Microorganisms. 2021 Feb 25;9(3):478. doi: 10.3390/microorganisms9030478.

ABSTRACT

As disease worsens in patients with cystic fibrosis (CF), Pseudomonas aeruginosa (PA) colonizes the lungs, causing pulmonary failure and mortality. Progressively, PA forms typical biofilms, and antibiotic treatments determine multidrug-resistant (MDR) PA strains. To advance new therapies against MDR PA, research has reappraised bacteriophages (phages), viruses naturally infecting bacteria. Because few in vitro studies have tested phages on CF PA biofilms, general reliability remains unclear. This study aimed to test in vitro newly isolated environmental phage activity against PA isolates from patients with CF at Bambino Gesù Children's Hospital (OBG), Rome, Italy. After testing in vitro phage activities, we combined phages with amikacin, meropenem, and tobramycin against CF PA pre-formed biofilms. We also investigated new emerging morphotypes and bacterial regrowth. We obtained 22 newly isolated phages from various environments, including OBG. In about 94% of 32 CF PA isolates tested, these phages showed in vitro PA lysis. Despite poor efficacy against chronic CF PA, five selected-lytic-phages (Φ4_ZP1, Φ9_ZP2, Φ14_OBG, Φ17_OBG, and Φ19_OBG) showed wide host activity. The Φ4_ZP1-meropenem and Φ14_OBG-tobramycin combinations significantly reduced CF PA biofilms (p < 0.001). To advance potential combined phage-antibiotic therapy, we envisage further in vitro test combinations with newly isolated phages, including those from hospital environments, against CF PA biofilms from early and chronic infections.

PMID:33668889 | DOI:10.3390/microorganisms9030478

Diagnostics (Basel). 2021 Feb 13;11(2):299. doi: 10.3390/diagnostics11020299.

ABSTRACT

In Austria, newborns have been screened for cystic fibrosis (CF) by analyzing immunoreactive trypsinogen (IRT) from dried blood spots (DBS)s for nearly 20 years. Recently, pancreatitis-associated protein (PAP) analysis was introduced as a second-tier test with the aim of reducing recalls for second DBS cards while keeping sensitivity high. For 28 months, when IRT was elevated (65-130 ng/mL), PAP was measured from the first DBS (n = 198,927) with a two-step cut-off applied. For the last 12 months of the observation period (n = 85,421), an additional IRT×PAP cut-off was introduced. If PAP or IRT×PAP were above cut-off, a second card was analyzed for IRT and in case of elevated values identified as screen-positive. Above 130 ng/mL IRT in the first DBS, newborns were classified as screen-positive. IRT analysis of first DBS resulted in 1961 (1%) tests for PAP. In the first 16 months, 26 of 93 screen-positive were confirmed to have CF. Two false-negatives have been reported (sensitivity = 92.8%). Importantly, less than 30% of families compared to the previous IRT-IRT screening scheme had to be contacted causing distress. Adding IRT×PAP caused a marginally increased number of second cards and sweat tests to be requested during this period (15 and 3, respectively) compared to the initial IRT-PAP scheme. One case of confirmed CF was found due to IRT×PAP, demonstrating an increase in sensitivity. Thus, the relatively simple and economical algorithm presented here performs effectively and may be a useful model for inclusion of CF into NBS panels or modification of existing schemes.

PMID:33668470 | DOI:10.3390/diagnostics11020299

Epilepsia. 2021 Mar;62(3):698-708. doi: 10.1111/epi.16821.

ABSTRACT

OBJECTIVE: The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy.

METHODS: Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy.

RESULTS: Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively.

SIGNIFICANCE: These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.

PMID:33666943 | DOI:10.1111/epi.16821

BMJ Paediatr Open. 2021 Feb 17;5(1):e000958. doi: 10.1136/bmjpo-2020-000958. eCollection 2021.

ABSTRACT

OBJECTIVE: To determine: (1) which biological/lifestyle, psychological and/or social factors are associated with fatigue among children with a chronic disease and (2) how much each of these factors contributes to explaining variance in fatigue.

DESIGN AND SETTING: This was a cross-sectional study across two children's hospitals.

PATIENTS: We included children aged 8-18 years who visited the outpatient clinic with cystic fibrosis, an autoimmune disease or postcancer treatment.

MAIN OUTCOME MEASURES: Fatigue was assessed using the PedsQL Multidimensional Fatigue Scale. Generic biological/lifestyle, psychological and social factors were assessed using clinical assessment tools and questionnaires. Multiple linear regression analyses were used to test the associations between these factors and fatigue. Finally, a multivariable regression model was used to determine which factor(s) have the strongest effect on fatigue.

RESULTS: A total of 434 out of 902 children were included (48% participation rate), with a median age of 14.5 years; 42% were male. Among these 434 children, 21.8% were severely fatigued. Together, all biopsychosocial factors explained 74.6% of the variance in fatigue. More fatigue was uniquely associated with poorer physical functioning, more depressive symptoms, more pressure at school, poorer social functioning and older age.

CONCLUSIONS: Fatigue among children with a chronic disease is multidimensional. Multiple generic biological/lifestyle, psychological and social factors were strongly associated with fatigue, explaining 58.4%; 65.8% and 50.0% of the variance in fatigue, respectively. Altogether, almost three-quarters of the variance in fatigue was explained by this biopsychosocial model. Thus, when assessing and treating fatigue, a transdiagnostic approach is preferred, taking into account biological, psychological and social factors.

PMID:33665374 | PMC:PMC7893660 | DOI:10.1136/bmjpo-2020-000958

Cell Death Dis. 2021 Mar 4;12(3):241. doi: 10.1038/s41419-021-03526-w.

ABSTRACT

Pseudomonas aeruginosa is a common respiratory pathogen in cystic fibrosis (CF) patients which undergoes adaptations during chronic infection towards reduced virulence, which can facilitate bacterial evasion of killing by host cells. However, inflammatory cytokines are often found to be elevated in CF patients, and it is unknown how chronic P. aeruginosa infection can be paradoxically associated with both diminished virulence in vitro and increased inflammation and disease progression. Thus, we investigated the relationship between the stimulation of inflammatory cell death pathways by CF P. aeruginosa respiratory isolates and the expression of key inflammatory cytokines. We show that early respiratory isolates of P. aeruginosa from CF patients potently induce inflammasome signaling, cell death, and expression of IL-1β by macrophages, yet little expression of other inflammatory cytokines (TNF, IL-6 and IL-8). In contrast, chronic P. aeruginosa isolates induce relatively poor macrophage inflammasome signaling, cell death, and IL-1β expression but paradoxically excessive production of TNF, IL-6 and IL-8 compared to early P. aeruginosa isolates. Using various mutants of P. aeruginosa, we show that the premature cell death of macrophages caused by virulent bacteria compromises their ability to express cytokines. Contrary to the belief that chronic P. aeruginosa isolates are less pathogenic, we reveal that infections with chronic P. aeruginosa isolates result in increased cytokine induction due to their failure to induce immune cell death, which results in a relatively intense inflammation compared with early isolates.

PMID:33664232 | DOI:10.1038/s41419-021-03526-w

BMC Pediatr. 2021 Mar 4;21(1):108. doi: 10.1186/s12887-021-02575-6.

ABSTRACT

BACKGROUND: The prevalence of monogenic diabetes is estimated to be 1.1-6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years.

METHODS: This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively.

RESULTS: Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness.

CONCLUSIONS: Genetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling.

PMID:33663443 | DOI:10.1186/s12887-021-02575-6

Pharmacol Ther. 2021 Mar 1:107826. doi: 10.1016/j.pharmthera.2021.107826. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) lung disease results from mutations in the CFTR anion channel that reduce anion and fluid secretion by airway epithelia. Impaired secretion compromises airway innate defence mechanisms and leads to bacterial colonization, excessive inflammation and tissue damage; thus, restoration of CFTR function is the goal of many CF therapies. CFTR channels are activated by cyclic nucleotide-dependent protein kinases. The second messengers 3'5'-cAMP and 3'5'-cGMP are hydrolysed by a large family of cyclic nucleotide phosphodiesterases that provide subcellular spatial and temporal control of cyclic nucleotide-dependent signalling. Selective inhibition of these enzymes elevates cyclic nucleotide levels, leading to activation of CFTR and other downstream effectors. Here we examine members of the PDE family that are likely to regulate CFTR-dependent ion and fluid secretion in the airways and discuss other actions of PDE inhibitors that can influence cyclic nucleotide-regulated mucociliary transport, inflammation and bronchodilation. Finally, we review PDE inhibitors and the potential benefits they could provide as CF therapeutics.

PMID:33662448 | DOI:10.1016/j.pharmthera.2021.107826

Bol Med Hosp Infant Mex. 2021;78(1):29-33. doi: 10.24875/BMHIM.20000216.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a potentially mortal disease characterized by a chronic pulmonary disease with persistent airway infection. Children with this disease are more susceptible to respiratory infections due to the limitation in mucociliary transport and anatomical disruption of the bronchial tree. SARS-CoV-2 causes COVID-19, a respiratory illness related to exacerbations of chronic pulmonary pathologies in children, such as CF and asthma. There are not enough case reports on pediatric patients with SARS-CoV-2 infection and CF, for which we share our experience.

CASE REPORT: A 22-month-old male patient diagnosed with CF presented in the hospital with cough, fever, and increased respiratory work. The patient received supplemental oxygen and antibiotic and antiviral therapy. Positive results for type B influenza and RT-PCR (reverse transcription-polymerase chain reaction) for SARS-CoV-2 were obtained. Due to the persistence of respiratory difficulty, high-flow therapy was initiated, with a good response. After an episode of hypoxemia, bradycardia, and increased respiratory work secondary to accumulated secretions, orotracheal intubation and invasive mechanical ventilation were performed. The patient evolved with clinical and gasometric improvement. After 10 days of in-hospital antibiotic management with adequate clinical evolution, the patient was discharged to complete oral treatment and home isolation.

CONCLUSIONS: We present a case of chronic respiratory disease and SARS-CoV-2 infection with severity criteria in a pediatric patient. The evolution was favorable with timely support management and antibiotic therapy in a third-level hospital.

PMID:33661877 | DOI:10.24875/BMHIM.20000216

JMIR Form Res. 2021 Mar 4;5(3):e24302. doi: 10.2196/24302.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a rare, life-shortening, multiorgan disease, the treatment of which has seen significant increases in the life expectancy of those with CF. Many advances in CF care are thanks to the dedicated and active participation of people with CF as research participants. Unfortunately, most CF research teams still do not fully partner with people with CF or their caregivers.

OBJECTIVE: The aim of this study was to determine the interest, knowledge gaps, and desired format for patient-centered outcomes research (PCOR) training in the CF community.

METHODS: We surveyed patients, caregivers, researchers, research staff, and diverse health care providers via list servers and social media outreach about their knowledge of, experience with, and preferences for PCOR training components. We followed the survey with 3 small-group discussion sessions with 22 participants who completed the survey to establish consensus and prioritize key learning components of a PCOR training program. We summarized results using descriptive statistics.

RESULTS: A total of 170 participants completed the survey (patients/caregivers: 96/170, 56.5%; researchers/health care providers: 74/170, 43.5%). Among providers, 26% (19/74) were physicians/advanced practice providers, 20% (15/74) were nurses, and 54% (40/74) were from other disciplines. Among all participants, 86.5% (147/170) expressed interest in learning about PCOR, although training topics and training format differed between the patient/caregiver and researcher/health care provider groups. Before participating in PCOR, patients/caregivers wanted to understand more about expectations of them as partners on PCOR research teams (82/96, 85%). Meanwhile, researchers/health care providers desired information on how to include outcomes important to patients/caregivers (55/74, 74%) and the quality and impact of PCOR research (52/74, 70% and 51/74, 69%, respectively). Patients/caregivers were most interested in learning about the time commitment as a PCOR team member (75/96, 78%). Researchers/health care providers wanted to receive training about how to establish trust (47/74, 64%) and maintain confidentiality (47/74, 64%) when including patient or caregiver partners on the PCOR team. During follow-up discussions, participants emphasized the importance of addressing the traditional patient/caregiver and researchers/health care provider hierarchy by teaching about transparency, appreciation, creating a common language between the groups, and providing specific training on "how" to do PCOR.

CONCLUSIONS: Our findings suggest CF community members are interested in PCOR. A high-quality training program would fill a current deficit in methodological research. This assessment identified the topics and formats desired and can be used to develop targeted training to enhance meaningful PCOR in CF.

PMID:33661127 | DOI:10.2196/24302

Am J Audiol. 2021 Mar 4:1-9. doi: 10.1044/2020_AJA-20-00117. Online ahead of print.

ABSTRACT

Purpose Individuals with cystic fibrosis (CF) are often treated with intravenous (IV) aminoglycoside (AG) antibiotics to manage life-threatening bacterial infections. Preclinical animal data suggest that, in addition to damaging cochlear hair cells, this class of antibiotics may cause cochlear synaptopathy and/or damage to higher auditory structures. The acoustic reflex growth function (ARGF) is a noninvasive, objective measure of neural function in the auditory system. A shallow ARGF (small reflex-induced changes in middle ear function with increasing elicitor level) has been associated with synaptopathy due to noise exposure in rodent and human studies. In this study, the ARGF was obtained in CF patients with normal hearing, some of whom have been treated with IV AGs, and a control group without CF. The hypothesis was that patients with IV-AG exposure would have a shallow ARGF due to cochlear synaptopathy caused by ototoxicity. Method Wideband ARGFs were examined in four groups of normal-hearing participants: a control group of 29 individuals without CF; and in 57 individuals with CF grouped by lifetime IV-AG exposure: 15 participants with no exposure, 21 with low exposure, and 21 with high exposure. Procedures included pure-tone audiometry, clinical immittance, wideband acoustic immittance battery, including ARGFs, and transient evoked otoacoustic emissions. Results CF subjects with normal pure-tone thresholds and either high or low lifetime IV-AG exposure had enhanced ARGFs compared to controls and CF participants without IV-AG exposure. The groups did not differ in transient evoked otoacoustic emission signal-to-noise ratio. Conclusion These results diverge from the shallow ARGF pattern observed in studies of noise-induced cochlear synaptopathy and are suggestive of a central mechanism of auditory dysfunction in patients with AG-induced ototoxicity.

PMID:33661027 | DOI:10.1044/2020_AJA-20-00117

Stat Med. 2021 Mar 4. doi: 10.1002/sim.8927. Online ahead of print.

ABSTRACT

Modeling recurrent event data with multiple event types has drawn interest in recent biomedical studies due to its flexibility for understanding different risk factors for multiple recurrent event processes. However, in such data type, missing event type appears frequently because of various reasons such as recording ignorance or resource limitation. In this study, we aim to propose an inverse probability weighted estimation that is commonly used in the missing data literature to correct possibly biased estimation by a complete-case analysis. This approach is not limited to a specific form of the recurrent event model. We derive the large sample theory in a general form. We demonstrate that our approach can be applied to either multiplicative or additive rates model with practical sample size via comprehensive simulations. Nonmucoid and mucoid Pseudomonas aeruginosa infections of 14 888 patients in 2016 Cystic Fibrosis Foundation Patient Registry data are analyzed to show that, without including 12% events with missing event type in the analysis, several factors may be misidentified as risk factors for the nonmucoid type of infections.

PMID:33660283 | DOI:10.1002/sim.8927

Clin Child Fam Psychol Rev. 2021 Mar 4. doi: 10.1007/s10567-021-00345-5. Online ahead of print.

ABSTRACT

Individuals with cystic fibrosis (CF) are at high risk of clinically significant anxiety, which can be related to lower treatment adherence and poorer health outcomes. Additionally, up to half of the parents/caregivers of children with CF experience clinically significant anxiety. Research has focussed on CF youth aged 13 years and older, leaving anxiety among school-aged children (aged 6-12 years) largely unstudied. This review aimed to synthesize research on anxiety among children with CF and their parents, examining prevalence, risk factors, and relationships between parent and child factors. Four electronic databases were searched, and publications were included if participants were children (or parents of children) with CF with a mean age between 6 and 12 years, and a standardized anxiety measure was used. Data from fourteen studies were extracted for descriptive synthesis; however, no studies focussed exclusively on the age range of 6-12 years. Results generally indicated that anxiety is highly prevalent in both child and parent populations; anxiety was the most prevalent mental health condition among children with CF, and anxiety was higher among CF populations than control populations among both children and parents. However, there were disparities, with some papers finding low rates of anxiety, and results on the relationship between anxiety and health outcomes varying greatly. Several risk factors were identified, but few were corroborated. There is an overall deficiency of research in this area, particularly examining the relationships between parent and child anxiety, and anxiety and health outcomes. Further research on suitable screening and intervention practices is also required.

PMID:33660071 | DOI:10.1007/s10567-021-00345-5

Fac Rev. 2020 Dec 14;9:23. doi: 10.12703/r/9-23. eCollection 2020.

ABSTRACT

Almost every ecosystem on this planet is teeming with microbial communities made of diverse bacterial species. At a reductionist view, many of these bacteria form pairwise interactions, but, as the field of view expands, the neighboring organisms and the abiotic environment can play a crucial role in shaping the interactions between species. Over the years, a strong foundation of knowledge has been built on isolated pairwise interactions between bacteria, but now the field is advancing toward understanding how cohabitating bacteria and natural surroundings affect these interactions. Use of bottom-up approaches, piecing communities together, and top-down approaches that deconstruct communities are providing insight on how different species interact. In this review, we highlight how studies are incorporating more complex communities, mimicking the natural environment, and recurring findings such as the importance of cooperation for stability in harsh environments and the impact of bacteria-induced environmental pH shifts. Additionally, we will discuss how omics are being used as a top-down approach to identify previously unknown interspecies bacterial interactions and the challenges of these types of studies for microbial ecology.

PMID:33659955 | PMC:PMC7886066 | DOI:10.12703/r/9-23

Front Cell Dev Biol. 2021 Feb 15;9:630654. doi: 10.3389/fcell.2021.630654. eCollection 2021.

ABSTRACT

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF-related diabetes (CFRD) is one of the most prevalent comorbidities of CF. Altered glucose homeostasis has been reported in CF patients. The mechanism has not been fully elucidated. Besides the consequence of pancreatic endocrine dysfunction, we focus on insulin-responsive tissues and glucose transportation to explain glucose homeostasis alteration in CFRD. Herein, we found that CFTR knockout mice exhibited insulin resistance and glucose tolerance. Furthermore, we demonstrated insulin-induced glucose transporter 4 (GLUT4) translocation to the cell membrane was abnormal in the CFTR knockout mice muscle fibers, suggesting that defective intracellular GLUT4 transportation may be the cause of impaired insulin responses and glucose homeostasis. We further demonstrated that PI(4,5)P2 could rescue CFTR related defective intracellular GLUT4 transportation, and CFTR could regulate PI(4,5)P2 cellular level through PIP5KA, suggesting PI(4,5)P2 is a down-stream signal of CFTR. Our results revealed a new signal mechanism of CFTR in GLUT4 translocation regulation, which helps explain glucose homeostasis alteration in CF patients.

PMID:33659254 | PMC:PMC7917208 | DOI:10.3389/fcell.2021.630654

Front Cell Dev Biol. 2021 Feb 15;9:600711. doi: 10.3389/fcell.2021.600711. eCollection 2021.

ABSTRACT

Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types-including mesenchymal stromal cells (MSCs)-under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.

PMID:33659247 | PMC:PMC7917181 | DOI:10.3389/fcell.2021.600711

Sci Rep. 2021 Mar 3;11(1):5020. doi: 10.1038/s41598-021-84525-x.

ABSTRACT

Mycobacterium abscessus is emerging as a cause of recalcitrant chronic pulmonary infections, particularly in people with cystic fibrosis (CF). Biofilm formation has been implicated in the pathology of this organism, however the role of biofilm formation in infection is unclear. Two colony-variants of M. abscessus are routinely isolated from CF samples, smooth (MaSm) and rough (MaRg). These two variants display distinct colony morphologies due to the presence (MaSm) or absence (MaRg) of cell wall glycopeptidolipids (GPLs). We hypothesized that MaSm and MaRg variant biofilms might have different mechanical properties. To test this hypothesis, we performed uniaxial mechanical indentation, and shear rheometry on MaSm and MaRg colony-biofilms. We identified that MaRg biofilms were significantly stiffer than MaSm under a normal force, while MaSm biofilms were more pliant compared to MaRg, under both normal and shear forces. Furthermore, using theoretical indices of mucociliary and cough clearance, we identified that M. abscessus biofilms may be more resistant to mechanical forms of clearance from the lung, compared to another common pulmonary pathogen, Pseudomonas aeruginosa. Thus, the mechanical properties of M. abscessus biofilms may contribute to the persistent nature of pulmonary infections caused by this organism.

PMID:33658597 | DOI:10.1038/s41598-021-84525-x

Nat Commun. 2021 Mar 3;12(1):1399. doi: 10.1038/s41467-021-21718-y.

ABSTRACT

Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway.

PMID:33658521 | DOI:10.1038/s41467-021-21718-y

Trop Doct. 2021 Mar 3:49475521998182. doi: 10.1177/0049475521998182. Online ahead of print.

ABSTRACT

Micro-gallbladder is a rare clinical entity and mostly linked with cystic fibrosis (CF), which is an autosomal recessive disease involving a protein Cystic fibrosis transmembrane conductance regulator (CFTR) which regulates secretion and absorption in the pulmonary, reproductive and gastrointestinal systems including the liver. Biliary secretion becomes hyperviscous, leading to cholestasis and partial obstruction of the cystic duct. This causes recurrent cholecystitis and gallstone formation. Ultimately, atrophy of the gallbladder results, thus a 'micro-gallbladder' defined as being <2-3 cm in length and 0.5-1.5 cm in width. A shrunken gallbladder from recurrent attacks of gallstone-induced cholecystitis is not typically termed as a micro-gallbladder. Laparoscopic cholecystectomy is definitive treatment for symptomatic micro-gallbladder, even though most cases are managed conservatively without surgery. We report a case of symptomatic micro-gallbladder in a non-CF patient, managed successfully by laparoscopic cholecystectomy.

PMID:33657938 | DOI:10.1177/0049475521998182

Am J Perinatol. 2021 Mar 3. doi: 10.1055/s-0041-1725146. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to evaluate palivizumab (PVZ) use, trends in indications, and outcomes of respiratory illness hospitalizations (RIH) and respiratory syncytial virus hospitalizations (RSVH).

STUDY DESIGN: It involves a large, Canadian prospective (2005-2017) observational multicenter study of children at high risk for RSV infection.

RESULTS: A total of 25,003 infants (56.3% male) were enrolled at 32 sites; 109,579 PVZ injections were administered. Indications included: prematurity (63.3%); "miscellaneous" (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%). The "miscellaneous" group increased over time (4.4% in 2005-2006 to 22.5% in 2016-2017) and included: trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual "unclassified" group. Adherence measured by expected versus actual doses plus correct interdose interval was 64.7%. A total of 2,054 RIH occurred (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH 1.6%). Risk factors for RSVH included having siblings, attending daycare, family history of atopy, smoking exposure, and crowded household. Infants with 5 risk factors were 9.0 times (95% CI or confidence interval 4.4-18.2; p < 0.0005) more likely to have RSVH than infants without risk factors. Three adverse events occurred; none were fatal.

CONCLUSION: Results are relevant to both clinicians and decision-makers. We confirmed the safety of PVZ. Use of PVZ increased steadily for children with miscellaneous conditions and medical complexity. Medical and social factors pose a risk for severe RIH and RSVH with accompanying burden of illness. A vaccine that protects against RSV is urgently required.

KEY POINTS: · Main indications were prematurity (63.3%); "miscellaneous" (17.8%); hemodynamically significant congenital heart disease (10.5%); bronchopulmonary dysplasia/chronic lung disease (8.4%).. · The proportion of children in the "miscellaneous" group, comprised of those with trisomy 21, airway anomalies, pulmonary disorders, cystic fibrosis, neurological impairments, immunocompromised, cardiac aged >2 years, multiple conditions, and a residual "unclassified" group, increased over time (4.4% in 2005-2006 to 22.5% in 2016-2017).. · Respiratory illness-related hospitalization occurred in 2,054 children (6.9%); 198 (9.6%) required intubation. Three hundred thirty-seven hospitalized children were RSV-positive (overall RSVH: 1.6%)..

PMID:33657636 | DOI:10.1055/s-0041-1725146

Med Ultrason. 2021 Mar 3. doi: 10.11152/mu-3059. Online ahead of print.

ABSTRACT

Ultrasound (US) is an ideal diagnostic tool for paediatric patients owning to its high spatial and temporal resolution, real-time imaging, and lack of ionizing radiation and bedside availability. In the current World Federation of Societies for Ultra-sound in Medicine and Biology (WFUMB) paper series so far (part I) the topic has been introduced and the technical require-ments explained. In the present paper the use of US in the lung in paediatric patients is analysed. Lung diseases including the interstitial syndrome, bacterial pneumonia and viral infections, CoViD findings, atelectasis, lung consolidation, bronchiolitis and congenital diseases of the respiratory system including congenital pulmonary airway malformation (CPAM) and sequester but also pneumothorax are discussed.

PMID:33657190 | DOI:10.11152/mu-3059