Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024 Jan-Feb;16(1):e1944. doi: 10.1002/wnan.1944.

ABSTRACT

Microbial biofilms are complex three-dimensional structures where sessile microbes are embedded in a polymeric extracellular matrix. Their resistance toward the host immune system as well as to a diverse range of antimicrobial treatments poses a serious health and development threat, being in the top 10 global public health threats declared by the World Health Organization. In an effort to combat biofilm-related microbial infections, several strategies have been developed to independently eliminate biofilms or to complement conventional antibiotic therapies. However, their limitations leave room for other treatment alternatives, where the application of nanotechnology to biofilm eradication has gained significant relevance in recent years. Their small size, penetration efficiency, and the design flexibility that they present makes them a promising alternative for biofilm infection treatment, although they also present set-backs. This review aims to describe the main possibilities and limitations of nanomedicine against biofilms, while covering the main aspects of biofilm formation and study, and the current therapies for biofilm treatment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

PMID:38403876 | DOI:10.1002/wnan.1944

An Pediatr (Engl Ed). 2024 Feb 24:S2341-2879(24)00034-6. doi: 10.1016/j.anpede.2024.02.005. Online ahead of print.

NO ABSTRACT

PMID:38403534 | DOI:10.1016/j.anpede.2024.02.005

Vaccines (Basel). 2024 Jan 30;12(2):145. doi: 10.3390/vaccines12020145.

ABSTRACT

Disparities in vaccination coverage for coronavirus disease 2019 (COVID-19) in the United States (U.S.) are consistent barriers limiting our ability to control the spread of disease, particularly those by age and race/ethnicity. This study examines the association between previous vaccination for common adult infectious diseases and vaccination for SARS-CoV-2 among a cohort of veterans in the U.S. Sociodemographic and clinical data were utilized from three databases within the Veterans Health Administration included in the electronic health record. We examined the association of previous vaccination for common adult vaccinations through six separate multivariable logistic regression analyses, one for each previous vaccine exposure, adjusting for demographic and clinical variables. We also examined the association of receiving any one of the six common adult vaccinations and vaccination against SARS-CoV-2. Adjusted models indicate higher odds of vaccination for SARS-CoV-2 among those who received each of the previous vaccinations. Significant differences were also noted by race/ethnicity and age. Veterans who recorded receiving any one of the previous vaccinations for common adult infections had significantly greater odds of receiving any vaccination against SARS-CoV-2. Understanding veterans' previous vaccination status can assist researchers and clinicians in impacting the uptake of novel vaccines, such as vaccination against SARS-CoV-2.

PMID:38400129 | PMC:PMC10893293 | DOI:10.3390/vaccines12020145

Viruses. 2024 Feb 14;16(2):292. doi: 10.3390/v16020292.

ABSTRACT

This study aimed to evaluate and compare the performance of three anti-S and one anti-N assays that were available to the project in detecting antibody levels after three commonly used SARS-CoV-2 vaccines (Pfizer, Moderna, and Johnson & Johnson). It also aimed to assess the association of age, sex, race, ethnicity, vaccine timing, and vaccine side effects on antibody levels in a cohort of 827 individuals. In September 2021, 698 vaccinated individuals donated blood samples as part of the Association for Diagnostics & Laboratory Medicine (ADLM) COVID-19 Immunity Study. These individuals also participated in a comprehensive survey covering demographic information, vaccination status, and associated side effects. Additionally, 305 age- and gender-matched samples were obtained from the ADLM 2015 sample bank as pre-COVID-19-negative samples. All these samples underwent antibody level analysis using three anti-S assays, namely Beckman Access SARS-CoV-2 IgG (Beckman assay), Ortho Clinical Diagnostics VITROS Anti-SARS-CoV-2 IgG (Ortho assay), Siemens ADVIA Centaur SARS-CoV-2 IgG (Siemens assay), and one anti-N antibody assay: Bio-Rad Platelia SARS-CoV-2 Total Ab assay (BioRad assay). A total of 827 samples (580 COVID-19 samples and 247 pre-COVID-19 samples) received results for all four assays and underwent further analysis. Beckman, Ortho, and Siemens anti-S assays showed an overall sensitivity of 99.5%, 97.6%, and 96.9%, and specificity of 90%, 100%, and 99.6%, respectively. All three assays indicated 100% sensitivity for individuals who received the Moderna vaccine and boosters, and over 99% sensitivity for the Pfizer vaccine. Sensitivities varied from 70.4% (Siemens), 81.5% (Ortho), and 96.3% (Beckman) for individuals who received the Johnson & Johnson vaccine. BioRad anti-N assays demonstrated 46.2% sensitivity and 99.25% specificity based on results from individuals with self-reported infection. The highest median anti-S antibody levels were measured in individuals who received the Moderna vaccine, followed by Pfizer and then Johnson & Johnson vaccines. Higher anti-S antibody levels were significantly associated with younger age and closer proximity to the last vaccine dose but were not associated with gender, race, or ethnicity. Participants with higher anti-S levels experienced significantly more side effects as well as more severe side effects (e.g., muscle pain, chills, fever, and moderate limitations) (p < 0.05). Anti-N antibody levels only indicated a significant correlation with headache. This study indicated performance variations among different anti-S assays, both among themselves and when analyzing individuals with different SARS-CoV-2 vaccines. Caution should be exercised when conducting large-scale studies to ensure that the same platform and/or assays are used for the most effective interpretation of the data.

PMID:38400067 | PMC:PMC10891747 | DOI:10.3390/v16020292

J Cyst Fibros. 2024 Feb 23:S1569-1993(24)00027-4. doi: 10.1016/j.jcf.2024.02.012. Online ahead of print.

ABSTRACT

BACKGROUND: Biofilm-associated pulmonary infections pose therapeutic challenges in cystic fibrosis patients, especially when involving multiple bacterial species. Enzymatic degradation of the biofilm matrix may offer a potential solution to enhance antibiotic efficacy. This study investigated the repurposing of DNase I, commonly used for its mucolytic activity in cystic fibrosis, to target extracellular DNA within biofilms, as well as potential synergies with alginate lyase and broad-spectrum antibiotics in dual-species biofilms of Pseudomonas aeruginosa and Staphylococcus aureus.

METHODS: Dual-species biofilms were grown in artificial sputum medium using S. aureus and P. aeruginosa isolated by pairs from the same patients and exposed to various combinations of enzymes, meropenem, or tobramycin. Activity was assessed by measuring biofilm biomass and viable counts. Matrix degradation and decrease in bacterial load were visualized using confocal microscopy. Biofilm viscoelasticity was estimated by rheology.

RESULTS: Nearly complete destruction of the biofilms was achieved only if combining the enzymatic cocktail with the two antibiotics, and if using supratherapeutic levels of DNase I and high concentrations of alginate lyase. Biofilms containing non-pigmented mucoid P. aeruginosa required higher antibiotic concentrations, despite low viscoelasticity. In contrast, for biofilms with pigmented mucoid P. aeruginosa, a correlation was observed between the efficacy of different treatments and the reduction they caused in elasticity and viscosity of the biofilm.

CONCLUSIONS: In this complex, highly drug-tolerant biofilm model, enzymes prove useful adjuvants to enhance antibiotic activity. However, the necessity for high enzyme concentrations emphasizes the need for thorough concentration-response evaluations and safety assessments before considering clinical applications.

PMID:38402083 | DOI:10.1016/j.jcf.2024.02.012

J Cyst Fibros. 2024 Feb 23:S1569-1993(24)00017-1. doi: 10.1016/j.jcf.2024.02.004. Online ahead of print.

ABSTRACT

BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) ≥1 year of age. To assess the impact of early LUM/IVA initiation on CF disease progression, a 6-year observational study leveraging data from existing CF patient registries is being conducted in children with CF homozygous for F508del (F/F genotype) who were aged 2 through 5 years at treatment initiation. Here we present interim results from this study focusing on data from the European CF Society Patient Registry (ECFSPR).

METHODS: The LUM/IVA cohort included children in the ECFSPR who started LUM/IVA between 15 January 2019 and 31 December 2020. Longitudinal trends in growth parameters, pulmonary exacerbations, hospitalizations, safety outcomes, and other effectiveness outcomes in the LUM/IVA cohort were compared to those in two modulator-naïve cohorts: (i) matched concurrent cohort heterozygous for F508del and a minimal function mutation (F/MF concurrent comparator cohort) and (ii) matched concurrent cohort with the F/F genotype from countries without commercial access to LUM/IVA as of 2020 (F/F concurrent comparator cohort).

RESULTS: The LUM/IVA cohort matched to the F/MF concurrent comparator cohort had 681 children and the LUM/IVA cohort matched to the F/F concurrent comparator cohort had 183 children. LUM/IVA cohorts had increases in body mass index percentiles relative to the matched F/MF and F/F concurrent comparator cohorts (mean difference in change from baseline: 8.4 [95% CI: 5.5, 11.3] and 11.8 [95% CI: 5.9, 17.7], respectively). Increases in height and weight percentiles were also observed in the LUM/IVA cohort relative to the F/MF and F/F concurrent comparator cohorts. Reductions in pulmonary exacerbations and hospitalizations relative to baseline and the F/F concurrent comparator cohort were seen in 2021.

CONCLUSIONS: This interim analysis showed favorable trends in clinical outcomes, including growth parameters, pulmonary exacerbations, and hospitalizations, suggesting an early beneficial effect of LUM/IVA treatment in children aged 2 through 5 years at treatment initiation.

PMID:38402082 | DOI:10.1016/j.jcf.2024.02.004

J Allergy Clin Immunol. 2024 Feb 22:S0091-6749(24)00189-1. doi: 10.1016/j.jaci.2024.01.027. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma is commonly reported in patients with a diagnosis of bronchiectasis.

OBJECTIVE: The aim of this study was to evaluate if patients with asthma and bronchiectasis had a different clinical phenotype and different outcomes compared to patients with bronchiectasis without concomitant asthma.

METHODS: Prospective observational pan-European registry (EMBARC) enrolling patients across 28 countries. Adult patients with CT confirmed bronchiectasis were reviewed at baseline and annual follow-up visits using an electronic case report form. Asthma was diagnosed by the local investigator. Follow-up data were used to explore differences in exacerbation frequency between groups using a negative binomial regression model. Survival analysis utilised Cox-proportional hazards regression.

RESULTS: 16963 patients with bronchiectasis were included for analysis. 5267 patients (31.0%) had investigator reported asthma. Patients with bronchiectasis and asthma (BE+A) were younger, more likely to be female and never smokers, and had a higher BMI than patients with bronchiectasis without asthma. BE+A was associated with a higher prevalence of rhinosinusitis and nasal polyps as well as eosinophilia and Aspergillus sensitization. BE+A had similar microbiology, but significantly lower severity of disease using the bronchiectasis severity index (BSI). The BE+A group were at increased risk of exacerbation after adjustment for severity of disease and multiple confounders. Inhaled corticosteroid use was associated with reduced mortality in BE+A patients (adjusted hazard ratio 0.78 (0.63-0.95)) and reduced risk of hospitalization, (rate ratio 0.67 (0.67-0.86)) compared to a control population without asthma and not receiving inhaled corticosteroid.

CONCLUSION: Combined bronchiectasis and asthma was common and was associated with an increased risk of exacerbations and improved outcomes with inhaled corticosteroid use. Unexpectedly we identified significantly lower mortality in patients with bronchiectasis and asthma.

PMID:38401857 | DOI:10.1016/j.jaci.2024.01.027

Clin Transplant. 2024 Feb;38(2):e15255. doi: 10.1111/ctr.15255.

ABSTRACT

INTRODUCTION: There is a lack of data regarding the peri-operative and long-term outcomes of kidney transplantation in cystic fibrosis (CF) patients. Herein, we report the peri-operative and long-term outcomes of kidney transplantation in CF patients.

MATERIALS AND METHODS: All CF patients who received a kidney transplant at the national kidney transplant center between 1993 and 2022 were identified. Recipients of the contralateral donor kidney were selected as a control group. Primary outcomes included 1-, 5-, and 10- year death-censored graft survival and overall survival. Secondary outcomes included peri-operative morbidity, acute graft rejection, delayed graft function (DGF), and length of stay (LOS).

RESULTS: Fourteen patients received a kidney transplant over the study period. Median age at transplantation was 35 (IQR 31, 40) years. The 1-, 5-, and 10-year death-censored graft survival was 92, 74, and 74% in the CF group compared to 100, 92, and 92% in the control group (p = .44). The 1-, 5-, and 10-year overall survival in the CF group was 85, 66, and 57% compared to 100, 92, and 82% in the control group (p = .036). There was no significant difference in peri-operative outcomes including LOS (10 vs. 11 days, p = .84), ICU admission (1 vs. 0 patients, p > .99), acute rejection episodes (2 vs. 1 patients, p > .99), and DGF (1 vs. 2 patients, p = .60).

CONCLUSION: CF patients have good long-term graft survival, however, overall survival was worse compared to a matched cohort. These data provide important information for transplant surgeons when considering suitable donor allografts in this unique patient population.

PMID:38400672 | DOI:10.1111/ctr.15255

Vaccines (Basel). 2024 Feb 17;12(2):207. doi: 10.3390/vaccines12020207.

ABSTRACT

Despite advances in therapies, bacterial chronic respiratory infections persist as life-threatening to patients suffering from cystic fibrosis (CF). Pseudomonas aeruginosa and bacteria of the Burkholderia cepacia complex are among the most difficult of these infections to treat, due to factors like their resistance to multiple antibiotics and ability to form biofilms. The lack of effective antimicrobial strategies prompted our search for alternative immunotherapies that can effectively control and reduce those infections among CF patients. Previous work from our group showed that the anti-BCAL2645 goat polyclonal antibody strongly inhibited Burkholderia cenocepacia to adhere and invade cultured epithelial cells. In this work, we showed that the polyclonal antibody anti-BCAL2645 also strongly inhibited the ability of P. aeruginosa to form biofilms, and to adhere and invade the human bronchial epithelial cell line CFBE41o-. The polyclonal antibody also inhibited, to a lesser extent, the ability of B. multivorans to adhere and invade the human bronchial epithelial cell line CFBE41o. We also show that the ability of B. cenocepacia, P. aeruginosa and B. multivorans to kill larvae of the Galleria mellonella model of infection was impaired when bacteria were incubated with the anti-BCAL2645 antibody prior to the infection. Our findings show that an antibody against BCAL2645 possesses a significant potential for the development of new immunotherapies against these three important bacterial species capable of causing devastating and often lethal infections among CF patients.

PMID:38400190 | DOI:10.3390/vaccines12020207

Molecules. 2024 Feb 10;29(4):821. doi: 10.3390/molecules29040821.

ABSTRACT

The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators-small molecules acting on the basic molecular defect in CF-have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA's) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.

PMID:38398574 | DOI:10.3390/molecules29040821

Biomedicines. 2024 Feb 14;12(2):431. doi: 10.3390/biomedicines12020431.

ABSTRACT

BACKGROUND: Electronic nose (eNose) technology can be used to characterize volatile organic compound (VOC) mixes in breath. While previous reports have shown that eNose can detect lung infections with pathogens such as Staphylococcus aureus (SA) in people with cystic fibrosis (CF), the clinical utility of eNose for longitudinally monitoring SA infection status is unknown.

METHODS: In this longitudinal study, a cloud-connected eNose, the SpiroNose, was used for the breath profile analysis of children with CF at two stable visits and compared based on changes in SA infection status between visits. Data analysis involved advanced sensor signal processing, ambient correction, and statistics based on the comparison of breath profiles between baseline and follow-up visits.

RESULTS: Seventy-two children with CF, with a mean (IQR) age of 13.8 (9.8-16.4) years, were studied. In those with SA-positive airway cultures at baseline but SA-negative cultures at follow-up (n = 19), significant signal differences were detected between Baseline and Follow-up at three distinct eNose sensors, i.e., S4 (p = 0.047), S6 (p = 0.014), and S7 (p = 0.014). Sensor signal changes with the clearance of SA from airways were unrelated to antibiotic treatment. No changes in sensor signals were seen in patients with unchanged infection status between visits.

CONCLUSIONS: Our results demonstrate the potential applicability of the eNose as a non-invasive clinical tool to longitudinally monitor pulmonary SA infection status in children with CF.

PMID:38398033 | DOI:10.3390/biomedicines12020431

Children (Basel). 2024 Feb 16;11(2):256. doi: 10.3390/children11020256.

ABSTRACT

Cystic fibrosis (CF) is one of the most common progressive life-shortening genetic conditions worldwide. Ground-breaking translational research has generated therapies that target the primary cystic fibrosis transmembrane conductance regulator (CFTR) defect, known as CFTR modulators. A crucial aspect of paediatric CF disease is the development and progression of irreversible respiratory disease in the absence of clinical symptoms. Accurate thoracic diagnostics have an important role to play in this regard. Chest radiographs are non-specific and insensitive in the context of subtle changes in early CF disease, with computed tomography (CT) providing increased sensitivity. Recent advancements in imaging hardware and software have allowed thoracic CTs to be acquired in paediatric patients at radiation doses approaching that of a chest radiograph. CFTR modulators slow the progression of CF, reduce the frequency of exacerbations and extend life expectancy. In conjunction with advances in CT imaging techniques, low-dose thorax CT will establish a central position in the routine care of children with CF. International guidelines regarding the choice of modality and timing of thoracic imaging in children with CF are lagging behind these rapid technological advances. The continued progress of personalised medicine in the form of CFTR modulators will promote the emergence of personalised radiological diagnostics.

PMID:38397368 | DOI:10.3390/children11020256

Children (Basel). 2024 Feb 2;11(2):185. doi: 10.3390/children11020185.

ABSTRACT

BACKGROUND: Atraumatic limping is a frequent cause of consultation in Pediatric Emergency Departments (PED) and often represents a challenge for pediatricians for its variability in etiology ranging from benign causes to potential crippling conditions. The aims of this research are to illustrate the clinical features of acute limping children (LC) and to identify the possible red flags that could help to make a diagnosis of severe pathologies.

METHODS: We carried out a retrospective study about non-traumatic limping children referred to the PED of Bambino Gesù Children's Hospital over a 2-year period. We divided the cohort into three groups based on the patient's age: toddlers, children and adolescents. We considered crippling conditions: oncologic etiologies, bone or neurological infections, epiphysiolysis, Perthes disease, Guillain Barrè syndrome and non-accidental injuries.

RESULTS: We analyzed 485 patients. At clinical evaluation, 19.5% of the patients presented at least one sign and/or symptom of red flags. Crippling conditions (6.2% of the total population) showed red flags in 36.7%. Transient synovitis of the hip was the most frequent diagnosis. We found crippling conditions in 30 patients, mostly represented by toddlers.

CONCLUSIONS: Our data suggest that toddlers and patients presenting red flags should be evaluated with particular suspicion because they have an increased risk of underlying severe conditions.

PMID:38397297 | DOI:10.3390/children11020185

Int J Mol Sci. 2024 Feb 17;25(4):2358. doi: 10.3390/ijms25042358.

ABSTRACT

Immunosuppression management in transplant recipients is a critical component of pharmacotherapy. This becomes particularly crucial when patients are exposed to multiple medications that may lead to pharmacological interactions, potentially compromising the effectiveness of immunosuppression. We present the case of a 46-year-old patient diagnosed with cystic fibrosis in childhood at our hospital, who underwent bilateral lung transplantation and is undergoing immunosuppressive therapy. The patient was hospitalized due to an acute pulmonary exacerbation. During the hospitalization, the patient was administered various classes of antibiotics while continuing the standard antirejection regimen of everolimus and mycophenolate. Plasma concentrations of immunosuppressants, measured after antibiotic therapy, revealed significantly lower levels than the therapeutic thresholds, providing the basis for formulating the hypothesis of a drug-drug interaction phenomenon. This hypothesis is supported by the rationale of antibiotic-induced disruption of the intestinal flora, which directly affects the kinetics of mycophenolate. These levels increased after discontinuation of the antimicrobials. Patients with CF undergoing lung transplantation, especially prone to pulmonary infections due to their medical condition, considering the enterohepatic circulation of mycophenolate mediated by intestinal bacteria, necessitate routine monitoring of mycophenolate concentrations during and immediately following the cessation of antibiotic therapies, that could potentially result in insufficient immunosuppression.

PMID:38397035 | DOI:10.3390/ijms25042358

Int J Mol Sci. 2024 Feb 15;25(4):2302. doi: 10.3390/ijms25042302.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a selective anion channel expressed in the epithelium of various organs. The most frequent mutation is F508del. This mutation leads to a misfolded CFTR protein quickly degraded via ubiquitination in the endoplasmic reticulum. Although preventing ubiquitination stabilizes the protein, functionality is not restored due to impaired plasma membrane transport. However, inhibiting the ubiquitination process can improve the effectiveness of correctors which act as chemical chaperones, facilitating F508del CFTR trafficking to the plasma membrane. Previous studies indicate a crosstalk between SUMOylation and ubiquitination in the regulation of CFTR. In this study, we investigated the potential of inhibiting SUMOylation to increase the effects of correctors and enhance the rescue of the F508del mutant across various cell models. In the widely used CFBE41o-cell line expressing F508del-CFTR, inhibiting SUMOylation substantially boosted F508del expression, thereby increasing the efficacy of correctors. Interestingly, this outcome did not result from enhanced stability of the mutant channel, but rather from augmented cytomegalovirus (CMV) promoter-mediated gene expression of F508del-CFTR. Notably, CFTR regulated by endogenous promoters in multiple cell lines or patient cells was not influenced by SUMOylation inhibitors.

PMID:38396982 | DOI:10.3390/ijms25042302

J R Coll Physicians Edinb. 2024 Feb 23:14782715241234078. doi: 10.1177/14782715241234078. Online ahead of print.

ABSTRACT

Pancreatic exocrine insufficiency (PEI) is an under-diagnosed condition. Untreated PEI can result in developing gastrointestinal symptoms and long-term complications including weight loss, nutrient deficiencies, sarcopenia and osteoporosis. Current best practice recommends testing for PEI in certain disorders including chronic pancreatitis, cystic fibrosis, pancreatic cancer and post-pancreatic surgery. However, there is increasing evidence that PEI is associated with a number of conditions in addition to the aforementioned diseases. These 'at-risk' conditions are a heterogeneous group of diseases, for example, diabetes mellitus, people living with human immunodeficiency virus, high alcohol intake, and coeliac disease. The pathophysiology of some of 'at-risk' conditions is becoming increasingly recognised; therefore, the list of associated conditions are in evolving process. We present a case of a 60-year-old male with Parkinson's disease and persistent abdominal pain who was found to have low faecal elastase levels indicative of severe PEI. His past medical history included none of the known risk factors for PEI. After examining the literature, we report a similar pathophysiological process underlying the development of pancreatitis and Parkinson's disease which is dysfunction of the Unfolded Protein Response. We suggest further research to assess the prevalence of PEI in the population of patients with Parkinson's disease.

PMID:38396339 | DOI:10.1177/14782715241234078

Nat Commun. 2024 Feb 23;15(1):1633. doi: 10.1038/s41467-024-45357-1.

ABSTRACT

Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions.

PMID:38395948 | PMC:PMC10891084 | DOI:10.1038/s41467-024-45357-1

Paediatr Respir Rev. 2024 Feb 12:S1526-0542(24)00014-9. doi: 10.1016/j.prrv.2024.01.004. Online ahead of print.

ABSTRACT

One hurdle in the management of CF, a disease characterized by progressive endobronchial infection, is the presence of hypersensitivity reactions to antimicrobials due to prolonged and repetitive treatment courses. The aim of this review is to compile existing data and provide insight to medical professionals on a long-debated topic for optimum patient care. Clinical studies were inducted from the last 15 years and filtered based on their relativity to drug hypersensitivity reactions (DHRs), antibiotics and CF. After completing the selection process, 10 clinical studies were thoroughly examined. The most frequent antibiotic group related to DHRs were beta-lactams. Frequency of the most common overall type of reaction (immediate or nonimmediate) differed among clinical studies. Although severe reactions seem rare comparatively, they do occur during and even after completion of treatment regimens. The prevalence of true drug allergies should be confirmed using a variety of tests available, however, should not be confused with overall DHR rates. Genetic mutations, gender and lifetime antibiotic dose were not related with an increased risk for DHR development. On the contrary, the most important factor according to most studies was the cumulative antimicrobial dose in a given period of time, especially when delivered parenterally. DHRs are an indisputable problem in the management of CF patients. Understanding possible risk factors and increased awareness is vital in both hospital and outpatient settings as early detection can decrease the severity of the reactions.

PMID:38395639 | DOI:10.1016/j.prrv.2024.01.004

Semin Respir Crit Care Med. 2024 Feb 23. doi: 10.1055/s-0044-1781426. Online ahead of print.

ABSTRACT

Community-acquired pneumonia (CAP) is globally one of the major causes of hospitalization and mortality. Severe CAP (sCAP) presents great challenges and need a comprehensive understanding of its long-term outcomes. Cardiovascular events and neurological impairment, due to persistent inflammation and hypoxemia, contribute to long-term outcomes in CAP, including mortality. Very few data are available in the specific population of sCAP. Multiple studies have reported variable 1-year mortality rates for patients with CAP up to 40.7%, with a clear influence by age, comorbidities, and disease severity. In terms of treatment, the potential protective role of macrolides in reducing mortality emphasizes the importance of appropriate empiric antibiotic therapy. This narrative review explores the growing interest in the literature focusing on the long-term implications of sCAP. Improved understanding of long-term outcomes in sCAP can facilitate targeted interventions and enhance posthospitalization care protocols.

PMID:38395062 | DOI:10.1055/s-0044-1781426

PLoS One. 2024 Feb 23;19(2):e0294120. doi: 10.1371/journal.pone.0294120. eCollection 2024.

ABSTRACT

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

PMID:38394229 | DOI:10.1371/journal.pone.0294120