J Mother Child. 2021 Jan 29;22(2):135-143. doi: 10.34763/devperiodmed.20182202.135143.

ABSTRACT

Tlenek azotu, powstający przy udziale enzymów z grupy syntaz tlenku azotu, spełnia w organizmie człowieka szereg istotnych funkcji, ale produkowany w nadmiarze wykazuje działanie prozapalne. Pomiary stężenia tlenku azotu w powietrzu wydychanym znajdują zastosowanie w diagnostyce i monitorowaniu nasilenia stanu zapalnego dróg oddechowych o podłożu eozynofilowym, nie powinny być jednak wykorzystywane jako samodzielny parametr w diagnozowaniu astmy lub monitorowaniu jej leczenia. Ocena stężeń tlenku azotu w powietrzu wydychanym znajduje również zastosowanie w ustalaniu patogenezy objawów u pacjentów z nieżytem nosa. Jest także pomocna w wykrywaniu i monitorowaniu współistniejącego eozynofilowego stanu zapalnego w dolnych drogach oddechowych u tych chorych. Wartości tlenku azotu w powietrzu wydychanym mogą być nieprawidłowe (zarówno obniżone, jak i podwyższone) w innych chorobach przewlekłych takich jak: mukowiscydoza, pierwotna dyskineza rzęsek oraz nieswoiste zapalenia jelit. Na wartości pomiaru wpływają liczne czynniki, takie jak: atopia, polimorfizmy genów syntaz tlenku azotu i parametry przemiany lipidowej organizmu. Oprócz pomiarów tlenku azotu w powietrzu wydychanym przydatne są także pomiary nosowego tlenku azotu, które znalazły zastosowanie w ocenie występowania oraz nasilenia zapalenia eozynofilowego w górnych drogach oddechowych.

Nitric oxide is produced by enzymes called nitric oxide synthases. It fulfills many important functions in the human body, but produced in excess amount has a proinflammatory activity. Fractional exhaled nitric oxide measurements are used in the diagnosis and monitoring of eosinophilic inflammation in the lower airways, but should not be used as an independent parameter to make a diagnosis of asthma or for the monitoring of asthma treatment. Evaluation of fractional exhaled nitric oxide concentrations is also used to determine the pathogenesis of symptoms in patients with rhinitis. In addition, they are helpful in detecting and monitoring eosinophilic inflammation in the lower respiratory tract that coexists with inflammation in the upper airways. Fractional exhaled nitric oxide concentrations may be abnormal (lowered or elevated) in other chronic diseases, such as cystic fibrosis, primary ciliary dyskinesia and inflammatory bowel diseases. Many factors, e.g. atopy, genetic polymorphisms of NOS, and the lipid profile affect the fractional exhaled nitric oxide measurement. Nasal nitric oxide measurement is useful in assessing the prevalence and severity of eosinophilic inflammation in the upper respiratory tract.

PMID:33742959 | DOI:10.34763/devperiodmed.20182202.135143

Mol Cell Biochem. 2021 Mar 19. doi: 10.1007/s11010-021-04051-2. Online ahead of print.

ABSTRACT

This was an observational cross-sectional study which was done to assess the expression profile of STATs and SOCS genes in cystic fibrosis. The mRNA was isolated from peripheral blood mononuclear cells of CF patients in exacerbation, colonization and post exacerbation phases of the disease. The relative gene expression level for SOCS 1, -3, -5 and STAT 1, -3,-4,-6 genes was quantified by Real-time PCR. The levels of IL-6 were also measured in the serum by ELISA. The expression of the Th1 pathway associated genes (SOCS1, SOCS5, STAT4 and STAT1) was downregulated while the expression of Th2/Th17 pathway genes (SOCS3, STAT3, STAT6) was upregulated in both exacerbation and colonization phases as compared to healthy controls. The serum levels of IL-6 were also elevated in both the disease groups. After antibiotic treatment, the expression of SOCS5 and STAT4 was increased while the expression of rest of the genes showed downregulation which shows a shift in immune response from Th2/Th17 to Th1. Our results suggest that infection alters the cytokine signaling pathway through modulation of STATs and SOCS genes which is not able to regulate the overstimulation of cytokine signaling further leading to chronic inflammation in CF.

PMID:33740185 | DOI:10.1007/s11010-021-04051-2

World J Microbiol Biotechnol. 2021 Mar 19;37(4):66. doi: 10.1007/s11274-021-03029-y.

ABSTRACT

Pseudomonas aeruginosa is one of the vulnerable opportunistic pathogens associated with nosocomial infections, cystic fibrosis, burn wounds and surgical site infections. Several studies have reported that quorum sensing (QS) systems are controlled the P. aeruginosa pathogenicity. Hence, the targeting of QS considered as an alternative approach to control P. aeruginosa infections. This study aimed to evaluate the anti-quorum sensing and antibiofilm inhibitory potential of Musa paradisiaca against Chromobacterium violaceum (ATCC 12472) and Pseudomonas aeruginosa. The methanol extract of M. paradisiacsa exhibits that better antibiofilm potential against P. aeruginosa. Then, the crude methanol extract was subjected to purify by column chromatography and collected the fractions. The mass-spectrometric analysis of a methanol extract of M. paradisiaca revealed that 1,8-cineole is the major compounds. 1, 8-cineole significantly inhibited the QS regulated violacein production in C. violaceum. Moreover, 1,8-cineole significantly inhibited the QS mediated virulence production and biofilm formation of P. aeruginosa without affecting their growth. The real-time PCR analysis showed the downregulation of autoinducer synthase and transcriptional regulator genes upon 1,8-cineole treatment. The findings of the present study strongly suggested that metabolite of M. paradisiaca impedes P. aeruginosa QS system and associated virulence productions.

PMID:33740144 | DOI:10.1007/s11274-021-03029-y

Sci Rep. 2021 Mar 18;11(1):6393. doi: 10.1038/s41598-021-85549-z.

ABSTRACT

Cystic fibrosis (CF) is characterized by an airway obstruction caused by a thick mucus due to a malfunctioning Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The sticky mucus restricts drugs in reaching target cells limiting the efficiency of treatments. The development of new approaches to enhance drug delivery to the lungs represents CF treatment's main challenge. In this work, we report the production and characterization of hybrid core-shell nanoparticles (hNPs) comprising a PLGA core and a dipalmitoylphosphatidylcholine (DPPC) shell engineered for inhalation. We loaded hNPs with a 7-mer peptide nucleic acid (PNA) previously considered for its ability to modulate the post-transcriptional regulation of the CFTR gene. We also investigated the in vitro release kinetics of hNPs and their efficacy in PNA delivery across the human epithelial airway barrier using an ex vivo model based on human primary nasal epithelial cells (HNEC) from CF patients. Confocal analyses and hNPs transport assay demonstrated the ability of hNPs to overcome the mucus barrier and release their PNA cargo within the cytoplasm, where it can exert its biological function.

PMID:33737583 | DOI:10.1038/s41598-021-85549-z

Bone. 2021 Mar 15:115929. doi: 10.1016/j.bone.2021.115929. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) bone disease (CFBD) has attracted considerable recent interest from researchers, although several aspects of CFBD pathophysiology remain poorly understood. The objective of this research was to investigate CFBD in children with CF and its relation to clinical and bone metabolism markers.

METHODS: In a prospective observational study of 68 patients with CF and 63 healthy controls, we studied bone turnover biomarkers and bone mineral density (BMD). The biomarkers included osteocalcin, total-alkaline phosphatase, bone-alkaline phosphatase, N-terminal propeptide of type-1-procollagen, osteoprotegerin (OPG), interleukine-6, tumor necrosis factor alpha (TNF-α), type-1-collagen cross-linked C-telopeptide (CTX), parathormone (PTH), 25-vitamin D, 1,25-vitamin D, calcium and phosphorus. BMD was examined in lumbar spine, comparing two healthy Spanish populations. Two regression analyses were applied to any significant associations to evaluate predictors of BMD and of CF, expressed as odds ratios (OR) with 95% confidence intervals.

RESULTS: After adjusting for age, sex, and height Z-score, gains in BMD LS in children and adolescents (6-16 years) with CF were not less than in healthy reference population. Patients with CF showed significant associations with different bone turnover biomarkers. Age, gender, body mass index, PTH, CTX and OPG were significant predictors of BMD (R2 = 0.866, p 〈0,001). Moreover, we found that PTH (OR = 1.070; 95%CI 1.019-1.123), and TNFα (OR = 2.173; 95%CI 1.514-3.118) were significantly linked to CF, and calcium (OR = 0.115; 95%CI 0.025-0.524), 1,25-vitamin D (OR = 0.979; 95%CI 0.9620.996) and OPG (OR = 0.189; 95%CI 0.073-0.489) were significant reduced.

CONCLUSION: A normal bone mineral density along with altered remodeling was found in CF patients with a normal nutritional status and without acute lung disease.

PMID:33737192 | DOI:10.1016/j.bone.2021.115929

Palliat Support Care. 2021 Mar 19:1-7. doi: 10.1017/S1478951521000274. Online ahead of print.

ABSTRACT

OBJECTIVES: Older people are not traditionally expected to become caregivers. For this reason, the experience of caregiving in older persons has not been explored adequately in the research on gender differences. The objective of this study was to assess the caregiver burden among older family members who care for cancer patients facing the end of their lives, in order to compare their differences according to gender (male vs. female).

METHODS: This is a cross-sectional study. A total of 102 older caregivers (aged ≥65 years) of hospice patients were interviewed through the Caregiver Burden Inventory (CBI). The sample group was divided into two gender subgroups.

RESULTS: Compared with male caregivers, the older female group reported significantly higher scores in the CBI-physical subscale (P = 0.028), and in the CBI, the overall score (P = 0.0399) confirmed by the generalized linear model (multivariate) evaluation that included possible predictors in the model. There were no significant differences in the other CBI subscale scores (time-dependent, developmental, social, and emotional).

SIGNIFICANCE OF RESULTS: Older female caregivers are at higher risk of experiencing burden and worse physical health compared with men. Further research is needed in modern palliative care to assess the role of gender differences in the experience of caregiving when the caregiver is an older person.

PMID:33736742 | DOI:10.1017/S1478951521000274

Sci Total Environ. 2021 Jun 1;771:145202. doi: 10.1016/j.scitotenv.2021.145202. Epub 2021 Jan 22.

ABSTRACT

Despite climate-change challenges, for most aquaculture species, physiological responses to different salinities during ambient extreme cold events remain unknown. Here, European seabass acclimatized at 3, 6, 12, and 30 PSU were subjected to 20 days of an ambient extreme winter cold event (8 °C), and monitored for growth and physiological performance. Growth performance decreased significantly (p < 0.05) in fish exposed at 3 and 30 PSU compared to 6 and 12 PSU. During cold stress exposure, serum Na+, Cl-, and K+ concentrations were significantly (p < 0.05) increased in fish exposed at 30 PSU. Serum cortisol, glucose, and blood urea nitrogen (BUN) were increased significantly (p < 0.05) in fish exposed at 3 and 30 PSU. In contrast, opposite trends were observed for serum protein, lactate, and triglycerides content during cold exposure. Transaminase activities [glutamic-pyruvate transaminase (GPT), glutamic oxaloacetic transaminase (GOT), lactic acid dehydrogenase (LDH), gamma-glutamyl-transaminase (γGGT)] were significantly higher in fish exposed at 3 and 30 PSU on days 10 and 20. The abundance of heat shock protein 70 (HSP70), tumor necrosis factor-α (TNF-α), cystic fibrosis transmembrane conductance (CFTR) were significantly (p < 0.05) increased in fish exposed at 3 and 30 PSU during cold shock exposure. In contrast, insulin-like growth factor 1 (Igf1) expression was significantly lower in fish exposed at 3 and 30 PSU. Whereas, on day 20, Na+/K+ ATPase α1 and Na+/K+/Cl- cotransporter-1 (NKCC1) were significantly upregulated in fish exposed at 30 PSU, followed by 12, 6, and 3 PSU. Results demonstrated that ambient extreme winter cold events induce metabolic and physiological stress responses and provide a conceivable mechanism by which growth and physiological fitness are limited at cold thermal events. However, during ambient extreme cold (8 °C) exposure, European seabass exhibited better physiological fitness at 12 and 6 PSU water, providing possible insight into future aquaculture management options.

PMID:33736134 | DOI:10.1016/j.scitotenv.2021.145202

Cochrane Database Syst Rev. 2021 Mar 18;3:CD001127. doi: 10.1002/14651858.CD001127.pub5.

ABSTRACT

BACKGROUND: Dornase alfa is currently used as a mucolytic to treat pulmonary disease (the major cause of morbidity and mortality) in cystic fibrosis. It reduces mucus viscosity in the lungs, promoting improved clearance of secretions. This is an update of a previously published review.

OBJECTIVES: To determine whether the use of dornase alfa in cystic fibrosis is associated with improved mortality and morbidity compared to placebo or other medications that improve airway clearance, and to identify any adverse events associated with its use.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and abstracts from conferences. Date of the most recent search of the Group's Cystic Fibrosis Register: 12 October 2020. Clinicaltrials.gov and the International Clinical Trials Registry Platform were also searched to identify unpublished or ongoing trials. Date of most recent search: 08 February 2021.

SELECTION CRITERIA: All randomised and quasi-randomised controlled trials comparing dornase alfa to placebo, standard therapy or other medications that improve airway clearance.

DATA COLLECTION AND ANALYSIS: Authors independently assessed trials against the inclusion criteria; two authors carried out analysis of methodological quality and data extraction. GRADE was used to assess the level of evidence.

MAIN RESULTS: The searches identified 74 trials, of which 19 (2565 participants) met our inclusion criteria. 15 trials compared dornase alfa to placebo or no dornase alfa (2447 participants); two compared daily dornase to hypertonic saline (32 participants); one compared daily dornase alfa to hypertonic saline and alternate day dornase alfa (48 participants); one compared dornase alfa to mannitol and the combination of both drugs (38 participants). Trial duration varied from six days to three years. Dornase alfa compared to placebo or no treatment Dornase alfa probably improved forced expiratory volume at one second (FEV1) at one month (four trials, 248 participants), three months (one trial, 320 participants; moderate-quality evidence), six months (one trial, 647 participants; high-quality evidence) and two years (one trial, 410 participants). Limited low-quality evidence showed treatment may make little or no difference in quality of life. Dornase alfa probably reduced the number of pulmonary exacerbations in trials of up to two years (moderate-quality evidence). One trial that examined the cost of care, including the cost of dornase alfa, found that the cost savings from dornase alfa offset 18% to 38% of the medication costs. Dornase alfa: daily versus alternate day One cross-over trial (43 children) found little or no difference between treatment regimens for lung function, quality of life or pulmonary exacerbations (low-quality evidence). Dornase alfa compared to other medications that improve airway clearance Results for these comparisons were mixed. One trial (43 children) showed dornase alfa may lead to a greater improvement in FEV1 compared to hypertonic saline (low-quality evidence), and one trial (23 participants) reported little or no differences in lung function between dornase alfa and mannitol or dornase alfa and dornase alfa plus mannitol (low-quality evidence). One trial (23 participants) found dornase alfa may improve quality of life compared to dornase alfa plus mannitol (low-quality evidence); other comparisons found little or no difference in this outcome (low-quality evidence). No trials in any comparison reported any difference between groups in the number of pulmonary exacerbations (low-quality evidence). When all comparisons are assessed, dornase alfa did not cause significantly more adverse effects than other treatments, except voice alteration and rash.

AUTHORS' CONCLUSIONS: There is evidence to show that, compared with placebo, therapy with dornase alfa may improve lung function in people with cystic fibrosis in trials lasting from one month to two years. There was a decrease in pulmonary exacerbations in trials of six months or longer, probably due to treatment. Voice alteration and rash appear to be the only adverse events reported with increased frequency in randomised controlled trials. There is not enough evidence to firmly conclude if dornase alfa is superior to other hyperosmolar agents in improving lung function.

PMID:33735508 | DOI:10.1002/14651858.CD001127.pub5

PLoS One. 2021 Mar 18;16(3):e0246897. doi: 10.1371/journal.pone.0246897. eCollection 2021.

ABSTRACT

OBJECTIVE: To report the clinical profile associated with G60 and I60 over a 4-year prospective observational period in 2 large cohorts of adult patients with CF.

METHODS: 319 patients were included (210 Canadian and 119 French) and classified according to their inclusion G60 (≥ or < 11.1 mmol/L) and the median inclusion I60 (≥ or < 24 mU/I). Forced expiratory volume in 1 second (FEV1), body mass index (BMI) were collected on OGTT days. Linear mixed regression models were used to assess the effect of G60 and I60.

RESULTS: High G60 was not associated to a lower FEV1 at inclusion and the follow-up decline was not higher in the high G60 group (Coefficient [95% CI]: -3.4 [-7.4;0.6], p = 0.0995.). There was no significant association between BMI and G60. Patients with high I60 tended to have a higher mean BMI (+0.5 kg/m2 [0.0 to 1.1], p = 0.05) but no interaction over time was observed.

CONCLUSIONS: High G60 is not associated with a lower lung function at inclusion nor its decline over a 4-year follow-up. High I60 is slightly associated to a higher weight at inclusion, but not with BMI evolution over time in adult patients.

PMID:33735186 | DOI:10.1371/journal.pone.0246897

Pediatr Allergy Immunol Pulmonol. 2021 Mar;34(1):15-22. doi: 10.1089/ped.2020.1317.

ABSTRACT

Background: Although the impulse oscillometry system (IOS) is a noninvasive, easily accessible, well-tolerated, and alternative test, routine use of IOS in cystic fibrosis (CF) patients is not widespread. In our unit, IOS is routinely used for the evaluation and follow-up of patients with CF. We aimed to show that IOS may be utilized as a complement for measuring pulmonary function in CF patients. Materials and Methods: Retrospective data collection and analysis of pulmonary function tests on CF patients followed at our center between January 1, 2018 and February 1, 2019. IOS and spirometry data were compared as correlated with patients' clinical exacerbation, treatment response, bronchodilator response, and trends during follow-up intervals. Results: There was a significant correlation between spirometry and IOS parameters in 70 patients. In exacerbation, Z5, R5-R10, AX, Fres, and delta R5-R20 were significantly increased and X5-X20 was significantly decreased compared with baseline in 25 patients. After treatment, IOS parameters were observed to return to baseline values. In the evaluation of bronchodilator response in 33 patients, significant changes in IOS (decrease in Z5, R5-R10, AX, Fres, and delta R5-R20, and increase in X5-X10) and in spirometry [increase in forced expiratory volume in 1 s (FEV1) and forced expiratory flow during the middle half of forced vital capacity (FEF25-75)] were found after bronchodilator. While there was no significant difference between spirometry values in follow-up visits in 31 patients, there was a significant increase in Z5% and R5%-R20%. Unlike other studies, there was a significant correlation between clinical scores and IOS. Conclusions: These results show that although IOS is not the gold standard method such as spirometry, it is an alternative method that can be used successfully in the evaluation and follow-up of CF patients. Clinical Trials.gov ID: 99166796-050.06.04.

PMID:33734877 | DOI:10.1089/ped.2020.1317

Am J Respir Crit Care Med. 2021 Mar 18. doi: 10.1164/rccm.202102-0509OC. Online ahead of print.

ABSTRACT

RATIONALE: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients aged 12 years and older with cystic fibrosis and at least one F508del-CFTR allele, but has not been evaluated in children <12 years of age.

OBJECTIVES: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes.

METHODS: In this 24-week open-label Phase 3 study, children (N=66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours) while children weighing ≥30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours).

MEASUREMENTS AND MAIN RESULTS: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most common reported adverse events (AEs) included cough, headache, and pyrexia; in most of the children who had AEs, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the ppFEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period compared to the pre-treatment baseline.

CONCLUSIONS: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03691779.

PMID:33734030 | DOI:10.1164/rccm.202102-0509OC

Pediatr Res. 2021 Mar 17. doi: 10.1038/s41390-021-01427-4. Online ahead of print.

ABSTRACT

BACKGROUND: Noninvasive assessments of liver fibrosis are currently used to evaluate cystic fibrosis (CF)-related liver disease. However, there is scarce data regarding their repeatability and reproducibility, especially in children with CF. The present study aimed to evaluate the repeatability and reproducibility of transient elastography (TE) (FibroScan®) and point shear-wave elastography using virtual touch quantification (pSWE VTQ) in children with CF.

METHODS: TE and pSWE VTQ were performed in 56 children with CF by two different operators. Analysis of repeatability and reproducibility was available in 33 patients for TE and 46 patients for pSWE VTQ. Intra- and interobserver agreement were assessed using the intraclass correlation coefficient (ICC) and their 95% confidence interval (CI), and Bland and Altman graphs.

RESULTS: For TE, ICC was 0.91 (0.83-0.95) for intraobserver agreement and 0.92 (95% CI: 0.86-0.96) for interobserver agreement. For pSWE VTQ, ICC was 0.83 (0.72-0.90) for intraobserver agreement and 0.67 (0.48-0.80) for interobserver agreement.

CONCLUSIONS: Both technics can be proposed in the follow-up of patients, according to their availability in CF centers.

IMPACT: This study shows that TE and pSWE VTQ are reliable methods to evaluate liver fibrosis in children with CF. This study shows for the first time that TE and pSWE VTQ are both repeatable and reproducible in children with CF. These data indicate that both TE and pSWE VTQ can be proposed for the follow-up of patients with CF, according to their availability in each CF center.

PMID:33731812 | DOI:10.1038/s41390-021-01427-4

Eur J Pediatr. 2021 Mar 16. doi: 10.1007/s00431-021-04017-y. Online ahead of print.

ABSTRACT

The aim of this study was to describe the frequency, major symptoms, and characteristics of colonic polyps in a cohort of children. A retrospective chart review of patients aged ≤ 18 years who were diagnosed with colonic polyp(s) from 2006 to 2019 in a tertiary hospital was included. Data collected included demographics, clinical presentation, interval of time between the onset of symptoms and the endoscopic diagnosis of colonic polyps, family history, characteristics of the polyp, and associated lesions. Over the study period, 35 Caucasian children were diagnosed with juvenile colonic polyps. Twenty-three patients (65.7%) were males. Lower gastrointestinal bleeding of a mean duration of 5.3 ± 4.9 months was the presenting symptom in nearly all cases (n = 34, 97%), and it was isolated in 17 patients. Clinical presentation did not significantly vary according to the age or the location or size of the polyp (p = 0.262, p = 1.000, and p = 0.149, respectively). The polyps were mainly located in the left colon (n = 29, 83%). Right colonic polyps were significantly larger than left colonic polyps (p = 0.037).Conclusion: Lower gastrointestinal bleeding represents the most common presentation of colonic polyps in children. Right-sided colonic polyps occur and may be even larger than left-sided ones. A total colonoscopy is therefore mandatory for all cases of suspected colonic polyps. This study represents a real-life contribution, and it can help improve the management strategies of this condition in childhood. What is Known: • Colonic polyps are quite common in children. • The majority of pediatric colonic polyps are solitary, benign, and located in the left colon. What is New: • Right-sided colonic polyps occur and may be even larger than left-sided ones. • A total colonoscopy is mandatory for all cases of suspected colonic polyps.

PMID:33728535 | DOI:10.1007/s00431-021-04017-y

Int J Telemed Appl. 2021 Feb 26;2021:6641853. doi: 10.1155/2021/6641853. eCollection 2021.

ABSTRACT

PURPOSE: The purpose of this study was to pilot a home-based pulmonary rehabilitation (PR) program administered via a telemedicine approach using a combination of fitness application and self-selected activity in lung transplant candidates with cystic fibrosis (CF).

METHODS: We recruited adult patients with CF. The main outcome was adherence, measured by number of sessions completed in 12 weeks. Secondary outcomes were adverse events, six-minute walk distance (6MWD), and dyspnea. Participants were provided a personalized exercise program and equipment including a fitness application that provided exercise videos, recorded exercise time, and corresponding heart rate. We reviewed data daily and provided text messages with feedback. We compared our study outcomes to a retrospective data set of CF patients who participated in a 24-session outpatient hospital-based PR program. Data presented as mean ± standard deviation.

RESULTS: Eleven patients participated in the home PR program, 45% female, age 33 ± 7 years, FEV1 27 ± 5% predicted. Sessions completed were 19 ± 12 home-based PR vs. 9 ± 4 hospital-based PR, p = .03. Fifty percent of the home-based group completed ≥24 sessions in 12 weeks versus 0% of the hospital-based patients (p = .03). There were no adverse events during exercise. Completers of the home-based program demonstrated a clinically meaningful lower decline in 6 MWD than noncompleters (6MWD -7 ± 15 vs. -86 ± 108 meters). Only one participant performed a post 6 MWD in the hospital-based PR.

CONCLUSION: Patients with severe CF demonstrated adherence to home PR delivered using fitness application and self-selected activity with no adverse events. This program style may be a viable solution for telerehabilitation in severe CF and is particularly relevant in the COVID era.

PMID:33727918 | PMC:PMC7935590 | DOI:10.1155/2021/6641853

mBio. 2021 Mar 16;12(2):e00006-21. doi: 10.1128/mBio.00006-21.

ABSTRACT

Culture-independent studies have revealed that chronic lung infections in persons with cystic fibrosis (pwCF) are rarely limited to one microbial species. Interactions among bacterial members of these polymicrobial communities in the airways of pwCF have been reported to modulate clinically relevant phenotypes. Furthermore, it is clear that a single polymicrobial community in the context of CF airway infections cannot explain the diversity of clinical outcomes. While large 16S rRNA gene-based studies have allowed us to gain insight into the microbial composition and predicted functional capacities of communities found in the CF lung, here we argue that in silico approaches can help build clinically relevant in vitro models of polymicrobial communities that can in turn be used to experimentally test and validate computationally generated hypotheses. Furthermore, we posit that combining computational and experimental approaches will enhance our understanding of mechanisms that drive microbial community function and identify new therapeutics to target polymicrobial infections.

PMID:33727344 | DOI:10.1128/mBio.00006-21

J Telemed Telecare. 2021 Mar 16:1357633X21998205. doi: 10.1177/1357633X21998205. Online ahead of print.

ABSTRACT

INTRODUCTION: The demand for Hospital in the Home has increased, especially as an avenue for treatment of respiratory exacerbations. However, a limiting factor of Hospital in the Home efficiency is excess travel. Telehealth can potentially increase in-home access to specialist care such as physiotherapy. This study examined clinical outcomes achieved with a hybrid telehealth model and assessed safety and efficiency.

METHOD: This study was an observational benchmarking study of Hospital in the Home physiotherapy episodes of care during respiratory exacerbations between January 2017-June 2019. The participants were young people aged 8-18 years, with cystic fibrosis receiving intravenous antibiotics and bi-daily physiotherapy. The intervention was physiotherapy via either a hybrid model (1× telehealth, 1× face-to-face session) or standard care (2× face-to-face sessions). The outcomes were frequency of return to at least 95% of baseline percentage predicted forced expiratory volume in the first second (ppFEV1), ppFEV1 change, adverse events, travel time and distance saved.

RESULTS: There were 82 episodes of Hospital in the Home; 41 hybrid and 41 standard care. Return to at least 95% of baseline was achieved in 49% of the hybrid group and 32% of standard care. Median ppFEV1 change was +6% for the hybrid group and +2% standard care. There were no adverse events. Estimated travel time and distance saved was 16,520 min and 12,301.2 km.

CONCLUSION: Preliminary information supports a hybrid telehealth physiotherapy model as an alternative to standard care for young people with cystic fibrosis during an exacerbation. Safety of telehealth in conjunction with home visits favoured its use to improve efficiency and capacity without added risk.

PMID:33726605 | DOI:10.1177/1357633X21998205

Hosp Pract (1995). 2021 Mar 16. doi: 10.1080/21548331.2021.1905413. Online ahead of print.

ABSTRACT

OBJECTIVES: Hemoptysis is a complication in cystic fibrosis (CF) patients, and is associated with pulmonary exacerbations and hospitalizations. Pancreatic insufficiency is common in CF patients, and therefore these patients may benefit from the use of vitamin K therapy.

METHODS: This was an observational study conducted in adult CF patients aiming to describe the utilization of vitamin K therapy in the setting of hemoptysis during an acute CF pulmonary exacerbation. An evaluation of hospital length of stay, time until the next pulmonary exacerbation, and 30-day re-admission rates were evaluated in CF patients who presented with hemoptysis and received vitamin K therapy.

RESULTS: The average dose of vitamin K therapy was 10 mg for an average duration of 4.9 ± 0.55 days for 38 adult CF patients included in this cohort. The median length of stay among patients who received vitamin K therapy was 8 days (IQR: 6 - 12 days). The median time until next hospital admission was 127 days (95% CI: 71.4 to 182.6 days), and the 30-day readmission rates were 7.89%. Two patients developed a thromboembolism after receiving vitamin K therapy.

CONCLUSIONS: Evidence for the use of vitamin K therapy in the setting of CF-related hemoptysis remains unclear, and warrants further safety and efficacy evaluation. Further prospective studies are needed to determine the appropriateness of dosing and duration of vitamin K therapy, as well as determining its role in the setting of the varying levels of hemoptysis during a pulmonary CF exacerbation.

PMID:33726579 | DOI:10.1080/21548331.2021.1905413

Pediatr Pulmonol. 2021 Mar 16. doi: 10.1002/ppul.25375. Online ahead of print.

ABSTRACT

BACKGROUND: For Australians living with Cystic Fibrosis (CF), increased longevity means greater consideration needs to be given to long-term endocrine sequelae such as CF-related bone disease. Deficits in bone mass accrual most likely occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual-energy x-ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population, and use this to guide a more streamlined approach to bone health screening.

METHODS: This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n=453). 202 patients had a DXA scan in the study period (191 with height-adjusted data) and 111 patients had more than one scan (108 with height-adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data.

RESULTS: The main predictor of future BMD was previous BMD Z score (p<0.001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1 ), age, history of previous fracture, oral corticosteroid use and number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1 and number of hospital admissions.

CONCLUSION: Second yearly scans may be unnecessary in children with an adequate DXA score on initial scan who remain clinically stable. However, clinical deterioration in those whose bone mineral density were previously normal, may require closer monitoring of bone health. We propose a guideline for frequency of DXA monitoring in relation to clinical risk factors. This article is protected by copyright. All rights reserved.

PMID:33724711 | DOI:10.1002/ppul.25375

Cochrane Database Syst Rev. 2021 Mar 8;3:CD003427. doi: 10.1002/14651858.CD003427.pub5.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is a group of inherited disorders that result in haemoglobin abnormalities and other complications. Injury to the spleen, among other factors, contribute to persons with SCD being particularly susceptible to infection. Infants and very young children are especially vulnerable. The 'Co-operative Study of Sickle Cell Disease' observed an incidence rate for pneumococcal septicaemia of 10 per 100 person-years in children under the age of three years. Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population. This is an update of a Cochrane Review which was first published in 2002, and previously updated, most recently in 2017. OBJECTIVES: To compare the effects of antibiotic prophylaxis against pneumococcus in children with SCD receiving antibiotic prophylaxis compared to those without in relation to: 1. incidence of Streptococcus pneumoniae infection; 2. mortality (as reported in the included studies); 3. drug-related adverse events (as reported in the included studies) to the individual and the community; 4. the impact of discontinuing at various ages on incidence of infection and mortality.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and also two clinical trials registries: ClinicalTrials.gov and the WHO International Registry Platform (not in 2020 given access issues relating to Covid-19 pandemic). Additionally, we carried out hand searching of relevant journals and abstract books of conference proceedings. Date of the most recent search: 25 January 2021.

SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with SCD with placebo, no treatment or a comparator drug.

DATA COLLECTION AND ANALYSIS: The standard methodological procedures expected by Cochrane were used. Both authors independently extracted data and assessed trial quality. The authors used the GRADE criteria to assess the certainty of the evidence.

MAIN RESULTS: Six trials were identified by the searches, of which three trials were eligible for inclusion. A total of 880 children, who were between three months to five years of age at randomization were included. The included studies were conducted in centres in the USA and in Kingston, Jamaica. In trials that investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% confidence interval 0.16 to 0.86) (two trials, 457 children) (low-certainty evidence), while for withdrawal the odds ratio was 0.49 (95% confidence interval 0.09 to 2.71) (one trial, 400 children) (low-certainty evidence). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age of five years. Overall, the certainty of the evidence for all outcomes was judged to be low. The results from the risk of bias assessment undertaken identified two domains in which the risk of bias was considered to be high, these were incomplete outcome data (attrition bias) (two trials) and allocation concealment (selection bias) (one trial). Domains considered to have a low risk of bias for all three trials were selective reporting (reporting bias) and blinding (performance and detection bias).

AUTHORS' CONCLUSIONS: The evidence examined was determined to be of low certainty and suggests that prophylactic penicillin significantly reduces risk of pneumococcal infection in children with homozygous SCD, and is associated with minimal adverse reactions. Further research may help to determine the ideal age to safely withdraw penicillin.

PMID:33724440 | DOI:10.1002/14651858.CD003427.pub5

ACS Infect Dis. 2021 Mar 16. doi: 10.1021/acsinfecdis.0c00682. Online ahead of print.

ABSTRACT

Burkholderia cepacia complex (Bcc) poses a serious health threat to people with cystic fibrosis or compromised immune systems. Infections often arise from Bcc strains, which are highly resistant to many classes of antibiotics, including β-lactams. β-Lactam resistance in Bcc is conferred largely via PenA-like β-lactamases. Avibactam was previously shown to be a potent inactivator of PenA1. Here, we examined the inactivation mechanism of PenA1, a class A serine carbapenemase from Burkholderia multivorans using β-lactamase inhibitors (β-lactam-, diazabicyclooctane-, and boronate-based) with diverse mechanisms of action. In whole cell based assays, avibactam, relebactam, enmetazobactam, and vaborbactam restored susceptibility to piperacillin against PenA1 expressed in Escherichia coli. The rank order of potency of inactivation in vitro based on kinact/KI or k2/K values (range: 3.4 × 102 to 2 × 106 M-1 s-1) against PenA1 was avibactam > enmetazobactam > tazobactam > relebactam > clavulanic acid > vaborbactam. The contribution of selected amino acids (S70, K73, S130, E166, N170, R220, K234, T237, and D276) in PenA1 toward inactivation was evaluated using site-directed mutagenesis. The S130A, R220A, and K234A variants of PenA1 were less susceptible to inactivation by avibactam. The R220A variant was purified and assessed via steady-state inhibition kinetics and found to possess increased Ki-app values and decreased kinact/KI or k2/K values against all tested inhibitors compared to PenA1. Avibactam was the most affected by the alanine replacement at 220 with a nearly 400-fold decreased acylation rate. The X-ray crystal structure of the R220A variant was solved and revealed loss of the hydrogen bonding network between residues 237 and 276 leaving a void in the active site that was occupied instead by water molecules. Michaelis-Menten complexes were generated to elucidate the molecular contributions of the poorer in vitro inhibition profile of vaborbactam against PenA1 (k2/K, 3.4 × 102 M-1 s-1) and was compared to KPC-2, a class A carbapenemase that is robustly inhibited by vaborbactam. The active site of PenA1 is larger than that of KPC-2, which impacted the ability of vaborbactam to form favorable interactions, and as a result the carboxylate of vaborbactam was drawn toward K234/T235 in PenA1 displacing the boronic acid from approaching the nucleophilic S70. Moreover, in PenA1, the tyrosine at position 105 compared to tryptophan in KPC-2, was more flexible rotating more than 90°, and as a result PenA1's Y105 competed for binding with the cyclic boronate vs the thiophene moiety of vaborbactam, further precluding inhibition of PenA1 by vaborbactam. Given the 400-fold decreased k2/K for the R220A variant compared to PenA1, acyl-enzyme complexes were generated via molecular modeling and compared to the PenA1-avibactam crystal structure. The water molecules occupying the active site of the R220A variant are unable to stabilize the T237 and D276 region of the active site altering the ability of avibactam to form favorable interactions compared to PenA1. The former likely impacts the ability of all inhibitors to effectively acylate this variant enzyme. Based on the summation of all evidence herein, the utility of these newer β-lactamase inhibitors (i.e., relebactam, enmetazobactam, avibactam, and vaborbactam) in combination with a β-lactam against B. multivorans producing PenA1 and the R220A variant is promising.

PMID:33723985 | DOI:10.1021/acsinfecdis.0c00682