Microbiol Spectr. 2024 Apr 23:e0400623. doi: 10.1128/spectrum.04006-23. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF), an inherited genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, results in sticky and thick mucosal fluids. This environment facilitates the colonization of various microorganisms, some of which can cause acute and chronic lung infections, while others may positively impact the disease. Rothia mucilaginosa, an oral commensal, is relatively abundant in the lungs of CF patients. Recent studies have unveiled its anti-inflammatory properties using in vitro three-dimensional lung epithelial cell cultures and in vivo mouse models relevant to chronic lung diseases. Apart from this, R. mucilaginosa has been associated with severe infections. However, its metabolic capabilities and genotype-phenotype relationships remain largely unknown. To gain insights into its cellular metabolism and genetic content, we developed the first manually curated genome-scale metabolic model, iRM23NL. Through growth kinetics and high-throughput phenotypic microarray testings, we defined its complete catabolic phenome. Subsequently, we assessed the model's effectiveness in accurately predicting growth behaviors and utilizing multiple substrates. We used constraint-based modeling techniques to formulate novel hypotheses that could expedite the development of antimicrobial strategies. More specifically, we detected putative essential genes and assessed their effect on metabolism under varying nutritional conditions. These predictions could offer novel potential antimicrobial targets without laborious large-scale screening of knockouts and mutant transposon libraries. Overall, iRM23NL demonstrates a solid capability to predict cellular phenotypes and holds immense potential as a valuable resource for accurate predictions in advancing antimicrobial therapies. Moreover, it can guide metabolic engineering to tailor R. mucilaginosa's metabolism for desired performance.IMPORTANCECystic fibrosis (CF) is a genetic disorder characterized by thick mucosal secretions, leading to chronic lung infections. Rothia mucilaginosa is a common bacterium found in various parts of the human body, acting as a normal part of the flora. In people with weakened immune systems, it can become an opportunistic pathogen, while it is prevalent and active in CF airways. Recent studies have highlighted its anti-inflammatory properties in the lower pulmonary system, indicating the intricate relationship between microbes and human health. Herein, we have developed the first manually curated metabolic model of R. mucilaginosa. Our study examined the previously unknown relationships between the bacterium's genotype and phenotype and identified essential genes that impact the metabolism under various conditions. With this, we opt for paving the way for developing new strategies in antimicrobial therapy and metabolic engineering, leading to enhanced therapeutic outcomes in cystic fibrosis and related conditions.

PMID:38652457 | DOI:10.1128/spectrum.04006-23

Antimicrob Agents Chemother. 2024 Apr 23:e0145623. doi: 10.1128/aac.01456-23. Online ahead of print.

ABSTRACT

Mycobacterium abscessus is an emerging opportunistic pathogen responsible for chronic lung diseases, especially in patients with cystic fibrosis. Treatment failure of M. abscessus infections is primarily associated with intrinsic or acquired antibiotic resistance. However, there is growing evidence that antibiotic tolerance, i.e., the ability of bacteria to transiently survive exposure to bactericidal antibiotics through physiological adaptations, contributes to the relapse of chronic infections and the emergence of acquired drug resistance. Yet, our understanding of the molecular mechanisms that underlie antibiotic tolerance in M. abscessus remains limited. In the present work, a mutant with increased cross-tolerance to the first- and second-line antibiotics cefoxitin and moxifloxacin, respectively, has been isolated by experimental evolution. This mutant harbors a mutation in serB2, a gene involved in L-serine biosynthesis. Metabolic changes caused by this mutation alter the intracellular redox balance to a more reduced state that induces overexpression of the transcriptional regulator WhiB7 during the stationary phase, promoting tolerance through activation of a WhiB7-dependant adaptive stress response. These findings suggest that alteration of amino acid metabolism and, more generally, conditions that trigger whiB7 overexpression, makes M. abscessus more tolerant to antibiotic treatment.

PMID:38651855 | DOI:10.1128/aac.01456-23

Int J Neonatal Screen. 2024 Apr 8;10(2):31. doi: 10.3390/ijns10020031.

ABSTRACT

There is increasing interest in using extended genetic sequencing (EGS) in newborn screening (NBS) for cystic fibrosis (CF). How this is implemented will change the number of children being given an uncertain outcome of CRMS/CFSPID (cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/CF Screen Positive Inconclusive Diagnosis), probable carrier results, and the number of missed CF diagnoses. An international survey of CF health professionals was used to gather views on two approaches to EGS-specific (may reduce detection of CRMS/CFSID but miss some CF cases) versus sensitive (may increase detection of CRMS/CFSPID but avoid missing more CF cases). Health professionals acknowledged the anxiety caused to parents (and health professionals) from the uncertainty surrounding the prognosis and management of CRMS/CFSPID. However, most preferred the sensitive approach, as overall, identifying more cases of CRMS/CFSPID was viewed as less physically and psychologically damaging than a missed case of CF. The importance of early diagnosis and treatment for CF to ensure better health outcomes and reducing diagnostic odysseys for parents were highlighted. A potential benefit to identifying more children with CRMS/CFSPID included increasing knowledge to obtain a better understanding of how these children should best be managed in the future.

PMID:38651396 | DOI:10.3390/ijns10020031

medRxiv [Preprint]. 2024 Apr 8:2024.04.06.24305022. doi: 10.1101/2024.04.06.24305022.

ABSTRACT

Continuous glucose monitors (CGM) provide patients and clinicians with valuable insights about glycemic control that aid in diabetes management. The advent of large language models (LLMs), such as GPT-4, has enabled real-time text generation and summarization of medical data. Further, recent advancements have enabled the integration of data analysis features in chatbots, such that raw data can be uploaded and analyzed when prompted. Studying both the accuracy and suitability of LLM-derived data analysis performed on medical time series data, such as CGM data, is an important area of research. The objective of this study was to assess the strengths and limitations of using an LLM to analyze raw CGM data and produce summaries of 14 days of data for patients with type 1 diabetes. This study used simulated CGM data from 10 different cases. We first evaluated the ability of GPT-4 to compute quantitative metrics specific to diabetes found in an Ambulatory Glucose Profile (AGP). Then, using two independent clinician graders, we evaluated the accuracy, completeness, safety, and suitability of qualitative descriptions produced by GPT-4 across five different CGM analysis tasks. We demonstrated that GPT-4 performs well across measures of accuracy, completeness, and safety when producing summaries of CGM data across all tasks. These results highlight the capabilities of using an LLM to produce accurate and safe narrative summaries of medical time series data. We highlight several limitations of the work, including concerns related to how GPT-4 may misprioritize highlighting instances of hypoglycemia and hyperglycemia. Our work serves as a preliminary study on how generative language models can be integrated into diabetes care through CGM analysis, and more broadly, the potential to leverage LLMs for streamlined medical time series analysis.

PMID:38645024 | PMC:PMC11030468 | DOI:10.1101/2024.04.06.24305022

J Lipid Res. 2024 Apr 20:100549. doi: 10.1016/j.jlr.2024.100549. Online ahead of print.

NO ABSTRACT

PMID:38649097 | DOI:10.1016/j.jlr.2024.100549

Mycopathologia. 2024 Apr 22;189(3):36. doi: 10.1007/s11046-024-00841-6.

NO ABSTRACT

PMID:38647695 | DOI:10.1007/s11046-024-00841-6

ISME J. 2024 Apr 22:wrae065. doi: 10.1093/ismejo/wrae065. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a cause of chronic respiratory tract infections in people with cystic fibrosis (CF), non-CF bronchiectasis and chronic obstructive pulmonary disease. Prolonged infection allows accumulation of mutations and horizontal gene transfer, increasing the likelihood of adaptive phenotypic traits. Adaptation is proposed to arise first in bacterial populations colonising upper airway environments. Here, we model this process using an experimental evolution approach. P. aeruginosa PAO1, which is not airway adapted, was serially passaged, separately, in media chemically reflective of upper or lower airway environments. To explore whether the CF environment selects for unique traits, we separately passaged PAO1 in airway-mimicking media with or without CF-specific factors. Our findings demonstrated that all airway environments - sinus and lungs, under CF and non-CF conditions - selected for loss of twitching motility, increased resistance to multiple antibiotic classes and a hyper-biofilm phenotype. These traits conferred increased airway colonisation potential in an in vivo model. CF-like conditions exerted stronger selective pressures, leading to emergence of more pronounced phenotypes. Loss of twitching was associated with mutations in type IV pili genes. Type IV pili mediate surface attachment, twitching and induction of cAMP signalling. We additionally identified multiple evolutionary routes to increased biofilm formation involving regulation of cyclic-di-GMP signalling. These included loss of function mutations in bifA and dipA phosphodiesterase genes and activating mutations in the siaA phosphatase. These data highlight that airway environments select for traits associated with sessile lifestyles and suggest upper airway niches support emergence of phenotypes that promote establishment of lung infection.

PMID:38647527 | DOI:10.1093/ismejo/wrae065

Laryngoscope. 2024 Apr 22. doi: 10.1002/lary.31447. Online ahead of print.

NO ABSTRACT

PMID:38647113 | DOI:10.1002/lary.31447

JCI Insight. 2024 Apr 22;9(8):e157229. doi: 10.1172/jci.insight.157229.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.

PMID:38646935 | DOI:10.1172/jci.insight.157229

J Med Econ. 2024 Apr 22:1-15. doi: 10.1080/13696998.2024.2340382. Online ahead of print.

ABSTRACT

Aims Non-cystic fibrosis bronchiectasis (NCFB) is a chronic progressive respiratory disorder occurring at a rate ranging from 4.2 to 278.1 cases per 100,000 persons, depending on age, in the United States. For many patients with NCFB, the presence of Pseudomonas aeruginosa (PA) makes treatment more complicated and typically has worse outcomes. Management of NCFB can be challenging, warranting a better understanding of the burden of illness for NCFB, treatments applied, healthcare resources used, and subsequent treatment costs. Comparing patients diagnosed with exacerbated NCFB, with or without PA on antibiotic utilization, treatments, and healthcare resources utilization and costs, was the purpose of this study.Materials and Methods This was a retrospective cohort study of commercial claims from IQVIA's PharMetrics Plus database (01/01/2006-12/31/2020). Study patients with a diagnosis of NCFB were stratified into two groups based on presence or absence of PA, then followed to identify demographic characteristics, comorbid conditions, antibiotic treatment regimen prescribed, healthcare resources utilized, and costs of care.Results The results showed that patients with exacerbated NCFB who were PA+ had significantly more oral antibiotic fills per patient per year, more inpatient admissions with a longer length of stay, and more outpatient encounters than those who were PA-. For costs, PA+ patients also had significantly greater total healthcare costs per patient when compared to those who were PA-.Conclusion Exacerbated NCFB with PA+ was associated with increased antibiotic usage, greater resource utilization, and increased costs. The major contributor to the cost differences was the use of inpatient services. Treatment strategies aimed at reducing the need for inpatient treatment could lessen the disparities observed in patients with NCFB.

PMID:38646702 | DOI:10.1080/13696998.2024.2340382

ACS Meas Sci Au. 2024 Feb 14;4(2):223-230. doi: 10.1021/acsmeasuresciau.3c00071. eCollection 2024 Apr 17.

ABSTRACT

O-glycosylation is a common post-translational modification that is essential for the defensive properties of mucus barriers. Incomplete and altered O-glycosylation is often linked to severe diseases, such as cancer, cystic fibrosis, and chronic obstructive pulmonary disease. Originating from a nontemplate-driven biosynthesis, mucin-type O-glycan structures are very complex. They are often present as heterogeneous mixtures containing multiple isomers. Therefore, the analysis of complex O-glycan mixtures usually requires hyphenation of orthogonal techniques such as liquid chromatography (LC), ion mobility spectrometry, and mass spectrometry (MS). However, MS-based techniques are mainly qualitative. Moreover, LC separation of O-glycans often lacks reproducibility and requires sophisticated data treatment and analysis. Here we present a mucin-type O-glycomics analysis workflow that utilizes hydrophilic interaction liquid chromatography for separation and fluorescence labeling for detection and quantification. In combination with mass spectrometry, a detailed analysis on the relative abundance of specific mucin-type O-glycan compositions and features, such as fucose, sialic acids, and sulfates, is performed. Furthermore, the average number of monosaccharide units of O-glycans in different samples was determined. To demonstrate universal applicability, the method was tested on mucins from different tissue types and mammals, such as bovine submaxillary mucins, porcine gastric mucins, and human milk mucins. To account for day-to-day retention time shifts in O-glycan separations and increase the comparability between different instruments and laboratories, we included fluorescently labeled dextran ladders in our workflow. In addition, we set up a library of glucose unit values for all identified O-glycans, which can be used to simplify the identification process of glycans in future analyses.

PMID:38645579 | PMC:PMC11027200 | DOI:10.1021/acsmeasuresciau.3c00071

bioRxiv [Preprint]. 2024 Apr 12:2024.04.08.588618. doi: 10.1101/2024.04.08.588618.

ABSTRACT

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

PMID:38645147 | PMC:PMC11030358 | DOI:10.1101/2024.04.08.588618

Infect Dis Health. 2024 Apr 20:S2468-0451(24)00024-5. doi: 10.1016/j.idh.2024.04.002. Online ahead of print.

ABSTRACT

BACKGROUND: Respiratory infection is a major cause of disease severity in people with cystic fibrosis (PwCF). This project aimed to establish the CF community's opinion regarding cross infection (CI), nebuliser hygiene, antimicrobial resistance, personal impact of microbiological findings and the role of the microbiology laboratory.

METHODS: A questionnaire was completed anonymously (n = 280; PwCF (n = 128), parents (n = 123); friends/family/carers/charity personnel (n = 29)) from 13 countries. Readability scores (Flesch Reading Ease (FRE), Flesch Kincaid Grade Level (FKGL)) were determined for CI/IP&C information from six national CF charities and 21 scientific abstracts.

RESULTS: Respondents (72.5%) indicated knowledge of laboratory aspects of CF microbiology was important, however implications of microbiological findings on personal health/well-being were of higher importance (p < 0.0001). Cross infection/infection prevention & control (CI/IP&C) was of highest importance (95.6% respondents) with 27.3% indicating they were not given adequate information, particularly in older respondents (50 y+) (p = 0.006) versus young adults (16-29 y) and respondents from the Middle East versus N. America (p = 0.022) and Europe (p = 0.045). Responses highlighted how CI/IP&C health literacy could be enhanced. Respondents (77.3%), particularly females (p < 0.0001), indicated they would increase the frequency of nebuliser disinfection following guidance on infection risks/best practice, therefore an educational video was prepared. CI/IP&C readability scores (mean ± sd) from CF charities (FRE 52.5 ± 10.8; FKGL 9.7 ± 2.3) were more readable (p < 0.0001) than scientific abstracts (FRE 13.3 ± 11.1; FKGL 16.9 ± 2.3), however not meeting the targets (FRE≥60 and FKGL≤8).

CONCLUSION: There is a requirement for further CI/IP&C evidence-based guidance, policies/guidelines, education awareness, best practice in the home environment and multi-modal communication, enabling the CF community to make informed choices on lifestyle behaviours.

PMID:38644104 | DOI:10.1016/j.idh.2024.04.002

Infect Dis Ther. 2024 Apr 21. doi: 10.1007/s40121-024-00967-6. Online ahead of print.

ABSTRACT

INTRODUCTION: Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators.

METHODS: In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM.

RESULTS: A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV.

CONCLUSIONS: Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

PMID:38643431 | DOI:10.1007/s40121-024-00967-6

Sci Rep. 2024 Apr 20;14(1):9056. doi: 10.1038/s41598-024-59658-4.

ABSTRACT

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [- 3.86% (95% CI - 5.28-2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [- 3.46% (95% CI - 4.95-1.96)] and Pseudomonas aeruginosa [- 2.80%95% CI (- 4.26-1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (- 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

PMID:38643191 | PMC:PMC11032396 | DOI:10.1038/s41598-024-59658-4

Lancet. 2024 Apr 15:S0140-6736(24)00757-8. doi: 10.1016/S0140-6736(24)00757-8. Online ahead of print.

ABSTRACT

BACKGROUND: Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-based interventions that enable public health researchers, policy makers, and other professionals to implement strategies that can mitigate diseases. It can also facilitate more rigorous monitoring of progress towards national and international health targets, such as the Sustainable Development Goals. For three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has filled that need. A global network of collaborators contributed to the production of GBD 2021 by providing, reviewing, and analysing all available data. GBD estimates are updated routinely with additional data and refined analytical methods. GBD 2021 presents, for the first time, estimates of health loss due to the COVID-19 pandemic.

METHODS: The GBD 2021 disease and injury burden analysis estimated years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries using 100 983 data sources. Data were extracted from vital registration systems, verbal autopsies, censuses, household surveys, disease-specific registries, health service contact data, and other sources. YLDs were calculated by multiplying cause-age-sex-location-year-specific prevalence of sequelae by their respective disability weights, for each disease and injury. YLLs were calculated by multiplying cause-age-sex-location-year-specific deaths by the standard life expectancy at the age that death occurred. DALYs were calculated by summing YLDs and YLLs. HALE estimates were produced using YLDs per capita and age-specific mortality rates by location, age, sex, year, and cause. 95% uncertainty intervals (UIs) were generated for all final estimates as the 2·5th and 97·5th percentiles values of 500 draws. Uncertainty was propagated at each step of the estimation process. Counts and age-standardised rates were calculated globally, for seven super-regions, 21 regions, 204 countries and territories (including 21 countries with subnational locations), and 811 subnational locations, from 1990 to 2021. Here we report data for 2010 to 2021 to highlight trends in disease burden over the past decade and through the first 2 years of the COVID-19 pandemic.

FINDINGS: Global DALYs increased from 2·63 billion (95% UI 2·44-2·85) in 2010 to 2·88 billion (2·64-3·15) in 2021 for all causes combined. Much of this increase in the number of DALYs was due to population growth and ageing, as indicated by a decrease in global age-standardised all-cause DALY rates of 14·2% (95% UI 10·7-17·3) between 2010 and 2019. Notably, however, this decrease in rates reversed during the first 2 years of the COVID-19 pandemic, with increases in global age-standardised all-cause DALY rates since 2019 of 4·1% (1·8-6·3) in 2020 and 7·2% (4·7-10·0) in 2021. In 2021, COVID-19 was the leading cause of DALYs globally (212·0 million [198·0-234·5] DALYs), followed by ischaemic heart disease (188·3 million [176·7-198·3]), neonatal disorders (186·3 million [162·3-214·9]), and stroke (160·4 million [148·0-171·7]). However, notable health gains were seen among other leading communicable, maternal, neonatal, and nutritional (CMNN) diseases. Globally between 2010 and 2021, the age-standardised DALY rates for HIV/AIDS decreased by 47·8% (43·3-51·7) and for diarrhoeal diseases decreased by 47·0% (39·9-52·9). Non-communicable diseases contributed 1·73 billion (95% UI 1·54-1·94) DALYs in 2021, with a decrease in age-standardised DALY rates since 2010 of 6·4% (95% UI 3·5-9·5). Between 2010 and 2021, among the 25 leading Level 3 causes, age-standardised DALY rates increased most substantially for anxiety disorders (16·7% [14·0-19·8]), depressive disorders (16·4% [11·9-21·3]), and diabetes (14·0% [10·0-17·4]). Age-standardised DALY rates due to injuries decreased globally by 24·0% (20·7-27·2) between 2010 and 2021, although improvements were not uniform across locations, ages, and sexes. Globally, HALE at birth improved slightly, from 61·3 years (58·6-63·6) in 2010 to 62·2 years (59·4-64·7) in 2021. However, despite this overall increase, HALE decreased by 2·2% (1·6-2·9) between 2019 and 2021.

INTERPRETATION: Putting the COVID-19 pandemic in the context of a mutually exclusive and collectively exhaustive list of causes of health loss is crucial to understanding its impact and ensuring that health funding and policy address needs at both local and global levels through cost-effective and evidence-based interventions. A global epidemiological transition remains underway. Our findings suggest that prioritising non-communicable disease prevention and treatment policies, as well as strengthening health systems, continues to be crucially important. The progress on reducing the burden of CMNN diseases must not stall; although global trends are improving, the burden of CMNN diseases remains unacceptably high. Evidence-based interventions will help save the lives of young children and mothers and improve the overall health and economic conditions of societies across the world. Governments and multilateral organisations should prioritise pandemic preparedness planning alongside efforts to reduce the burden of diseases and injuries that will strain resources in the coming decades.

FUNDING: Bill & Melinda Gates Foundation.

PMID:38642570 | DOI:10.1016/S0140-6736(24)00757-8

Cell Calcium. 2024 Apr 15;120:102885. doi: 10.1016/j.ceca.2024.102885. Online ahead of print.

ABSTRACT

When activated by increase in intracellular Ca2+, anoctamins (TMEM16 proteins) operate as phospholipid scramblases and as ion channels. Anoctamin 1 (ANO1) is the Ca2+-activated epithelial anion-selective channel that is coexpressed together with the abundant scramblase ANO6 and additional intracellular anoctamins. In salivary and pancreatic glands, ANO1 is tightly packed in the apical membrane and secretes Cl-. Epithelia of airways and gut use cystic fibrosis transmembrane conductance regulator (CFTR) as an apical Cl- exit pathway while ANO1 supports Cl- secretion mainly by facilitating activation of luminal CFTR and basolateral K+ channels. Under healthy conditions ANO1 modulates intracellular Ca2+ signals by tethering the endoplasmic reticulum, and except of glands its direct secretory contribution as Cl- channel might be small, compared to CFTR. In the kidneys ANO1 supports proximal tubular acid secretion and protein reabsorption and probably helps to excrete HCO3-in the collecting duct epithelium. However, under pathological conditions as in polycystic kidney disease, ANO1 is strongly upregulated and may cause enhanced proliferation and cyst growth. Under pathological condition, ANO1 and ANO6 are upregulated and operate as secretory channel/phospholipid scramblases, partly by supporting Ca2+-dependent processes. Much less is known about the role of other epithelial anoctamins whose potential functions are discussed in this review.

PMID:38642428 | DOI:10.1016/j.ceca.2024.102885

Phys Med Biol. 2024 Apr 19. doi: 10.1088/1361-6560/ad40f5. Online ahead of print.

ABSTRACT

Magnetic nanoparticles can be used as a targeted delivery vehicle for genetic therapies. Understanding how they can be manipulated within the complex environment of live airways is key to their application to cystic fibrosis and other respiratory diseases.&#xD;Approach: Dark-field X-ray imaging provides sensitivity to scattering information, and allows the presence of structures smaller than the detector pixel size to be detected. In this study, ultrafast directional dark-field synchrotron X-ray imaging was utlilised to understand how magnetic nanoparticles move within a live, anaesthetised, rat airway under the influence of static and moving&#xD;magnetic fields.&#xD;Main results: Magnetic nanoparticles emerging from an indwelling tracheal cannula were detectable during delivery, with dark-field imaging increasing the signal-to-noise ratio of this event by 3.5 times compared to the X-ray transmission signal. Particle movement as well as particle retention was evident. Dynamic magnetic fields could manipulate the magnetic particles in-situ.&#xD;Significance: This is the first evidence of the effectiveness of in-vivo dark-field imaging operating at these spatial and temporal resolutions, used to detect magnetic nanoparticles. These findings provide the basis for further development toward the effective use of magnetic nanoparticles, and advance their potential as an effective delivery vehicle for genetic agents in the airways of live organisms.

PMID:38640914 | DOI:10.1088/1361-6560/ad40f5

Diagn Microbiol Infect Dis. 2024 Apr 16;109(3):116296. doi: 10.1016/j.diagmicrobio.2024.116296. Online ahead of print.

ABSTRACT

Pulmonary infection due to Mycobacterium abscessus complex (MABC) usually occurs in children with underlying risk factors including cystic fibrosis (CF), chronic lung disease, and immunocompromised status, but rarely in immunocompetent children without underlying lung disease, especially in infants. We present a case of MABC pulmonary disease (MABC-PD) in an otherwise healthy 53-day-old male infant with one week of cough and respiratory distress. Computed tomography showed multiple masses across both lungs. Isolated mycobacteria from his bronchoalveolar lavage fluid were identified as MABC. We describe our complete evaluation, including immunodeficiency evaluation incorporating whole exome sequencing and our therapeutic process given complicated susceptibility pattern of the M. abscessus isolate, and review literature for MABC-PD in immunocompetent children. The infant was successfully treated through prolonged treatment with parenteral Amikacin, Cefoxitin, Linezolid, and Clarithromycin, combined with inhaled Amikacin.

PMID:38640607 | DOI:10.1016/j.diagmicrobio.2024.116296

J Aerosol Med Pulm Drug Deliv. 2024 Apr;37(2):100-110. doi: 10.1089/jamp.2024.29112.hxo.

ABSTRACT

Inhalation of liposomes formulated with phospholipids similar to endogenous lung surfactants and lipids offers biocompatibility and versatility within the pulmonary medicine field to treat a range of diseases such as lung cancer, cystic fibrosis and lung infections. Manipulation of the physicochemical properties of liposomes enables innovative design of the carrier to meet specific delivery, release and targeting requirements. This delivery system offers several benefits: improved pharmacokinetics with reduced toxicity, enhanced therapeutic efficacy, increased delivery of poorly soluble drugs, taste masking, biopharmaceutics degradation protection and targeted cellular therapy. This section provides an overview of liposomal formulation and delivery, together with their applications for different disease states in the lung.

PMID:38640446 | DOI:10.1089/jamp.2024.29112.hxo