J Pediatr. 2024 Aug 1:114220. doi: 10.1016/j.jpeds.2024.114220. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess whether beta-lactam extended or continuous beta-lactam infusions (EI/CI) improve clinical outcomes in children with proven or suspected bacterial infections.

STUDY DESIGN: We included observational and interventional studies that compared beta-lactam EI or CI with standard infusions in children less than 18 years old, and reported on mortality, hospital or intensive care unit LOS, microbiological cure and/or clinical cure. Data sources included PubMed, Medline, EBM Reviews, EMBASE, and CINAHL and were searched from January 1, 1980, to November 3, 2023. Thirteen studies (2,945 patients) were included: 5 randomized control trials (RCTs), and 8 observational studies. Indications for antimicrobial therapies and clinical severity varied, ranging from cystic fibrosis exacerbation to critically ill children with bacteriemia.

RESULTS: EI and CI were not associated with a reduction in mortality in RCTs (n = 1,464; RR 0.93, 95% CI 0.71, 1.21), but were in observational studies (n = 833; RR 0.43, 95% CI 0.19, 0.96). We found no difference in hospital length of stay. Results for clinical and microbiological cures were heterogeneous and reported as narrative review. The included studies were highly heterogeneous, limiting the strength of our findings. The lack of shared definitions for clinical and microbiological cure outcomes precluded analysis.

CONCLUSIONS: EI and CI were not consistently associated with reduced mortality or LOS in children. Results were conflicting regarding clinical and microbiological cures. More well-designed studies targeting high-risk populations are necessary to determine the efficacy of these alternative dosing strategies.

PMID:39097265 | DOI:10.1016/j.jpeds.2024.114220

Lancet Psychiatry. 2024 Jul 31:S2215-0366(24)00214-1. doi: 10.1016/S2215-0366(24)00214-1. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning.

METHODS: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study.

FINDINGS: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20).

INTERPRETATION: Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19.

FUNDING: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.

PMID:39096931 | DOI:10.1016/S2215-0366(24)00214-1

Lung. 2024 Aug 3. doi: 10.1007/s00408-024-00733-y. Online ahead of print.

ABSTRACT

PURPOSE: Pseudomonas aeruginosa is the predominant bacterial pathogen colonizing the cystic fibrosis (CF) lung. Mixed populations of nonmucoid and mucoid variants of P. aeruginosa have been isolated from the CF airway. While the association between mucoid variants and pulmonary function decline is well-established, their impact on inflammation and tissue damage in advanced CF lung disease remains unclear.

METHODS: This pilot study utilized 1 non-CF and 3 CF lung explants to examine lobar distribution, inflammation, and histopathology related to nonmucoid and mucoid P. aeruginosa infection. To study tissue damage, we developed a novel lung histopathology scoring system, the first applied to human CF lung biopsies, which is comprised of five indicators: bronchiolar epithelial infiltrate, luminal inflammation, peribronchial/bronchiolar infiltrate, peribronchiolar fibrosis, and alveolar involvement.

RESULTS: Mucoid P. aeruginosa variants were distributed throughout the CF lung but associated with greater concentrations of proinflammatory cytokines, IL-1β, TNF-α, IL-6, IL-8, and IFN-γ, and one anti-inflammatory cytokine, IL-10, compared to nonmucoid variants. CF lung explants exhibited higher histopathology scores compared to a non-CF lung control. In mixed-variant infection, nonmucoid constituents associated with increased bronchiolar epithelial infiltration, one indicator of histopathology.

CONCLUSION: This pilot study suggests ongoing interplay between host and bacterial elements in late-stage CF pulmonary disease. Mucoid P. aeruginosa infection correlates with inflammation regardless of lung lobe, whereas nonmucoid P. aeruginosa is associated with increased inflammatory cell infiltration. The development of a novel lung histopathology scoring system lays the groundwork for future large-cohort investigations.

PMID:39096413 | DOI:10.1007/s00408-024-00733-y

BMC Microbiol. 2024 Aug 3;24(1):290. doi: 10.1186/s12866-024-03441-y.

ABSTRACT

INTRODUCTION: Hormesis describes an inverse dose-response relationship, whereby a high dose of a toxic compound is inhibitory, and a low dose is stimulatory. This study explores the hormetic response of low concentrations of zinc oxide nanoparticles (ZnO NPs) toward Pseudomonas aeruginosa.

METHOD: Samples of P. aeruginosa, i.e. the reference strain, ATCC 27,853, together with six strains recovered from patients with cystic fibrosis, were exposed to ten decreasing ZnO NPs doses (0.78-400 µg/mL). The ZnO NPs were manufactured from Peganum harmala using a chemical green synthesis approach, and their properties were verified utilizing X-ray diffraction and scanning electron microscopy. A microtiter plate technique was employed to investigate the impact of ZnO NPs on the growth, biofilm formation and metabolic activity of P. aeruginosa. Real-time polymerase chain reactions were performed to determine the effect of ZnO NPs on the expression of seven biofilm-encoding genes.

RESULT: The ZnO NPs demonstrated concentration-dependent bactericidal and antibiofilm efficiency at concentrations of 100-400 µg/mL. However, growth was significantly stimulated at ZnO NPs concentration of 25 µg/mL (ATCC 27853, Pa 3 and Pa 4) and at 12.5 µg/mL and 6.25 µg/mL (ATCC 27853, Pa 2, Pa 4 and Pa 5). No significant positive growth was detected at dilutions < 6.25 µg/mL. similarly, biofilm formation was stimulated at concentration of 12.5 µg/mL (ATCC 27853 and Pa 1) and at 6.25 µg/mL (Pa 4). At concentration of 12.5 µg/mL, ZnO NPs upregulated the expression of LasB ( ATCC 27853, Pa 1 and Pa 4) and LasR and LasI (ATCC 27853 and Pa 1) as well as RhII expression (ATCC 27853, Pa 2 and Pa 4).

CONCLUSION: When exposed to low ZnO NPs concentrations, P. aeruginosa behaves in a hormetic manner, undergoing positive growth and biofilm formation. These results highlight the importance of understanding the response of P. aeruginosa following exposure to low ZnO NPs concentrations.

PMID:39095741 | DOI:10.1186/s12866-024-03441-y

Pancreatology. 2024 Jul 30:S1424-3903(24)00694-X. doi: 10.1016/j.pan.2024.07.015. Online ahead of print.

NO ABSTRACT

PMID:39095297 | DOI:10.1016/j.pan.2024.07.015

J Cyst Fibros. 2024 Aug 1:S1569-1993(24)00797-5. doi: 10.1016/j.jcf.2024.07.011. Online ahead of print.

ABSTRACT

BACKGROUND: The prevalence of fungi in cystic fibrosis (CF) lung infections is poorly understood and studies have focused on adult patients. We investigated the fungal diversity in children with CF using bronchoalveolar lavage (BAL) and induced sputum (IS) samples to capture multiple lung niches.

METHODS: Sequencing of the fungal ITS2 region and molecular mycobiota diversity analysis was performed on 25 matched sets of BAL-IS samples from 23 children collected as part of the CF-SpIT study (UKCRN14615; ISRCTNR12473810).

RESULTS: Aspergillus and Candida were detected in all samples and were the most abundant and prevalent genera, followed by Dipodascus, Lecanicillium and Simplicillium. The presumptive CF pathogens Exophiala, Lomentospora and Scedosporium were identified at variable abundances in 100 %, 64 %, and 24 % of sample sets, respectively. Fungal pathogens observed at high relative abundance (≥40 %) were not accurately diagnosed by routine culture microbiology in over 50 % of the cohort. The fungal communities captured by BAL and IS samples were similar in diversity and composition, with exception to C. albicans being significantly increased in IS samples. The respiratory mycobiota varied greatly between individuals, with only 13 of 25 sample sets containing a dominant fungal taxon. In 11/25 BAL sample sets, airway compartmentalisation was observed with diverse mycobiota detected from different lobes of the lung.

CONCLUSIONS: The paediatric mycobiota is diverse, complex and inadequately diagnosed by conventional microbiology. Overlapping fungal communities were identified in BAL and IS samples, showing that IS can capture fungal genera associated with the lower airway. Compartmentalisation of the lower airway presents difficulties for consistent mycobiota sampling.

PMID:39095260 | DOI:10.1016/j.jcf.2024.07.011

Eur J Obstet Gynecol Reprod Biol. 2024 Jul 5;301:49-54. doi: 10.1016/j.ejogrb.2024.07.006. Online ahead of print.

ABSTRACT

OBJECTIVE: Endogenous and exogenous hormonal factors have been associated with female breast, genital, and colorectal cancer risk. The aim of the present study is to conduct an evidence-based evaluation of the fraction of cancers attributable to and prevented by exogenous hormonal (i.e., combined oral contraceptives [COC] and combined estrogen-progestogen menopausal therapy [CEPMT]) and reproductive factors (i.e., parity and breastfeeding) in Italy.

STUDY DESIGN: We calculated the population attributable and prevented fractions combining relative risks and prevalence of exposure in Italian women. Italian cancer incidence and mortality data were extracted from national sources and used to estimate the number of cancer cases and deaths attributable to reproductive factors and exogenous hormones in Italy in 2020. For long-term effects, a 20-year latency period was considered.

RESULTS: COC were responsible for 4.4 % of breast and 10.9 % of cervical cancers in women aged 15-44, but also avoided 6.4 % of endometrial, 5.6 % of ovarian, and 2.9 % of colorectal cancers in women of all ages. Overall, COC use prevented 1174 cancer diagnoses and 577 cancer deaths. CEPMT caused 0.4 % of breast cancers at age 45-69. Low parity accounted for 8.1 %, 11.8 % and 15.5 % of breast, endometrial and ovarian cancers, respectively (6267 cases, 1796 deaths). Breastfeeding avoided 6.4 % of breast cancers (3775 cases, 897 deaths).

CONCLUSIONS: Our analysis quantified the complex effects of hormonal and reproductive factors on cancer burden in Italian women.

PMID:39094535 | DOI:10.1016/j.ejogrb.2024.07.006

Diabetologia. 2024 Aug 2. doi: 10.1007/s00125-024-06220-6. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: The aim of this study was to investigate insulin secretion, insulin sensitivity, disposition index and insulin clearance by glucose tolerance status in individuals with cystic fibrosis (CF) and exocrine pancreatic insufficiency.

METHODS: In a cross-sectional study, we conducted an extended (ten samples) OGTT in individuals with pancreatic-insufficient CF (PI-CF). Participants were divided into normal glucose tolerance (NGT), early glucose intolerance (EGI), impaired glucose tolerance (IGT) and CF-related diabetes (CFRD) groups. We used three different oral minimal models to assess insulin secretion, insulin sensitivity and insulin clearance during the OGTT. We evaluated insulin secretion using total secretion (Φ total), first-phase secretion (Φ dynamic) and second-phase secretion (Φ static) from the model, and we estimated the disposition index by multiplying Φ total and insulin sensitivity.

RESULTS: Among 61 participants (NGT 21%, EGI 33%, IGT 16%, CFRD 30%), insulin secretion indices (Φ total, dynamic and static) were significantly lower in the CFRD group compared with the other groups. Insulin sensitivity declined with worsening in glucose tolerance (p value for trend <0.001) and the disposition index declined between NGT and EGI and between IGT and CFRD. Those with CFRD had elevated insulin clearance compared with NGT (p=0.019) and low insulin secretion (Φ total) was also associated with high insulin clearance (p<0.001).

CONCLUSIONS/INTERPRETATION: In individuals with PI-CF, disposition index declined with incremental impairment in glucose tolerance due to a reduction in both insulin secretion and insulin sensitivity. Moreover in CF, reduced insulin secretion was associated with higher insulin clearance.

PMID:39093413 | DOI:10.1007/s00125-024-06220-6

Med Microbiol Immunol. 2024 Aug 2;213(1):17. doi: 10.1007/s00430-024-00801-3.

ABSTRACT

Carl Flügge is best known for the promotion of studies demonstrating the transmission of all manner of infections, but particularly tuberculosis, by coughed droplets. But it is seldom recognised that Flügge was also influential in a number of other fields comprising the practice of hygiene. One-hundred years following his death in 1923, we review literature related to the studies of Flügge and his colleagues and students and illustrate the particular emphasis he laid upon the environment within which disease and its transmission might be fostered or prevented, embracing and studying aspects essential to the health of any community ranging from fundamental microbiology in the laboratory to subjects as disparate as housing, clean water supply, nutrition, sanitation, socio-economic circumstances and climate. Very early in his career he promoted breast feeding for the prevention of seasonal gastro-enteritis and later the sheltering of cough as a means of preventing the transmission of infected respiratory droplets, not only as regards tuberculosis, but also concerning all manner of other respiratory infections. By the time of Flügge's death the complexification of available scientific methodologies comprising hygiene made it difficult for any individual to comprehend and study the wide range of hygiene-related subjects such as Flügge did. Carl Flügge was one of the last holistic hygienists and an originator of the study of environmental health as a pillar of hygiene.

PMID:39093331 | DOI:10.1007/s00430-024-00801-3

Int J Mol Med. 2024 Oct;54(4):81. doi: 10.3892/ijmm.2024.5405. Epub 2024 Aug 2.

ABSTRACT

TMEM16 proteins, which function as Ca2+‑activated Cl‑ channels are involved in regulating a wide variety of cellular pathways and functions. The modulators of Cl‑ channels can be used for the molecule‑based treatment of respiratory diseases, cystic fibrosis, tumors, cancer, osteoporosis and coronavirus disease 2019. The TMEM16 proteins link Ca2+ signaling, cellular electrical activity and lipid transport. Thus, deciphering these complex regulatory mechanisms may enable a more comprehensive understanding of the physiological functions of the TMEM16 proteins and assist in ascertaining the applicability of these proteins as potential pharmacological targets for the treatment of a range of diseases. The present review examined the structures, functions and characteristics of the different types of TMEM16 proteins, their association with the pathogenesis of various diseases and the applicability of TMEM16 modulator‑based treatment methods.

PMID:39092585 | DOI:10.3892/ijmm.2024.5405

APMIS. 2024 Aug 2. doi: 10.1111/apm.13453. Online ahead of print.

ABSTRACT

Sweat chloride concentration, a diagnostic feature in cystic fibrosis (CF), reflects CF transmembrane conductance regulator (CFTR) activity. CFTR modulator therapies, especially elexacaftor/tezacaftor/ivacaftor (ETI), has improved CF outcomes. We report nationwide, real-world data on sweat chloride concentration in people with CF (pwCF) with and without modulator therapies. All Danish pwCF with a minimum of one F508del allele were included. Sweat chloride measurements were stratified by genotype and modulator treatment. Differences were assessed using mixed-effects models. We included 977 sweat chloride measurements from 430 pwCF, 71% of which were F508del homozygous. Heterozygous and homozygous ETI-treated pwCF had an estimated mean sweat chloride concentration of 43 mmol/L (95% confidence interval: 39; 48) and 43 mmol/L (39; 47), respectively-48% and 59% lower than those without treatment. High variation in concentrations remained regardless of treatment status. Despite ETI treatment, 27% heterozygous and 23% homozygous pwCF had elevated concentrations (≥60 mmol/L). These real-world data confirm a substantial decrease in sweat chloride concentration during modulator treatment, especially ETI, where mean concentrations halved. However, large variation remained, including persistently high concentrations. These findings emphasize the potential of sweat chloride concentration as a treatment response biomarker and the need to explore its heterogeneity and relationship with clinical outcomes.

PMID:39092470 | DOI:10.1111/apm.13453

bioRxiv [Preprint]. 2024 Jul 23:2023.05.02.539166. doi: 10.1101/2023.05.02.539166.

ABSTRACT

The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in the molecular basis of cystic fibrosis (CF). The misfolding of the most common CF variant (ΔF508) remodels both the translational regulation and quality control of CFTR. Nevertheless, it is unclear how the misassembly of the nascent polypeptide may directly influence the activity of the translation machinery. In this work, we identify a structural motif within the CFTR transcript that stimulates efficient -1 ribosomal frameshifting and triggers the premature termination of translation. Though this motif does not appear to impact the interactome of wild-type CFTR, silent mutations that disrupt this RNA structure alter the association of nascent ΔF508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the ΔF508 CFTR channel at the plasma membrane and its pharmacological rescue by the CFTR modulators contained in the CF drug Trikafta. The effects of the RNA structure on ΔF508 CFTR appear to be attenuated in the absence of the ER membrane protein complex (EMC), which was previously found to modulate ribosome collisions during preemptive quality control of a misfolded CFTR homolog. Together, our results reveal that ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant. These findings suggest interactions between the nascent chain, quality control machinery, and ribosome may dynamically modulate ribosomal frameshifting in order to tune the processivity of translation in response to cotranslational misfolding.

PMID:39091758 | PMC:PMC11290997 | DOI:10.1101/2023.05.02.539166

Transl Gastroenterol Hepatol. 2024 Jun 12;9:47. doi: 10.21037/tgh-23-128. eCollection 2024.

ABSTRACT

BACKGROUND AND OBJECTIVE: Although more frequent in the adult population, rectal prolapse is a common anorectal condition that can occur in children and adolescents. While many cases spontaneously resolve without the need for intervention, the advent of newer minimally invasive procedures and operations have provided options for pediatric patients. Here, we review the pathophysiology, etiology, presentation, diagnosis and principles of management of rectal prolapse in the pediatric population as it has evolved over the past several decades.

METHODS: The literature was queried from free databases available to the public including the National Institute of Health National Library of Medicine MEDLINE and PubMed for manuscripts published from January 1, 1975 to December 1, 2023. Manuscripts without an accompanying English translation or those written entirely in foreign languages were excluded.

KEY CONTENT AND FINDINGS: Numerous conditions contribute to rectal prolapse in children, including constipation, gastrointestinal infectious and non-infectious etiologies, cystic fibrosis, malnutrition, neurogenic, anatomic, lead points, and abuse. Initial management of rectal prolapse is medical management, addressing the underlying condition associated with rectal prolapse along with attempted manual reduction. For patients with recurrent rectal prolapse, a variety of noninvasive and procedural management options are available including injection sclerotherapy and anal encirclement in addition to surgical rectopexy by open and newer minimally invasive methods.

CONCLUSIONS: Despite significant advances in the evaluation, procedural and surgical management of pediatric anorectal conditions in the last few decades, there continues to be substantial variation in clinicians' and surgeons' practice for the treatment of rectal prolapse in children and adolescents. Much remains to be studied in the future to improve clinical outcomes for this patient population.

PMID:39091664 | PMC:PMC11292101 | DOI:10.21037/tgh-23-128

Ther Adv Chronic Dis. 2024 Jul 30;15:20406223241264477. doi: 10.1177/20406223241264477. eCollection 2024.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has reduced many symptoms of cystic fibrosis (CF).

OBJECTIVES: We sought to identify the impact of ETI on both symptoms and treatment decisions among adults with CF.

DESIGN: Participants were enrolled in a cross-sectional study. Surveys were sent via a RedCap link. Semistructured interviews were administered remotely via Microsoft Teams. Interviews were audio recorded and professionally transcribed.

METHODS: We assessed Cystic Fibrosis Questionnaire-Revised (CFQ-R) subscales for physical, respiratory, emotion, and treatment, and analyzed semistructured interviews covering CF treatment regimens and daily living. Quantitative and qualitative results were analyzed separately and via a mixed-methods convergence coding matrix.

RESULTS: Twenty-four adults with CF taking ETI were included. CFQ-R subscale scores (mean scores/standard deviation) were physical (82.1/22.8), respiratory (83.7/11.2), emotion (65.3/14.2), and treatment (57.5/20.1). Three themes about decision-making for non-ETI-treatments emerged: (1) How I'm feeling, (2) Not noticing a difference, and (3) Uncertainty about long-term impact of modifying treatment regimens, and we found participants weighed each of these factors in their treatment decisions. Key findings from mixed-methods analysis show that among individuals experiencing higher CFQ-R scores for physical and respiratory compared to emotion and treatment, there were statements indicating that while those participants were experiencing better physical health, many continued their burdensome treatment regimens.

CONCLUSION: With little long-term data on the impact of reducing non-ETI treatments, participants weighed how they were feeling, treatment efficacy beliefs, and risk tolerance when making treatment decisions.

PMID:39091508 | PMC:PMC11292704 | DOI:10.1177/20406223241264477

Respir Med. 2024 Jul 30:107749. doi: 10.1016/j.rmed.2024.107749. Online ahead of print.

ABSTRACT

BACKGROUND: Regular physical activity (PA) offers significant health benefits on both short (i.e., emotional well-being) and long term (i.e., fewer hospitalizations) in Youth with Cystic Fibrosis (YwCF). Regardless, evidence on PA levels in YwCF compared to healthy controls (HC) is inconsistent. Additionally, PA is a multidimensional outcome influenced by several factors such as Quadriceps strength and functional performance. Therefore, we aimed to assess whether PA, Quadriceps strength and functional performance differ between YwCF and HC across different age groups (i.e., children and adolescents).

METHODS: YwCF aged 6-17 from two Belgian CF centres and age- and sex-matched HC were recruited. PA was measured with an ActiGraph GT3X+BT during 7 consecutive days. Isometric Quadriceps strength was assessed with a Hand Held Dynamometer and functional performance with a sit-to stand test (STS) and standing long jump (SLJ).

RESULTS: A total of 49 YwCF (44% male; 11.3±3.3 years) and 49 HC (48% male; 11.9±3.5 years) were included. On average days, YwCF performed 4±6.4 minutes less light PA and 7.5±6.7 minutes less moderate-to-vigorous PA compared to HC (p=0.04; p=0.01). The differences in moderate-to-vigorous PA seem more pronounced in children (6-11 years)(p=0.04). Furthermore, YwCF had similar Quadriceps strength to HC but had lower scores on the STS and SLJ (p=0.50, p=0.08; p=0.02).

CONCLUSIONS: This study shows lower PA levels and functional performance for YwCF, indicating that there is an urgent need for interventions promoting PA in YwCF. PA promotion will become increasingly important in the post modulator area to prevent health risks associated with low PA.

PMID:39089391 | DOI:10.1016/j.rmed.2024.107749

Eur J Med Chem. 2024 Jul 20;276:116691. doi: 10.1016/j.ejmech.2024.116691. Online ahead of print.

ABSTRACT

Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445. From the exploration of the chemical space around the hit structure, based on iterative cycles of chemical synthesis and functional testing, the class of 6,9-dihydro-5H-pyrrolo [3,2-h]quinazolines with corrector activity was discovered. Within a series of 38 analogues, two derivatives emerged as promising candidates and used for further insight to assess the mechanism of action. Both compounds, decorated with a benzensulfonylamino group at the pyrimidine moiety, were able to generate a dose-dependent increase in CFTR function, particularly in the presence of VX-809. Half-effective concentrations (EC50) were in the single digit micromolar range and decreased in the presence of VX-809 thus indicating a synergistic interaction with class 1 correctors. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF.

PMID:39089001 | DOI:10.1016/j.ejmech.2024.116691

Proc Natl Acad Sci U S A. 2024 Aug 6;121(32):e2304382121. doi: 10.1073/pnas.2304382121. Epub 2024 Aug 1.

ABSTRACT

Microbes rarely exist in isolation and instead form complex polymicrobial communities. As a result, microbes have developed intricate offensive and defensive strategies that enhance their fitness in these complex communities. Thus, identifying and understanding the molecular mechanisms controlling polymicrobial interactions is critical for understanding the function of microbial communities. In this study, we show that the gram-negative opportunistic human pathogen Pseudomonas aeruginosa, which frequently causes infection alongside a plethora of other microbes including fungi, encodes a genetic network which can detect and defend against gliotoxin, a potent, disulfide-containing antimicrobial produced by the ubiquitous filamentous fungus Aspergillus fumigatus. We show that gliotoxin exposure disrupts P. aeruginosa zinc homeostasis, leading to transcriptional activation of a gene encoding a previously uncharacterized dithiol oxidase (herein named as DnoP), which detoxifies gliotoxin and structurally related toxins. Despite sharing little homology to the A. fumigatus gliotoxin resistance protein (GliT), the enzymatic mechanism of DnoP from P. aeruginosa appears to be identical that used by A. fumigatus. Thus, DnoP and its transcriptional induction by low zinc represent a rare example of both convergent evolution of toxin defense and environmental cue sensing across kingdoms. Collectively, these data provide compelling evidence that P. aeruginosa has evolved to survive exposure to an A. fumigatus disulfide-containing toxin in the natural environment.

PMID:39088389 | DOI:10.1073/pnas.2304382121

Orbit. 2024 Aug 1:1-6. doi: 10.1080/01676830.2024.2375317. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the results of a minimally invasive combined endoscopic and eyelid crease/medial suprabrow incision approach in collaboration with oculoplastic and sinus surgeons for the treatment of recurrent/recalcitrant sino-orbital mucoceles.

METHODS: Eighteen cases of recurrent/recalcitrant sino-orbital mucoceles, treated in collaboration with oculoplastic and sinus surgeons at the University of Michigan, were retrospectively reviewed. The recurrence of mucocele, reduction in proptosis, and complications were evaluated.

RESULTS: The mean age at the time of surgery was 49 years (range: 17-76 years). All cases had a history of previous sinus or orbital surgeries for mucoceles. Among 18 cases, eight were due to chronic sinus infections, six due to trauma, three due to Schneiderian papilloma, and one case was secondary to an inflammatory sinus disease. Thirteen cases (72%) presented with orbital or facial cellulitis, while five cases (38%) experienced periocular swelling and limited extraocular motility. Following a mean follow-up of 19 months (range: 1-76 months)), recurrence was observed in two cases (11%): one in a cystic fibrosis patient with chronic sinusitis, and the other in a case of Schneiderian papilloma. The mean pre-operative proptosis in the affected eye was 2.78 mm, with an average decrease of 2.33 mm after surgery. Complications occurred in two cases, including one case of hypoesthesia in the forehead and one case of post-operative strabismus.

CONCLUSION: Our series of 18 cases of recurrent/recalcitrant mucoceles, with only two cases of recurrence, demonstrates that this minimally invasive approach can be successfully employed for advanced sino-orbital disease, with a low rate of adverse outcomes and aesthetically pleasing results.

PMID:39087716 | DOI:10.1080/01676830.2024.2375317

Pediatr Int. 2024 Jan-Dec;66(1):e15787. doi: 10.1111/ped.15787.

ABSTRACT

BACKGROUND: The increasing worldwide prevalence of multidrug-resistant (MDR) bacteria underscores the pressing demand for innovative therapeutic solutions. Ceftazidime-avibactam (CAZ-AVI) represents a promising new drug combination that has received approval for specific infection types. However, there is limited information regarding its application in pediatric patients.

METHODS: This study investigates the effectiveness and adverse reactions associated with CAZ-AVI treatment in pediatric patients with life-threatening infections caused by MDR pathogens. The study was conducted at a tertiary children's hospital between December, 2021 and July, 2023.

RESULTS: A total of 21 patients with life-threatening infections caused by MDR pathogens were enrolled in the study. All patients had underlying medical conditions: 10 had cerebral palsy, four had congenital neurometabolic disease, two had Nieman-Pick disease, two had cystic fibrosis, two had primary immunodeficiency, and one had leukemia. Among these, 12 patients had tracheostomies. Eight patients received CAZ- AVI monotherapy, and 13 patients received combination therapy. Microbiological eradication was achieved in 18 patients (85.7%), and a clinical response was observed in 20 patients (95.2%). Two patients (9.5%) experienced relapse with the same bacteria. One patient developed anaphylaxis, and one patient had elevated creatine phosphokinase levels that normalized following discontinuation of treatment. One patient died during the study period due to gastrointestinal bleeding.

CONCLUSIONS: Ceftazidime-avibactam may be a promising new drug option for the treatment of life-threatening infections caused by MDR Gram-negative microorganisms in pediatric patients. However, further studies with larger case series are needed to further evaluate the efficacy and safety of CAZ-AVI in this population.

PMID:39087252 | DOI:10.1111/ped.15787

Med Clin North Am. 2024 Sep;108(5):843-869. doi: 10.1016/j.mcna.2024.03.011. Epub 2024 Jun 12.

ABSTRACT

Newer medications and devices, as well as greater understanding of the benefits and limitations of existing treatments, have led to expanded treatment options for patients with lung disease. Treatment advances have led to improved outcomes for patients with asthma, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension, and cystic fibrosis. The risks and benefits of available treatments are substantially variable within these heterogeneous disease groups. Defining the role of newer therapies mandates both an understanding of these disorders and overall treatment approaches. This section will review general treatment approaches in addition to focusing on newer therapies for these conditions..

PMID:39084837 | DOI:10.1016/j.mcna.2024.03.011