Nucleic Acids Res. 2022 Jul 27:gkac576. doi: 10.1093/nar/gkac576. Online ahead of print.

ABSTRACT

Ribosomes are remarkable in their malleability to accept diverse aminoacyl-tRNA substrates from both the same organism and other organisms or domains of life. This is a critical feature of the ribosome that allows the use of orthogonal translation systems for genetic code expansion. Optimization of these orthogonal translation systems generally involves focusing on the compatibility of the tRNA, aminoacyl-tRNA synthetase, and a non-canonical amino acid with each other. As we expand the diversity of tRNAs used to include non-canonical structures, the question arises as to the tRNA suitability on the ribosome. Specifically, we investigated the ribosomal translation of allo-tRNAUTu1, a uniquely shaped (9/3) tRNA exploited for site-specific selenocysteine insertion, using single-molecule fluorescence. With this technique we identified ribosomal disassembly occurring from translocation of allo-tRNAUTu1 from the A to the P site. Using cryo-EM to capture the tRNA on the ribosome, we pinpointed a distinct tertiary interaction preventing fluid translocation. Through a single nucleotide mutation, we disrupted this tertiary interaction and relieved the translation roadblock. With the continued diversification of genetic code expansion, our work highlights a targeted approach to optimize translation by distinct tRNAs as they move through the ribosome.

PMID:35882385 | DOI:10.1093/nar/gkac576

Bol Med Hosp Infant Mex. 2022;79(3):193-198. doi: 10.24875/BMHIM.21000084.

ABSTRACT

BACKGROUND: Aquagenic keratoderma is triggered in the palms and soles after contact with water, and is characterized by the appearance of translucent papules forming macerated plaques. It may be associated with medications and diseases such as cystic fibrosis, atopy, and malnutrition, or be idiopathic.

CASE REPORT: We describe the case of a 17-year-old female patient with chronic functional abdominal pain. She presented with a 2-month history of "wrinkling" of palms after contact with water. After stimulation with water, palmar hyperlinearity and whitish, translucent papules forming macerated-looking plaques with a central depression were observed. Dermoscopically, we observed whitish and anfractive structures with coral appearance and microdroplets of water. In the histological study, we observed continuous hyperkeratosis and acrosyringium dilation from the middle dermis to the stratum corneum. With the clinical presentation and histological findings, aquagenic keratoderma was diagnosed, and treatment was started with partial improvement.

CONCLUSIONS: Aquagenic keratoderma is an underdiagnosed entity. Despite its indolent course, it could be considered as a marker of a systemic disease such as cystic fibrosis. Since the discussion about the terminology of the disease has arisen, we considered adjusting to a descriptive nomenclature, proposing the term whitish macerated aquagenic plaques of the acrosyringium. It is necessary to continue reporting these cases to understand the disease better and offer adequate management and comprehensive follow-up to the patients.

PMID:35882021 | DOI:10.24875/BMHIM.21000084

J Pediatr Gastroenterol Nutr. 2022 Jul 25. doi: 10.1097/MPG.0000000000003569. Online ahead of print.

ABSTRACT

OBJECTIVES: Known as pediatric medical traumatic stress (PMTS), posttraumatic stress symptoms from medical experiences have not been explored in children with chronic gastrointestinal diseases. This cross-sectional study of children and adolescents with inflammatory bowel disease, chronic pancreatitis and cystic fibrosis, aimed to: 1) estimate the prevalence of medical potentially traumatic events (PTEs) and PMTS, 2) explore potential risk factors for PMTS, and 3) explore potential consequences of PMTS.

METHODS: This cross-sectional study used validated, self-report measures to evaluate PTEs and PMTS. Descriptive statistics and regression analyses were used to achieve study objectives.

RESULTS: Over two-thirds of children reported a medical PTE (91 of 132, 69%). Forty-eight had PMTS symptoms (36%). PMTS was associated with medication burden, emergency and intensive care visits, and parent posttraumatic stress disorder in multivariate analysis. Potential consequences associated with PMTS included school absenteeism, home opioid use, poor quality of life, and parent missed work.

CONCLUSIONS: A substantial portion of our cohort reported medical PTEs and PMTS. The exploratory analysis identified potential associations between PMTS and illness factors, parent posttraumatic stress disorder, and functional impairments. Further studies of PMTS detection, prevention and treatment are integral to optimizing these children's health and quality of life.An infographic is available for this article at: http://links.lww.com/MPG/C881.

PMID:35881966 | DOI:10.1097/MPG.0000000000003569

Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2123017119. doi: 10.1073/pnas.2123017119. Epub 2022 Jul 26.

ABSTRACT

Staphylococcus aureus is an opportunistic pathogen and chief among bloodstream-infecting bacteria. S. aureus produces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection with S. aureus using RNA-sequencing (RNA-Seq). We found that the overall transcriptional response to S. aureus was weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection with S. aureus resulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverse S. aureus clones but absent in blood exposed to heat-killed S. aureus or blood infected with the less virulent staphylococcal species Staphylococcus epidermidis. Notably, this signature was also present in patients with S. aureus bacteremia. We identified the master regulator S. aureus exoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. The S. aureus-mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-type S. aureus elicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lacking saeRS. Thus, S. aureus blunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.

PMID:35881802 | DOI:10.1073/pnas.2123017119

J Med Internet Res. 2022 Jul 26;24(7):e36691. doi: 10.2196/36691.

ABSTRACT

BACKGROUND: Mobile apps are becoming increasingly popular, with 5.70 million apps available in early 2021. Smartphones can provide portable and convenient access to health apps. Here, we consider apps for people with one of the estimated 7000 rare conditions, which are defined as having an incidence of <1 in 2000. The needs of people with rare conditions are known to be different from those of people with more common conditions. The former may be socially isolated (not knowing anyone else who has the condition) and may not be able to find reliable information about the disorder.

OBJECTIVE: The aim of this review is to search for apps developed specifically for people diagnosed with a rare disease and to assess them for quality using the Mobile App Rating Scale (MARS). We examine features that address 6 identified needs of people with a rare disorder and make recommendations for future developers.

METHODS: Google Play Store (Android) and Apple App Store (iOS) were searched for relevant health-related apps specifically for rare diseases. The search included the names of 10 rare disease groups. App quality was determined using MARS, assessing app engagement, functionality, aesthetics, and information.

RESULTS: We found 29 relevant apps (from a total of 2272) addressing 14 rare diseases or disease groups. The most common rare conditions addressed were cystic fibrosis (n=6), hemophilia (n=5), and thalassemia (n=5). The most common app features were web-based information and symptom trackers. The mean MARS score was 3.44 (SD 0.84). Lowest scores were for engagement.

CONCLUSIONS: Most apps provided factual and visual information, providing tools for self-monitoring and resources to help improve interactions during health consultations. App origin and quality varied greatly. Developers are recommended to consider ways to make appropriate apps more easily identifiable to consumers, to always include high-quality information, improve engagement, provide qualitative evaluations of the app, and include consumers and clinicians in the design.

PMID:35881435 | DOI:10.2196/36691

Nat Genet. 2022 Jul 25. doi: 10.1038/s41588-022-01131-x. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.

PMID:35879412 | DOI:10.1038/s41588-022-01131-x

J Cyst Fibros. 2022 Jul 22:S1569-1993(22)00600-2. doi: 10.1016/j.jcf.2022.07.002. Online ahead of print.

ABSTRACT

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

PMID:35879227 | DOI:10.1016/j.jcf.2022.07.002

Nurs Crit Care. 2022 Jul 25. doi: 10.1111/nicc.12829. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic placed unprecedented stress on the National Health Service and critical care units including those with Extracorporeal Membrane Oxygenation (ECMO) facility as this intervention had proved successful with H1N1 patients in 2009. To successfully care for the influx of ECMO patients, an ECMO clinical support team (ECST) formed by redeployed staff was created to assist critical care nurses.

AIM: This service evaluation aims to review the experience of critical care nursing staff working with an ECST during the period of increased provision of ECMO care.

DESIGN: A UK-based single-site qualitative service evaluation was followed.

METHOD: Critical care nursing staff's feedback was anonymously collected using a paper questionnaire designed for this project. Data were analysed using inductive content analysis.

FINDINGS: Approximately 40 critical care nurses were invited to complete a questionnaire, 19 (48%) of whom completed it within the available timeframe. A variety of themes were identified including 'Prior knowledge of ECST', 'Management matters', 'ECST in action', 'ECST response', 'Emotions' and 'Overall experience of the ECST'. Staff initially reported apprehension regarding a new team and training responsibilities. Following the rollout of the ECST, nurses' accounts described the utilization of the ECST and subsequent stress relief. Feedback commented on the ECST's positive attitude, effective team working with the critical care team and provision of moral support. Nurses' gratitude was strongly conveyed throughout, with many expressing the positive effect of the ECST on staff emotional well-being.

CONCLUSION: The implementation of the ECST provided clinical and emotional support to nurses. The ECST demonstrated the effective use of redeployed health care staff to support the critical care unit at a time of a significant increase in patients requiring ECMO. This could be used as a model to enhance staffing levels in the event of future viral outbreaks.

PMID:35878876 | DOI:10.1111/nicc.12829

Pharmacol Ther. 2022 Jul 22:108249. doi: 10.1016/j.pharmthera.2022.108249. Online ahead of print.

ABSTRACT

Fine control over chloride homeostasis in the lung is required to maintain membrane excitability, transepithelial transport as well as intra- and extracellular ion and water homeostasis. Over the last decades, a growing number of chloride channels and transporters have been identified in the cells of the pulmonary vasculature and the respiratory tract. The importance of these proteins is underpinned by the fact that impairment of their physiological function is associated with functional dysregulation, structural remodeling, or hereditary diseases of the lung. This paper reviews the field of chloride channels and transporters in the lung and discusses chloride channels in disease processes such as viral infections including SARS-CoV- 2, pulmonary arterial hypertension and cystic fibrosis. Although chloride channels have become a hot research topic in recent years, remarkably few of them have been targeted by pharmacological agents. As such, we complement the putative pathophysiological role of chloride channels here with a summary of their therapeutic potential.

PMID:35878810 | DOI:10.1016/j.pharmthera.2022.108249

Toxins (Basel). 2022 Jul 6;14(7):464. doi: 10.3390/toxins14070464.

ABSTRACT

Staphylococcus aureus is a very common Gram-positive bacterium, and S. aureus infections play an extremely important role in a variety of diseases. This paper describes the types of virulence factors involved, the inflammatory cells activated, the process of host cell death, and the associated diseases caused by S. aureus. S. aureus can secrete a variety of enterotoxins and other toxins to trigger inflammatory responses and activate inflammatory cells, such as keratinocytes, helper T cells, innate lymphoid cells, macrophages, dendritic cells, mast cells, neutrophils, eosinophils, and basophils. Activated inflammatory cells can express various cytokines and induce an inflammatory response. S. aureus can also induce host cell death through pyroptosis, apoptosis, necroptosis, autophagy, etc. This article discusses S. aureus and MRSA (methicillin-resistant S. aureus) in atopic dermatitis, psoriasis, pulmonary cystic fibrosis, allergic asthma, food poisoning, sarcoidosis, multiple sclerosis, and osteomyelitis. Summarizing the pathogenic mechanism of Staphylococcus aureus provides a basis for the targeted treatment of Staphylococcus aureus infection.

PMID:35878202 | DOI:10.3390/toxins14070464

Acta Radiol. 2022 Jul 25:2841851221111486. doi: 10.1177/02841851221111486. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies support magnetic resonance angiography (MRA) as a diagnostic tool for pulmonary arterial disease.

PURPOSE: To determine MRA image quality and reproducibility, and the dependence of MRA image quality and reproducibility on disease severity in patients with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF).

MATERIAL AND METHODS: Twenty patients with COPD (mean age 66.5 ± 8.9 years; FEV1% = 42.0 ± 13.3%) and 15 with CF (mean age 29.3 ± 9.3 years; FEV1% = 66.6 ± 15.8%) underwent morpho-functional chest magnetic resonance imaging (MRI) including time-resolved MRA twice one month apart (MRI1, MRI2), and COPD patients underwent non-contrast computed tomography (CT). Image quality was assessed visually using standardized subjective 5-point scales. Contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) were measured by regions of interest. Disease severity was determined by spirometry, a well-evaluated chest MRI score, and by computational CT emphysema index (EI) for COPD.

RESULTS: Subjective image quality was diagnostic for all MRA at MRI1 and MRI2 (mean score = 4.7 ± 0.6). CNR and SNR were 4 43.8 ± 8.7 and 50.5 ± 8.7, respectively. Neither image quality score nor CNR or SNR correlated with FEV1% or chest MRI score for COPD and CF (r = 0.239-0.248). CNR and SNR did not change from MRI1 to MRI2 (P = 0.434-0.995). Further, insignificant differences in CNR and SNR between MRA at MRI1 and MRI2 did not correlate with FEV1% nor chest MRI score in COPD and CF (r = -0.238-0.183), nor with EI in COPD (r = 0.100-0.111).

CONCLUSION: MRA achieved diagnostic quality in COPD and CF patients and was highly reproducible irrespective of disease severity. This supports MRA as a robust alternative to CT in patients with underlying muco-obstructive lung disease.

PMID:35876445 | DOI:10.1177/02841851221111486

EClinicalMedicine. 2022 Jul 18;51:101572. doi: 10.1016/j.eclinm.2022.101572. eCollection 2022 Sep.

ABSTRACT

BACKGROUND: Birt-Hogg-Dubé syndrome is a rare genetic tumor syndrome characterized by renal cell cancer, lung bullae, pneumothorax, and fibrofolliculoma. Patients with such orphan tumor disorders are at risk of not receiving a timely diagnosis. In the present, gender-sensitive study, we analyzed the delay between onset of symptoms and diagnosis of Birt-Hogg-Dubé syndrome.

METHODS: Clinical data of 158 patients from 91 unrelated families were collected. FLCN mutation testing was performed in index patients and family members.

FINDINGS: The occurrence of the first symptom (fibrofolliculoma, pneumothorax or renal cell cancer) was rarely followed by a timely diagnosis of Birt-Hogg-Dubé syndrome and did so significantly less often in female (1.3%) compared to male (11.4%) patients (chi-square 6.83, p-value 0.009). Only 17 out of 39 renal cell cancers (7/17 female, 10/22 male patients) were promptly recognized as a symptom of Birt-Hogg-Dubé syndrome. Patients in which renal cell cancer was initially not recognized as a symptom of Birt-Hogg-Dubé syndrome waited 9.7 years (females SD 9.2, range 1-29) and 8.8 years (males, SD 4.1, range 2-11) for their diagnosis, respectively. Four (three female, one male) patients developed renal cell cancer twice before the genetic tumor syndrome was diagnosed. The delay between fibrofolliculoma or pneumothorax as a first symptom and diagnosis of Birt-Hogg-Dubé syndrome was considerable but not significantly different between females and males (18.1/17.19 versus 16.1/18.92 years). Furthermore, 73 patients were only diagnosed due to family history (delay 15.1 years in females and 17.4 years in males).

INTERPRETATION: The delay between onset of symptoms and diagnosis of Birt-Hogg-Dubé syndrome can be substantial and gender-dependent, causing considerable health risks for patients and their families. It is therefore important to create more awareness of Birt-Hogg-Dubé syndrome and resolve gender biases in diagnostic work-up.

FUNDING: None declared.

PMID:35875814 | PMC:PMC9304907 | DOI:10.1016/j.eclinm.2022.101572

Transl Perioper Pain Med. 2022;9(2):438-444. Epub 2022 Jun 6.

ABSTRACT

Cystic fibrosis (CF) is one of chronic illness affecting many different organs. Although the outcome of CF patients undergoing procedures was not favorable more than half a century ago, it showed a continuous improvement based on the previous reports. However, recent outcome report of CF patients' procedural outcomes is limited. We analyzed CF patients who underwent procedures from 2010 to 2020 in our institution. The mortality of 1,903 procedures performed in 430 CF patients was 0.74%, seen in high-risk procedures such as lung transplantation. We also analyzed the perioperative profiles of CF patients who underwent functional endoscopic sinus surgery (FESS). We identified the preoperative pulmonary function testing result to be predictive of postoperative hospital stay.

PMID:35875368 | PMC:PMC9302475

Int J Mol Cell Med. 2021 Fall;10(4):277-287. doi: 10.22088/IJMCM.BUMS.10.4.277. Epub 2022 Jun 6.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa (Pa) is a major concern for immunocompromised and cystic fibrosis patients. Chronic lung infections caused by Pa are generally considered incurable, in part, due to the bacteria's ability to form persister cells. These variants are categorized as being phenotypically dormant and highly tolerant to antibiotic treatment. Currently, the mechanisms involved in Pa persister cell formation is poorly understood. One promising candidate is the Pa filamentation induced by cAMP (FIC) domain containing toxin (PaFicT), which like other FIC toxins transiently inhibits cell growth. Genetic knockout and complementation by single copy chromosomal insertion was used to characterize paficT involvement in Pa persister cell formation. Toxicity and the PaFicT active site were examined by overexpression of wild-type and mutant protein variants. Antibiotic tolerance of PaFicT-induced Pa persister cells, was measured by minimum inhibitory concentration (MIC) analysis and compared to parental mostly non-persister populations. Deletion of paficT resulted in a 7.2-fold reduction in persister cell formation, which was fully complemented by re-insertion of the gene. Expression of PaFicT significantly increased persister cell formation by 5.9-fold, and this phenotype required a functional FIC active site motif. Unlike growing cell populations, PaFicT-induced persister cells were unaffected by 4 h treatment with 10 × MIC meropenem and showed an increased survival of 6.2 × 105-fold to tobramycin under the same conditions. Alternatively, survival of both persisters and parental, mostly non-persister, populations were below detectable levels following amikacin treatment. Results indicate a potential major involvement of PaFicT in Pa persister cell formation and multidrug tolerance.

PMID:35875333 | PMC:PMC9273157 | DOI:10.22088/IJMCM.BUMS.10.4.277

Strength Cond J. 2022 Feb;44(1):111-118. doi: 10.1519/ssc.0000000000000641. Epub 2021 Apr 27.

ABSTRACT

Cystic fibrosis (CF) is the most prevalent hereditary life-threatening disease in the Caucasian population. With the improvement in clinical care, individuals with CF are living longer, and CF-related diabetes (CFRD) has emerged as a major complication. The diagnosis of CFRD is associated with shortening survival, increasing morbidity, worsening physical capacity, and body composition. Engagement in exercise training has become a prominent nonpharmacologic intervention that aims to improve fitness and clinical outcomes in individuals with CF and CFRD. This column will specifically focus on the potential benefits of resistance training and provide recommendations for children and adolescents with CF and CFRD.

PMID:35874931 | PMC:PMC9307104 | DOI:10.1519/ssc.0000000000000641

Indian J Clin Biochem. 2022 Jul;37(3):275-284. doi: 10.1007/s12291-021-01004-w. Epub 2021 Nov 12.

ABSTRACT

Neuromyelitis optica spectrum disorders (NMOSD) is a demyelinating autoimmune disease affecting the central nervous system causing inflammatory lesions in the optic nerves, spinal cord and other vital areas of CNS. The clinical manifestations include acute transverse myelitis with paraplegia and optic neuritis with impaired vision. In the present study we focussed on comparative expression of serum proteins between NMOSD variants and control. The study has identified a plethora of novel and unexplored acute phase proteins involved in lipid transport and myelination in perspective of NMOSD. The serum proteins obtained after albumin globulin depletion were subjected to LC-MS/MS. The commonly altered proteins in all NMOSD variants with respect to control were smaug homolog protein and serum amyloid A. Truncated breast and ovarian cancer susceptibility protein and cystic fibrosis transmembrane conductance regulator protein were specifically upregulated and can act as potential biomarkers for neuromyelitis optica with autoantibody negativity to Aquaporin - 4 (AQP-4) and myelin oligodendrocyte (MOG) immunoglobulins. In addition, the uniquely downregulated proteins such as antithrombin III and histidine rich glycoprotein in NMO/MOG autoantibody negative samples can be accounted for its dysregulated fibrinolysis associated with NMO. The differentially expressed proteins were involved in cholesterol transport, synaptic vesicle mediated transport, neurotransmission and immune regulation which are closely associated with myelin formation and protection.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12291-021-01004-w.

PMID:35873620 | PMC:PMC9300782 | DOI:10.1007/s12291-021-01004-w

Front Genet. 2022 Jul 6;13:883199. doi: 10.3389/fgene.2022.883199. eCollection 2022.

NO ABSTRACT

PMID:35873457 | PMC:PMC9298864 | DOI:10.3389/fgene.2022.883199

J Cyst Fibros. 2022 Jul 21:S1569-1993(22)00628-2. doi: 10.1016/j.jcf.2022.07.010. Online ahead of print.

ABSTRACT

OBJECTIVE: We evaluated whether implementation of cystic fibrosis (CF) newborn screening (NBS) leads to equitable timeliness of initial evaluation. We compared age at first event (AFE, age at sweat test, encounter and/or care episode) between infants categorized as Black/African American, American Indian/ Native Alaskan, Asian, and/or Hispanic and/or other (Group 1) to White and not Hispanic infants (Group 2).

METHODS: This retrospective cohort study from the Cystic Fibrosis Foundation Patient Registry (CFFPR) included infants born 2010-2018. Race and ethnicity categories followed US Census definitions. The primary outcome was AFE; the secondary outcome was weight for age (WFA) z-score averaged 12 to < 24 months. We compared distributions by Wilcoxon rank-sum test and proportions by Chi-square or Fisher's exact tests. A nested cohort study used a linear mixed effects model of variables that affect WFA, chosen a priori, to evaluate associations with 1-year WFA z-score.

RESULTS: Among 6354 infants, 21% were in Group 1. Group 1 median AFE was 31 days (IQR 19, 49) and Group 2 was 22 days (IQR 14,36) (p< .001). Median WFA z-score at 1-2 years was lower in Group 1. In 3017 infants with complete data on variables of interest, AFE, Black race, CFTR variant class I-III, prematurity and public insurance were associated with lower 1-year WFA z-score.

CONCLUSIONS: Differences in AFE for infants with CF from historically marginalized groups may exacerbate long standing health disparities. We speculate that inequitable identification of CFTR gene variants and/or bias may influence timeliness of evaluation after an out-of-range NBS.

PMID:35871976 | DOI:10.1016/j.jcf.2022.07.010

J Cyst Fibros. 2022 Jul 21:S1569-1993(22)00627-0. doi: 10.1016/j.jcf.2022.07.009. Online ahead of print.

ABSTRACT

BACKGROUND: Aspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.

METHODS: Frequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010-2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.

RESULTS: Pa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02-1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.

CONCLUSIONS: Pa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

PMID:35871975 | DOI:10.1016/j.jcf.2022.07.009

J Cyst Fibros. 2022 Jul 21:S1569-1993(22)00625-7. doi: 10.1016/j.jcf.2022.07.008. Online ahead of print.

ABSTRACT

BACKGROUND: CHEC-SC is an ongoing epidemiologic study characterizing modulator-induced sweat chloride (SC) responses across the CF population, with interim results available prior to the availability of triple combination modulator therapy.

METHODS: Eligible participants had been prescribed a modulator for ≥90 days with re-enrollment allowed upon establishment of a new modulator. Pre-modulator SC values were obtained from chart review; post-modulator sweat was collected and analyzed locally. SC changes were descriptively summarized with biologic sex effects adjusted for age, weight, and CFTR genotype. Heterogeneity in ivacaftor SC response was characterized in relation to published CFTR functional responses.

RESULTS: 1848 participants provided 2004 SC measurements, 26.2% on ivacaftor, 39.1% on lumacaftor/ivacaftor, and 34.7% on tezacaftor/ivacaftor. Average SC changes for all modulators were consistent with those reported in previous clinical studies, with greater variation in SC response observed among rarer mutations and notable shifts in the proportion with SC <60mmol/L independent of the magnitude of SC change. Ivacaftor induced in vitro CFTR functional change was significantly correlated with ivacaftor-modulated SC response (Pearson correlation= ‒0.52, 95% CI: ‒0.773, ‒0.129). Average SC change from ivacaftor to tezacaftor/ivacaftor was ‒4.9 mmol/L (n=17,95% CI:‒9.3, ‒0.5) and differed from those switching from lumacaftor/ivacaftor (10.0 mmol/L, n=139, 95% CI:7.8,12.3). Sex at birth was not associated with SC response.

CONCLUSIONS: CHEC-SC is the largest study characterizing modulator-induced SC changes across the CF population. There was a strong association between ivacaftor induced in vitro CFTR function and SC response across a genotypically heterogenous cohort. Biological sex was not associated with SC response.

PMID:35871974 | DOI:10.1016/j.jcf.2022.07.008