J Cyst Fibros. 2024 Oct 16:S1569-1993(24)01790-9. doi: 10.1016/j.jcf.2024.09.022. Online ahead of print.

ABSTRACT

BACKGROUND: The constellation of hypertension, truncal obesity, impaired fasting glucose, low high-density lipoprotein, and hypertriglyceridemia is known as metabolic syndrome (MetSyn) and is associated with cardiovascular and other diseases. Elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) is associated with weight gain but effects on cardiovascular risk are unknown. This study sought to investigate ETI exposure and risk for development of MetSyn in pwCF.

METHODS: A prospective cohort study including pwCF ≥ 18 years old exposed to ETI was performed. All data for calculating MetSyn was collected from the electronic medical record at initiation and 1 year ± 3 months after starting ETI. A total of 152 pwCF exposed to ETI and 34 pwCF never exposed to CF transmembrane conductance regulator modulators were included in the analysis. Changes to hypertension classification was also examined over this period.

RESULTS: After 1 year of ETI there was an increase in MetSyn from 13 to 30 pwCF, p < 0.0001. No new cases of MetSyn were seen in the group not exposed to ETI. After 1 year of ETI, more people met criteria for class 1 (BP 130-139/90-99 mm Hg) or class 2 hypertension (BP ≥140/≥90 mm Hg) regardless of prior modulator exposure, p < 0.0001.

CONCLUSIONS: Exposure to ETI for 1 year resulted in an increased number of cases of MetSyn. There was an increased incidence of hypertension associated with ETI exposure. Additional studies are needed to further examine this trend and to determine if these changes will translate to cardiovascular complications over time.

PMID:39419654 | DOI:10.1016/j.jcf.2024.09.022

ACS Chem Biol. 2024 Oct 17. doi: 10.1021/acschembio.4c00571. Online ahead of print.

ABSTRACT

Mutations in creatine transporter SLC6A8 cause creatine transporter deficiency (CTD), which is responsible for 2% of all cases of X-linked intellectual disability. CTD has no current treatments and has a high unmet medical need. Inspired by the transformational therapeutic impact of small molecule "correctors" for the treatment of cystic fibrosis, which bind to mutated versions of the CFTR ion channel to promote its trafficking to the cell surface, we sought to identify small molecules that could stabilize SLC6A8 as a potential treatment for CTD. We leveraged a novel chemoproteomic technology for ligand discovery, reactive affinity probe interaction discovery, to identify small-molecule fragments with photoaffinity handles that bind to SLC6A8 in a cellular environment. We synthesized a library of irreversible covalent analogs of these molecules to characterize in functional assays, which revealed molecules that could promote the trafficking of mutant SLC6A8 variants to the cell surface. Further medicinal chemistry was able to identify reversible drug-like small molecules that both promoted trafficking of the transporter and also rescued creatine uptake. When profiled across the 27 most prevalent 27 SLC6A8 missense variants, we found that 10-20% of patient mutations were amenable to correction by our molecules. These results were verified in an endogenous setting using the CRISPR knock-in of selected missense alleles. We established in vivo proof-of-mechanism for correctors in a novel CTD mouse model with the P544L patient-defined variant knocked in to the SLC6A8 locus, where treatment with our orally bioavailable and brain penetrant tool corrector increased brain creatine levels in heterozygous female mice, validating correctors as a potential therapeutic approach for CTD.

PMID:39418577 | DOI:10.1021/acschembio.4c00571

J Physiol. 2024 Oct 17. doi: 10.1113/JP287289. Online ahead of print.

ABSTRACT

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100 mm) for 12 h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

PMID:39418107 | DOI:10.1113/JP287289

JAMA Netw Open. 2024 Oct 1;7(10):e2441127. doi: 10.1001/jamanetworkopen.2024.41127.

NO ABSTRACT

PMID:39418025 | DOI:10.1001/jamanetworkopen.2024.41127

Am J Respir Cell Mol Biol. 2024 Oct 17. doi: 10.1165/rcmb.2023-0209OC. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is the most common inherited disorder and is characterized by an inflammatory phenotype. Here, we found that in bronchial epithelium reconstituted form lung tissue biopsies from patients with CF, the RNA-binding protein tristetraprolin (TTP), a key regulator of inflammation, is dysregulated in cells that strongly express cytokines and interleukins. TTP activity is regulated by extensive post-translational modifications, particularly phosphorylation. We found that in addition to mRNA downregulation, phosphorylated TTP (which cannot bind to mRNA) accumulated in CF cultures, suggesting that the imbalance in TTP phosphorylation status could contribute to the inflammatory phenotype in CF. We confirmed TTP destabilizing role on IL8 mRNA through its 3'UTR sequence in CF cells. We next demonstrated that TTP phosphorylation is mainly regulated by MK2 through activation of ERK, which also was hyperphosphorylated. TTP is considered a mRNA decay factor with some exception, and we present a new positive role of TTP in CF cultures. We determined that TTP binds to specific ARE motifs on the 3'UTR of mRNA sequences and also, for the first time, to the 3'UTR of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) where TTP binding stabilizes the mRNA level. This study identified new partners that can be targeted in CF and proposes a new way to control CFTR gene expression.

PMID:39417720 | DOI:10.1165/rcmb.2023-0209OC

Pediatr Pulmonol. 2024 Oct 17. doi: 10.1002/ppul.27337. Online ahead of print.

ABSTRACT

The severity of lung disease as well as other disease manifestations have dramatically improved in those patients with cystic fibrosis (CF) that both have mutations responsive to small molecule- based therapies with CF transmembrane regulator (CFTR) modulators and do have access to these drugs. Unfortunately, these medications are not available to many patients with CF across the globe with access largely limited to high income countries. For those eligible to CFTR modulators new questions have arisen regarding the ongoing need for other medications addressing CF lung disease as well current care models with tight monitoring. This article aims to summarize how CF care may change in the future making a plea to expand the availability of highly effective medications to every child with CF that could benefit from treatment.

PMID:39417643 | DOI:10.1002/ppul.27337

Postgrad Med J. 2024 Oct 17:qgae144. doi: 10.1093/postmj/qgae144. Online ahead of print.

ABSTRACT

BACKGROUND: To determine the conditions that prevented transplant in patients referred to our center due to end-stage lung disease.

STUDY DESIGN: Descriptive study.

PLACE AND DURATION OF THE STUDY: Department of lung transplant clinic, Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey, from December 2017 to January 2022.

METHODS: Patients with end-stage lung disease referred to our clinic were retrospectively evaluated with regard to reasons for exclusion, diagnosis, and demographic data. The Karnofsky Performance Status scoring scale was used to measure the functional status of the patients.

RESULTS: A total of 311 patients were evaluated during the study period. The mean age was 44.2 (range 4-73) years. There were 207 (66.6%) male patients. The most common indications were idiopathic interstitial pneumonia in 104 (33.4%) patients, chronic obstructive pulmonary disease in 53 (17%) patients, bronchiectasis in 49 (15.7%) patients, and cystic fibrosis in 28 (9%) patients. Of the patients, 106 (34%) were not appropriate candidates for a lung transplant. The most common reasons for refusal were preventable situations such as activity limitation and poor performance in 53 (50%) patients, weight in 49 (46.2%) patients, and smoking in 10 (9.4%) patients.

CONCLUSION: Impaired performance status was the most common cause of lung transplant exclusion. Weight and smoking were preventable causes of exclusion. Implementing pulmonary rehabilitation in very few patients was the most important handicap. It is believed that providing optimal treatment with a multidisciplinary approach and timely referral to transplant centers will significantly reduce the reasons for exclusion. Key message What is already known on this topic? Referring lung transplant candidates to clinics at the earliest stage is essential for assessing their condition and exploring treatment options. What this study adds? Factors like smoking, obesity, and muscle loss can hinder the transplantation process; thus, timely interventions are crucial. The primary reason for excluding candidates from lung transplantation is the decline in performance status. How this study might affect research, practice or policy? Programs focused on smoking cessation, weight management, and muscle strengthening can play a vital role in enhancing patients' health before transplantation. It is imperative to expand and enhance the accessibility of pulmonary rehabilitation programs.

PMID:39417288 | DOI:10.1093/postmj/qgae144

bioRxiv [Preprint]. 2024 Oct 7:2024.10.07.617039. doi: 10.1101/2024.10.07.617039.

ABSTRACT

Investigation of chronic cystic fibrosis (CF) lung infections has been limited by a lack of murine models that reproduce obstructive lung pathology, chronicity of bacterial infections, and complex inflammation in human CF lung pathology. Three different approaches have been used separately to address these limitations, including using transgenic Scnn1b-Tg mice overexpressing a lung epithelial sodium channel to mimic the mucus-rich and hyperinflammatory CF lung environment, using synthetic CF sputum medium (SCFM) in an acute infection to induce bacterial phenotypes consistent with human CF, or using agar beads to promote chronic infections. Here, we combine these three models to establish a chronic Pseudomonas aeruginosa lung infection model using SCFM agar beads and Scnn1b- Tg mice (SCFM-Tg-mice) to recapitulate nutrients, mucus, and inflammation characteristic of the human CF lung environment. Like people with CF, SCFM-Tg-mice failed to clear bacterial infections. Lung function measurements showed that infected SCFM-Tg-mice had decreased inspiratory capacity and compliance, elevated airway resistance, and significantly reduced FVC and FEV0.1. Using spectral flow cytometry and multiplex cytokine arrays we show that, like people with CF, SCFM-Tg-mice developed inflammation characterized by eosinophil infiltration and Th2 lymphocytic cytokine responses. Chronically infected SCFM-Tg-mice developed an exacerbated mix of innate and Th1, Th2, and Th17-mediated inflammation, causing higher lung cellular damage, and elevated numbers of unusual Siglec F + neutrophils. Thus, SCFM-Tg-mice represents a powerful tool to investigate bacterial pathogenesis and potential treatments for chronic CF lung infections and reveal a potential role for Siglec F + neutrophils in CF inflammation.

IMPORTANCE: Host-pathogen interaction studies of Pseudomonas aeruginosa cystic fibrosis (CF) lung infections have been hampered by limitations of mouse infection models. Here we combine synthetic CF sputum medium (SCFM) agar beads and Scnn1b -Tg transgenic mice to model the mucus obstructed airways and complex inflammatory characteristic of the human cystic fibrosis lung environment. In this model, which we name SCFM-Tg-mice, we use SCFM to cause changes in bacterial gene expression consistent with sputum collected from people with CF and the Scnn1b-Tg mice produce excessive airway mucus like people with CF. We show that SCMF-Tg-mice infected with P. aeruginosa have defects in lung function and increased inflammation that is consistent with human CF lung infections. This model can be adapted for other bacterial species and can be used to test hypotheses about bacterial pathogenesis and potential treatments in a CF human-like system.

PMID:39416002 | PMC:PMC11482824 | DOI:10.1101/2024.10.07.617039

Nat Commun. 2024 Oct 16;15(1):8906. doi: 10.1038/s41467-024-53329-8.

ABSTRACT

Macrolides are widely used antibiotics for the treatment of bacterial airway infections. Due to its elevated minimum inhibitory concentration in standardized culture media, Pseudomonas aeruginosa is considered intrinsically resistant and, therefore, antibiotic susceptibility testing against macrolides is not performed. Nevertheless, due to macrolides' immunomodulatory effect and suppression of virulence factors, they are used for the treatment of persistent P. aeruginosa infections. Here, we demonstrate that macrolides are, instead, effective antibiotics against P. aeruginosa airway infections in an Air-Liquid Interface (ALI) infection model system resembling the human airways. Importantly, macrolide treatment in both people with cystic fibrosis and primary ciliary dyskinesia patients leads to the accumulation of uL4 and uL22 ribosomal protein mutations in P. aeruginosa which causes antibiotic resistance. Consequently, higher concentrations of antibiotics are needed to modulate the macrolide-dependent suppression of virulence. Surprisingly, even in the absence of antibiotics, these mutations also lead to a collateral reduction in growth rate, virulence and pathogenicity in airway ALI infections which are pivotal for the establishment of a persistent infection. Altogether, these results lend further support to the consideration of macrolides as de facto antibiotics against P. aeruginosa and the need for resistance monitoring upon prolonged macrolide treatment.

PMID:39414850 | DOI:10.1038/s41467-024-53329-8

MAGMA. 2024 Oct 16. doi: 10.1007/s10334-024-01209-z. Online ahead of print.

ABSTRACT

Standard quantitative abdominal MRI techniques are time consuming, require breath-holds, and are susceptible to patient motion artifacts. Magnetic resonance fingerprinting (MRF) is naturally multi-parametric and quantifies multiple tissue properties, including T1 and T2. This work includes T2* and off-resonance mapping into a free-breathing MRF framework utilizing a pilot tone navigator. The new acquisition and reconstruction are compared to current clinical standards. Prospective. Ten volunteers. 3 T scanner, Quadratic-RF MRF, Balanced SSFP, Inversion recovery spin-echo, LiverLab. MRI ROIs were evaluated in the liver, spleen, pancreas, kidney (cortex and medulla), and paravertebral muscle by two abdominal imaging investigators for ten healthy adult volunteers for clinical standard, breath-Hold (BH) qRF-MRF, and free-breathing qRF-MRF with pilot-tone (PT) acquisitions. Bland-Altman analysis as well as Student's T tests were used to evaluate and compare the respective ROI analyses. Quantitative values between breath-Hold (BH) and free-breathing qRF-MRF with pilot-tone (PT) results show good agreement with clinical standard T1 and T2 quantitative mapping, and Dixon q-VIBE (acquired using the Siemens LiverLAB). In this work, we show free-breathing abdominal MRF (T1, T2) with T2* results that are quantitatively comparable to current breath-hold MRF and clinical techniques.

PMID:39414686 | DOI:10.1007/s10334-024-01209-z

BMJ Case Rep. 2024 Oct 15;17(10):e262156. doi: 10.1136/bcr-2024-262156.

ABSTRACT

Central venous catheters including totally implantable venous access devices (TIVADs) have revolutionised the management of pulmonary infections and exacerbations in patients with cystic fibrosis (CF). While being better tolerated by the patient, these have allowed aggressive intravenous antibiotic therapies during recurrent hospitalisations. Given improvement in procedural strategies and operator experience, many patients with CF undergo lung transplants in the course of their disease nowadays. TIVADs can be associated with thrombosis leading to superior vena cava (SVC) obstruction and SVC syndrome which can pose a challenge, especially during the transplant surgery. We describe a case of successful management of SVC syndrome in a patient with CF undergoing a lung transplant, highlighting the strategies used to minimise risks associated with such a procedure.

PMID:39414317 | DOI:10.1136/bcr-2024-262156

Sci Total Environ. 2024 Oct 14:176938. doi: 10.1016/j.scitotenv.2024.176938. Online ahead of print.

ABSTRACT

As revealed by culture-independent methodologies, disruption of the normal lung microbiota (LM) configuration (LM dysbiosis) is a potential mediator of adverse effects from inhaled chemicals. LM, which consists of microbiota in the upper and lower respiratory tract, is influenced by various factors, including inter alia environmental exposures. LM dysbiosis has been associated with multiple respiratory pathologies such as asthma, lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Chemically-induced LM dysbiosis appears to play significant roles in human respiratory diseases, as has been shown for some air pollutants, cigarette smoke and some inhalable chemical antibiotics. Lung microbiota are also linked with the central nervous system (CNS) in the so-called lung-brain axis. Inhaled chemicals that undergo mucociliary clearance may be linked to respiratory conditions through gut microbiota (GM) dysbiosis in the so-called Gut-Lung axis. However, current linkages of various disease states to LM appears to be associative, with causal linkages requiring further studies using more robust approaches, methods and techniques that are different from those applied in studies involving (GM). Most importantly, the sampling techniques determine the level of risk of cross contamination. Furthermore, the development of continuous or semi-continuous systems designed to replicate the lung microbiome will go a long way to further LM dysbiosis studies. These challenges notwithstanding, the preponderance of evidence points to the significant role of LM-mediated chemical toxicity in human disease and conditions.

PMID:39414049 | DOI:10.1016/j.scitotenv.2024.176938

Microb Pathog. 2024 Oct 14:107016. doi: 10.1016/j.micpath.2024.107016. Online ahead of print.

ABSTRACT

PURPOSE: Staphylococcus aureus is one of the most prevalent pathogens in cystic fibrosis (CF), being of special relevance those methicillin-resistant (MRSA). The livestock-associated (LA)-MRSA lineage CC398 is an emerging problem, specially related to pig-farming (PF) environments. The objective was to characterize the S. aureus isolates recovered from CF-patients in a Spanish hospital located in a region with high-PF activity.

METHODS: Forty-two isolates were obtained (January-November/2022) and characterized (one/patient). The antimicrobial resistance phenotype/genotype was evaluated by Microscan/PCR. The presence of virulence and Immune Evasion Cluster (IEC) genes as well as the agr type was determined by PCR. MLST and spa-typing were studied by PCR-sequencing.

RESULTS: Nine of the 42 isolates were MRSA (21.4%), and 8 of them multidrug resistant (MDR). Among MRSA, 6 spa-types were detected, assigned to CC1, CC5, CC8, CC30, and CC398. Four MRSA isolates belonged to the lineage CC398-t011-IEC negative (animal adapted-clade, LA-MRSA). The remaining 33 isolates were methicillin-susceptible (MSSA), of 26 spa-types and associated with 11 CCs (predominant: CC5, CC30, and CC398). Seven MSSA isolates were of the lineage CC398 (spa-types t034, t108, t571, t20352); four of them were IEC-positive and erm(T)-positive (t571, and t20352, human-adapted CC398 clade), being IEC-negative the remaining three. The tst and eta/etb genes were identified in 12 and 2 isolates, respectively (none CC398). Small-colony-variants were demonstrated in 9 isolates (two CC398, both MDR).

CONCLUSION: The lineage CC398 was very frequent among CF-patients (26.2%), both among MSSA and MRSA. The emergence of LA-MRSA-CC398 in CF-patients requires monitorization, especially in hospitals of high-PF-regions.

PMID:39413853 | DOI:10.1016/j.micpath.2024.107016

Hypertension. 2024 Nov;81(11):2248-2250. doi: 10.1161/HYPERTENSIONAHA.124.23716. Epub 2024 Oct 16.

NO ABSTRACT

PMID:39413203 | DOI:10.1161/HYPERTENSIONAHA.124.23716

Nucleic Acids Res. 2024 Oct 16:gkae889. doi: 10.1093/nar/gkae889. Online ahead of print.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa infects the airways of people with cystic fibrosis (CF) and produces a virulence factor Cif that is associated with worse outcomes. Cif is an epoxide hydrolase that reduces cell-surface abundance of the cystic fibrosis transmembrane conductance regulator (CFTR) and sabotages pro-resolving signals. Its expression is regulated by a divergently transcribed TetR family transcriptional repressor. CifR represents the first reported epoxide-sensing bacterial transcriptional regulator, but neither its interaction with cognate operator sequences nor the mechanism of activation has been investigated. Using biochemical and structural approaches, we uncovered the molecular mechanisms controlling this complex virulence operon. We present here the first molecular structures of CifR alone and in complex with operator DNA, resolved in a single crystal lattice. Significant conformational changes between these two structures suggest how CifR regulates the expression of the virulence gene cif. Interactions between the N-terminal extension of CifR with the DNA minor groove of the operator play a significant role in the operator recognition of CifR. We also determined that cysteine residue Cys107 is critical for epoxide sensing and DNA release. These results offer new insights into the stereochemical regulation of an epoxide-based virulence circuit in a critically important clinical pathogen.

PMID:39413156 | DOI:10.1093/nar/gkae889

PLoS One. 2024 Oct 16;19(10):e0308299. doi: 10.1371/journal.pone.0308299. eCollection 2024.

ABSTRACT

In cystic fibrosis (CF), there is abnormal translocation and function of the cystic fibrosis transmembrane conductance regulator (CFTR) and an upregulation of the epithelial sodium channel (ENaC). This leads to hyperabsorption of sodium and fluid from the airway, dehydrated mucus, and an increased risk of respiratory infections. In this study, we performed a proteomic assessment of differentially regulated proteins from CF and non-CF small airway epithelial cells (SAEC) that are sensitive to Mycobacterium avium. CF SAEC and normal non-CF SAEC were infected with M. avium before the cells were harvested for protein. Protein kinase C (PKC) activity was greater in the CF cells compared to the non-CF cells, but the activity was significantly attenuated in both cell types after infection with M. avium compared to vehicle. Western blot and densitometric analysis showed a significant increase in cathepsin B protein expression in M. avium infected CF cells. Myristoylated alanine rich C-kinase substrate (MARCKS) protein was one of several differentially expressed proteins between the groups that was identified by mass spectrometry-based proteomics. Total MARCKS protein expression was greater in CF cells compared to non-CF cells. Phosphorylation of MARCKS at serine 163 was also greater in CF cells compared to non-CF cells after treating both groups of cells with M. avium. Taken together, MARCKS protein is upregulated in CF cells and there is decreased phosphorylation of the protein due to a decrease in PKC activity and presumably increased cathepsin B mediated proteolysis of the protein after M. avium infection.

PMID:39413095 | DOI:10.1371/journal.pone.0308299

Pediatr Pulmonol. 2024 Oct 16. doi: 10.1002/ppul.27330. Online ahead of print.

NO ABSTRACT

PMID:39412420 | DOI:10.1002/ppul.27330

J Pediatr Pharmacol Ther. 2024 Oct;29(5):539-543. doi: 10.5863/1551-6776-29.5.539. Epub 2024 Oct 14.

ABSTRACT

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was given US Food and Drug Administration approval based on its therapeutic benefits to treat patients with cystic fibrosis (CF) who had at least 1 allele of the CF transmembrane conductance regulator (CFTR) with phenylalanine deleted at position 508 (F508del). The increase in genotyping studies has increased the frequency of use of CFTR modulators; however, severe allergic reactions to CFTR modulators have also been described. It is critical to avoid the offending medication and select alternative treatments while dealing with drug allergies. Drug desensitization may be taken into consideration in situations where there is no other option. This article describes home desensitization treatment for a patient with CF who developed a maculopapular rash following CFTR modulator medication. There are currently no alternative drugs for CFTR modulators, which are crucial for patients with CF, and limited experience is available with allergic reactions to these drugs. It is important to establish desensitization protocols in order to control drug reactions to CFTR modulators, which are vital for individuals with CF.

PMID:39411414 | PMC:PMC11472403 | DOI:10.5863/1551-6776-29.5.539

Sisli Etfal Hastan Tip Bul. 2024 Sep 30;58(3):389-394. doi: 10.14744/SEMB.2024.65983. eCollection 2024.

ABSTRACT

OBJECTIVES: Current guidelines suggest that patients with cystic fibrosis (CF), who are over the age of 10, should be annually evaluated with oral glucose tolerance test (OGTT). In this study, it was aimed to evaluate the OGTT results in patients above the age of 10, who were followed up in our center with the diagnosis of CF.

METHODS: In the study, 46 patients with CF at the age of 10 and above, who underwent OGTT were included. Data such as gender, age at diagnosis, anthropometric measurements, lung function (FEV1 %) and the OGTT results were obtained. In the analysis, the patient groups with normal glucose tolerance (NGT) and abnormal glucose tolerance(AGT) were compared.

RESULTS: NGT was found in 37(80.4%) of the patients, and AGT was found in 9(19.5%) of the patients. The median fasting glucose levels of the patients in the NGT group and the mean glucose levels measured at 120 minutes in the OGTT were found to be lower compared to the patients in the AGT group(p<0.005). Although the mean body weight, height, VKİ-SDS, FEV1in the AGT group were found to be lower than the patients in the NGT group, the difference was not statistically significant (p>0.05).

CONCLUSION: We detected AGT in approximately 1 out of 5 patients with CF who were at the age of 10 and above. Almost half (44.4%) of the patients with AGT were found to have normal fasting blood glucose levels. Therefore, cystic fibrosis-related diabetes screening should be performed with OGTT instead of fasting blood glucose in patients with CF.

PMID:39411039 | PMC:PMC11472201 | DOI:10.14744/SEMB.2024.65983

Lancet Reg Health Eur. 2024 Jul 3;44:100996. doi: 10.1016/j.lanepe.2024.100996. eCollection 2024 Sep.

ABSTRACT

BACKGROUND: COVID-19 dramatically reshaped mortality across Europe. This study aimed to assess its impact on total mortality in European countries taking into consideration the relationship with selected country-level socioeconomic indicators, non-pharmaceutical interventions, and vaccine uptake.

METHODS: We obtained weekly mortality data from 2010 to 2023 from the Short-term Mortality Fluctuations data series, the annual population data from the United Nations archives, selected sociodemographic and economic indicators from the World Bank's database, the stringency index and the percentage of the population fully vaccinated from Our World in Data. A quasi-Poisson regression model trained on pre-pandemic years was used to estimate expected number of deaths in 2020-2023 in 29 European countries. Excess mortality was estimated using three different metrics: excess deaths (number), relative excess mortality (% different from expected deaths) and age-standardized excess death rate per 10,000 population. The relationship between socioeconomic indicators and excess mortality was evaluated using linear regression models, which included both linear and quadratic terms for the predictors to account for possible non-linear relationships.

FINDINGS: We estimated 1,642,586 excess deaths (95% confidence interval, CI: 1,607,161-1,678,010) across all countries over the four years (+8.0% compared to the expected number of deaths). Excess mortality was mainly concentrated in 2020-2022 (0.52 million excess deaths in 2020, 0.57 million in 2021 and 0.44 million in 2022), with no substantial excess (0.11 million) estimated for 2023. Over the period 2020-23, the highest number of excess deaths was estimated for Italy (227,736 deaths, +8.7%), Poland (223,735 deaths, +13.7%), and Germany (218,111 deaths, +5.6%), while the highest excesses in relative terms were in Bulgaria (72,328 deaths, +17.2%), Lithuania (23,813 deaths, +16.1%), and Slovakia (31,984 deaths, +14.9%). The age-standardised death rates ranged from 1.8 per 10,000 population in Sweden to 24.7 in Bulgaria. The percentage of the population living below the poverty line and the Gini index were significantly associated with an increased excess death rate, with p-values for the linear and quadratic terms being 0.003 and 0.003 for the Gini index, and 0.024 and 0.017 for the population living below the poverty line. Conversely, gross domestic product per capita (p-values for the linear and quadratic terms: <0.001, 0.003), health expenditure (0.001, 0.273) and the percentage of people fully vaccinated by the end of 2021 (<0.001, 0.989) or 2022 (0.001, 0.890) were inversely associated with excess death rate. No significant association was observed with population density and stringency index.

INTERPRETATION: The observed geographic disparities in total mortality excess across Europe can be related to differences in socioeconomic contexts, as well as to suboptimal vaccine uptakes in some countries.

FUNDING: This research was supported by European Union (EU) funding within the NextGeneration EU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT). The funding source had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

PMID:39410937 | PMC:PMC11473197 | DOI:10.1016/j.lanepe.2024.100996