Eur Respir Rev. 2024 Oct 30;33(174):240071. doi: 10.1183/16000617.0071-2024. Print 2024 Oct.

ABSTRACT

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

PMID:39477350 | DOI:10.1183/16000617.0071-2024

J Am Pharm Assoc (2003). 2024 Oct 28:102270. doi: 10.1016/j.japh.2024.102270. Online ahead of print.

ABSTRACT

BACKGROUND: High treatment burden can adversely impact health outcomes in people with cystic fibrosis (PwCF). There is a continued need for medication adherence education and further research to evaluate impact of CF pharmacist interventions in an ambulatory care setting.

OBJECTIVE(S): To evaluate whether pharmacist integration into an outpatient adult CF clinic can positively impact patient satisfaction and medication adherence through various pharmacist-based interventions.

METHODS: At a single urban medical center, a clinical pharmacist on an adult CF care team conducted comprehensive counseling sessions with PwCF. During these visits, types of pharmacist interventions were documented. Patients were provided a baseline and post-counseling survey to assess satisfaction with the pharmacist visit. Adherence to cystic fibrosis transmembrane regulator (CFTR) modulator and mucolytics were tracked 12 months before and 12 months after the counseling session.

RESULTS: A total of 723 pharmacist interventions were performed throughout 100 pharmacist visits in 100 PwCF. Most common interventions were inhaler technique education (17%), drug interaction identification (12%), provision of drug education material (12%), and medication refills (12%). Prior to any intervention, 97% of patients felt they could benefit from a pharmacist visit. Post-counseling survey results demonstrated that 98% of patients found pharmacist counseling to be beneficial. Medication adherence rate prior to pharmacy intervention was 81.9% for CFTR modulators and 62.5% for mucolytics, and 86.9% (p=0.143) and 63.6% (p=0.773), respectively, after pharmacist intervention.

CONCLUSION: Integration of a clinical pharmacist within the CF clinic can help improve satisfaction and understanding of medication use among PwCF. Nearly all PwCF favorably perceived pharmacist counseling. We report that various pharmacist interventions including optimizing medication use knowledge, reinforcing adherence strategies, and streamlining timely access to treatment can contribute to enhanced care of PwCF.

PMID:39477207 | DOI:10.1016/j.japh.2024.102270

Am J Pathol. 2024 Oct 28:S0002-9440(24)00394-8. doi: 10.1016/j.ajpath.2024.09.008. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. Pseudomonas aeruginosa and Staphylococcus aureus are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent co-infections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus co-infection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of S. aureus have been associated with P. aeruginosa infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung co-infection with P. aeruginosa and S. aureus, using clinical and laboratory derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats co-infected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung, but only the combination of P. aeruginosa and clinical normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. In regression analyses, damage was associated with a higher burden of P. aeruginosa, indicating that chronic co-infection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when co-infecting S. aureus exhibits the SCV phenotype.

PMID:39476957 | DOI:10.1016/j.ajpath.2024.09.008

Vaccine. 2024 Oct 29;42(26):126476. doi: 10.1016/j.vaccine.2024.126476. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative, opportunistic pathogen that infects immunocompromised individuals, especially in the hospital setting. This bacterium is an important pathogen in people with weakened immune systems, injuries, and other underlying physiologic dysfunctions. P. aeruginosa is responsible for up to 20 % of all hospital-acquired pneumonias. It is one of the major causes of nosocomial infections and has been noted to be one of the most common bacteria co-infecting patients with COVID-19 or causing super-infections following COVID-19 infections. Despite improvements in antimicrobial therapy and hospital care, P. aeruginosa bacteremia and pneumonia remain fatal in about 30 % of cases. P. aeruginosa is also the leading cause of chronic life-threatening lung infections in cystic fibrosis patients. This bacterium is naturally antibiotic resistant, and infections are notoriously difficult to treat once established, with no vaccine available. We have previously shown that elongation factor-Tu (EF-Tu), a protein best known for its role in protein synthesis, is surface exposed on P. aeruginosa. As this protein is highly expressed, evolutionally conserved, and essential, we hypothesized it would make a good vaccine target. In this study, we found that P. aeruginosa EF-Tu is immunogenic in people, and that mice can develop an immune response following immunization with recombinant P. aeruginosa EF-Tu. Furthermore, immunized mice were protected from subsequent P. aeruginosa pneumonia and transfer of this vaccine antisera to naïve mice resulted in decreased colonization. Altogether these findings support the consideration of EF-Tu as a new vaccine candidate against P. aeruginosa.

PMID:39476472 | DOI:10.1016/j.vaccine.2024.126476

Neurology. 2024 Nov 26;103(10):e210001. doi: 10.1212/WNL.0000000000210001. Epub 2024 Oct 30.

ABSTRACT

OBJECTIVES: To describe a novel subtype of autoimmune myopathy, immune-mediated megaconial myopathy (IMMM), myopathologically characterized by giant mitochondria (megaconia).

METHODS: In this case series, we reviewed the Mayo Clinic Muscle Pathology database, between 2018 and 2023, to identify patients with megaconial pathology, subacute progressive weakness, and hyperCKemia, clinically resembling myositis. We recruited 1 patient from another institute, who had similar clinicopathologic features.

RESULTS: Five patients were identified. Age at onset of weakness ranged from 19 to 45.5 years. All patients had proximal weakness, elevated creatine kinase levels (1,214 to 5,920 U/L), negative myositis antibodies, necrotizing myopathology, and nonnecrotic myofibers harboring giant mitochondria. Immunohistochemical studies conducted in 4 patients showed sarcolemmal MHC-1 and C5b9 immunoreactivities. Megaconial pathology was considered pathognomonic of congenital muscular dystrophy due to biallelic pathogenic variants in CHKB. Sequencing of CHKB in 4/5 patients was unrevealing. Immunomodulatory therapy improved weakness and hyperCKemia in 4 treated patients. Of interest, all patients had coexisting pancreatic diseases (3 cystic fibrosis-related exocrine pancreatic insufficiency, 1 pancreatic cancer, and 1 pancreatitis).

DISCUSSION: In addition to incurable CHKB-congenital muscular dystrophy, giant mitochondria can also occur in this new subtype of treatable autoimmune myopathy, IMMM. The association between IMMM and pancreatic disorders remains to be elucidated.

PMID:39475687 | DOI:10.1212/WNL.0000000000210001

mSphere. 2024 Oct 30:e0067124. doi: 10.1128/msphere.00671-24. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is characterized by chronic airway obstruction, infection, and inflammation leading to progressive loss of lung function and eventual respiratory failure. Omadacycline, a tetracycline antibiotic, demonstrates in vitro activity against key CF pathogens, substantial lung penetration, and increasing clinical evidence for the treatment of lung infections in people with CF (PwCF). Preliminary in vitro data demonstrate that omadacycline exhibits anti-inflammatory activity. This study aims to determine the anti-inflammatory effects of omadacycline in vitro and in a murine model of lipopolysaccharide (LPS)-induced lung neutrophilia. In vitro, THP-1-derived macrophages were treated with omadacycline (20-100 µg/mL) 30 minutes prior to LPS stimulation. Pro-inflammatory cytokine (TNF-α, IL-1β/6), chemokine (CXCL-1/2), and MMP-9 levels were analyzed after 24 hours by ELISA. Omadacycline's effects on IL-8-induced human neutrophil chemotaxis were also investigated. In vivo, omadacycline (2.5-30 mg/kg), comparators dexamethasone (1 mg/kg), and azithromycin (30 mg/kg) were administered 1 hour before and 6 hours after intranasal LPS challenge, respectively. Leukocyte counts and differentials in bronchoalveolar lavage fluid (BALF), inflammatory mediator levels in BALF and lung homogenates, pulmonary edema markers, and the severity of lung injury were evaluated 24 hours or 48 hours post-challenge. Treatment with omadacycline in vitro resulted in significant, dose-dependent reductions in IL-6, CXCL-1, and MMP-9 expression and inhibition of IL-8-induced neutrophil chemotaxis. In vivo, omadacycline yielded protective and therapeutic effects by reducing the production of proinflammatory cytokines and chemokines and neutrophil infiltration into the lungs, along with modestly improving lung injury severity. These preclinical results suggest that omadacycline may provide dual anti-bacterial and anti-inflammatory activities relevant to chronic lung infection treatment in PwCF.IMPORTANCENontuberculous mycobacteria, particularly Mycobacterium abscessus complex (MABSC), are a major concern for people with cystic fibrosis (PwCF) due to their association with deteriorating lung function. A substantial barrier to effective treatment is the limited number of safe and effective antibiotics. Omadacycline offers a potential advancement in managing MABSC infections in cystic fibrosis due to its activity, effective penetration into pulmonary secretions, improved tolerability, and good oral bioavailability as shown in healthy volunteers. Our study is the first to explore omadacycline's effects in a model of sterile lung inflammation and acute lung injury. We found that omadacycline not only has potent anti-bacterial properties but also exhibits anti-inflammatory effects, reducing lung inflammation and injury in our preclinical models. These findings underscore omadacycline's potential as a dual-action therapy for lung infections in PwCF, indicating significant potential to improve patient outcomes and guide more effective antimicrobial therapy decisions.

PMID:39475317 | DOI:10.1128/msphere.00671-24

mBio. 2024 Oct 30:e0297024. doi: 10.1128/mbio.02970-24. Online ahead of print.

ABSTRACT

Mycobacteria produce a large repertoire of surface-exposed lipids with major biological functions. Among these lipids, trehalose polyphleates (TPPs) are instrumental in the infection of Mycobacterium abscessus by the therapeutic phage BPs. However, while the biosynthesis and transport of TPPs across the membrane by MmpL10 have been reported, the role of TPPs in host infection remains enigmatic. Here, we addressed whether the loss of TPPs influences interactions with macrophages and the virulence of M. abscessus. As anticipated, the deletion of mmpL10 in smooth (S) and rough (R) variants of M. abscessus abrogated TPP production, which was rescued upon gene complementation. Importantly, infection of human THP-1 cells with the mmpL10 mutants was associated with decreased intramacrophage survival and a reduced proportion of infected cells. The rough mmpL10 mutant showed an impaired capacity to block phagosomal acidification and was unable to co-localize with Galectin-3, a marker of phagosomal membrane damage. This suggests that TPPs participate, directly or indirectly, in phagolysosomal fusion and in phagosomal membrane damage to establish cytosolic communication. The TPP defect that affects the fitness and virulence of M. abscessus was further demonstrated in zebrafish embryos using a rough clinical strain resistant to phage BPs and harboring a frameshift mutation in mmpL10. Infection with this strain was correlated with a slight decrease in embryo survival and a reduced bacterial burden as compared to the corresponding parental and complemented derivatives. Together, these results indicate that TPPs are important surface lipids contributing to the pathogenicity of M. abscessus.IMPORTANCETrehalose polyphleates (TPPs) are complex lipids associated with the mycobacterial cell surface and were identified 50 years ago. While the TPP biosynthetic pathway has been described recently, the role of these lipids in the biology of mycobacteria remains yet to be established. The wide distribution of TPPs across mycobacterial species suggests that they may exhibit important functions in these actinobacteria. Here, we demonstrate that Mycobacterium abscessus, an emerging multidrug-resistant pathogen that causes severe lung diseases in cystic fibrosis patients, requires TPPs for survival in macrophages and virulence in a zebrafish model of infection. These findings support the importance of this underexplored family of lipids in mycobacterial pathogenesis.

PMID:39475242 | DOI:10.1128/mbio.02970-24

Front Microbiol. 2024 Oct 9;15:1477836. doi: 10.3389/fmicb.2024.1477836. eCollection 2024.

ABSTRACT

OBJECTIVE: The emergence of resistance to colistin, the last resort for treating severe infections caused by Pseudomonas aeruginosa, poses a significant threat to public health. This meta-analysis aimed to investigate the prevalence of colistin resistance in clinical isolates of P. aeruginosa.

METHOD: A comprehensive search of MEDLINE (PubMed), Web of Science, and Scopus databases was conducted to identify relevant articles published until December 2023. Subsequently, a meta-analysis was performed using Stata software to examine the pooled prevalence of colistin resistance and to conduct subgroup analyses.

RESULTS: A total of 619 studies were included in the meta-analysis, revealing a global prevalence of colistin resistance of 1% among all P. aeruginosa isolates. Furthermore, cystic fibrosis patients exhibited the highest resistance to colistin, with a prevalence of 7% among the examined diseases.

CONCLUSION: The increase in colistin resistance in P. aeruginosa in recent years from 2% (in the period of 2006-2010) to 5% (in the period of 2020-2023) underscores the need for implementing infection prevention programs, using appropriate treatment regimens, and disseminating comprehensive information on antimicrobial resistance patterns. These measures are crucial for addressing this growing public health concern.

PMID:39473844 | PMC:PMC11520190 | DOI:10.3389/fmicb.2024.1477836

Turk J Med Sci. 2024 Jun 4;54(5):1154-1164. doi: 10.55730/1300-0144.5894. eCollection 2024.

ABSTRACT

BACKGROUND/AIM: Misfolded proteins are eliminated by a process known as endoplasmic reticulum-associated protein degradation (ERAD). ERAD has an impact on a variety of illnesses, such as diabetes, cystic fibrosis, cancer, and neurological conditions. As one of the many proteins involved in ERAD, this study is focused on p97/valosin-containing protein (VCP) and small VCP-interacting protein (SVIP). The existence and function of SVIP and p97/VCP in various types of pancreatic cancer have not yet been investigated. The study's objectives are to examine the expressions of SVIP and p97/VCP in two pancreatic cancer types and to show whether these proteins aid in the invasion and migration of pancreatic cancer cells.

MATERIALS AND METHODS: In this work, MIA PaCa-2 and PANC-1 human cell lines were examined. Immunocytochemistry and immunofluorescence were performed to detect the cellular localization and presence of p97/VCP and SVIP in pancreatic cancer cells. Following p97/VCP siRNA and SVIP siRNA transfection of the cells, protein expressions were assessed using Western blot analysis. The effects of this suppression on cell invasion and migration were determined using the xCELLigence real-time analysis system (RTAC).

RESULTS: In the nucleus and cytoplasm of MIA PaCa-2 and PANC-1 cells, p97/VCP and SVIP immunoexpressions were seen. The decrease in protein expressions of p97/VCPsi and SVIPsi was significant in pancreatic cells compared to the controlsi. The p97/VCP siRNA transfection reduced the invasion and migration of MIA PaCa-2 and PANC-1 cells. In addition, the SVIP siRNA suppression resulted in increasing the invasion and migration ability of both cells. This study also demonstrated, for the first time, SVIP expression in MIA PaCa-2 and PANC-1 cells.

CONCLUSION: Overall, the findings show the differential expression and function of p97/VCP and SVIP in pancreas ductal adenocarcinoma cells. The potential of the pancreatic cancer cells to migrate and invade altered when the two cell lines were transfected with p97/VCPsi and SVIPsi.

PMID:39473740 | PMC:PMC11518332 | DOI:10.55730/1300-0144.5894

Mol Ther. 2024 Oct 28:S1525-0016(24)00688-9. doi: 10.1016/j.ymthe.2024.10.028. Online ahead of print.

ABSTRACT

Nonsense mutations, often resulting from single nucleotide substitutions, produce mRNA harboring a premature termination codon (PTC), which causes the premature termination of protein synthesis. This produces truncated and non-functional proteins, which cause different genetic diseases, including cystic fibrosis (CF). This work aims to investigate the ability of NV848, (N-(5-methyl-1,2,4-oxadiazol-3-yl)acetamide), a translational readthrough-inducing drug (TRID), to rescue cystic fibrosis transmembrane conductance regulator (CFTR) protein expression in a murine model characterized by the G542X nonsense mutation in CFTR gene. In vitro experiments assessed the drug's stability in human hepatic metabolism and in vivo investigations on wild-type mice allowed to clarify the distribution of the drug to the target organs. Moreover, its efficacy in recovering CFTR protein after chronic treatment was assessed in G542X homozygous mice. Our results provide valuable insights into the biodistribution and therapeutic attributes of NV848, representing a promising therapeutic tool for enhanced clinical outcomes in individuals affected by CF with nonsense mutations.

PMID:39473179 | DOI:10.1016/j.ymthe.2024.10.028

Sci Rep. 2024 Oct 29;14(1):25907. doi: 10.1038/s41598-024-77375-w.

ABSTRACT

P. aeruginosa employs specific quorum sensing (QS) mechanisms to orchestrate biofilm formation, enhancing resistance to host defences. In physiological conditions, QS molecules permeate the lung environment and cellular membrane to reach the cytoplasmic Aryl Hydrocarbon Receptor (AhR) that is pivotal for activating the immune response against infection. In pathological conditions like cystic fibrosis (CF) this interkingdom communication is altered, favouring P. aeruginosa persistence and chronic infection. Here, we aim to investigate the molecular journey of QS molecules from CF-like environments to the cytoplasm by quantifying via HPLC-MS the permeability of selected QS molecules (quinolones, lactones, and phenazines) through in vitro models of the two main biological lung barriers: CF-mucus and cellular membrane. While QS molecules not activating AhR exhibit intermediate permeability through the cellular membrane model (PAMPA) (1.0-4.0 × 10-6 cm/s), the AhR-activating molecule (pyocyanin) shows significantly higher permeability (8.6 ± 1.4 × 10-6 cm/s). Importantly, combining the CF mucus model with PAMPA induces a 50% decrease in pyocyanin permeability, indicating a strong mucus-shielding effect with pathological implications in infection eradication. This study underscores the importance of quantitatively describing the AhR-active bacterial molecules, even in vitro, to offer new perspectives for understanding P. aeruginosa virulence mechanisms and for proposing new antibacterial therapeutic approaches.

PMID:39472521 | DOI:10.1038/s41598-024-77375-w

J Cyst Fibros. 2024 Oct 28:S1569-1993(24)01801-0. doi: 10.1016/j.jcf.2024.10.006. Online ahead of print.

ABSTRACT

BACKGROUND: This study aims to characterize the uptake of elexacaftor/tezacaftor/ivacaftor (ETI) following Food and Drug Administration (FDA) approval in October 2019.

METHODS: People with cystic fibrosis (PwCF) ≥12 years enrolled in the CF Foundation Patient Registry (CFFPR) from 2019-2022 with at least one copy of F508del were included. We calculated summary statistics according to ETI prescription status. We used a Kaplan-Meier estimator to determine median days to ETI prescription to identify differences in prescription uptake by lung function, race, and ethnicity and a Cox proportional hazards model to identify risk factors associated with timing of first ETI prescription.

RESULTS: A total of 17,183 people (91 %) were prescribed ETI. The median time to prescription was 121 days (95 % CI: 119, 122), with 75 % prescribed within 311 days (95 % CI: 301, 325). PwCF prescribed ETI were younger, had lower lung function, more pulmonary exacerbations in the prior year, earlier age of diagnosis, and were more likely to have been prescribed another CFTR modulator (if eligible). Public health insurance, ppFEV1 >90, Black race and Hispanic ethnicity were associated with lower hazards (e.g., later) of ETI prescription whereas prior modulator prescription, pancreatic insufficiency, increased exacerbation frequency and prior infections were associated with a higher hazard (earlier) of prescription.

CONCLUSIONS: While over 90 % of eligible individuals were prescribed ETI within three years, time of first prescription was associated with demographic factors and disease severity. Further research should investigate the reasons for this delay and approaches to reduce time to initiation for ETI and future therapies.

PMID:39472230 | DOI:10.1016/j.jcf.2024.10.006

Life Sci. 2024 Oct 27:123186. doi: 10.1016/j.lfs.2024.123186. Online ahead of print.

ABSTRACT

Personalized medicine has transformed the treatment of cystic fibrosis (CF), providing customized therapeutic approaches based on individual genetic profiles. This review explores the genetic foundations of CF, focusing on mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and their implications for the development of the disease. The advent of genetic testing has enabled the association of specific mutations to disease severity, leading to the development of CFTR modulators like Ivacaftor, Lumacaftor, and Tezacaftor. Beyond CFTR mutations, genetic modifiers, including gene replacement therapy, genetic manipulation, lentivirus, and non-viral gene therapy formulations, along with environmental factors, play critical roles in influencing disease expression and outcomes. The identification of these modifiers is essential for optimizing therapeutic strategies. Emerging biomarkers, including inflammatory markers and pulmonary function indicators, aid in early disease detection and monitoring progression. Omics technologies are uncovering novel biomarkers, enabling more precise disease management. Pharmacogenomics has become integral to CF care, allowing for personalized approaches that consider genetic variations influencing drug metabolism, especially in antibiotics and anti-inflammatory therapies. The future of CF treatment lies in precision therapies, including CFTR modulators and cutting-edge techniques like gene therapy and CRISPR-Cas9 for mutation correction. As research evolves, these advances can improve patient outcomes while minimizing adverse effects. Ethical considerations and regulatory challenges remain critical as personalized medicine advances, ensuring equitable access and the long-term effectiveness of these innovative therapies.

PMID:39471902 | DOI:10.1016/j.lfs.2024.123186

Am J Physiol Gastrointest Liver Physiol. 2024 Oct 29. doi: 10.1152/ajpgi.00302.2024. Online ahead of print.

NO ABSTRACT

PMID:39470598 | DOI:10.1152/ajpgi.00302.2024

Microbiol Resour Announc. 2024 Oct 29:e0104724. doi: 10.1128/mra.01047-24. Online ahead of print.

ABSTRACT

In cystic fibrosis, bacteria-bacteriophage interaction in the lower airways is poorly understood. We present the near-complete genome of the uncultured Siphovirus-like bacteriophage, Staphylococcus aureus phage COMBAT-CF_PAR1, isolated from the lower airways. The genome spans 41,510 bp with 33.45% guanine-cytosine content and contains 65 open reading frames.

PMID:39470239 | DOI:10.1128/mra.01047-24

Monaldi Arch Chest Dis. 2024 Oct 24. doi: 10.4081/monaldi.2024.3033. Online ahead of print.

ABSTRACT

Predictors of outcomes are essential to identifying severe COVID-19 cases and optimizing treatment and care settings. The respiratory rate-oxygenation (ROX) index, originally introduced for predicting the failure of non-invasive support in acute hypoxemic respiratory failure (AHRF), has not been extensively studied over time during hospitalization. This multicenter prospective observational study analyzed COVID-19-related AHRF patients admitted to eight Italian hospitals during the second pandemic wave. The study assessed the ROX index using receiver operator characteristic curves and areas under the curve with 95% confidence intervals to predict treatment failure, defined as endotracheal intubation (ETI) or death. A total of 227 patients (69.2% males) were enrolled, with a median arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio at admission of 248 (interquartile range: 170-295). Nearly one-third (29.5%) required ETI or died during hospitalization. Those who experienced treatment failure were older (median age 70 versus 61 years, p<0.001), more likely to be current or former smokers (8.5% versus 6.4% and 42.4% versus 25.5%, p=0.039), had a higher prevalence of cardiovascular diseases (74.6% versus 46.3%, p<0.001), and had a lower PaO2/FiO2 ratio at presentation (median 229 versus 254, p=0.014). Gender, body mass index, and other comorbidities showed no significant differences. In patients who failed treatment, the ROX index was higher at presentation and worsened sharply by days 3 and 4. Conversely, in patients who survived without requiring ETI, the ROX index remained stable and reduced after 5-6 days. The ROX index's predictive ability improved notably by the third day of hospitalization, with the best cut-off value identified at 8.53 (sensitivity 75%, specificity 68%). Kaplan-Meier curves indicated that a ROX index of 8.53 or lower on days 1, 2, or 3 was associated with a higher risk of treatment failure. Thus, a single ROX index assessment on day 3 is more informative than its variability over time, with values of 8.53 or lower predicting non-invasive respiratory support failure in hospitalized COVID-19 patients.

PMID:39470221 | DOI:10.4081/monaldi.2024.3033

Pediatr Pulmonol. 2024 Oct 29. doi: 10.1002/ppul.27364. Online ahead of print.

ABSTRACT

INTRODUCTION: The diagnosis of cystic fibrosis (CF) can impact the mental health of caregivers. This study aimed to explore prevalence of postpartum depression (PPD) symptoms in caregivers of infants with CF or CFTR-related metabolic syndrome (CRMS).

METHODS: This prospective, observational study was conducted in a CF clinic at a tertiary hospital over 4 years. Caregivers of infants with CF/CRMS completed serial surveys over the first year of life. Surveys included the Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire-9 (PHQ-9) and the General Anxiety Disorder-7 (GAD-7). A control group of healthy infant caregivers was used for comparative analysis of EPDS scores.

RESULTS: Analyses were conducted on 55 caregivers of 42 infants with CF/CRMS and 915 caregivers of healthy infants. Caregivers of infants with CF/CRMS had a significantly higher prevalence of elevated EPDS scores and higher mean EPDS scores for visit 1 (age 1-2mo) and visit 3 (age 6-9mo) compared to healthy controls (p < 0.001 for both). There was a higher prevalence of caregivers identifying thoughts of self-harm in the CF/CRMS cohort (8.3%) compared to caregivers of healthy controls (1.2%) at visit 1 (p = 0.015) and at visit 3 (CF/CRMS 8.8%; control 1.7%; p = 0.030). EPDS scores correlated with PHQ-9 and GAD-7 scores, particularly earlier in the infant's life.

CONCLUSIONS: Caregivers of infants with CF/CRMS may be at higher risk of PPD and thoughts of self-harm when compared to healthy controls. Given what is known about the impact of PPD on mental and physical health of children, early identification is vital for this population.

PMID:39469979 | DOI:10.1002/ppul.27364

J Pharm Pharm Sci. 2024 Oct 14;27:13635. doi: 10.3389/jpps.2024.13635. eCollection 2024.

ABSTRACT

The COVID-19 pandemic has raised concern regarding respiratory system diseases and oral inhalation stands out as an attractive non-invasive route of administration for pulmonary diseases such as chronic bronchitis, cystic fibrosis, COVID-19 and community-acquired pneumonia. In this context, we encapsulated azithromycin in polycaprolactone nanoparticles functionalized with phospholipids rich in dipalmitoylphosphatidylcholine and further produced a fine powder formulation by spray drying with monohydrated lactose. Nanoparticles obtained by the emulsion/solvent diffusion-evaporation technique exhibited a mean hydrodynamic diameter around 195-228 nm with a narrow monomodal size distribution (PdI < 0.2). Nanoparticle dispersions were spray-dried at different inlet temperatures, atomizing air-flow, aspirator air flow, and feed rate, using lactose as a drying aid, resulting in a maximal process yield of 63% and an encapsulation efficiency of 83%. Excipients and the dry powder formulations were characterized in terms of morphology, chemical structure, thermal analyses and particle size by SEM, FTIR, DSC/TGA and laser light diffraction. The results indicated spherical particles with 90% at 4.06 µm or below, an adequate size for pulmonary delivery. Aerosolization performance in a NGI confirmed good aerodynamic properties. Microbiological assays showed that the formulation preserves AZM antimicrobial effect against Staphylococcus aureus and Streptococcus pneumoniae strains, with halos above 18 mm. In addition, no formulation-related cytotoxicity was observed against the human cell lines BEAS-2B (lung epithelial), HUVEC (endothelial) and HFF1 (fibroblasts). Overall, the approach described here allows the production of AZM-PCL nanoparticles incorporated into inhalable microparticles, enabling more efficient pulmonary therapy of lung infections.

PMID:39469425 | PMC:PMC11513329 | DOI:10.3389/jpps.2024.13635

Infect Drug Resist. 2024 Oct 25;17:4637-4642. doi: 10.2147/IDR.S486519. eCollection 2024.

ABSTRACT

BACKGROUND: Pseudomonas aeruginosa is a significant cause of morbidity and mortality in intensive care units, and is prevalent in nosocomial infections and cystic fibrosis. The increasing rates of antimicrobial resistance (AMR) complicate the treatment of P. aeruginosa infections, especially because of the multidrug resistance (MDR), extensively drug-resistant (XDR), and pan-drug resistant (PDR) strains.

CASE PRESENTATION: We report the case of a 4-year-old male with severe burns covering 45% of his body surface who developed nosocomial PDR P. aeruginosa infection at the University Teaching Hospital of Kigali (CHUK) in Rwanda. A wound culture yielded a PDR P. aeruginosa isolate that was resistant to all the tested antimicrobials, with intermediate resistance to colistin. However, the patient improved with a combination of ceftazidime and amikacin following cessation of fever and successful skin grafting. The patient was discharged on day 95.

CONCLUSION: P. aeruginosa is a common hospital-acquired pathogen that is particularly challenging to treat, owing to its antimicrobial resistance profile and biofilm production. Antibiotic-resistant strains are a significant public health threat, especially in pediatric burn units. This case underscores the critical need to strengthen infection prevention and control measures together with robust antimicrobial stewardship programs. Molecular characterization of this PDR strain will yield further details regarding its virulence and genotyping.

PMID:39469095 | PMC:PMC11516630 | DOI:10.2147/IDR.S486519

JMIR Form Res. 2024 Oct 28;8:e51753. doi: 10.2196/51753.

ABSTRACT

BACKGROUND: Currently, patients with cystic fibrosis do not routinely monitor their respiratory function at home.

OBJECTIVE: This study aims to assess the clinical validity of using different connected health devices at home to measure 5 physiological parameters to help prevent exacerbations on a personalized basis from the perspective of patient empowerment.

METHODS: A multicenter interventional pilot study including 36 patients was conducted. Statistical process control-the cumulative sum control chart (CUSUM)-was used with connected health device measures with the objective of sending patients alerts at a relevant time in order to identify their individual risk of exacerbations. Associated patient education was delivered. Quantitative and qualitative data were collected.

RESULTS: One-half (18/36) of the patients completed the protocol through the end of the study. During the 12-month intervention, 6162 measures were collected with connected health devices, 387 alerts were sent, and 33 exacerbations were reported. The precision of alerts to detect exacerbations was weak for all parameters, which may be partly related to the low compliance of patients with the measurements. However, a decrease in the median number of exacerbations from 12 months before the study to after the 12-month intervention was observed for patients.

CONCLUSIONS: The use of connected health devices associated with statistical process control showed that it was not acceptable for all patients, especially because of the burden related to measurements. However, the results suggest that it may be promising, after adaptations, for early identification and better management of exacerbations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03304028; https://clinicaltrials.gov/study/NCT03304028.

PMID:39467550 | DOI:10.2196/51753