Improved glucose tolerance after initiation of Elexacaftor / Tezacaftor / Ivacaftor in adults with cystic fibrosis.

BACKGROUND: The novel triple CFTR modulator therapy Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) improves lung function, body mass index (BMI), sinus clearance, and quality of life in patients with cystic fibrosis. Whether treatment with ELX/TEZ/IVA is associated with improved glucose tolerance is unknown. METHODS: This cohort study included adults with CF and at least one copy of F508del.. Study assessments before treatment and at least 3 months after ELX/TEZ/IVA initiation included an oral glucose tolerance test (OGTT) with glucose and insulin measurements, BMI, lung function test, and sweat chloride levels. We used an analysis of response profiles to calculate changes in outcomes. RESULTS: 33 patients (27.8 ± 6.3 years; 73% male; 64% F508del homozygous) were included. After a median of 184 [IQR, 107 - 278] days following treatment initiation 16 (48.5%) patients improved their glucose tolerance category, while 13 (39.4%) remained unchanged and 4 (12.1%) deteriorated. Overall, 60, 90 and 120 min OGTT glycemia decreased significantly from 11.9 ± 2.7 mmol/l to 10.6 ± 2.8 mmol/l (p = 0.012), 10.4 ± 3.0 mmol/l to 8.4 ± 3.6 mmol/l (p = 0.002) and 7.3 ± 3.1 mmol/l to 5.7 ± 3.0 mmol/l (p = 0.012). HbA1c levels also improved significantly, from 5.50±0.24% to 5.39±0.25% (p = 0.039). CONCLUSION: In adult patients with CF and at least one copy of F508del, treatment with the triple CFTR modulator was associated with possible improvement of glucose tolerance without increases of insulin secretion. Early initiation of treatment as assessed through long-term prospective trials is mandatory to demonstrate if decreased glucose control is preventable or even reversible.

The cytotoxic effect of Clostridioides difficile pore-forming toxin CDTb.

Clostridioides (C.) difficile is clinically highly relevant and produces several AB-type protein toxins, which are the causative agents for C. difficile-associated diarrhea and pseudomembranous colitis. Treatment with antibiotics can lead to C. difficile overgrowth in the gut of patients due to the disturbed microbiota. C. difficile releases large Rho/Ras-GTPase glucosylating toxins TcdA and TcdB, which are considered as the major virulence factors for C. difficile-associated diseases. In addition to TcdA and TcdB, C. difficile strains isolated from severe cases of colitis produce a third toxin called CDT. CDT is a member of the family of clostridial binary actin ADP-ribosylating toxins and consists of two separate protein components. The B-component, CDTb, binds to the receptor and forms a complex with and facilitates transport and translocation of the enzymatically active A-component, CDTa, into the cytosol of target cells by forming trans-membrane pores through which CDTa translocates. In the cytosol, CDTa ADP-ribosylates G-actin causing depolymerization of the actin cytoskeleton and, eventually, cell death. In the present study, we report that CDTb exhibits a cytotoxic effect in the absence of CDTa. We show that CDTb causes cell rounding and impairs cell viability and the epithelial integrity of CaCo-2 monolayers in the absence of CDTa. CDTb-induced cell rounding depended on the presence of LSR, the specific cellular receptor of CDT. The isolated receptor-binding domain of CDTb was not sufficient to cause cell rounding. CDTb-induced cell rounding was inhibited by enzymatically inactive CDTa or a pore-blocker, implying that CDTb pores in cytoplasmic membranes contribute to cytotoxicity.

Predictors of changes in subjective daytime sleepiness in response to CPAP therapy withdrawal in OSA: A post-hoc analysis.

Subjective sleepiness is the hallmark symptom of untreated obstructive sleep apnea (OSA) and leads to an increased risk of motor vehicle accidents and impaired quality of life. Continuous positive airway pressure (CPAP) is the standard therapy for OSA and improves sleepiness. The aim was to identify factors that might predict recurrence of sleepiness in times off CPAP and to define OSA patient types with a likely effect of CPAP on sleepiness. A post-hoc analysis of six clinical trials, including 132 patients with OSA effectively treated with CPAP prior to study inclusion, who were allocated to 2 weeks of CPAP withdrawal, was conducted to assess predictors of a change in subjective sleepiness. A multivariate regression model was used to assess predictors of a change in the Epworth Sleepiness Scale (ESS) score. In response to CPAP withdrawal, the median apnea-hypopnea index (AHI) and the ESS score significantly increased compared to baseline on CPAP by 32.6/hr (95% CI, 28.8, 36.4)/hr and 2.5 (95% CI, 1.8,3.2), respectively (p < .001), in the included 132 patients. There was an independent positive association of AHI (Coef. [95% CI] 0.04 [0.01, 0.08]) with an increase in ESS score upon CPAP withdrawal, and an independent negative association of age (coef. [95% CI], -0.10 [-0.18, -0.2]), ESS on CPAP (coef. [95% CI], -0.21 [-0.40, -0.015]) and active smoking status (coef. [95% CI], -1.22 [-2.26, -0.17]). These findings suggest that younger patients with a low residual sleepiness on CPAP and a recurrence of more severe OSA during CPAP withdrawal are at highest risk of suffering from a clinically relevant return of daytime sleepiness in times off CPAP.

Obstructive sleep apnoea and the progression of thoracic aortic aneurysm: a prospective cohort study.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with an increased prevalence of aortic aneurysms and it has also been suggested that severe OSA furthers aneurysm expansion in the abdomen. We evaluated whether OSA is a risk factor for the progression of ascending thoracic aortic aneurysm (TAA). METHODS: Patients with TAA underwent yearly standardised echocardiographic measurements of the ascending aorta over 3 years and two level III sleep studies. The primary outcome was the expansion rate of TAA in relation to the apnoea-hypopnoea index (AHI). Secondary outcomes included surveillance for aortic events (composite end-points of rupture/dissection, elective surgery or death). RESULTS: Between July 2014 and March 2020, 230 patients (median age 70 years, 83.5% male) participated in the cohort. At baseline, 34.8% of patients had AHI ≥15 events·h-1. There was no association between TAA diameter and AHI at baseline. After 3 years, mean±sd expansion rates were 0.55±1.25 mm at the aortic sinus and 0.60±1.12 mm at the ascending aorta. In the regression analysis, after controlling for baseline diameter and cardiovascular risk factors, there was strong evidence for a positive association of TAA expansion with AHI (aortic sinus estimate 0.025 mm, 95% CI 0.009-0.040 mm; p<0.001 and ascending aorta estimate 0.026 mm, 95% CI 0.011-0.041 mm; p=0.001). 20 participants (8%) experienced an aortic event; however, there was no association with OSA severity. CONCLUSION: OSA may be a modest but independent risk factor for faster TAA expansion and thus potentially contributes to life-threatening complications in aortic disease.

A few more steps lead to improvements in endothelial function in severe and very severe COPD.

INTRODUCTION: Cardiovascular disease is among the most prevalent concomitant chronic diseases in COPD. Physical activity (PA) modifies endothelial function and is commonly impaired in COPD. However, studies directly investigating the effects of increased PA on endothelial function in COPD are lacking. We investigated the effect of changes in PA on endothelial function in patients with severe to very severe COPD. Furthermore, we determined which variables modify this effect. MATERIALS AND METHODS: This is a secondary outcome analysis from a randomised controlled trial investigating the effects of combined PA counselling and pedometer-based feedback in COPD. We analysed the change in PA based on three visits during one year. We measured PA using a validated triaxial accelerometer, and endothelial function using flow-mediated dilation. RESULTS: Data was analysed from 54 patients, which provided 101 change scores. Multiple regression modelling, including adjustment for baseline step count, showed strong evidence for an association between changes in flow-mediated dilation and changes in PA (p < 0.001). The analysis of several effect modificators showed no evidence of any influence on the interaction between PA and endothelial function: smoking status (p = 0.766), severity of airflow obstruction (p = 0.838), exacerbation frequency (p = 0.227), lung diffusion capacity of carbon monoxide % pred. (p = 0.735). CONCLUSION: We found strong evidence that increasing steps per day ameliorates the heavily impaired endothelial function in patients with severe and very severe COPD. Further studies should examine which factors influence this relationship in a positive or negative manner.

Increased augmentation index in patients with Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascular disease progression (e.g. arterial aneurysms, dissections, and ruptures) in EDS patients are still missing. Recently, applanation tonometry derived augmentation index (AIx), an indirect marker of arterial stiffness, has shown to be positively associated with progression of aortic disease in Marfan syndrome. In this study, we assessed aortic AIx in patients with EDS and matched healthy controls. METHODS: We performed noninvasive applanation tonometry in 61 adults with EDS (43 women and 18 men aged 39.3 ± 14.6 years) and 61 age-, gender-, height-, and weight-matched healthy controls. Radial artery pulse waveforms were recorded and analyzed using the SphygmoCor System (AtCor Medical, Sydney, NSW, Australia). Calculated AIx was adjusted to a heart rate of 75/min. Groups were compared and association between AIx and EDS was determined by univariate and multivariate regression analysis. RESULTS: EDS patients were categorized in classical type EDS (34%), hypermobile type EDS (43%), vascular type EDS (5%), or remained unassignable (18%) due to overlapping features. EDS patients showed a significantly increased aortic AIx compared to healthy controls (22.8% ± 10.1 vs 14.8% ± 14.0, p < 0.001). EDS showed a positive association with AIx; independent of age, sex, height, blood pressure, medication, and pack years of smoking. CONCLUSIONS: Patients with EDS showed elevated AIx, indicating increased arterial stiffness when compared to healthy controls. Further investigations are needed in order to assess the prognostic value of increased AIx for cardiovascular outcomes in patients with EDS.

Arterial Stiffness Increases Over Time in Relation to Lung Diffusion Capacity: A Longitudinal Observation Study in COPD.

Background: Cardiovascular events are, after cancer, the most common cause of death in COPD patients. Arterial stiffness is an independent predictor of all-cause mortality and cardiovascular events. Several cross-sectional studies have confirmed increased arterial stiffness in patients with COPD. Various mechanisms in the development of arterial stiffness in COPD such as reduced lung function or systemic inflammation have been proposed. However, clinical predictors of arterial stiffness that had been reported in cross-sectional studies have not yet been confirmed in a longitudinal setting. We have assessed the course of augmentation index (AIx) - a measure of systemic arterial stiffness - and possible predictors in a cohort of COPD patients over a period of up to 7 years. Methods: COPD patients underwent annual AIx measurement by applanation tonometry for a maximum duration of 7 years. Additionally, we performed annual assessments of lung function, blood gases, systemic inflammation, serum lipids and blood pressure. Associations between the course of AIx and potential predictors were investigated through a mixed effect model. Results: Seventy-six patients (mean (SD) age 62.4 (7.1), male 67%) were included. The AIx showed a significant annual increase of 0.91% (95% CI 0.21/1.60) adjusted for baseline. The change in diffusion capacity (DLco), low-density lipoprotein (LDL), and high-sensitivity c-reactive protein (hsCRP) was independently associated with the increasing evolution of AIx (Coef. - 0.10, p<0.001, Coef. 1.37, p=0.003, and Coef. 0.07, p=0.033, respectively). Conclusion: This study demonstrated a meaningful increase in arterial stiffness in COPD over time. A greater annual increase in arterial stiffness was associated with the severity of emphysema (measured by DLco), systemic inflammation, and dyslipidaemia. Clinical Trial Registration: www.ClinicalTrials.gov, NCT01527773.