Staphylococcus aureus is the most prevalent cystic fibrosis (CF) pathogen. During chronic airway infections, S. aureus adaptation to antibiotics includes evolving small colony variants (SCVs). ...Observational studies correlate SCVs with deteriorating lung function in CF, but it is unclear whether SCVs
disease progression or if they are markers of intensified treatment. G. E. Bollar, J. D. Keith, A. M. Oden, M. R. Kiedrowski, and S. E. Birket (Infect Immun 90:e00237-22, 2022, https://doi.org/10.1128/iai.00237-22) provide intriguing new experimental evidence that an SCV elicits greater inflammation than its normal colony progenitor strain in CF rats.
Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. Advanced CF is characterized by a deficit in mucociliary ...transport (MCT), a process that traps and propels bacteria out of the lungs, but whether this deficit occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn piglets with CF. Cholinergic stimulation, which elicits mucus secretion, substantially reduced microdisk movement. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. Thus, impaired MCT is a primary defect in CF, suggesting that submucosal glands and tethered mucus may be targets for early CF treatment.
•39 studies investigated HPA functioning as a predictor of antidepressant response.•Non-responders did not differ from responders in pre-treatment CRH and ACTH.•Non-responders had higher cortisol in ...studies with a specific methodological profile.
Although antidepressants are effective, around 50% of depressed patients are non-responsive. At the same time, some patients show alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Due to interactions with central monoaminergic systems, these may profit less from antidepressants.
To determine whether non-responders and responders differed in pre-treatment HPA axis functioning, the Cochrane Library, EMBASE, MEDLINE, and PsycINFO were searched. Studies using patients with depression being treated with antidepressants, and including both a pre-treatment HPA and a post-treatment response measure were included. Standardised mean differences were calculated for meta-analysis.
Thirty-nine studies were included. Non-responders and responders did not differ in pre-treatment corticotropin-releasing hormone or adrenocorticotropic hormone. Meta-regression showed non-responders had comparably higher pre-treatment cortisol in studies measuring cortisol non-invasively, not reporting sample storage, failing to control for age, and excluding patients with comorbidities.
Only studies with a specific methodological profile seem to be able to show that the more marked depressed patients’ alterations in the HPA axis, the less likely they are to profit from antidepressants.
Many patients with depressive disorders demonstrate resistance to psychological therapy. A frequent finding is hypothalamic-pituitary-adrenal (HPA) axis alterations. As cortisol is known to modulate ...cognitive processes, those patients may be less likely to profit from psychological therapy.
To conduct a systematic review and meta-analysis on cortisol as a predictor of psychological therapy response.
The Cochrane Library, EMBASE, MEDLINE and PsycINFO databases were searched. Records were included if they looked at patients with any depressive disorder engaging in psychological therapy, with a pre-treatment cortisol and a post-treatment symptom measure.
Eight articles satisfied our selection criteria. The higher the cortisol levels before starting psychological therapy, the more symptoms patients with depression experienced at the end of treatment and/or the smaller their symptom change.
Our findings suggest that patients with depression with elevated HPA functioning are less responsive to psychological therapy.
Highlights • Does cortisol predict psychotherapy response in anxiety disorders? • Comprehensive systematic review and meta-analysis • No relationship between basal (unstimulated) cortisol and ...treatment response • Higher cortisol during exposure predicted better responses in systematic review • Meta-analysis did not confirm this
Linezolid is an antibiotic used to treat serious
infections. Resistance to linezolid is considered rare but could emerge with repeated dosing. We recently reported widespread prescription of ...linezolid for a cohort of patients with cystic fibrosis (CF). The goals of this study were to determine the incidence of linezolid-resistant methicillin-resistant
(MRSA) in CF and identify molecular mechanisms for linezolid resistance. We identified patients who cultured
resistant to linezolid with minimum inhibitory concentration (MIC) >4 at the University of Iowa CF Center between 2008 and 2018. We obtained isolates from these patients and retested susceptibility to linezolid using broth microdilution. We used whole genome sequencing to perform phylogenetic analysis of linezolid-resistant isolates and examine sequences for mutations or accessory genes that confer linezolid resistance. Between 2008 and 2018, 111 patients received linezolid, and 4 of these patients cultured linezolid-resistant
. We sequenced 11 resistant and 21 susceptible isolates from these 4 subjects. Phylogenetic analysis indicated that linezolid resistance developed in ST5 or ST105 backgrounds. Three individuals had linezolid-resistant
with a G2576T mutation in 23S rRNA. One of these subjects additionally had a
hypermutating
that produced five resistant isolates with multiple ribosomal subunit mutations. In one subject, the genetic basis for linezolid resistance was unclear. We conclude that linezolid resistant
can occur through multiple genetic mechanisms in patients with repeated exposure to this antibiotic. IMPORTANCE Patients with cystic fibrosis have persistent lung infections with
that require extensive antibiotic treatments. Linezolid, an antibiotic given by oral or intravenous route, is prescribed repeatedly for patients whose lung disease has progressed. After treatment with linezolid,
strains can evolve antibiotic resistance through multiple genetic mechanisms. In addition to a common mutation in the 23S ribosomal RNA known to confer linezolid resistance,
strains can evolve novel resistance based on a combination of mutations affecting the bacterial ribosome. This combination of mutations was observed in a strain that exhibited hypermutation owing to the loss of the DNA repair genes
and
. In this cohort of patients with cystic fibrosis, linezolid resistance was transient, possibly due to the growth disadvantage of resistant strains. However, ongoing chronic exposure to linezolid may create optimal conditions for the future emergence of resistance to this critical antibiotic.
:
and
often infect the airways in cystic fibrosis (CF). Because registry studies show higher prevalence of
versus
in older patients with CF, a common assumption is that
replaces
over time.
,
can ...outgrow and kill
. However, it is unknown how rapidly
replaces
in patients with CF.
: We studied a longitudinal cohort of children and adults with CF who had quantitative sputum cultures. We determined the abundance of
and
in cfu/ml. We determined the duration and persistence of infections and measured longitudinal changes in culture positivity and abundance for each organism.
: Between 2004 and 2017, 134 patients had ≥10 quantitative cultures, with median observation time of 10.15 years. One hundred twenty-four patients had at least one positive culture for
, and 123 had at least one positive culture for
. Both species had median abundance of >10
cfu/ml. Culture abundance was stable over time for both organisms. There was an increase in the prevalence of
/
coinfection but no decrease in
prevalence within individuals over time.
:
and
are abundant in CF sputum cultures. Contrary to common assumption, we found no pattern of replacement of
by
. Many patients with CF have durable long-term coinfection with these organisms. New strategies are needed to prevent and treat these infections.
Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar ...bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C‐terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C‐terminal domain, which includes sequence motifs necessary for the function of human paralogs ABCA1, ABCA4, and the bacterial homolog DrrA. This observation suggests the C‐terminal domain is also required for normal function of ABCA3.
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