory infection but also alleviated lung tissue damage caused by infection. Moreover, P5 effectively alleviated excessive mucin secretion in vitro and in vivo by inhibiting inflammatory transcription factors, epidermal growth factor receptor, and signal transducer and activator of transcription 3-key regulators of mucin expression, a hallmark of inflammatory respiratory diseases. These findings highlight the therapeutic potential of P5 in treating MDR A. baumannii infections and associated inflammatory respiratory conditions.

PMID:39612861 | DOI:10.1016/j.biopha.2024.117724

Hum Immunol. 2024 Nov 28;86(1):111187. doi: 10.1016/j.humimm.2024.111187. Online ahead of print.

ABSTRACT

Small extracellular vesicles (sEVs) isolated from plasma of lung transplant recipients (LTRs) with chronic lung allograft dysfunction (CLAD) contain increased levels of lung associated self-antigens, Kα1 tubulin and collagen V, and decreased expression of the tumor suppressor liver kinase B1 (LKB1). In this study, sEVs were isolated from plasma collected from LTRs with or without cystic fibrosis (CF) from multiple centers at the onset of CLAD and 6 and 12 months before clinical diagnosis of CLAD (n = 32) as well as from time-matched stable controls (n = 25). sEVs were analyzed for Kα1 tubulin, collagen V, and LKB1 by western blot. Exoview R200, a functionalized microarray chip was employed to characterize the LKB1 in sEVs. EVs from non-CF LTRs had higher levels of lung self-antigens (p < 0.05) and lower levels of LKB1 (p = 0.024) 12 months before CLAD diagnosis than those from time-matched stable LTRs; however, in CF LTRs, only LKB1 levels were lower (p = 0.0005) 6 months before diagnosis. Further characterization of sEVs 6 months before CLAD in CF LTRs also demonstrated significantly lower numbers of LKB1 and LKB1/CD9 + sEV particles. Reduced LKB1 in circulating sEVs offers a potential biomarker for the risk of CLAD in LTRs with CF.

PMID:39612537 | DOI:10.1016/j.humimm.2024.111187

Int J Nanomedicine. 2024 Nov 23;19:12461-12481. doi: 10.2147/IJN.S479937. eCollection 2024.

ABSTRACT

INTRODUCTION: Given the increasing frequency of drug-resistant bacteria and the limited progress in developing new antibiotics, it is necessary to explore new methods of combating microbial infections. Nanoparticles, particularly silver nanoparticles (Ag-NPs), have shown exceptional antibacterial characteristics; however, elevated concentrations of Ag-NPs can produce noticeable levels of toxicity in mammalian cells.

AIM: This study examined the potential synergistic effect of combining a low dosage of Ag-NPs and anti-pseudomonas drugs against Pseudomonas aeruginosa (ATCC strain) and eleven clinical isolates from cystic fibrosis patients.

METHODS: The Ag-NPs were chemically produced by utilizing a seed extract from Peganum Harmala and characterized via ultraviolet-visible spectroscopy and scanning electron microscopy. The broth microdilution technique was utilized to investigate the minimum inhibitory concentration (MIC) of Ag-NPs and eight antibiotics (Piperacillin, Ciprofloxacin, Levofloxacin, Meropenem, Amikacin, Ceftazidime, Gentamicin, Aztreonam). The fractional inhibitory concentration index (FICI) was determined via the checkerboard method to evaluate the synergistic effects of Ag-NPs and various antibiotics.

RESULTS: The biosynthesized Ag-NPs were uniformly spherical and measured around 15 nm in size. When combined with antibiotics, Ag-NP produced statistically significant reductions in the amount of antibiotics required to completely prevent P. aeruginosa growth for all strains. The findings revealed that the MIC of Ag-NPs was 15 ug/mL for all strains which decreased substantially when administered with antibiotics at a dose of 1.875-7.5 ug/mL. The majority of Ag-NP and antibiotic combinations exhibited a synergistic or partially synergistic impact. This was particularly noticeable in combinations containing Meropenem, Ciprofloxacin, and Aztreonam (in which the FIC index was less than or equal to 0.5).

CONCLUSION: The findings revealed that combining Ag-NPs with antibiotics was more effective than using Ag-NPs or antibiotics in isolation and that combinations of Ag-NPs and antimicrobial agents displayed synergistic activity against the majority of strains assessed.

PMID:39611007 | PMC:PMC11602434 | DOI:10.2147/IJN.S479937

Cureus. 2024 Oct 28;16(10):e72556. doi: 10.7759/cureus.72556. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa, an aerobic Gram-negative bacillus, is one of the primary causes of severe healthcare-associated infections, especially in people with compromised immune systems or those who are critically ill. It is common in patients with burn injuries, cystic fibrosis, and organ transplants, causing serious infections like pneumonia and septicemia. Carbapenem resistance, driven by mechanisms such as drug efflux and beta-lactamase production, including metallo-β-lactamases, poses a significant clinical threat. Multidrug-resistant (MDR) strains lead to nosocomial outbreaks with high morbidity and mortality. This study aims to assess the prevalence and resistance patterns of Pseudomonas aeruginosa to optimize treatments and inform antibiotic policies.

MATERIAL AND METHODS: This cross-sectional study was conducted in the Department of Microbiology for a period of one year (November 2022 to November 2023). In total, 118 clinical specimens were processed for identification and antimicrobial sensitivity testing using the Kirby-Bauer disk diffusion technique, following the Clinical and Laboratory Standards Institute guidelines.

RESULT: Out of the 118 clinical samples, urine samples yielded the highest number of isolates (50%), followed by the pus samples (28.81%). Male patients accounted for 67.8% of the isolates, and female patients 32.2%. The highest prevalence was observed in the 41-60 age group, representing 33.90% of the cases. Eighty-seven percent of the isolates were from the inpatient department. In total, 28.86% of the isolates came from the surgery ward. Pseudomonas aeruginosa demonstrated the highest sensitivity to cefepime (31.3%), followed by amikacin (26.3%), and the slightest sensitivity to imipenem and piperacillin.

CONCLUSION: Pseudomonas aeruginosa is a frequently isolated organism and is becoming increasingly resistant to standard medications. Notably, aminoglycosides (such as amikacin) and cephalosporins (such as cefepime) demonstrated efficacy against Pseudomonas, though the frequency of MDR strains is rising. The current investigation provides valuable insights into the incidence of Pseudomonas aeruginosa and its susceptibility to various antibiotics, which will guide the adoption of improved patient care and infection control methods.

PMID:39610569 | PMC:PMC11602418 | DOI:10.7759/cureus.72556

J Ayub Med Coll Abbottabad. 2024 Apr-Jun;36(2):245-250. doi: 10.55519/JAMC-02-12876.

ABSTRACT

BACKGROUND: Antibiotic resistance is one of the most urgent public health concerns. Biofilm formation is well linked with chronic wounds, chronic obstructive pulmonary disease, urinary tract infections, and cystic fibrosis. Our goal was to assess the biofilm activity of P. aeruginosa and the individual and combined anti-biofilm forming activity of probiotic Lactobacillus acidophilus and Pomegranate peel extract Punica granatum L., against P. aeruginosa.

METHODS: A total of 150 swabs of urine, blood, pus, and CSF were collected from PNS Shifa Hospital Karachi, and P. aeruginosa was isolated and identified according to standard bacteriological methods. The ability of P. aeruginosa to form biofilms was assessed using a microtiter plate assay.

RESULTS: The anti-biofilm forming activity of pomegranate peels extract against P. aeruginosa was 29.26±19.09 whereas the anti-biofilm forming activity of Lactobacillus acidophilus against P. aeruginosa was 0.5×106. When used in combination, there was significant synergistic activity between Punica granatum L. (pomegranate peel extract) and Lactobacillus acidophilus.

CONCLUSIONS: The unique synergistic mixture of natural product extracts and probiotics has demonstrated more efficiency against rapidly evolving pathogens, serving as promising candidates for developing biofilm inhibitors and perhaps proving as possible environmentally friendly agents against bacteria that produce antibiotic-resistant biofilms.

PMID:39609958 | DOI:10.55519/JAMC-02-12876

BMC Med. 2024 Nov 28;22(1):562. doi: 10.1186/s12916-024-03785-2.

ABSTRACT

BACKGROUND: The causal pathway between different dietary patterns (DPs) and gastric adenocarcinoma (GA) remains largely unexplored. The study aimed to identify DPs and evaluate how selected nutrients mediate the relationship between DPs and GA.

METHODS: This multicenter case-control study in Brazil involved 1751 participants (600 cases, 377 endoscopic controls, and 774 hospital controls). DPs were identified through exploratory factor analysis. A counterfactual-based mediation analysis was performed to decompose the total effect of DPs on GA into direct and indirect effects mediated by saturated fatty acids, added sugars, total fiber, and sodium intakes. Effects were expressed as ORs and 95% CIs.

RESULTS: Two DPs were identified-"unhealthy dietary pattern" (UDP) and "healthy dietary pattern" (HDP), which were associated with an increased and decreased risk of GA, respectively. Added sugars partly mediated the association between UDP and GA (percentage mediated between 7.3 and 21.7%), while sodium intake mediated most of the association between HDP and GA (percentage mediated between 52.4 and 100%). No significant mediating effects were detected for saturated fatty acids and total fiber.

CONCLUSIONS: This study contributes innovative insights into the DPs-GA relationships, highlighting the significant mediating roles of sodium and added sugars, offering valuable information for preventive strategies and public health interventions targeting GA.

PMID:39609810 | DOI:10.1186/s12916-024-03785-2

Commun Biol. 2024 Nov 28;7(1):1590. doi: 10.1038/s42003-024-07290-3.

ABSTRACT

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, 99.2%, and 99.7% host reads, respectively. Host depletion effects varied by sample type, generally increasing microbial reads, species and functional richness; this was mediated by higher effective sequencing depth. Rarefaction curves showed species richness saturation at 0.5-2 million microbial reads. Most methods did not change Morisita-Horn dissimilarity for BAL and nasal samples although the proportion of gram-negative bacteria decreased for sputum from pwCF. Freezing did not affect the viability of Staphylococcus aureus but reduced the viability of Pseudomonas aeruginosa and Enterobacter spp.; this was mitigated by adding a cryoprotectant. QIAamp-based host depletion minimally impacted gram-negative viability even in non-cryoprotected frozen isolates. While some host depletion methods may shift microbial composition, metagenomics sequencing without host depletion severely underestimates microbial diversity of respiratory samples due to shallow effective sequencing depth and is not recommended.

PMID:39609616 | DOI:10.1038/s42003-024-07290-3

Gene Ther. 2024 Nov 28. doi: 10.1038/s41434-024-00499-1. Online ahead of print.

ABSTRACT

We are often confronted with a simple question, "which gene editing technique is the best?"; the simple answer is "there isn't one". In 2021, a year after prime editing first made its mark, we evaluated the landscape of this potentially transformative advance in genome engineering towards getting treatments to the clinic [1]. Nearly 20% of the papers we cited were still in pre-print at the time which serves to indicate how early-stage the knowledge base was at that time. Now, three years later, we take a look at the landscape and ask what has been learnt to ensure this tech is broadly accessible, highlighting some key advances, especially those that push this towards the clinic. A big part of the appeal of prime editing is its ability to precisely edit DNA without double stranded breaks, and to install any of the 12 possible single-nucleotide conversion events as well as small insertions and/or deletions, or essentially any combination thereof. Over the last few decades, other transformative and Nobel prize-winning technologies that rely on Watson-Crick base-pairing such as PCR, site-directed mutagenesis, RNA interference, and one might say, "classic" CRISPR, were swiftly adopted across labs around the world because of the speed with which mechanistic rules governing their efficiency were determined. Whilst this perspective focuses on the context of gene therapy applications of prime editing, we also further look at the recent studies which have increased our understanding of the mechanism of PEs and simultaneously improved the efficiency and diversity of the PE toolbox.

PMID:39609594 | DOI:10.1038/s41434-024-00499-1

Nat Commun. 2024 Nov 28;15(1):10360. doi: 10.1038/s41467-024-54666-4.

ABSTRACT

Nontuberculous mycobacterium (NTM) infections are challenging to manage and are frequently non-responsive to aggressive but poorly-tolerated antibiotic therapies. Immunosuppressed lung transplant patients are susceptible to NTM infections and poor patient outcomes are common. Bacteriophages present an alternative treatment option and are associated with favorable clinical outcomes. Similarly, dual beta-lactam combinations show promise in vitro, but clinical use is sparse. We report here a patient with an uncontrolled Mycobacterium abscessus infection following a bilateral lung transplant and failed antibiotic therapy. Both smooth and rough colony morphotype strains were initially present, but treatment with two phages that kill the rough strain - including epigenetic-modification to overcome restriction - resulted in isolation of only the smooth strain. The rough and smooth strains have similar antibiotic susceptibilities suggesting that the phages specifically eliminated the rough strain. Dual beta-lactam therapy with meropenem and ceftazidime-avibactam provided further clinical improvement, and the phages act synergistically with meropenem in vitro.

PMID:39609405 | DOI:10.1038/s41467-024-54666-4

Nat Commun. 2024 Nov 28;15(1):9987. doi: 10.1038/s41467-024-53994-9.

ABSTRACT

Bacteriophage (phage) therapy is a promising therapeutic modality for multidrug-resistant bacterial infections, but its application is mainly limited to personalized therapy due to the narrow host range of individual phages. While phage cocktails targeting all possible bacterial receptors could theoretically confer broad coverage, the extensive diversity of bacteria and the complexity of phage-phage interactions render this approach challenging. Here, using screening protocols for identifying "complementarity groups" of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent the emergence of bacterial resistance. We also discover characteristic interactions between phage complementarity groups and particular antibiotic classes, facilitating the prediction of phage-antibiotic as well as phage-phage interactions. Using this strategy, we create three phage-antibiotic cocktails, each demonstrating efficacy against ≥96% of 153 Pseudomonas aeruginosa clinical isolates, including biofilm cultures, and demonstrate comparable efficacy in an in vivo wound infection model. We similarly develop effective Staphylococcus aureus phage-antibiotic cocktails and demonstrate their utility of combined cocktails against polymicrobial (mixed P. aeruginosa/S. aureus) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for the development of effective, broad-spectrum phage-antibiotic cocktails, paving the way for off-the-shelf phage-based therapeutics to combat multidrug-resistant bacterial infections.

PMID:39609398 | DOI:10.1038/s41467-024-53994-9

Front Med. 2024 Nov 29. doi: 10.1007/s11684-024-1106-2. Online ahead of print.

ABSTRACT

Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient's peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.

PMID:39609360 | DOI:10.1007/s11684-024-1106-2

Pediatr Pulmonol. 2024 Nov 28:e27428. doi: 10.1002/ppul.27428. Online ahead of print.

NO ABSTRACT

PMID:39607352 | DOI:10.1002/ppul.27428

Pediatr Pulmonol. 2024 Nov 28. doi: 10.1002/ppul.27416. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator modulator therapies (CFTR-MT) have altered management, reducing exacerbations and slowing pulmonary function decline. Nevertheless, it is still uncertain if the benefits of CFTR-MTs last when they are stopped. This study aimed to assess pulmonary function changes, and exacerbation rates during and after CFTR-MT use in adult cystic fibrosis patients.

METHODS: Between 2018 and 2022, we conducted a study involving adult CF patients who initially used CFTR-MTs but later discontinued them due to reimbursement issues. The study was divided into three phases: predrug (T1), in-drug (T2), and postdrug (T3). We recorded pulmonary function tests, laboratory and culture results, and the number of exacerbations.

RESULTS: The study involved 33 patients, with 28 (84.8%) receiving Elexacaftor/Tezacaftor/Ivacaftor and 5 (15.2%) receiving Ivacaftor. The median treatment and interruption durations were 3.1 (IQR = 2.9-5.7), and 2.5 (IQR = 1.5-4.0) months, respectively. The mean FEV1% was 54.3% (± 26.6), 70.4% (± 27.4), and 60.2% (± 26.5) during T1, T2, and T3, respectively (p < 0.001). The mean FVC% was 65.5% (± 23.9) in T1, increased to 81.5% (± 24.5) in T2, and decreased to 71.6% (± 25.9) in T3 (p < 0.001). The number of Psedomonas aeruginosa, and Aspergillus positive sputum cultures decreased significantly with drug use (T1: 72.7%, 39.4%; T2: 48.5%, 9.1%; T3: 45.5%, 18.2%; p = 0.014, p = 0.004, respectively). The median number of hospitalizations was 1.0 (0-5.0) in T1, 0 (0-0) in T2, and 0 (0-1.0) in T3.

CONCLUSION: This study revealed that CFTR-MTs are effective even in the short term for adult CF patients, but their beneficial effects quickly diminish after discontinuation. Real-life data obtained as a result of discontinuation of drugs due to reimbursement problems has highlighted the significance of regular and uninterrupted use of modulators.

PMID:39607351 | DOI:10.1002/ppul.27416

Front Med (Lausanne). 2024 Nov 12;11:1401473. doi: 10.3389/fmed.2024.1401473. eCollection 2024.

ABSTRACT

INTRODUCTION: Segmentation of lung structures in medical imaging is crucial for the application of automated post-processing steps on lung diseases like cystic fibrosis (CF). Recently, machine learning methods, particularly neural networks, have demonstrated remarkable improvements, often outperforming conventional segmentation methods. Nonetheless, challenges still remain when attempting to segment various imaging modalities and diseases, especially when the visual characteristics of pathologic findings significantly deviate from healthy tissue.

METHODS: Our study focuses on imaging of pediatric CF patients [mean age, standard deviation (7.50 ± 4.6)], utilizing deep learning-based methods for automated lung segmentation from chest magnetic resonance imaging (MRI). A total of 165 standardized annual surveillance MRI scans from 84 patients with CF were segmented using the nnU-Net framework. Patient cases represented a range of disease severities and ages. The nnU-Net was trained and evaluated on three MRI sequences (BLADE, VIBE, and HASTE), which are highly relevant for the evaluation of CF induced lung changes. We utilized 40 cases for training per sequence, and tested with 15 cases per sequence, using the Sørensen-Dice-Score, Pearson's correlation coefficient (r), a segmentation questionnaire, and slice-based analysis.

RESULTS: The results demonstrated a high level of segmentation performance across all sequences, with only minor differences observed in the mean Dice coefficient: BLADE (0.96 ± 0.05), VIBE (0.96 ± 0.04), and HASTE (0.95 ± 0.05). Additionally, the segmentation quality was consistent across different disease severities, patient ages, and sizes. Manual evaluation identified specific challenges, such as incomplete segmentations near the diaphragm and dorsal regions. Validation on a separate, external dataset of nine toddlers (2-24 months) demonstrated generalizability of the trained model achieving a Dice coefficient of 0.85 ± 0.03.

DISCUSSION AND CONCLUSION: Overall, our study demonstrates the feasibility and effectiveness of using nnU-Net for automated segmentation of lung halves in pediatric CF patients, showing promising directions for advanced image analysis techniques to assist in clinical decision-making and monitoring of CF lung disease progression. Despite these achievements, further improvements are needed to address specific segmentation challenges and enhance generalizability.

PMID:39606627 | PMC:PMC11600534 | DOI:10.3389/fmed.2024.1401473