J Cyst Fibros. 2021 Aug 25:S1569-1993(21)01337-0. doi: 10.1016/j.jcf.2021.07.018. Online ahead of print.

ABSTRACT

BACKGROUND: The effects of lumacaftor-ivacaftor on cystic fibrosis transmembrane conductance regulator (CFTR)-associated liver disease remain unclear. The objective of the study was to describe the effect of this treatment on features of liver involvement in a cystic fibrosis (CF) adolescent population homozygous for F508del.

METHODS: Clinical characteristics, liver blood tests, abdominal ultrasonography (US), and pancreas and liver proton density fat fraction (PDFF) by magnetic resonance imaging, were obtained at treatment initiation and at 12 months for all patients. Biomarkers of CFTR activity (sweat chloride test, nasal potential difference, and intestinal current measurement) were assessed at initiation and at 6 months therapy.

RESULTS: Of the 37 patients who started ivacaftor/lumacaftor treatment, 28 were eligible for analysis. In this group, before treatment initiation, 4 patients were diagnosed with multinodular liver and portal hypertension, 19 with other forms of CF liver involvement, and 5 with no signs of liver involvement. During treatment, no hepatic adverse reactions were documented, and no patient developed liver failure. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyl transferase (GGT) decreased significantly following initiation of lumacaftor-ivacaftor, and remained so after 12 months treatment. This was not correlated with changes in clinical status, liver and pancreas US and PDFF, fecal elastase, or lumacaftor-ivacaftor serum levels. The most "responsive" patients demonstrated a significant increase in biomarkers of CFTR activity.

CONCLUSIONS: These results may suggest a potential beneficial effect of CFTR modulators on CF liver disease and warrant further investigation in larger, prospective studies.

PMID:34454846 | DOI:10.1016/j.jcf.2021.07.018

J Cyst Fibros. 2021 Aug 25:S1569-1993(21)01346-1. doi: 10.1016/j.jcf.2021.08.005. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF)-specialized nutrition care strives to meet normal infant growth, but the relationship of dietitian assessments to weight outcomes is unknown. We characterize nutrition management for inadequate weight gain and assess association of dietitian assessments and center-level weight-for-age Z-scores (WAZ).

METHODS: We used encounter data from 226 infants across 28 US CF Centers from the Baby Observational Nutritional study between January 2012 through December 2017. We identified dietitian assessments and consensus guideline-recommended responses to inadequate weight gain: calorie increases, pancreatic enzyme replacement therapy (PERT) increases, or shortened time to next visit. We compared center assessments by funnel plot and summarize median WAZ by center.

RESULTS: Of 2,527 visits, 808 (32%) visits had identified inadequate weight gain, distributed in 216 infants. Assessments occurred in 1953 visits (77%), but varied widely between centers (range 17% - 98%). For inadequate weight gain, most and least common responses were calorie increase (64%) and PERT increase (21%). Funnel plot analysis identified 4 high-performers for frequent dietitian assessments (range 92% - 98%) and 4 under-performers (range 17% - 56%). High-performers treated inadequate weight gain more often with adequate calories (24/30, 80% v. 12/23, 52%) and closer follow up (104/164, 63% v. 60/120, 49%) compared to under-performers. Three of 4 high-performing sites met center nutrition goals for positive median WAZ at 2 years old unlike 3 under-performers (WAZHigh 0.33 v. WAZLow -0.15), despite similar patient characteristics.

CONCLUSION: We characterized multicenter variation in dietitian assessments, identifying opportunities to improve care delivery to target early nutrition outcomes.

PMID:34454845 | DOI:10.1016/j.jcf.2021.08.005

Trials. 2021 Aug 28;22(1):578. doi: 10.1186/s13063-021-05457-5.

ABSTRACT

The SARS-CoV-2 pandemic has disrupted clinical trials worldwide. The European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) has tracked clinical trial disruption by surveying its 58 trial sites across 17 European countries and collated information on measures to mitigate the impact of the pandemic and ensure trial continuity. Here, we present recommendations on how to reduce the risk of SARS-CoV-2 exposure to patients and trial staff by implementing remote trial visits where possible, using home assessments, video and phone calls, electronic consent, and home delivery of study drugs. We discuss the practicalities of remote source data verification, protocol amendments, changing trial site location, and staff absences and home working. We outline recommendations on how to protect trial outcomes, including home assessments, safety reporting, protocol deviations, and recruitment challenges. Finally, we discuss the importance of continued access to study drugs via extension trials for some patients. This guidance was co-created from the shared knowledge and experience of sites in our network and was re-distributed directly to all ECFS-CTN sites to help mitigate the impact of further waves of the SARS-CoV-2 pandemic. We will also use this guidance to assist companies, academia, and consortia with future protocol design and risk mitigation plans. This guidance can be applied to clinical trials in other diseases and could help sites that are not supported by clinical trial networks.

PMID:34454570 | DOI:10.1186/s13063-021-05457-5

Life Sci. 2021 Aug 25:119908. doi: 10.1016/j.lfs.2021.119908. Online ahead of print.

ABSTRACT

Genetic disorders and congenital abnormalities are present in 2-5% of births all over the world and can cause up to 50% of all early childhood deaths. The establishment of sophisticated and controlled techniques for customizing DNA manipulation is significant for the therapeutic role in such disorders and further research on them. One such technique is CRISPR that is significant towards optimizing genome editing and therapies, metabolic fluxes as well as artificial genetic systems. CRISPR-Cas9 is a molecular appliance that is applied in the areas of genetic and protein engineering. The CRISPR-CAS system is an integral element of prokaryotic adaptive immunity that allows prokaryotic cells to identify and kill any foreign DNA. The Gene editing property of CRISPR finds various applications like diagnostics and therapeutics in cancer, neurodegenerative disorders, genetic diseases, blindness, etc. This review discusses applications of CRISPR as a therapeutic in various disorders including several genetic diseases (including sickle cell anemia, blindness, thalassemia, cystic fibrosis, hereditary tyrosinemia type I, duchenne muscular dystrophy, mitochondrial disorders), Cancer, Huntington's disease and viral infections (like HIV, COVID, etc.) along with the prospects concerning them. CRISPR-based therapy is also being researched and defined for COVID-19. The related mechanism of CRISPR has been discussed alongside highlighting challenges involved in therapeutic applications of CRISPR.

PMID:34453943 | DOI:10.1016/j.lfs.2021.119908

J Cyst Fibros. 2021 Jul;20(4):562-563. doi: 10.1016/j.jcf.2021.07.011.

NO ABSTRACT

PMID:34452731 | DOI:10.1016/j.jcf.2021.07.011

Pharmaceutics. 2021 Jul 27;13(8):1157. doi: 10.3390/pharmaceutics13081157.

ABSTRACT

Nanomaterials provide enormous opportunities to overcome the limitations of conventional ocular delivery systems, such as low therapeutic efficacy, side effects due to the systemic exposure, or invasive surgery. Apart from the more common ocular disorders, there are some genetic diseases, such as cystic fibrosis, that develop ocular disorders as secondary effects as long as the disease progresses. These patients are more difficult to be pharmacologically treated using conventional drug routes (topically, systemic), since specific pharmacological formulations can be incompatible, display increased toxicity, or their therapeutic efficacy decreases with the administration of different kind of chemical molecules. Magnetic nanoparticles can be used as potent drug carriers and magnetic hyperthermia agents due to their response to an external magnetic field. Drugs can be concentrated in the target point, limiting the damage to other tissues. The other advantage of these magnetic nanoparticles is that they can act as magnetic resonance imaging agents, allowing the detection of the exact location of the disease. However, there are some drawbacks related to their use in drug delivery, such as the limitation to maintain efficacy in the target organ once the magnetic field is removed from outside. Another disadvantage is the difficulty in maintaining the therapeutic action in three dimensions inside the human body. This review summarizes all the application possibilities related to magnetic nanoparticles in ocular diseases.

PMID:34452117 | DOI:10.3390/pharmaceutics13081157

Pharmaceuticals (Basel). 2021 Aug 9;14(8):785. doi: 10.3390/ph14080785.

ABSTRACT

Around 12% of hereditary disease-causing mutations are in-frame nonsense mutations. The expression of genes containing nonsense mutations potentially leads to the production of truncated proteins with residual or virtually no function. However, the translation of transcripts containing premature stop codons resulting in full-length protein expression can be achieved using readthrough agents. Among them, only ataluren was approved in several countries to treat nonsense mutation Duchenne muscular dystrophy (DMD) patients. This review summarizes ataluren's journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia. Additionally, data on its pharmacokinetics and mechanism of action are presented. The range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising. What is more, experiments in which ataluren did not show its readthrough activity are also included, and reasons for their failures are discussed.

PMID:34451881 | DOI:10.3390/ph14080785

Pathogens. 2021 Aug 13;10(8):1020. doi: 10.3390/pathogens10081020.

ABSTRACT

Aspergillus is increasingly associated with lung inflammation and mucus plugging in early cystic fibrosis (CF) disease during which conidia burden is low and strains appear to be highly diverse. It is unknown whether clinical Aspergillus strains vary in their capacity to induce epithelial inflammation and mucus production. We tested the hypothesis that individual colonising strains of Aspergillus fumigatus would induce different responses. Ten paediatric CF Aspergillus isolates were compared along with two systemically invasive clinical isolates and an ATCC reference strain. Isolates were first characterised by ITS gene sequencing and screened for antifungal susceptibility. Three clusters (A-C) of Aspergillus isolates were identified by ITS. Antifungal susceptibility was variable, particularly for itraconazole. Submerged CF and non-CF monolayers as well as differentiated primary airway epithelial cell cultures were incubated with conidia for 24 h to allow germination. None of the clinical isolates were found to significantly differ from one another in either IL-6 or IL-8 release or gene expression of secretory mucins. Clinical Aspergillus isolates appear to be largely homogenous in their mucostimulatory and immunostimulatory capacities and, therefore, only the antifungal resistance characteristics are likely to be clinically important.

PMID:34451484 | DOI:10.3390/pathogens10081020

Pathogens. 2021 Aug 3;10(8):978. doi: 10.3390/pathogens10080978.

ABSTRACT

In the lungs of patients with cystic fibrosis (CF), the main pathogen Pseudomonas aeruginosa is often co-isolated with other microbes, likely engaging in inter-species interactions. In the case of chronic co-infections, this cohabitation can last for a long time and evolve over time, potentially contributing to the clinical outcome. Interactions involving the emerging pathogens Achromobacter spp. have only rarely been studied, reporting inhibition of P. aeruginosa biofilm formation. To evaluate the possible evolution of such interplay, we assessed the ability of Achromobacter spp. isolates to affect the biofilm formation of co-isolated P. aeruginosa strains during long-term chronic co-infections. We observed both competition and cohabitation. An Achromobacter sp. isolate secreted exoproducts interfering with the adhesion ability of a co-isolated P. aeruginosa strain and affected its biofilm formation. Conversely, a clonal Achromobacter sp. strain later isolated from the same patient, as well as two longitudinal strains from another patient, did not show similar competitive behavior against its P. aeruginosa co-isolates. Genetic variants supporting the higher virulence of the competitive Achromobacter sp. isolate were found in its genome. Our results confirm that both inter-species competition and cohabitation are represented during chronic co-infections in CF airways, and evolution of these interplays can happen even at the late stages of chronic infection.

PMID:34451442 | DOI:10.3390/pathogens10080978

Pathogens. 2021 Jul 29;10(8):957. doi: 10.3390/pathogens10080957.

ABSTRACT

Prevailing dogma indicates that the lung of cystic fibrosis (CF) individuals is infected by multiple pathogens due to the abundant accumulation of mucus, which traps most of inhaled organisms. However, this hypothesis does not explain how specific opportunists, like Pseudomonas aeruginosa, are selected in the CF lung to cause chronic disease. This strongly suggests that other factors than mucus are accrued in the human airway and might predispose to bacterial disease, especially by P. aeruginosa. In this review we discuss the role of macrophage metabolites, like succinate and itaconate, in P. aeruginosa pneumonia. We analyze how dysfunction of the CF transmembrane conductance regulator (CFTR) favors release of these metabolites into the infected airway, and how P. aeruginosa exploits these elements to induce transcriptomic and metabolic changes that increase its capacity to cause intractable disease. We describe the host and pathogen pathways associated with succinate and itaconate catabolism, mechanisms of bacterial adaptation to these determinants, and suggest how both experimental settings and future therapies should consider macrophage metabolites abundance to better study P. aeruginosa pathogenesis.

PMID:34451421 | DOI:10.3390/pathogens10080957

Pathogens. 2021 Jul 21;10(8):920. doi: 10.3390/pathogens10080920.

ABSTRACT

Non-tuberculous mycobacteria (NTM) have been recognized as a causative agent of various human diseases, including severe infections in immunocompromised patients, such as people living with HIV. The most common species identified is the Mycobacterium avium-intracellulare complex (MAI/MAC), accounting for a majority of infections. Despite abundant information detailing the clinical significance of NTM, little is known about host-pathogen interactions in NTM infection. MicroRNAs (miRs) serve as important post-transcriptional regulators of gene expression. Using a microarray profile, we found that the expression of miR-155 and cyclo-oxygenase 2 (COX-2) is significantly increased in bone-marrow-derived macrophages from mice and human monocyte-derived macrophages from healthy volunteers that are infected with NTM. Antagomir against miR-155 effectively suppressed expression of COX-2 and reduced Prostaglandin E2(PGE2) secretion, suggesting that COX-2/PGE2 expression is dependent on miR-155. Mechanistically, we found that inhibition of NF-κB activity significantly reduced miR-155/COX-2 expression in infected macrophages. Most importantly, blockade of COX-2, E-prostanoid receptors (EP2 and EP4) enhanced killing of MAI in macrophages. These findings provide novel mechanistic insights into the role of miR-155/COX-2/PGE2 signalling and suggest that induction of these pathways enhances survival of mycobacteria in macrophages. Defining host-pathogen interactions can lead to novel immunomodulatory therapies for NTM infections which are difficult to treat.

PMID:34451384 | DOI:10.3390/pathogens10080920

S D Med. 2021 Jul;74(7):344-346.

NO ABSTRACT

PMID:34450000

Pediatr Pulmonol. 2021 Aug 27. doi: 10.1002/ppul.25649. Online ahead of print.

ABSTRACT

The objective of our cross-sectional study was to assess the relationships between indices of multiple breath washout (MBW) and impulse oscillometry system (IOS) in cystic fibrosis in forty consecutive children (median age 8.1 years) in stable condition and to evaluate whether cut-off values of IOS indices may help to avoid MBW, which is time-consuming. IOS measurements took a median duration of 3 min, while MBW measurements took a median duration of 49 min. Lung Clearance Index (LCI2.5% ) depicted significant linear correlations with z-scores of R5Hz, R5-20Hz, X5Hz, AX and Fres (r2 = 0.27 to 0.51). Receiver-operator characteristic curves were constructed and showed that the best compromise was obtained with the z-score of Fres, with a cut-off value of -1.37 that had a sensitivity of 0.966, a specificity of 0.636 and a negative predictive value of 0.875. This z-score is useful for excluding increased LCI2.5% when below -1.37 using the reference set of Gochicoa et al. In conclusion, IOS measurement is easily and rapidly obtained in children and may be clinically useful for excluding increased LCI2.5% , thus allowing the time-consuming MBW test to be avoided. This article is protected by copyright. All rights reserved.

PMID:34449977 | DOI:10.1002/ppul.25649

Pediatr Rep. 2021 Aug 7;13(3):483-489. doi: 10.3390/pediatric13030055.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immune deficit (PID) mainly characterized by hypogammaglobulinemia. In addition to increased susceptibility to infections and several immune-mediated manifestations, patients with CVID frequently develop bronchiectasis because of recurrent respiratory infections. This occurrence could be more likely if the diagnosis of CVID is delayed, as it often happens in less resourced clinical settings. A 15-year-old female patient was admitted to a tertiary hospital in Kazakhstan for consultation regarding a previous and established diagnosis of bronchiectasis. The clinical history was characterized by recurrent respiratory infections for several years, in addition to the development of a mixed restrictive-obstructive respiratory syndrome. Therefore, she underwent chest computerized tomography, which confirmed the presence of multiple and bilateral bronchiectasis. The clinical discussion on this patient highlighted that serum immunoglobulins were never measured previously and, thus, their assessment was strongly recommended. Based on that, a diagnosis of CVID was finally achieved, and the patient started the appropriate immunoglobulin replacement therapy. To our knowledge, this report is the first English-language publication on CVID and bronchiectasis from Central Asia. Bronchiectasis is currently an important medical problem in developing countries and populations with low socioeconomic status, where the diagnosis of the underlying cystic fibrosis and non-cystic fibrosis comorbidities can be delayed and more difficult than in countries with more accessible health care systems and facilities. This case report emphasized this important clinical issue in Central Asia and should raise the medical attention and awareness of this health problem, in order to improve the diagnostic timing and rate.

PMID:34449684 | DOI:10.3390/pediatric13030055

Curr Gastroenterol Rep. 2021 Aug 27;23(10):17. doi: 10.1007/s11894-021-00817-2.

ABSTRACT

PURPOSE OF REVIEW: While commonly associated with pulmonary manifestations, cystic fibrosis (CF) is a systemic disease with wide-ranging effects on the gastrointestinal (GI) tract. This article reviews major recent updates in gastroenterological CF care and research.

RECENT FINDINGS: The high burden of GI symptoms in CF has led to recent studies assessing GI-specific symptom questionnaires and scoring systems. Intestinal dysbiosis potentially contributes to gastrointestinal symptoms in patients with CF and an increased risk of gastrointestinal cancers in CF. An increased incidence of colorectal cancer (CRC) has led to CF-specific CRC screening and surveillance recommendations. Pharmacologic therapies targeting specific cystic fibrosis transmembrane conductance regulator (CFTR) mutations have shown promise in treating GI manifestations of CF. New research has highlighted the importance of intestinal dysbiosis in CF. Future studies should assess whether CFTR modulators affect the gut microbiome and whether altering the gut microbiome will impact GI symptoms and GI cancer risk.

PMID:34448955 | DOI:10.1007/s11894-021-00817-2

Int Forum Allergy Rhinol. 2021 Aug 26. doi: 10.1002/alr.22875. Online ahead of print.

ABSTRACT

BACKGROUND: Hypoxia due to closure at the ostiomeatal complex is widely considered one of the major pathogenic mechanisms leading to chronic inflammation in chronic rhinosinusitis (CRS). The objective of this study was to develop and characterize an oxygen-generating biomaterial (OGB) as an innovative treatment strategy for CRS.

METHODS: An OGB was fabricated by coating hydrophobic beeswax (BW, 15mg or 30mg) on the surface of calcium peroxide - catalase complex (CPO-CA, 30mg) and characterized using scanning electron microscopy (SEM). In vitro releases of both oxygen and hydrogen peroxide (H2 O2 ) were spectrophotometrically quantified, and cytotoxicity in human sinonasal epithelial cells (HSNECs) was evaluated. The influence of OGB on transepithelial Cl- secretion was also determined by pharmacologically manipulating HSNECs, cultured under hypoxic conditions, in Ussing chambers.

RESULTS: Three groups of OGBs: (1) CPO only; (2) CPO coated with CA and BW (1:1 ratio, CPO-CA(1)-BW(1)); and (3) CPO coated with CA and BW (1:0.5 ratio, CPO-CA(1)-BW(0.5) were analyzed for accumulated oxygen release over 7 days: highest release (mmol/mg) was observed in CPO-CA(1)-BW(1) = 0.11 ± 0.003, followed by CPO-CA(1)-BW(0.5) = 0.08 ± 0.010, and CPO = 0.05 ± 0.004 (p < 0.0001). H2 O2 production (mM) was significantly higher in CPO (1.87 ± 0.50) compared to CPO-CA (1)-BW(1) (0.00 ± 0.00) (p < 0.001) after 24 h. CPO-CA(1)-BW(1) showed significantly reduced cytotoxicity and increased Cl- transport compared to the CPO group.

CONCLUSION: A novel OGB (CPO-CA-BW complex) exhibited sustained oxygen release over 7 days without significant cytotoxicity after 24 h in vitro. Preclinical studies evaluating the efficacy of OGB in CRS are warranted, especially for potential therapy in an obstruction-based CRS model.

PMID:34448372 | DOI:10.1002/alr.22875

Balkan J Med Genet. 2021 Jul 27;24(1):41-46. doi: 10.2478/bjmg-2021-0015. eCollection 2021 Jun.

ABSTRACT

There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).

PMID:34447658 | PMC:PMC8366466 | DOI:10.2478/bjmg-2021-0015

Front Genet. 2021 Aug 10;12:719437. doi: 10.3389/fgene.2021.719437. eCollection 2021.

ABSTRACT

Congenital disorders of glycosylation (CDG) are a widely acknowledged group of metabolic diseases. PMM2-CDG is the most frequently diagnosed CDG with a prevalence as high as one in 20,000. In contrast, the prevalence of other CDG types remains unknown. This study aimed to analyze the estimated prevalence of different N-linked protein glycosylation disorders. We extracted allele frequencies for diverse populations from The Genome Aggregation Database (gnomAD), encompassing variant frequency information from 141,456 individuals. To identify pathogenic variants, we used the ClinVar database as a primary source. High confidence loss-of-function variants as defined by the LOFTEE algorithm were also classified as pathogenic. After summing up population frequencies for pathogenic alleles, estimated disease birth prevalence values with confidence intervals were calculated using the Bayesian method. We first validated our approach using two more common recessive disorders (cystic fibrosis and phenylketonuria) by showing that the estimated prevalences calculated from population allele frequencies were in accordance with previously published epidemiological studies. Among assessed 27 autosomal recessive N-glycosylation disorders, the only disease with estimated birth prevalence higher than one in 100,000 was PMM2-CDG (in both, all gnomAD individuals and those with European ancestry). The combined prevalence of 27 different N-glycosylation disorders was around one in 22,000 Europeans but varied considerably across populations. We will show estimated prevalence data from diverse populations and explain the possible pitfalls of this analysis. Still, we are confident that these data will guide CDG research and clinical care to identify CDG across populations.

PMID:34447415 | PMC:PMC8383291 | DOI:10.3389/fgene.2021.719437

Eur J Hum Genet. 2021 Aug 26. doi: 10.1038/s41431-021-00952-4. Online ahead of print.

ABSTRACT

Cascade genetic testing is the identification of individuals at risk for a hereditary condition by genetic testing in relatives of people known to possess particular genetic variants. Cascade testing has health system implications, however cascade costs and health effects are not considered in health technology assessments (HTAs) that focus on costs and health consequences in individual patients. Cascade health service use must be better understood to be incorporated in HTA of emerging genetic tests for children. The purpose of this review was to characterise published research related to patterns and costs of cascade health service use by relatives of children with any condition diagnosed through genetic testing. To this end, a scoping literature review was conducted. Citation databases were searched for English-language papers reporting uptake, costs, downstream health service use, or cost-effectiveness of cascade investigations of relatives of children who receive a genetic diagnosis. Included publications were critically appraised, and findings were synthesised. Twenty publications were included. Sixteen had a paediatric proband population; four had a combined paediatric and adult proband population. Uptake of cascade testing varied across diseases, from 37% for cystic fibrosis, 39% to 65% for hypertrophic cardiomyopathy, and 90% for rare monogenic conditions. Two studies evaluated costs. It was concluded that cascade testing in the child-to-parent direction has been reported in a variety of diseases, and that understanding the scope of cascade testing will aid in the design and conduct of HTA of emerging genetic technologies to better inform funding and policy decisions.

PMID:34446836 | DOI:10.1038/s41431-021-00952-4

Nat Commun. 2021 Aug 26;12(1):5145. doi: 10.1038/s41467-021-25484-9.

ABSTRACT

Mycobacterium abscessus (MAB) is an emerging pathogen that leads to chronic lung infections. To date, the global population structure of non-cystic fibrosis (CF) MAB and evolutionary patterns of drug resistance emergence have not been investigated. Here we construct a global dataset of 1,279 MAB whole genomes from CF or non-CF patients. We utilize whole genome analysis to assess relatedness, phylogeography, and drug resistance evolution. MAB isolates from CF and non-CF hosts are interspersed throughout the phylogeny, such that the majority of dominant circulating clones include isolates from both populations, indicating that global spread of MAB clones is not sequestered to CF contexts. We identify a large clade of M. abscessus harboring the erm(41) T28C mutation, predicted to confer macrolide susceptibility in this otherwise macrolide-resistant species. Identification of multiple evolutionary events within this clade, consistent with regain of wild type, intrinsic macrolide resistance, underscores the critical importance of macrolides in MAB.

PMID:34446725 | DOI:10.1038/s41467-021-25484-9