Glob Med Genet. 2024 Sep 16;11(4):319-329. doi: 10.1055/s-0044-1790558. eCollection 2024 Dec.

ABSTRACT

In the fields of medicine and bioscience, gene editing is increasingly recognized as a promising therapeutic approach for treating pathogenic variants in humans and other living organisms. With advancements in technology and knowledge, it is now understood that most genetic defects are caused by single-base pair variants. The ability to substitute genes using genome editing tools enables scientists and doctors to cure genetic diseases and disorders. Starting with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas, the technology has evolved to become more efficient and safer, leading to the development of base and prime editors. Furthermore, various approaches are used to treat genetic disorders such as hemophilia, cystic fibrosis, and Duchenne muscular dystrophy. As previously mentioned, most genetic defects leading to specific diseases are caused by single-base pair variants, which can occur at many locations in corresponding gene, potentially causing the same disease. This means that, even when using the same genome editing tool, results in terms of editing efficiency or treatment effectiveness may differ. Therefore, different approaches may need to be applied to different types of diseases. Prevalently, due to the safety of adeno-associated virus (AAV) vectors in gene therapy, most clinical trials of gene therapy are based on AAV delivery methods. However, despite their safety and nonintegration into the host genome, their limitations, such as confined capacity, dosage-dependent viral toxicity, and immunogenicity, necessitate the development of new approaches to enhance treatment effects. This review provides the structure and function of each CRISPR-based gene editing tool and focuses on introducing new approaches in gene therapy associated with improving treatment efficiency.

PMID:39583120 | PMC:PMC11405120 | DOI:10.1055/s-0044-1790558

NAR Mol Med. 2024 Nov 6;1(4):ugae017. doi: 10.1093/narmme/ugae017. eCollection 2024 Oct.

ABSTRACT

There is a major need for therapeutics that treat disease caused by premature termination codons (PTCs). Splice-switching antisense oligonucleotides (ASOs) can be directed to block splicing and cause exon skipping, a process that can be used to effectively remove PTCs from an mRNA. This ASO-induced exon skipping can restore protein coding potential when the exons on either side of the skipped exon are in the same reading frame, or symmetrical. We demonstrate the potential of this approach as a therapeutic using the cystic fibrosis (CF) transmembrane regulator (CFTR) gene, which has CF-associated, PTC-causing variants in all 27 of its exons. We functionally screened all CFTR isoforms that can be generated by deletion of symmetrical exons and identify four that are functionally responsive to CFTR modulators. We identified ASOs that induce skipping of these exons and show that they recover CFTR function in airway cells derived from individuals with CFTR PTC variants. This study demonstrates that systematic functional analysis of in-frame exon-deleted protein isoforms can successfully identify targets for ASO-based splice-switching therapies, a therapeutic concept that can be broadly applied to any multi-exon protein-coding gene disrupted by PTCs.

PMID:39582793 | PMC:PMC11579696 | DOI:10.1093/narmme/ugae017

Front Nutr. 2024 Nov 7;11:1477674. doi: 10.3389/fnut.2024.1477674. eCollection 2024.

ABSTRACT

BACKGROUND: When people with cystic fibrosis (PwCFs) are treated with cystic fibrosis transmembrane conductance regulator protein modulator (CFTRm), it leads to changes in body composition. An easy, non-invasive, and reproducible method to assess this is by means of electrical bioimpedance measurement, which complements the information provided by the already-known anthropometric parameters.

METHODS: Seventeen adults with cystic fibrosis in treatment with elexacaftor-tezacaftor-ivacaftor (ETI) were recruited for a prospective, longitudinal, single-center study over 12 months. Study variables included weight, body mass index (BMI), and body composition by bioelectrical impedance analysis (BIA) [including fat mass (FM) and fat-free mass (FFM)].

RESULTS: At 12 months, there was an increase in overweight patients (5.9% vs. 23.5%) and a statistically significant increase in BMI at 6 and 12 months. An increase in FM and FFM was observed at 12 months. The increase was greater in FM (95% CI) from a baseline of 1.77% (0.00-3.54; p = 0.050) at 6 months and 2.64% (0.48-4.81; p = 0.020) at 12 months.

CONCLUSION: After treatment with ETI, there was an increase in weight, BMI, and FM more than FFM in PwCF. These changes would be confirmed in long-term studies to improve nutritional management.

PMID:39582664 | PMC:PMC11582979 | DOI:10.3389/fnut.2024.1477674

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241253945. doi: 10.1177/17534666241253945.

ABSTRACT

BACKGROUND: Immunodeficiencies (IDs) are conditions caused by immune system dysfunctions which predispose to chronic infections. Cystic fibrosis (CF) patients are characterized by the presence of bronchiectasis filled with hyper-viscous secretions that constitute the ideal environment for infections. Although CF and IDs might share similarities in the pathophysiological mechanism of bronchiectasis development, they each offer different treatment options. We hypothesize that the introduction of a bundle of tests would increase the number of ID diagnoses among adults with Cystic Fibrosis Transmembrane conductance Regulator (CFTR) dysfunction.

OBJECTIVES: The primary objectives of this study were (1) assessing the prevalence of IDs in CF and (2) defining clinical characteristics of adults with both CF and IDs. The secondary objectives were: (1) assessing the prevalence of IDs in CFTR-Related Disorder (CFTR-RD) patients; (2) comparing the prevalence of IDs in CF and CFTR-RD; (3) comparing the prevalence of treatable IDs in CF and CFTR-RD.

DESIGN: We conducted an observational, prospective, consecutive study on a cohort of 190 adult patients affected by CF or CFTR-RD.

METHODS: Blood samples underwent a standardized immunological screening, including complete white blood count, IgG, IgA, IgM, IgG subclasses, total IgE, lymphocyte subsets, and HIV test. Comprehensive clinical history was assessed to identify risk factors for secondary IDs.

RESULTS: We identify a high prevalence of immunodeficiencies among the entire cohort: 34 (20.1%) CF patients and 10 (47.6%) CFTR-RD patients are diagnosed with IDs via a blood screening. No statistically significant difference in terms of clinical characteristics was found between immunocompromised and immunocompetent CF patients.

CONCLUSION: We identify a high prevalence of immunodeficiencies in both CF and CFTR-RD.

PMID:39582115 | DOI:10.1177/17534666241253945

Clin Pharmacokinet. 2024 Nov 24. doi: 10.1007/s40262-024-01440-w. Online ahead of print.

ABSTRACT

BACKGROUND: Omadacycline offers a potential advancement in the management of infections in people with cystic fibrosis (CF) because of its spectrum of activity, intrapulmonary penetration, and oral bioavailability. A prospective single-dose, single-arm study was conducted to characterize the pharmacokinetic (PK) profile of omadacycline in people with CF, considering the known alterations in PK observed in this population (NCT04460586, 2020-07-01).

METHODS: Plasma samples were obtained from nine adults with CF who received a single dose of intravenous omadacycline 100 mg over 0.5 h followed by a 1-week washout and an oral dose of omadacycline 300 mg. The data were analyzed using noncompartmental PK.

RESULTS: The maximum plasma concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-∞) after intravenous administration of omadacycline were similar between healthy volunteers and people with CF. The absorption kinetics of oral omadacycline, encompassing both the rate (Cmax and time to Cmax [tmax]) and the extent (AUC0-∞), also showed consistency between healthy volunteers and people with CF. The absolute bioavailability of the oral tablet formulation of omadacycline in people with CF (31.2%) was also consistent with that observed in healthy volunteers (34.5%). In comparing the two routes of administration, intravenous omadacycline 100 mg provided plasma exposures equivalent to those with oral omadacycline 300 mg in people with CF, as evidenced by geometric mean ratios for both AUC0-∞ (0.9381; 90% confidence intervals [CI] 0.6783-1.2975) and Cmax (0.7746; 90% CI 0.5478-1.0951).

CONCLUSIONS: Overall, the similarity in plasma PK observed in this study when comparing healthy volunteers and infected patients indicates that no dosing alterations are necessary when using omadacycline in people with CF.

PMID:39581957 | DOI:10.1007/s40262-024-01440-w

J Cyst Fibros. 2024 Nov 23:S1569-1993(24)01813-7. doi: 10.1016/j.jcf.2024.11.004. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has been effective in improving several outcomes in people living with cystic fibrosis (pwCF). Although clinical guidance regarding maintenance therapies has not changed, staff reports indicate that individuals reduce some therapies. This study aimed to evaluate ETI's effect on utilization of routine therapies among pwCF in Denmark.

METHODS: We included all pwCF initiating ETI between 1 September 2020 and 31 October 2022. Utilization of routine therapies was analysed by drug class (e.g., gastrointestinal medications) and individual treatments (e.g., pancreatic enzymes) before and after ETI initiation using national registry data. Odds ratios (ORs) for prescription redemptions pre- and post-ETI were calculated to assess ETIs impact on the use of routine therapies.

RESULTS: The study population consisted of 351 individuals. Median age was 23 years (IQR 14-32) and mean ppFEV1 was 76 (SD 22) at index. Two-year follow-up was available for 205 individuals. Two years post ETI initiation, the one-year prevalence was reduced for airway medications, (89.5 % to 75.1 %) and inhaled antibiotics (59.5 % to 42.9 %.). OR for redeeming a prescription two years post-ETI initiation (95 % CI) was reduced for four out of five drug classes: airway medications (OR: 0.24 [0.19; 0.29]), inhaled antibiotics (OR: 0.28 [0.2; 0.39]), oral antibiotics (OR: 0.49 [0.41; 0.58]), gastrointestinal medications (OR: 0.66 [0.57; 0.77]).

CONCLUSION: Two years after ETI initiation, reductions in the use of several routine therapies were observed in a national cohort of pwCF, with the largest declines in airway medications and antibiotics. These findings highlight ETI's real-world impact beyond conventional clinical metrics.

PMID:39581783 | DOI:10.1016/j.jcf.2024.11.004

J Cyst Fibros. 2024 Nov 23:S1569-1993(24)01809-5. doi: 10.1016/j.jcf.2024.11.001. Online ahead of print.

NO ABSTRACT

PMID:39581782 | DOI:10.1016/j.jcf.2024.11.001

J Cyst Fibros. 2024 Nov 24:S1569-1993(24)01810-1. doi: 10.1016/j.jcf.2024.11.002. Online ahead of print.

ABSTRACT

BACKGROUND: Adults with cystic fibrosis (AWCF) have higher rates of depression and anxiety than comparable community members. This multisite randomized waitlist-controlled trial tested the efficacy of "Coping and Learning to Manage Stress with CF" (CALM), a 6-session+booster telehealth intervention to improve depression and anxiety symptoms (primary outcomes) and perceived stress, coping self-efficacy, and key health-related quality of life domains (secondary outcomes).

METHODS: AWCF reporting mild to severe symptoms of depression and/or anxiety were randomized to receive CALM immediately (immediate, n = 66) or after a 13-week delay (waitlist, n = 66). Group differences post-intervention and at 1-month were examined via linear mixed models. Maintenance of treatment gains from baseline to 3-month follow-up was examined using combined data from both groups. Effect size calculations using Cohen's d assessed treatment effect magnitude.

RESULTS: Compared to the waitlist group, those that received CALM immediately reported lower depression and anxiety symptoms post-intervention and at 1-month follow-up (ps<0.001). For depression there was a large effect size post-intervention (d = 0.85) and a medium effect size at 1-month follow-up (d = 0.70); anxiety had a medium effect size post-intervention (d = 0.65) and at 1-month follow-up (d = 0.66). The immediate group also reported significantly higher coping self-efficacy, less stress, and increased vitality post-CALM and at 1-month follow-up (ps<0.01). Treatment gains were maintained at 3-month follow-up for all outcomes.

CONCLUSIONS: CALM was efficacious for AWCF in reducing symptoms of depression, anxiety, and perceived stress while improving coping self-efficacy and vitality with evidence of treatment sustainability. Next steps are dissemination and implementation to CF psychosocial clinicians.

PMID:39581781 | DOI:10.1016/j.jcf.2024.11.002

Respir Med. 2024 Nov 22:107882. doi: 10.1016/j.rmed.2024.107882. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor, Tezacaftor, Ivacaftor (ETI) became available in the UK in August 2020 to treat people with Cystic Fibrosis (CF) aged > 12 years. We report a real-world study of clinical outcomes in young people treated with ETI at our CF centre within the first two years of its availability.

METHODS: Participants aged 12-17 were identified within our clinic, with demographic data supplemented by the UK CF registry. Comprehensive outcome data spanning two years pre- and two years post-initiation of CFTR modulators were compiled from various local sources, including patient records, medication delivery logs, and clinical notes.

RESULTS: Of the 62 patients started on ETI (32 male, mean age 13.3 years), most (76%) were homozygous for the F508del mutation. Three discontinuations occurred: one pregnancy, two related to side effects. Adherence was high (Proportion of Days covered >90% both years). Following ETI initiation there was a significant increase in mean FEV1% (+11.7 units; 95% CI 7.4 - 15.6), sustained throughout the two-year treatment period. There was no association between baseline lung function and the degree of improvement or rate of decline post-treatment. Improvements were similar for all treatable genotypes. BMI z-score increased by 0.25 units after four months of treatment, returning to baseline by 24 months. Intravenous antibiotic use decreased by 88% (median IV days/year reduced from 32 to 4 days, p < 0.01).

CONCLUSIONS: ETI use in adolescents in a real-world setting led to sustained improvements in health outcomes, consistent with those seen in open trial extension studies.

PMID:39581272 | DOI:10.1016/j.rmed.2024.107882

J Biomol Struct Dyn. 2024 Nov 24:1-16. doi: 10.1080/07391102.2024.2431666. Online ahead of print.

ABSTRACT

Antimicrobial resistance is recognized as a major worldwide public health dilemma in the current century. Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen, causes nosocomial infections like respiratory tract infections, urinary tract infections, dermatitis, and cystic fibrosis. It manifests antibiotic resistance via intrinsic, acquired, and adaptive pathways, where efflux pumps function in the extrusion of antibiotics from the cell. MexB protein, part of the tripartite efflux pumps MexAB-OprM present in P.aeruginosa, expels the penems and β-lactam antibiotics, thereby enhancing Pseudomonas resistance. The current study was intended to screen around 1602 clinically approved drugs to understand their ability to inhibit the MexB protein. Amongst them, the top 5 drug molecules were selected based on the binding energies for analyzing their physio-chemical and toxicity properties. Lomitapide was found to have the maximum negative binding energy followed by Nilotinib, whereas Nilotinib's number of hydrogen bonds was higher than that of Lomitapide. ADMET study revealed that all 5 drug molecules had limited solubility. Also, Lomitapide and Venetoclax showed low bioavailability scores, while Nilotinib, Eltrombopag, and Conivaptan demonstrated higher potential for therapeutic levels. A molecular dynamic simulation study of the 5 drugs against MexB was carried out for 200 nanoseconds. The RMSD, RMSF, Hydrogen bond formation, Radius of gyration, SASA, PCA, DCCM, DSSP and MM-PBSA binding energy calculation along with demonstrated high stability of the MexB-Nilotinib complex with lesser distortions. Our study concludes, that Nilotinib is a potential inhibitor and can be developed as a therapeutic agent against MexB protein for controlling P. aeruginosa infections.

PMID:39580714 | DOI:10.1080/07391102.2024.2431666

Commun Med (Lond). 2024 Nov 23;4(1):246. doi: 10.1038/s43856-024-00616-6.

ABSTRACT

BACKGROUND: Respiratory tract infections (RTIs) drive lung function decline in children with cystic fibrosis (CF). While the respiratory microbiota is clearly associated with RTI pathogenesis in infants without CF, data on infants with CF is scarce. We compared nasal microbiota development between infants with CF and controls and assessed associations between early-life nasal microbiota, RTIs, and antibiotic treatment in infants with CF.

METHODS: We included 50 infants with CF and 30 controls from two prospective birth cohorts followed throughout the first year of life. We collected 1511 biweekly nasal swabs and analyzed the microbiota after amplifying the V3-V4 region of the 16S rRNA gene. We conducted structured weekly interviews to assess respiratory symptoms and antibiotic treatment. We calculated generalized additive mixed models and permutational analysis of variance.

RESULTS: Here, we show that the nasal microbiota is already altered before the first RTI or antibiotic treatment in infants with CF. Microbiota diversity differs between infants with CF and controls following RTIs and/or antibiotic treatment. CF infants with lower α-diversity have a higher number of subsequent RTIs.

CONCLUSIONS: Early nasal microbiota alterations may reflect predisposition or predispose to RTIs in infants with CF, and further change after RTIs and antibiotic treatment. This highlights the potential of targeting the nasal microbiota in CF-related RTI management, while also questioning current practices in the era of novel modulator therapies.

PMID:39580540 | DOI:10.1038/s43856-024-00616-6

J Intern Med. 2024 Nov 23. doi: 10.1111/joim.20034. Online ahead of print.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disease. Due to difficulty accessing diagnostic services and a lack of awareness of the syndrome, clinicians often fail to recognize the classic phenotype, leading to missed diagnoses.

METHODS: Relevant medical records were accessed through The BIG DATA QUERY AND ANALYSIS SYSTEM of Peking Union Medical College Hospital from September 1, 2012 to March 31, 2024. The search strategy included the following key terms: (bronchiectasis OR atelectasis OR recurrent cough OR recurrent expectoration OR hemoptysis) AND (sinusitis OR nasal polyps OR otitis media OR neonatal pneumonia OR neonatal respiratory distress OR ectopic pregnancy OR infertility OR artificial insemination OR assisted reproduction OR hydrocephalus OR congenital heart disease OR organ laterality defect OR right-sided heart OR semen OR consanguineous marriage). Patients were filtered according to inclusion and exclusion criteria, and those with clinical suspicion of PCD were invited for screening, which included nasal nitric oxide and whole exome sequencing.

RESULTS: A total of 874 medical records were retrieved. After filtering based on inclusion and exclusion criteria, 65 patients with clinical suspicion of PCD were identified, 21 of whom accepted our invitation to complete PCD-related screening. Among them, four were diagnosed with PCD, one was diagnosed with cystic fibrosis, and one was diagnosed with immunodeficiency-21.

CONCLUSIONS: This is the first study to use an electronic medical record retrieval system to identify missed diagnoses PCD. We believe that the methods used in this study can be extended to other rare diseases in the future.

PMID:39578984 | DOI:10.1111/joim.20034

Nat Metab. 2024 Nov 22. doi: 10.1038/s42255-024-01170-0. Online ahead of print.

ABSTRACT

Cushing's syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing's syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing's syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing's syndrome.

PMID:39578649 | DOI:10.1038/s42255-024-01170-0

Oncoimmunology. 2024 Dec 31;13(1):2432059. doi: 10.1080/2162402X.2024.2432059. Epub 2024 Nov 21.

ABSTRACT

Few clinical studies investigated the putative link between the activation of immunogenic cell death (ICD) and the oncological outcome. Recent data, published in a Phase 1b trial, demonstrated that an ICD-associated surge in the plasma concentration of high-mobility group box 1 (HMGB1) indicates favorable prognosis in patients with advanced leiomyosarcomas treated with the combination of doxorubicin, dacarbazine and nivolumab.

PMID:39572927 | PMC:PMC11587826 | DOI:10.1080/2162402X.2024.2432059

J Cyst Fibros. 2024 Nov 21:S1569-1993(24)01811-3. doi: 10.1016/j.jcf.2024.11.003. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has profoundly affected the health and lives of many people with CF (pwCF). The rapid change in health for pwCF taking ETI provided them an opportunity to reflect on what "being healthy" means. The goal of this secondary analysis was to document changes in the health and well-being of pwCF after starting ETI, beyond the expected physical benefits.

METHODS: The Qualitative Understanding of Experiences with the SIMPLIFY Trial (QUEST) study evaluated pwCF's experiences on ETI, including participation in a withdrawal study, treatment burden, and experiences of health. Two sixty-minute interviews were conducted approximately four months apart, audio-recorded and transcribed. A phenomenological approach was used to identify text of interest and create a formal codebook.

RESULTS: Ninety-one pwCF (mean age=27.8 years; range 14-67; 51 % male) and 23 caregivers of the teenagers completed at least one interview. Beyond the expected benefits of ETI, four themes were identified: (1) Night and Day Change in Health, (2) Reduced Cognitive Burden, (3) Shifting to Managing Overall Wellness and Co-Morbidities, and (4) Social/Self Identity Changes.

CONCLUSION: ETI has raised pwCF's expectations for their health and well-being. Current symptom and QOL measures may no longer capture the less perceptible ways pwCF on ETI experience changes in symptoms or health. CF care may need to adapt to focus more on general health, managing other comorbidities, and planning for the future.

PMID:39578180 | DOI:10.1016/j.jcf.2024.11.003

Chemosphere. 2024 Nov 20:143783. doi: 10.1016/j.chemosphere.2024.143783. Online ahead of print.

ABSTRACT

Estuaries and lagoons are characterized by fluctuating salinity and significant amounts of microplastics (MPs) and are increasingly subjected to various anthropogenic pressures. We investigated whether the accumulation of MPs in the gills of fish inhabiting these fragile ecosystems alters osmoregulation and, consequently, their ability to tolerate fluctuating salinity. The effects of a 15-day exposure to an environmentally relevant concentration (20 μg/L) of spherical polystyrene microplastics (PS-MPs) with a diameter of 5 μm were assessed in the Mediterranean killifish Aphanius fasciatus, focusing on tissue and gene expression changes related to factors of paracellular and transcellular permeability of the gill epithelium during the transition from seawater to freshwater. Our results revealed that PS-MPs indirectly impaired osmoregulation, particularly in fresh water, through their toxic effects on the gill tissue. Toxicity was evidenced by epithelial lifting, a decrease in the proportion of secondary lamellae available for gas exchange, and upregulation of superoxide dismutase and heat shock protein genes. Furthermore, exposure to PS-MPs directly affected gill epithelial permeability by maintaining relatively high paracellular permeability through the downregulation of claudin 3 and by modifying the expression of the transcellular transporter Na+/K+-ATPase and cystic fibrosis transmembrane conductance regulator in the gill epithelium. Overall, these findings confirm the toxic effects of PS-MPs on gill tissue and demonstrate, for the first time, that environmentally relevant concentrations of MPs adversely affect gill epithelium permeability during decreased salinity acclimation in the euryhaline fish A. fasciatus.

PMID:39577801 | DOI:10.1016/j.chemosphere.2024.143783

J Natl Cancer Inst. 2024 Nov 22:djae288. doi: 10.1093/jnci/djae288. Online ahead of print.

ABSTRACT

BACKGROUND: Rising cancer incidence, particularly for colorectal cancer, has been reported in young adults. This study examined whether this is related to an increase in mortality.

METHODS: We analysed World Health Organization (WHO) mortality data among young adults aged 25-49 in 15 most populous upper-middle and high-income countries from 1990 to 2021 with reliable data. Mid-year populations were retrieved from the United Nations for the American Countries and from the WHO for the other countries. We compared age-standardised mortality rates (ASMRs) in 2019-2021 to 2009-2011 and performed joinpoint regression analysis for all cancers and selected most common cancer sites: colorectum, pancreas, lung and breast.

RESULTS: In 2019-2021, the highest ASMRs (per 100,000) were in Romanian males (38.6) and Argentinian females (45.9), while the lowest ones in Japan (males: 16.3; females: 22.7). ASMRs for colorectal cancers increased in 2019-2021 compared to 2009-2011 in nine countries among men and in seven countries among women. The highest increases were in the UK (males: +26.1%; females: +33.7%), Canada (males: +25.3%), and Mexico (males: +33.5%; females: +29.7%). Long-term analysis over the last three decades showed declining trends in total cancer mortality in the majority of countries, in lung cancer mortality across all countries, and in breast cancer in all countries except in Latin America.

CONCLUSIONS: While mortality from common cancers has generally decreased over the past three decades, mortality from colorectal cancer has increased in some countries. This highlights the need to control the obesity epidemic and implement targeted surveillance strategies in young populations.

PMID:39576674 | DOI:10.1093/jnci/djae288

mBio. 2024 Nov 22:e0145624. doi: 10.1128/mbio.01456-24. Online ahead of print.

ABSTRACT

Chronic lung infections are the primary cause of morbidity and early mortality in cystic fibrosis (CF) and, as such, have been the subject of a great deal of research. Subsequently, they have become one of the key paradigms for polymicrobial infections. The literature, however, has traditionally focused on the presence of pathogens in isolation or univariate measures like number of species to predict decline of lung function and ignores large swathes of data. Here, we suggest that looking at the interactions between species identified by 16S rRNA gene sequencing, rather than at species singularly, could elucidate hitherto unknown properties of these complicated infections. To confirm this, pooled samples from studies conducted by our laboratory, sequenced using the same pipeline, were used to assess microbiome-wide associations to lung function. We found pathogenic interactions between species were limited to the most abundant species, which were composed of canonical CF pathogens (including Pseudomonas, Staphylococcus, Stenotrophomonas, and Achromobacter) and commensals. This observation is crucial for better understanding of polymicrobial infections and treatment of these conditions while providing a simple framework for expanding this research into other disease states. The adoption of ecological principles into infection science can provide better understanding and options to those suffering from chronic conditions. The statistical ecology approach presented here enables clear hypotheses from observational data that can be ratified through subsequent manipulative experimental studies. Moreover, it can also be used to support the design and construction of clinically relevant in vitro models of polymicrobial infections.

IMPORTANCE: Research studies have repeatedly demonstrated that chronic lung infection in cystic fibrosis is polymicrobial and consequently does not adhere to the single microbe-based Koch's postulates. Despite the plethora of evidence, the role of the constituent taxa present is largely unknown. Here we demonstrate how an ecological modeling perspective on lung infection microbiota can tease out potential interactions that alter progression of disease. Using techniques akin to genome-wide association studies, we show and validate 22 taxa, present in the chronic respiratory disease associated with cystic fibrosis, which have significant interactions that are negatively associated with patient lung function, the majority of which are "non-pathogenic" organisms. This work highlights the need to understand the interactive landscapes of the microbiomes to fully appreciate the complexity and treat chronic lung infections. Furthermore, this presents testable hypotheses for manipulative experiments in model systems to elucidate key mechanisms to driving disease progression.

PMID:39576107 | DOI:10.1128/mbio.01456-24

J Pediatr Gastroenterol Nutr. 2024 Nov 22. doi: 10.1002/jpn3.12406. Online ahead of print.

ABSTRACT

Handgrip strength (HGS) is a simple measurement of maximum voluntary muscle strength and is widely used as a single indicator of overall muscle strength. This systematic review summarized the evidence about the relation between HGS and health outcomes in hospitalized children or chronically ill children. The primary outcome was the number of hospital days in a 2-month period for outpatients and the length of hospital stay for inpatients. After a systematic search in PubMed, Embase, Lilacs, and the Cochrane Library, 9282 unique papers were screened, 24 included. Studies assessed HGS in children with cystic fibrosis, neuromuscular disease, chronic kidney disease, type 1 diabetes mellitus, asthma, cardiac disease, juvenile idiopathic arthritis, intestinal failure, surgical patients, and a mixed hospitalized population. One study reported that children experienced a decline in HGS during hospitalization which was associated with prolonged hospital stay. Another reported no relation with the number of hospital days in 5 years. No studies reported on the association between HGS and infectious complications or antibiotic use. We did find a positive correlation between HGS and quality of life, different nutritional parameters and inflammatory biochemical markers. We concluded that the relation between HGS and hospital stay in children is poorly studied. HGS showed promise as a functional biomarker for children with chronic health conditions when inflammation is involved, but more attention should be paid to the methodological aspects of assessing HGS.

PMID:39575709 | DOI:10.1002/jpn3.12406

Cureus. 2024 Oct 22;16(10):e72142. doi: 10.7759/cureus.72142. eCollection 2024 Oct.

ABSTRACT

An allergic reaction to infections with Aspergillus fumigatus causes allergic bronchopulmonary aspergillosis (ABPA). This response often can worsen underlying symptoms of previously well-controlled diseases, such as asthma or cystic fibrosis. Due to the nature of the symptoms, patients with ABPA are often regarded as just having worsening asthma control or are treated for a different disease entirely. Even when diagnosed, the treatment is often formulaic and not tailored to the patient directly. This report will discuss the case of a 63-year-old man with a background of asthma who presented with recurrent chest infections, in which treatment with antibiotics and steroids did not resolve his symptoms. A diagnosis of ABPA was made following investigations, which has led to better control of his symptoms on long-term antifungal treatment.

PMID:39575033 | PMC:PMC11581136 | DOI:10.7759/cureus.72142