Gen Physiol Biophys. 2024 May;43(3):197-207. doi: 10.4149/gpb_2024007.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel uses positively charged amino-acid side-chains to form binding sites for permeating anions. These binding sites have been investigated experimentally using a number of anionic probes. Mutations that alter the distribution of positive and negative charges within the pore have differential effects on the binding of monovalent versus divalent anions. This study uses patch clamp recording from wild-type and pore-mutant forms of CFTR to investigate small trivalent anions (Co(NO2)63-, Co(CN)3- and IrCl63-) as potential probes of anion binding sites. These anions caused weak block of Cl- permeation in wild-type CFTR (Kd ≥ 700 μM) when applied to the intracellular side of the membrane. Mutations that increase the density of positive charge within the pore (E92Q, I344K, S1141K) increased the binding affinity of these anions 80-280-fold, and also greatly increased the voltage-dependence of block, consistent with fixed charges in the pore affecting monovalent : multivalent anion selectivity. However, high-affinity pore block by Co(NO2)63-apparently did not alter channel gating, a hallmark of high-affinity binding of divalent Pt(NO2)42- ions within the pore. This work increases the arsenal of probes available to investigate anion binding sites within Cl- channel pores.

PMID:38774920 | DOI:10.4149/gpb_2024007

Clin Exp Hepatol. 2023 Dec;9(4):405-409. doi: 10.5114/ceh.2023.132264. Epub 2023 Nov 28.

ABSTRACT

AIM OF THE STUDY: The presence of macroenzymes may mimic treatment related hepatotoxicity.

MATERIAL AND METHODS: We present a female subject who developed high alanine aminotransferase (ALT)/aspartate aminotransferase (AST) activity during cystic fibrosis transmembrane regulator (CFTR) modulator therapy.

RESULTS: The differential work-up did not show any underlying liver disease. CFTR modulators were stopped with subsequent normalization and immediate rise of ALT/AST after modulators were restarted, which was interpreted as the presentation of CFTR modulator hepatotoxicity. Before permanent CFTR modulators' discontinuation the patient's blood was tested for the presence of macroALT/macroAST and the result was positive. The patient is continuing a CFTR modulator treatment that is being supervised using standard laboratory tests and a test detecting the presence of macroenzymes. At three subsequent measurements the tests showed the presence of macroenzymes.

CONCLUSIONS: Our patient shows that increased ALT/AST during CFTR modulator therapy may be related to the induction of macroenzymes and not necessarily to hepatotoxicity. Patients with high ALT/AST activity should be considered for testing for the presence of macroenzymes.

PMID:38774202 | PMC:PMC11103804 | DOI:10.5114/ceh.2023.132264

Future Healthc J. 2024 Apr 20;11(2):100130. doi: 10.1016/j.fhj.2024.100130. eCollection 2024 Jun.

ABSTRACT

Air pollution (AP) significantly jeopardises health, with the Royal College of Physicians accepting the adverse effects of AP are not being sufficiently communicated to patients by healthcare professionals (HCP). To explore HCPs' understanding and attitudes toward AP and its health impacts, we conducted a service evaluation survey in a group of hospital doctors. A questionnaire comprising 20 questions about AP and its health associations was completed by 133 hospital doctors working at University Hospital Southampton NHS Foundation Trust, UK. While 65% (n = 86) of respondents strongly agreed that AP is relevant to health, 79% (n = 105) felt insufficiently trained on AP and its health associations. The survey shows that HCPs' knowledge of AP and its connection to poor health is a major barrier in discussions with patients. Further research is needed to understand whether these views are nationally shared among HCPs and to explore the most effective strategies for enhancing AP awareness.

PMID:38774033 | PMC:PMC11106822 | DOI:10.1016/j.fhj.2024.100130

APMIS. 2024 May 21. doi: 10.1111/apm.13427. Online ahead of print.

ABSTRACT

The vast majority of people with cystic fibrosis (pwCF) have untreated secondary chronic rhinosinusitis (CRS). Whereas the introduction of the cystic fibrosis transmembrane conductance regulator modulator (CFTRm) treatment regime has improved the lung function of pwCF, few studies have been published examining the effect on sinonasal symptoms in children. Our aim was to explore the effect of double CFTRm treatment on CRS and olfaction in children with CF. pwCF were included in this non-randomized cross-sectional study, where an otolaryngologist performed a complete ENT examination before initiating treatment with elaxacaftor/tezacaftor/ivacaftor (ETI). Twenty-three pwCF aged 6-12 years were included. Eighteen of 23 patients were on a double CFTRm treatment, and 5 patients were CFTRm naive, respectively. Altogether, 19 had normal olfaction, 20 had none or mild CRS symptoms according to SNOT-22, and 14 had a normal endoscopy. None of the patients had symptoms of chronic rhinosinusitis lasting for more than 12 weeks, thus none of the patients fulfilled the criteria for CRS. Children with CF treated with double CFTRm have few to no symptoms of CRS and normal olfaction, which is an improvement compared with children following treatment modalities prior to CFTRm.

PMID:38773823 | DOI:10.1111/apm.13427

NPJ Digit Med. 2024 May 21;7(1):126. doi: 10.1038/s41746-024-01127-3.

ABSTRACT

Generalization – the ability of AI systems to apply and/or extrapolate their knowledge to new data which might differ from the original training data – is a major challenge for the effective and responsible implementation of human-centric AI applications. Current debate in bioethics proposes selective prediction as a solution. Here we explore data-based reasons for generalization challenges and look at how selective predictions might be implemented technically, focusing on clinical AI applications in real-world healthcare settings.

PMID:38773304 | PMC:PMC11109198 | DOI:10.1038/s41746-024-01127-3

Lung. 2024 May 21. doi: 10.1007/s00408-024-00700-7. Online ahead of print.

ABSTRACT

We are entering the post-antibiotic era. Antimicrobial resistance (AMR) is a critical problem in chronic lung infections resulting in progressive respiratory failure and increased mortality. In the absence of emerging novel antibiotics to counter AMR infections, bacteriophages (phages), viruses that infect bacteria, have become a promising option for chronic respiratory infections. However, while personalized phage therapy is associated with improved outcomes in individual cases, clinical trials demonstrating treatment efficacy are lacking, limiting the therapeutic potential of this approach for respiratory infections. In this review, we address the current state of phage therapy for managing chronic respiratory diseases. We then discuss how phage therapy may address major microbiologic obstacles which hinder disease resolution of chronic lung infections with current antibiotic-based treatment practices. Finally, we highlight the challenges that must be addressed for successful phage therapy clinical trials. Through this discussion, we hope to expand on the potential of phages as an adjuvant therapy in chronic lung infections, as well as the microbiologic challenges that need to be addressed for phage therapy to expand beyond personalized salvage therapy.

PMID:38772946 | DOI:10.1007/s00408-024-00700-7

Am J Physiol Lung Cell Mol Physiol. 2024 May 21. doi: 10.1152/ajplung.00052.2024. Online ahead of print.

ABSTRACT

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade increasing evidence from preclinical models suggests that cells, which are not normally resident in the lung can be utilized to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathologic remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of "-omics" technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference.

PMID:38772903 | DOI:10.1152/ajplung.00052.2024

Int J Mycobacteriol. 2024 Jan 1;13(1):34-39. doi: 10.4103/ijmy.ijmy_205_23. Epub 2024 Mar 15.

ABSTRACT

BACKGROUND: In patients with cystic fibrosis (CF), representatives of the fast-growing Mycobacterium abscessus complex (MABSc) are often distinguished, but the culture of the material taken from such patients increases the growth time. We analyzed the terms of cultivation of MABSc representatives on dense nutrient media and also evaluated the productivity of a modified nutrient medium based on agar for the isolation of Burkholderia cepacia complex (BCC).

METHODS: Sixty-four strains of MABSc isolated from patients with CF and suspected tuberculosis were analyzed. The material from the patients was cultured on a universal chromogenic medium, 5% blood agar, yolk-salt agar, selective medium for isolation of BCC, and Löwenstein-Jensen medium. The cultures were incubated for 5 days (37°C, aerobic conditions), after for 23 days (28°C, aerobic conditions). The productivity of the developed nutrient medium was evaluated by the number of cells that gave visible growth after culturing 0.1 mL of a bacterial suspension of 103 CFU/mL.

RESULTS: 76.8% of the strains grew in a 2-week period, and 23.2% of the strains were obtained at a later date from 18 to 28 days (average: 21.23 days). The modified medium with a concentration of 240 mg of iron (III) polymaltose hydroxide proved to be the most optimal for the isolation of MABSc.

CONCLUSION: When using a chromogenic medium for culture material from patients with CF, it is necessary to extend incubation up to 28 days to increase the probability of MABSc isolation. The modified BCC medium showed a good selectivity result but required further investigation.

PMID:38771277 | DOI:10.4103/ijmy.ijmy_205_23

Pediatr Pulmonol. 2024 May 21. doi: 10.1002/ppul.27051. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs target the underlying defect and improve CFTR function. They are a part of standard care in many countries, but not all patients are eligible for these drugs due to age and genotype. Here, we aimed to determine the characteristics of non-eligible patients for CFTR modulators in the CF registry of Turkey (CFRT) to highlight their clinical needs.

METHODS: This retrospective cohort study included CF patient data from the CFRT in 2021. The decision of eligibility for the CFTR modulator was determined according to the 'Vertex treatment-Finder' on the Vertex® website. Demographic and clinical characteristics of patients were compared between eligible (group 1) and ineligible (group 2) groups for CFTR modulators.

RESULTS: Among the study population (N = 1527), 873 (57.2%) were in group 1 and 654 (42.8%) were in group 2. There was no statistical difference between groups regarding sex, meconium ileus history, diagnoses via newborn screening, FEV1 z-score, CF-associated complications, organ transplant history, and death. Patients in group 2 had a higher incidence of pancreatic insufficiency (87.7% vs. 83.2%, p = .010), lower median height z-scores (-0.87 vs. -0.55, p < .001), lower median body mass index z-scores (-0.65 vs. -0.50, p < .001), longer days receiving antibiotics due to pulmonary exacerbation (0 [interquartile range, IQR: 0-2] vs. 0 [IQR: 0-7], p = 0.001), and more non-invasive ventilation support (2.6% vs. 0.9%, p = 0.008) than patients in group 1.

CONCLUSION: The ineligible group had worse clinical outcomes than the eligible group. This highlights their need for life-changing drugs to improve clinical outcomes.

PMID:38771207 | DOI:10.1002/ppul.27051

Br J Pharmacol. 2024 May 21. doi: 10.1111/bph.16417. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated.

EXPERIMENTAL APPROACH: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed.

KEY RESULTS: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development.

CONCLUSION AND IMPLICATION: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

PMID:38770951 | DOI:10.1111/bph.16417

Heliyon. 2024 May 9;10(10):e30895. doi: 10.1016/j.heliyon.2024.e30895. eCollection 2024 May 30.

ABSTRACT

The Burkholderia cepacia complex (Bcc) is a gram-negative bacillus, which is intrinsically resistant to several used antibiotics, and is now recognized as a group of opportunistic pathogens in Cystic Fibrosis patients. Here, for the first time, we report the case of a patient with New Delhi metallo β-lactamase (NDM)-positive Bcc lower respiratory tract infection in Iran. The patient was a 57-year-old male admitted to our hospital due to breathlessness, with a history of pulmonary thromboembolism and hypertension. On day 14, the patient underwent bronchoscopy and a bronchoalveolar lavage (BAL) specimen was taken. BAL culture grew Bcc. The drug resistance analysis showed positive NDM resistance, with susceptibility to only quinolones, therefore, levofloxacin was prescribed to the patient. He was discharged from the hospital on the 20th day, 4 days after the initiation of levofloxacin therapy, and died at home on the fifth day after discharge. This is the first report of a lung infection caused by an extensively drug-resistant NDM-positive Bcc strain in Iran.

PMID:38770338 | PMC:PMC11103520 | DOI:10.1016/j.heliyon.2024.e30895

Mol Ther Nucleic Acids. 2024 May 8;35(2):102197. doi: 10.1016/j.omtn.2024.102197. eCollection 2024 Jun 11.

NO ABSTRACT

PMID:38766524 | PMC:PMC11101720 | DOI:10.1016/j.omtn.2024.102197

J Clin Transl Endocrinol. 2024 Apr 20;36:100344. doi: 10.1016/j.jcte.2024.100344. eCollection 2024 Jun.

ABSTRACT

Cystic fibrosis (CF) has been traditionally viewed as a disease that affects White individuals. However, CF occurs among all races, ethnicities, and geographic ancestries. The disorder results from mutations in the CF transmembrane conductance regulator (CFTR). Varying incidence of CF is reported among Black, Indigenous, and People of Color (BIPOC), who typically exhibit worse clinical outcomes. These populations are more likely to carry rare CFTR variants omitted from newborn screening panels, leading to disparities in care such as delayed diagnosis and treatment. In this study, we present a case-in-point describing an individual of Gambian descent identified with CF. Patient genotype includes a premature termination codon (PTC) (c.2353C>T) and previously undescribed single nucleotide deletion (c.1970delG), arguing against effectiveness of currently available CFTR modulator-based interventions. Strategies for overcoming these two variants will likely include combinations of PTC suppressors, nonsense mediated decay inhibitors, and/or alternative approaches (e.g. gene therapy). Investigations such as the present study establish a foundation from which therapeutic treatments may be developed. Importantly, c.2353C>T and c.1970delG were not detected in the patient by traditional CFTR screening panels, which include an implicit racial and ethnic diagnostic bias as these tests are comprised of mutations largely observed in people of European ancestry. We suggest that next-generation sequencing of CFTR should be utilized to confirm or exclude a CF diagnosis, in order to equitably serve BIPOC individuals. Additional epidemiologic data, basic science investigations, and translational work are imperative for improving understanding of disease prevalence and progression, CFTR variant frequency, genotype-phenotype correlation, pharmacologic responsiveness, and personalized medicine approaches for patients with African ancestry and other historically understudied geographic lineages.

PMID:38765466 | PMC:PMC11099334 | DOI:10.1016/j.jcte.2024.100344

J Cyst Fibros. 2024 May 18:S1569-1993(24)00061-4. doi: 10.1016/j.jcf.2024.04.016. Online ahead of print.

ABSTRACT

BACKGROUND: Patient-derived intestinal organoids (PDIOs) show great potential as in vitro drug testing platform for personalised medicine in Cystic Fibrosis and oncology. PDIOs can be generated by culturing adult stem cells obtained through rectal forceps biopsy or suction biopsy, but the safety of these procedures and the success rates of generating organoids after shipment to a centralized lab using these procedures has not been studied in this context. We here report the safety and success rates of both biopsy procedures and the subsequent generation of PDIOs in the international multicentre HIT-CF Organoid Study.

METHODS: 502 biopsy procedures were conducted, on 489 adult people with Cystic Fibrosis from 33 different hospitals across 12 countries. Depending on the preference of the hospital, either rectal forceps biopsies or suction biopsies were obtained and internationally shipped to a central laboratory for organoid generation.

RESULTS: No adverse events were reported for 280 forceps biopsy procedures, while 222 rectal suction biopsy procedures resulted in 2 adverse events, namely continued bleeding and a probably nonrelated gastroenteritis. The success rate of organoid generation from all biopsies was 95%, and the main reason for failure was insufficient sample viability (3.2%).

CONCLUSION: Our results indicate that both rectal suction biopsy and forceps biopsy procedures are safe procedures. The high success rates of PDIO generation from the obtained tissue samples demonstrate the feasibility of the organoid technology for personalised in vitro testing in an international setting.

PMID:38763840 | DOI:10.1016/j.jcf.2024.04.016

Respir Res. 2024 May 18;25(1):211. doi: 10.1186/s12931-024-02835-w.

ABSTRACT

BACKGROUND: Bronchiectasis is a condition characterized by abnormal and irreversible bronchial dilation resulting from lung tissue damage and can be categorized into two main groups: cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Both diseases are marked by recurrent infections, inflammatory exacerbations, and lung damage. Given that infections are the primary drivers of disease progression, characterization of the respiratory microbiome can shed light on compositional alterations and susceptibility to antimicrobial drugs in these cases compared to healthy individuals.

METHODS: To assess the microbiota in the two studied diseases, 35 subjects were recruited, comprising 10 NCFB and 13 CF patients and 12 healthy individuals. Nasopharyngeal swabs and induced sputum were collected, and total DNA was extracted. The DNA was then sequenced by the shotgun method and evaluated using the SqueezeMeta pipeline and R.

RESULTS: We observed reduced species diversity in both disease cohorts, along with distinct microbial compositions and profiles of antimicrobial resistance genes, compared to healthy individuals. The nasopharynx exhibited a consistent microbiota composition across all cohorts. Enrichment of members of the Burkholderiaceae family and an increased Firmicutes/Bacteroidetes ratio in the CF cohort emerged as key distinguishing factors compared to NCFB group. Staphylococcus aureus and Prevotella shahii also presented differential abundance in the CF and NCFB cohorts, respectively, in the lower respiratory tract. Considering antimicrobial resistance, a high number of genes related to antibiotic efflux were detected in both disease groups, which correlated with the patient's clinical data.

CONCLUSIONS: Bronchiectasis is associated with reduced microbial diversity and a shift in microbial and resistome composition compared to healthy subjects. Despite some similarities, CF and NCFB present significant differences in microbiome composition and antimicrobial resistance profiles, suggesting the need for customized management strategies for each disease.

PMID:38762736 | DOI:10.1186/s12931-024-02835-w

Nat Commun. 2024 May 18;15(1):4247. doi: 10.1038/s41467-024-48442-7.

ABSTRACT

The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.

PMID:38762483 | DOI:10.1038/s41467-024-48442-7

J Cyst Fibros. 2024 May 18:S1569-1993(24)00069-9. doi: 10.1016/j.jcf.2024.05.006. Online ahead of print.

ABSTRACT

Novel drug therapy targeting the defective cystic fibrosis transmembrane conductance regulator protein has the potential to significantly enhance the quality of life for numerous patients with cystic fibrosis. However, in some countries social insurance does not pay for modulators because these drugs are extremely expensive. This study sought to understand the impact on the health of children whose modulator treatments were interrupted because of legal procedures and delivery processes. Our study identified that the significant increase in percent-predicted forced expiratory volume levels (FEV1) and BMI z-score values associated with modulator therapies decreased sharply with their discontinuation. Significant worsening in FEV1, BMI z-scores, and BW z-scores were detected in the first follow-up visit after therapy discontinuation within 1 month. Eight patients had a reduction of FEV1 of more than 10%. The findings suggest that modulatory treatment continuation is important, and it is crucial that treatment is not interrupted.

PMID:38762388 | DOI:10.1016/j.jcf.2024.05.006

Lancet. 2024 May 18;403(10440):2162-2203. doi: 10.1016/S0140-6736(24)00933-4.

ABSTRACT

BACKGROUND: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.

METHODS: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.

FINDINGS: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).

INTERPRETATION: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.

FUNDING: Bill & Melinda Gates Foundation.

PMID:38762324 | DOI:10.1016/S0140-6736(24)00933-4

Eur J Pediatr. 2024 May 18. doi: 10.1007/s00431-024-05585-5. Online ahead of print.

NO ABSTRACT

PMID:38761224 | DOI:10.1007/s00431-024-05585-5

Mol Cancer. 2024 May 18;23(1):106. doi: 10.1186/s12943-024-02020-z.

ABSTRACT

Aging and cancer exhibit apparent links that we will examine in this review. The null hypothesis that aging and cancer coincide because both are driven by time, irrespective of the precise causes, can be confronted with the idea that aging and cancer share common mechanistic grounds that are referred to as 'hallmarks'. Indeed, several hallmarks of aging also contribute to carcinogenesis and tumor progression, but some of the molecular and cellular characteristics of aging may also reduce the probability of developing lethal cancer, perhaps explaining why very old age (> 90 years) is accompanied by a reduced incidence of neoplastic diseases. We will also discuss the possibility that the aging process itself causes cancer, meaning that the time-dependent degradation of cellular and supracellular functions that accompanies aging produces cancer as a byproduct or 'age-associated disease'. Conversely, cancer and its treatment may erode health and drive the aging process, as this has dramatically been documented for cancer survivors diagnosed during childhood, adolescence, and young adulthood. We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.

PMID:38760832 | PMC:PMC11102267 | DOI:10.1186/s12943-024-02020-z