Life (Basel). 2023 May 31;13(6):1305. doi: 10.3390/life13061305.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. With the advent of highly effective modulator therapy targeting the abnormal CFTR protein, people with CF (PwCF) are living more than 40 years longer than the pre-modulator therapy era. As a result, PwCF are facing new challenges of managing similar comorbidities affecting the average aging population. While CF is notoriously identified as a chronic respiratory disease, the multisystem presence of the CFTR gene can contribute to other organ-related complications acutely, but also heighten the likelihood of chronic conditions not routinely encountered in this cohort. In this overview, we will focus on risk factors and epidemiology for PwCF as they relate to cardiovascular disease, dyslipidemia, CF-related diabetes, pulmonary hypertension, obstructive sleep apnea, CF-liver disease, bone health and malignancy. With increased awareness of diseases affecting a newly aging CF population, a focus on primary and secondary prevention will be imperative to implementing a comprehensive care plan to improve long-term morbidity and mortality.

PMID:37374088 | DOI:10.3390/life13061305

J Pers Med. 2023 May 31;13(6):924. doi: 10.3390/jpm13060924.

ABSTRACT

(1) Background: Cystic fibrosis (CF) is a disease with well-documented clinical differences between female and male patients. However, this gender gap is very poorly studied at the molecular level. (2) Methods: Expression differences in whole blood transcriptomics between female and male CF patients are analyzed in order to determine the pathways related to sex-biased genes and assess their potential influence on sex-specific effects in CF patients. (3) Results: We identify sex-biased genes in female and male CF patients and provide explanations for some sex-specific differences at the molecular level. (4) Conclusion: Genes in key pathways associated with CF are differentially expressed between sexes, and thus may account for the gender gap in morbidity and mortality in CF.

PMID:37373913 | DOI:10.3390/jpm13060924

Int J Mol Sci. 2023 Jun 19;24(12):10358. doi: 10.3390/ijms241210358.

ABSTRACT

Despite the promising results of new CFTR targeting drugs designed for the recovery of F508del- and class III variants activity, none of them have been approved for individuals with selected rare mutations, because uncharacterized CFTR variants lack information associated with the ability of these compounds in recovering their molecular defects. Here we used both rectal organoids (colonoids) and primary nasal brushed cells (hNEC) derived from a CF patient homozygous for A559T (c.1675G>A) variant to evaluate the responsiveness of this pathogenic variant to available CFTR targeted drugs that include VX-770, VX-809, VX-661 and VX-661 combined with VX-445. A559T is a rare mutation, found in African-Americans people with CF (PwCF) with only 85 patients registered in the CFTR2 database. At present, there is no treatment approved by FDA (U.S. Food and Drug Administration) for this genotype. Short-circuit current (Isc) measurements indicate that A559T-CFTR presents a minimal function. The acute addition of VX-770 following CFTR activation by forskolin had no significant increment of baseline level of anion transport in both colonoids and nasal cells. However, the combined treatment, VX-661-VX-445, significantly increases the chloride secretion in A559T-colonoids monolayers and hNEC, reaching approximately 10% of WT-CFTR function. These results were confirmed by forskolin-induced swelling assay and by western blotting in rectal organoids. Overall, our data show a relevant response to VX-661-VX-445 in rectal organoids and hNEC with CFTR genotype A559T/A559T. This could provide a strong rationale for treating patients carrying this variant with VX-661-VX-445-VX-770 combination.

PMID:37373505 | DOI:10.3390/ijms241210358

Int J Mol Sci. 2023 Jun 17;24(12):10266. doi: 10.3390/ijms241210266.

ABSTRACT

Introducing or correcting disease-causing mutations through genome editing in human pluripotent stem cells (hPSCs) followed by tissue-specific differentiation provide sustainable models of multiorgan diseases, such as cystic fibrosis (CF). However, low editing efficiency resulting in extended cell culture periods and the use of specialised equipment for fluorescence activated cell sorting (FACS) make hPSC genome editing still challenging. We aimed to investigate whether a combination of cell cycle synchronisation, single-stranded oligodeoxyribonucleotides, transient selection, manual clonal isolation, and rapid screening can improve the generation of correctly modified hPSCs. Here, we introduced the most common CF mutation, ΔF508, into the CFTR gene, using TALENs into hPSCs, and corrected the W1282X mutation using CRISPR-Cas9, in human-induced PSCs. This relatively simple method achieved up to 10% efficiency without the need for FACS, generating heterozygous and homozygous gene edited hPSCs within 3-6 weeks in order to understand genetic determinants of disease and precision medicine.

PMID:37373413 | DOI:10.3390/ijms241210266

Biomedicines. 2023 Jun 19;11(6):1754. doi: 10.3390/biomedicines11061754.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful and easy-to-perform test for diagnosis and follow-up in clinical practice. Regarding CFRD treatment, although insulin is the classic approved pharmacological option, incretins could also be a helpful alternative in early stages. CGM could be also a useful tool to measure the early response to this therapy.

METHODS: We studied 25 CF patients with abnormal OGTT results and compared glucose and insulin levels during the OGTTs with CGM results as a tool for early CFRD diagnosis. In addition, we evaluated glycaemic control with CGM before and after treatment with sitagliptin.

RESULTS: A correlation was found between lower plasma insulin levels during the OGTTs and higher average sensor glucose (p = 0.009) and hyperglycaemic excursions (p = 0.017). The CGM data on sitagliptin treatment (n = 25) showed an average glycaemic improvement from 124.2 to 117.2 mg/dL (p = 0.002) with a 5.6-point standard deviation of glucose decrease (p < 0.001). Hyperglycaemic excursions ≥200 mg/dL diminished 57.1% (p = 0.021). Both time in range and time above 180 mg/dL improved during treatment (p = 0.036 and p = 0.006, respectively).

CONCLUSION: CGM is a useful tool that offers valuable information for both the diagnosis and the management of CFRD. Lower plasma insulin levels during OGTTs are associated with a poor ambulatory glucose profile in CGM. Sitagliptin could play an important role in the treatment of the early stages of CFRD.

PMID:37371849 | DOI:10.3390/biomedicines11061754

Biomedicines. 2023 Jun 15;11(6):1725. doi: 10.3390/biomedicines11061725.

ABSTRACT

Dysfunction of neutrophils in patients with cystic fibrosis (CF) is best characterized in bronchoalveolar lavage (BAL), whereas peripheral blood neutrophils are less examined, and the results are contradictory, especially in younger populations. Therefore, this work aimed to study functional and phenotypic changes in circulating neutrophils in children with CF. The study included 19 CF children (5-17 years) and 14 corresponding age-matched healthy children. Isolated neutrophils were cultured either alone or with different stimuli. Several functions were studied: apoptosis, NET-osis, phagocytosis, and production of reactive oxygen species (ROS), neutrophil elastase (NE), and 11 cytokines. In addition, the expression of 20 molecules involved in different functions of neutrophils was evaluated by using flow cytometry. CF neutrophils showed reduced apoptosis and lower production of NE and IL-18 compared to the healthy controls, whereas IL-8 was augmented. All of these functions were further potentiated after neutrophil stimulation, which included higher ROS production and the up-regulation of CD11b and IL-10 expression. NET-osis was higher only when neutrophils from moderate-severe CF were treated with Pseudomonas aeruginosa, and the process correlated with forced expiratory volume in the first second (FEV1). Phagocytosis was not significantly changed. In conclusion, circulating neutrophils from children with CF showed fewer impaired changes in phenotype than in function. Functional abnormalities, which were already present at the baseline levels in neutrophils, depended on the type of stimuli that mimicked different activation states of these cells at the site of infection.

PMID:37371820 | DOI:10.3390/biomedicines11061725

Biomedicines. 2023 May 26;11(6):1540. doi: 10.3390/biomedicines11061540.

ABSTRACT

OBJECTIVES: Monoclonal antibodies (mAbs) have proven to be a valuable tool against COVID-19, mostly among subjects with risk factors for progression to severe illness. Tixagevimab/cilgavimab (TIX/CIL), a combination of two Fc-modified human monoclonal antibodies, has been recently approved to be employed as early treatment.

METHODS: Two groups of immunocompromised patients exposed to different early treatments (i.e., TIX/CIL vs. other mAbs [casirivimab/imdevimab, bamlanivimab/etesevimab, sotrovimab]) were compared in terms of clinical outcomes (hospitalisation and mortality within 14 days from administration) and time to the negativity of nasal swabs. We used either Pearson's chi-square or Fisher's exact test for categorical variables, whereas the Wilcoxon rank-sum test was employed for continuous ones. Kaplan-Meier curves were produced to compare the time to nasopharyngeal swab negativity.

RESULTS: Early treatment with TIX/CIL was administered to 19 immunocompromised patients, while 89 patients received other mAbs. Most of them were solid organ transplant recipients or suffering from hematologic or solid malignancies. Overall, no significant difference was observed between the two groups regarding clinical outcomes. In the TIX/CIL group, one patient (1/19, 5.3%), who was admitted to the emergency room within the first 14 days from treatment and was hospitalised due to COVID-19 progression, died. Regarding the time to nasal swab negativity, no significant difference (p = 0.088) emerged.

CONCLUSIONS: Early treatment of SARS-CoV-2 infection with TIX/CIL showed favourable outcomes in a small group of immunocompromised patients, reporting no significant difference compared to similar patients treated with other mAbs.

PMID:37371635 | DOI:10.3390/biomedicines11061540

Biomolecules. 2023 Jun 6;13(6):949. doi: 10.3390/biom13060949.

ABSTRACT

Recent developments in CFTR modulator drugs have had a significant transformational effect on the treatment of individuals with Cystic Fibrosis (CF) who carry the most frequent F508del-CFTR mutation in at least one allele. However, the clinical effects of these revolutionary drugs remain limited by their inability to fully restore the plasma membrane (PM) stability of the rescued mutant channels. Here, we shed new light on the molecular mechanisms behind the reduced half-life of rescued F508del-CFTR at the PM of airway cells. We describe that YES1 protein kinase is enriched in F508del-CFTR protein PM complexes, and that its interaction with rescued channels is mediated and dependent on the adaptor protein YAP1. Moreover, we show that interference with this complex, either by depletion of one of these components or inhibiting YES1 activity, is sufficient to significantly improve the abundance and stability of modulator-rescued F508del-CFTR at the surface of airway cells. In addition, we found that this effect was mediated by a decreased phosphorylation of the scaffold protein SHC1, a key regulator of MAPK pathway activity. In fact, we showed that depletion of SHC1 or inhibition of MAPK pathway signaling was sufficient to improve rescued F508del-CFTR surface levels, whereas an ectopic increase in pathway activation downstream of SHC1, through the use of a constitutively active H-RAS protein, abrogated the stabilizing effect of YES1 inhibition on rescued F508del-CFTR. Taken together, our findings not only provide new mechanistic insights into the regulation of modulator-rescued F508del-CFTR membrane stability, but also open exciting new avenues to be further explored in CF research and treatment.

PMID:37371529 | DOI:10.3390/biom13060949

Cells. 2023 Jun 6;12(12):1555. doi: 10.3390/cells12121555.

ABSTRACT

Cystic fibrosis (CF) is a monogenic recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator gene (CFTR). Remarkable progress in basic research has led to the discovery of highly effective CFTR modulators. Now ~90% of CF patients are treatable. However, these modulator therapies are not curative and do not cover the full spectrum of CFTR mutations. Thus, there is a continued need to develop a complete and durable therapy that can treat all CF patients once and for all. As CF is a genetic disease, the ultimate therapy would be in-situ repair of the genetic lesions in the genome. Within the past few years, new technologies, such as CRISPR/Cas gene editing, have emerged as an appealing platform to revise the genome, ushering in a new era of genetic therapy. This review provided an update on this rapidly evolving field and the status of adapting the technology for CF therapy.

PMID:37371025 | DOI:10.3390/cells12121555

Antibiotics (Basel). 2023 Jun 20;12(6):1078. doi: 10.3390/antibiotics12061078.

ABSTRACT

Delafloxacin (DLX) is a recently approved fluoroquinolone with broad activity against common cystic fibrosis (CF) pathogens, including multidrug-resistant Pseudomonas aeruginosa (MDR-Psa). Delafloxacin has been previously shown to have excellent lung and biofilm penetration and enhanced activity at lower pH environments, such as those that would be observed in the CF lung. We analyzed six Psa strains isolated from CF sputum and compared DLX to ciprofloxacin (CPX) and levofloxacin (LVX). Minimum inhibitory concentrations (MICs) were determined for DLX using standard culture media (pH 7.3) and artificial sputum media (ASM), a physiologic media recapitulating the CF lung microenvironment (pH 6.9). Delafloxacin activity was further compared to CPX and LVX in an in vitro CF sputum time-kill model at physiologically relevant drug concentrations (Cmax, Cmed, Cmin). Delafloxacin exhibited 2- to 4-fold MIC reductions in ASM, which corresponded with significant improvements in bacterial killing in the CF sputum time-kill model between DLX and LVX at Cmed (p = 0.033) and Cmin (p = 0.004). Compared to CPX, DLX demonstrated significantly greater killing at Cmin (p = 0.024). Overall, DLX demonstrated favorable in vitro activity compared to alternative fluoroquinolones against MDR-Psa. Delafloxacin may be considered as an option against MDR-Psa pulmonary infections in CF.

PMID:37370396 | DOI:10.3390/antibiotics12061078

Antibiotics (Basel). 2023 Jun 17;12(6):1069. doi: 10.3390/antibiotics12061069.

ABSTRACT

Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 (72%) were positive for SCVs. Characterization included genotyping, SCCmec types, auxotrophy, biofilm production, antibiotic susceptibilities and tolerance, and resistance acquisition rates. Whole-genome sequencing revealed that several patients were colonized with prototypical and SCV-related clones. Some clonal pairs showed acquisition of aminoglycoside resistance that was not explained by aminoglycoside-modifying enzymes, suggesting a mutation-based process. The characteristics of SCVs that could play a role in resistance acquisition were thus investigated further. For instance, SCV isolates produced more biofilm (p < 0.05) and showed a higher survival rate upon exposure to ciprofloxacin and vancomycin compared to their prototypic associated clones. SCVs also developed spontaneous rifampicin resistance mutations at a higher frequency. Accordingly, a laboratory-derived SCV (ΔhemB) acquired resistance to ciprofloxacin and gentamicin faster than its parent counterpart after serial passages in the presence of sub-inhibitory concentrations of antibiotics. These results suggest a role for SCVs in the establishment of persistent antibiotic-resistant clones in adult CF patients.

PMID:37370388 | DOI:10.3390/antibiotics12061069

Sci Rep. 2023 Jun 27;13(1):10433. doi: 10.1038/s41598-023-37492-4.

ABSTRACT

Cystic fibrosis related diabetes (CFRD) is observed in 20-50% of adults with cystic fibrosis (CF). Pancreas abnormalities on imaging, e.g. pancreas lipomatosis, are frequent in subjects with CF. We hypothesized that specific abnormalities may characterize patients with CFRD. We performed a retrospective study comparing the computed tomography (CT) of participants with CF with or without diabetes ("CFRD" and "CF control" groups). We classified the pancreas on imaging according to 3 categories: normal, partial lipomatosis and complete lipomatosis of the pancreas. We also assessed the presence or absence of pancreatic calcifications. Forty-one CFRD and 53 CF control participants were included. Only 2% of the patients with CFRD had a normal pancreas, as compared with 30% of the participants from the CF control group (p = 0.0016). Lipomatosis was more frequent in subjects with CFRD and was related to exocrine pancreatic insufficiency (EPI) and to severe CFTR mutations (classes I to III). Nine participants with diabetes (22%) presented with pancreatic calcifications, versus none of the control participants (p = 0.0003). In conclusion, pancreas imaging was almost always abnormal in subjects with CFRD, while it was normal in a third of the CF control subjects. Pancreatic calcifications were specific of subjects with CFRD.

PMID:37369827 | DOI:10.1038/s41598-023-37492-4

J Fungi (Basel). 2023 Jun 13;9(6):660. doi: 10.3390/jof9060660.

ABSTRACT

Pneumocystis pneumonia (PcP) is a serious complication of many significant immunocompromising conditions. Prior incidence estimates in Wales are based on PcP's presentation in the HIV and transplant populations. The objectives were to describe the incidence of PcP in Wales using laboratory reporting measures and assess the impact of underlying immunosuppression cause on mortality. All positive PCR results for PcP between 2015 and 2018 were identified. The total number of unique positives with clinical and radiological correlation was 159 patients, a mean of 39.75 annually. The healthcare records of these patients were reviewed. The mortality at one month was 35.2% and 49.1% at one year. HIV remains the commonest cause of immunosuppression but has lower mortality than non-HIV conditions (12% vs. 59% at one year, p < 0.00001). Non-HIV conditions were categorised as life-threatening and non-life threatening but had a non-significant mortality (66% vs. 54%; p = 0.149), highlighting the negative impact of PcP. An incidence of PcP in Wales of 1.23-1.26 cases per 100,000 has been identified, 32-35% greater than the upper limit previously estimated. There is high mortality in non-HIV patients regardless of immunosuppression cause. A heightened awareness of PcP in these groups will hasten diagnosis and potentially improve mortality.

PMID:37367596 | DOI:10.3390/jof9060660

Adv Respir Med. 2023 May 31;91(3):224-238. doi: 10.3390/arm91030018.

ABSTRACT

A substantial increase in broad-spectrum antibiotics as empirical therapy in patients with community-acquired pneumonia (CAP) has occurred over the last 15 years. One of the driving factors leading to that has been some evidence showing an increased incidence of drug-resistant pathogens (DRP) in patients from a community with pneumonia, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Research has been published attempting to identify DRP in CAP through the implementation of probabilistic approaches in clinical practice. However, recent epidemiological data showed that the incidence of DRP in CAP varies significantly according to local ecology, healthcare systems and countries where the studies were performed. Several studies also questioned whether broad-spectrum antibiotic coverage might improve outcomes in CAP, as it is widely documented that broad-spectrum antibiotics overuse is associated with increased costs, length of hospital stay, drug adverse events and resistance. The aim of this review is to analyze the different approaches used to identify DRP in CAP patients as well as the outcomes and adverse events in patients undergoing broad-spectrum antibiotics.

PMID:37366804 | DOI:10.3390/arm91030018

Allergy. 2023 Jun 27. doi: 10.1111/all.15788. Online ahead of print.

ABSTRACT

BACKGROUND: A modified grass allergen subcutaneous immunotherapy (SCIT) product with MicroCrystalline Tyrosine and monophosphoryl lipid-A as an adjuvant system (Grass MATA MPL [PQ Grass]) is being developed as short-course treatment of grass-pollen allergic rhinitis (SAR) and/or rhinoconjunctivitis. We sought to evaluate the combined symptom and medication score (CSMS) of the optimized cumulative dose of 27,600 standardized units (SU) PQ Grass in a field setting prior to embarking on a pivotal Phase III trial.

METHODS: In this exploratory, randomized, double-blind, placebo-controlled trial subjects were enrolled across 14 sites (Germany and the United States of America). Six pre-seasonal subcutaneous injections of PQ Grass (using conventional or extended regimens) or placebo were administered to 119 subjects (aged 18-65 years) with moderate-to-severe SAR with or without asthma that was well-controlled. The primary efficacy endpoint was CSMS during peak grass pollen season (GPS). Secondary endpoints included Rhinoconjunctivitis Quality of Life Questionnaire standardized (RQLQ-S) and allergen-specific IgG4 response.

RESULTS: The mean CSMS compared to placebo was 33.1% (p = .0325) and 39.5% (p = .0112) for the conventional and extended regimens, respectively. An increase in IgG4 was shown for both regimens (p < .01) as well as an improvement in total RQLQ-S for the extended regimen (mean change -0.72, p = .02). Both regimens were well-tolerated.

CONCLUSIONS: This trial demonstrated a clinically relevant and statistically significant efficacy response to PQ Grass. Unprecedented effect sizes were reached for grass allergy of up to ≈40% compared to placebo for CSMS after only six PQ Grass injections. Both PQ Grass regimens were considered equally safe and well-tolerated. Based on enhanced efficacy profile extended regime will be progressed to the pivotal Phase III trial.

PMID:37366581 | DOI:10.1111/all.15788

Cell Cycle. 2023 Jun 26:1-21. doi: 10.1080/15384101.2023.2228089. Online ahead of print.

ABSTRACT

MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease.Abbreviations: Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3β (GSK3β); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor β1 (TGF-β1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).

PMID:37365840 | DOI:10.1080/15384101.2023.2228089

Child Adolesc Psychiatry Ment Health. 2023 Jun 26;17(1):80. doi: 10.1186/s13034-023-00630-x.

ABSTRACT

BACKGROUND: Adolescents and young adults (AYA) with a chronic somatic disease (CD) have a 3-fold higher risk of post-traumatic stress disorder (PTSD) than healthy controls. In addition, elevated post-traumatic stress symptoms (PTSS) have a negative impact on CD severity, treatment adherence, health problems and functional impairment. However, a more detailed understanding of this comorbidity is lacking.

METHODS: AYA with type 1 diabetes mellitus, juvenile idiopathic arthritis or cystic fibrosis (12-21 years of age) and elevated anxiety and/or depression symptoms, as well as their reference persons (≥ 18 years of age), completed online questionnaires in self- or observer report. The most stressful event related to the CD was reported descriptively. Questionnaires were used to assess PTSS, anxious and depressive symptoms, actual overall health, coping, personal growth and social support. Qualitative content analysis, linear regression models and correlations were used for mixed methods analysis.

RESULTS: According to the reports of n = 235 AYA (mean age 15.61; 73% girls) and n = 70 reference persons, four categories were identified as the most stressful events due to CD: (1) psychological burden (40% of AYA / 50% of reference persons); (2) CD self-management (32% / 43%); (3) social burden (30% / 27%); and (4) physical impairment (23% / 16%). 37% of AYA reported clinically relevant PTSS due to CD. The best predictors of PTSS severity were anxious-depressive symptoms, emotional coping, personal growth and current overall health (F(4, 224) = 59.404, R² = 0.515, p < .001). Of all categories, psychological (β = 0.216, p = .002) and social burden (β = 0.143, p = .031) showed significant association with the severity of PTSS (F(4, 230) = 4.489, R² = 0.072, p = .002). The more categories the most stressful event addressed, the higher was the PTSS symptom severity (r = .168, p = .010).

CONCLUSIONS: Many AYA showed clinically relevant PTSS and reported experiencing stressful events in several areas of life through their CD. The association between the stressful event categories and other variables could help identify AYA with CD who need psychological interventions the most.

TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00016714, registered on 25/03/2019 and DRKS00017161, registered on 17/09/201.

PMID:37365570 | DOI:10.1186/s13034-023-00630-x

Paediatr Respir Rev. 2023 Jun 17:S1526-0542(23)00038-6. doi: 10.1016/j.prrv.2023.06.002. Online ahead of print.

ABSTRACT

We present the case of a child given a CFSPID designation in early life who was later reclassified as having CF based on a combination of recurrent respiratory symptoms and CFTR functional testing, despite normal sweat chloride levels. Here we demonstrate the importance of monitoring these children, each time reviewing the diagnosis based on updated understanding of individual CFTR mutation phenotypes or clinical findings inconsistent with the designation. This case identifies situations in which the CFSPID designation should be challenged, and gives an approach for this when CF is suspected.

PMID:37365112 | DOI:10.1016/j.prrv.2023.06.002

J Cyst Fibros. 2023 Jun 24:S1569-1993(23)00817-2. doi: 10.1016/j.jcf.2023.06.003. Online ahead of print.

ABSTRACT

BACKGROUND: Historically, body mass index (BMI) >50th percentile has represented optimal nutritional status in children with cystic fibrosis (CF) due to its positive association with lung function. Body composition parameters including fat-free mass index (FFMI) have been suggested as a more physiological nutrition benchmark.

AIMS: (1) describe changes in body composition with age and gender; (2) assess the correlation between measures of nutritional status (FFMI-z, FMI-z, BMI-z) and lung function (forced expiratory volume in one second predicted; FEV1pp).

METHODS: This retrospective, mixed cross-sectional and serial measures study consisted of children with CF (8 to 18 years) attending Sydney Children's Hospital (2007-2020). FFMI and fat mass index (FMI) were taken from biennial dual energy x-ray absorptiometry (DXA) scans. Z-scores were derived using Well's reference population [1]. Repeated measures correlation analyses assessed correlations between FFMI-z, FMI-z, and BMI-z with FEV1pp.

RESULTS: 339 DXA reports were analysed from 137 patients. There were slight downwards trends in BMI-z and FMI-z, and an upwards trend in FFMI-z with increasing age and across both genders. Females had higher FMI-z and FFMI-z than males from 12.5 years. There was a weak, positive correlation between FEV1pp and BMI-z (r = 0.14, p = 0.04), and FFMI-z (r = 0.25, p<0.001). FMI-z had no correlation with FEV1pp (r=-0.06, p = 0.41).

CONCLUSION: Deficits in FFMI exist despite increasing trends with age. FFMI-z and BMI-z had a weak, positive correlation with FEV1pp. In contemporary cohorts, nutritional status (reflected by surrogate markers such as FFMI and BMI) may be less influential upon lung function than in previous decades. [1]: Wells, J.C., et al. Body-composition reference data for simple and reference techniques and a 4-component model: a new UK reference child. Am. J. Clin. Nutr.96, 1316-1326 (2012).

PMID:37365079 | DOI:10.1016/j.jcf.2023.06.003

Clin Pediatr Endocrinol. 2023;32(3):155-160. doi: 10.1297/cpe.2022-0069. Epub 2023 Mar 19.

ABSTRACT

Pseudo-Bartter syndrome (PBS) develops owing to renal or extrarenal chloride loss, leading to hypokalemic alkalosis. Whereas most adult cases result from diuretic/laxative abuse, many infantile cases occur secondary to cystic fibrosis. Rarely, infantile PBS is caused by renal salt loss with anomalies of the kidney/urinary tract or genetic disorders, such as Dent disease. Here, we report the case of a 10-mo-old girl with a one-month history of decreased formula intake and 5.6% body weight loss. She showed typical laboratory findings as PBS, including hypokalemia (2.7 mEq/L) and high levels of bicarbonate (32.7 mEq/L) with a plasma renin activity of 399 ng/mL/h. With minimum supplementation of potassium and sodium, an improvement in body mass index, from -1.13 SD to +0.52 SD, with complete resolution of laboratory data was obtained in approximately one month. No causative mutations were identified in candidate genes for Bartter-Gitelman syndrome. Due to profound hypochloruria (< 15 mEq/L), PBS of renal origin was unlikely. In addition, extrarenal chloride loss did not seem to be the case, because the patient never manifested gastrointestinal symptoms. Therefore, we speculate that a temporary decrease in chloride intake, coupled with the putative genetic/epigenetic disadvantage of chloride retention, such as a subtle renal leak, may be responsible for the PBS in our patient.

PMID:37362166 | PMC:PMC10288294 | DOI:10.1297/cpe.2022-0069