Pharmaceuticals (Basel). 2023 Mar 8;16(3):410. doi: 10.3390/ph16030410.

ABSTRACT

Cystic fibrosis (CF) is a potentially fatal monogenic disease that causes a progressive multisystemic pathology. Over the last decade, the introduction of CF transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has profoundly modified the lives of many people with CF (PwCF) by targeting the fundamental cause of the disease. These drugs consist of the potentiator ivacaftor (VX-770) and the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). In particular, the triple combination of CFTR modulators composed of elexacaftor, tezacaftor, and ivacaftor (ETI) represents a life-changing therapy for the majority of PwCF worldwide. A growing number of clinical studies have demonstrated the safety and efficacy of ETI therapy in both short- and long-term (up to two years of follow-up to date) and its ability to significantly reduce pulmonary and gastrointestinal manifestations, sweat chloride concentration, exocrine pancreatic dysfunction, and infertility/subfertility, among other disease signs and symptoms. Nevertheless, ETI therapy-related adverse effects have also been reported, and close monitoring by a multidisciplinary healthcare team remains vital. This review aims to address and discuss the major therapeutic benefits and adverse effects reported by the clinical use of ETI therapy for PwCF.

PMID:36986509 | DOI:10.3390/ph16030410

Microorganisms. 2023 Mar 3;11(3):651. doi: 10.3390/microorganisms11030651.

ABSTRACT

Non-fermenting Gram-negative bacilli (NFGNB), such as Pseudomonas aeruginosa and Acinetobacter baumannii, are among the major opportunistic pathogens involved in the global antibiotic resistance epidemic. They are designated as urgent/serious threats by the Centers for Disease Control and Prevention and are part of the World Health Organization's list of critical priority pathogens. Also, Stenotrophomonas maltophilia is increasingly recognized as an emerging cause for healthcare-associated infections in intensive care units, life-threatening diseases in immunocompromised patients, and severe pulmonary infections in cystic fibrosis and COVID-19 individuals. The last annual report of the ECDC showed drastic differences in the proportions of NFGNB with resistance towards key antibiotics in different European Union/European Economic Area countries. The data for the Balkans are of particular concern, indicating more than 80% and 30% of invasive Acinetobacter spp. and P. aeruginosa isolates, respectively, to be carbapenem-resistant. Moreover, multidrug-resistant and extensively drug-resistant S. maltophilia from the region have been recently reported. The current situation in the Balkans includes a migrant crisis and reshaping of the Schengen Area border. This results in collision of diverse human populations subjected to different protocols for antimicrobial stewardship and infection control. The present review article summarizes the findings of whole-genome sequencing-based resistome analyses of nosocomial multidrug-resistant NFGNBs in the Balkan countries.

PMID:36985224 | DOI:10.3390/microorganisms11030651

Microorganisms. 2023 Feb 27;11(3):597. doi: 10.3390/microorganisms11030597.

ABSTRACT

There has been growing interest in the complex host-microbe interactions within the human gut and the role these interactions play in systemic health and disease. As an essential metabolic organ, the liver is intimately coupled to the intestinal microbial environment via the portal venous system. Our understanding of the gut-liver axis comes almost exclusively from studies of adults; the gut-liver axis in children, who have unique physiology and differing gut microbial communities, remains poorly understood. Here, we provide a comprehensive overview of common pediatric hepatobiliary conditions and recent studies exploring the contributions of the gut microbiota to these conditions or changes of the gut microbiota due to these conditions. We examine the current literature regarding the microbial alterations that take place in biliary atresia, pediatric non-alcoholic fatty liver disease, Wilson's disease, cystic fibrosis, inflammatory bowel disease, and viral hepatitis. Finally, we propose potential therapeutic approaches involving modulation of the gut microbiota and the gut-liver axis to mitigate the progression of pediatric liver disease.

PMID:36985171 | DOI:10.3390/microorganisms11030597

J Pers Med. 2023 Mar 3;13(3):469. doi: 10.3390/jpm13030469.

ABSTRACT

BACKGROUND: Insulin secretion and glucose tolerance is annually assessed in patients with cystic fibrosis (PwCF) through oral glucose tolerance tests (OGTTs) as a screening measure for cystic fibrosis-related diabetes. We aimed to describe the distribution and provide reference quartiles of OGTT-related variables in the Italian cystic fibrosis population.

METHODS: Cross-sectional study of PwCF receiving care in three Italian cystic fibrosis centers of excellence, from 2016 to 2020. We performed a modified 2-h OGTT protocol (1.75 g/kg, maximum 75 g), sampling at baseline and at 30-min intervals, analyzing plasma glucose, serum insulin, and C-peptide. The modified OGTT allowed for the modeling of β cell function. For all variables, multivariable quantile regression was performed to estimate the median, the 25th, and 75th percentiles, with age, sex, and pancreatic insufficiency as predictors.

RESULTS: We have quantified the deterioration of glucose tolerance and insulin secretion with age according to sex and pancreatic insufficiency, highlighting a deviation from linearity both for patients <10 years and >35 years of age.

CONCLUSIONS: References of OGTT variables for PwCF provide a necessary tool to not only identify patients at risk for CFRD or other cystic fibrosis-related complications, but also to evaluate the effects of promising pharmacological therapies.

PMID:36983651 | DOI:10.3390/jpm13030469

J Pers Med. 2023 Feb 28;13(3):448. doi: 10.3390/jpm13030448.

ABSTRACT

Cystic fibrosis is a genetic disorder caused by a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene defect. Many across the globe suffer the debilitating symptoms. The aim of this commentary is to briefly cover various aspects related to the disease in the Arab world and then in Qatar.

PMID:36983631 | DOI:10.3390/jpm13030448

J Clin Med. 2023 Mar 21;12(6):2403. doi: 10.3390/jcm12062403.

ABSTRACT

Asthma is caused by complex interactions between environmental and genetic factors. Various genes have been implicated as potential risk factors in the development of asthma; among them is cystic fibrosis transmembrane conductance regulator (CFTR) gene. The aim of this systematic review was to investigate the association of CFTR mutation heterozygosity with the development of asthma, by updating the existing data with recent studies' findings. Therefore, a systematic review of the literature was conducted on Pubmed, ESBCO (Cinahl) and Scopus Databases up to December 2022. After the eligibility assessment, 17 studies were included in this review. Nine of them supported a lack of relationship between CFTR mutation heterozygosity and asthma susceptibility, and eight reported a positive association. Consequently, more extensive research is needed through high-quality studies to provide valid evidence and highlight the clinical benefits of identifying CFTR mutations in asthma patients, their impact on asthma severity, or treatment perspectives.

PMID:36983403 | DOI:10.3390/jcm12062403

Int J Mol Sci. 2023 Mar 13;24(6):5504. doi: 10.3390/ijms24065504.

ABSTRACT

Sleep-disordered breathing (SDB) comprises different diseases characterized by abnormal respiratory patterns during sleep including obstructive sleep apnea. SDB prevalence and impact in patients with chronic respiratory infections have been only marginally studied. The purpose of this narrative review is to report the prevalence and impact of SDB in chronic respiratory infections, including cystic fibrosis (CF), bronchiectasis and mycobacterial infections, and explore the possible pathophysiological mechanisms. Common pathophysiological mechanisms, underlying SDB onset in all chronic respiratory infections, include inflammation, which plays a central role, chronic nocturnal cough and pain, excessive production of mucous plugs, presence of obstructive and/or restrictive ventilatory impairment, upper airways involvement, and comorbidities, such as alteration of nutritional status. SDB may affect about 50% of patients with bronchiectasis. The severity of the disease, e.g., patients colonized with P. aeruginosa and frequent exacerbators, as well as comorbidities, such as chronic obstructive pulmonary disease and primary ciliary dyskinesia, may impact SDB onset. SDB may also frequently complicate the clinical course of both children and adults with CF, impacting the quality of life and disease prognosis, suggesting that their routine assessment should be incorporated into the clinical evaluation of patients from the first stages of the disease regardless of suggestive symptoms, in order to avoid late diagnosis. Finally, although the prevalence of SDB in patients with mycobacterial infections is uncertain, extrapulmonary manifestations, particularly nasopharyngeal locations, and concomitant symptoms, such as body pain and depression, may act as atypical predisposing factors for their development.

PMID:36982578 | DOI:10.3390/ijms24065504

Int J Mol Sci. 2023 Mar 8;24(6):5199. doi: 10.3390/ijms24065199.

ABSTRACT

An Italian, 46-year-old female patient carrying the complex allele p.[R74W;V201M;D1270N] in trans with CFTR dele22_24 was diagnosed at the Cystic Fibrosis (CF) Center of Verona as being affected by CF-pancreatic sufficient (CF-PS) in 2021. The variant V201M has unknown significance, while both of the other variants of this complex allele have variable clinical consequences, according to the CFTR2 database, with reported clinical benefits for treatment with ivacaftor + tezacaftor and ivacaftor + tezacaftor + elexacaftor in patients carrying the R74W-D1270N complex allele, which are currently approved (in USA, not yet in Italy). She was previously followed up by pneumologists in northern Italy because of frequent bronchitis, hemoptysis, recurrent rhinitis, Pseudomonas aeruginosa lung colonization, bronchiectasis/atelectasis, bronchial arterial embolization and moderately compromised lung function (FEV1: 62%). Following a sweat test with borderline results, she was referred to the Verona CF Center where she presented abnormal values in both optical beta-adrenergic sweat tests and intestinal current measurement (ICM). These results were consistent with a diagnosis of CF. CFTR function analyses were also performed in vitro by forskolin-induced swelling (FIS) assay and short-circuit currents (Isc) in the monolayers of the rectal organoids. Both of these assays showed significantly increased CFTR activity following treatment with the CFTR modulators. Western-blot analysis revealed increased fully glycosylated CFTR protein after treatment with correctors, in line with the functional analysis. Interestingly, tezacaftor, together with elexacaftor, rescued the total organoid area under steady-state conditions, even in the absence of the CFTR agonist forskolin. In conclusion, in ex vivo and in vitro assays, we measured a residual function that was significantly enhanced by in vitro incubation with CFTR modulators, especially by ivacaftor + tezacaftor + elexacaftor, suggesting this combination as a potentially optimal treatment for this case.

PMID:36982273 | DOI:10.3390/ijms24065199

Children (Basel). 2023 Mar 15;10(3):554. doi: 10.3390/children10030554.

ABSTRACT

Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) is a new CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulator treatment, used over the last few years, which has shown an improvement in different clinical outcomes in patients with cystic fibrosis (CF). The objective of this study was a systematic research of the literature on the efficacy and safety of this CFTR modulator on patients with CF. A search of Pubmed was conducted for randomized clinical trials and observational studies published from 2012 to September 2022. The included full manuscripts comprised nine clinical trials and 16 observational studies, whose participants were aged ≥12 years or were children 6-11 years old with at least one Phe508del mutation and/or advanced lung disease (ALD). These studies reported that ELX/TEZ/IVA has a significant positive effect on the lung function of patients with CF, by ameliorating parameters such as FEV1, LCI, pulmonary exacerbations or sweat chloride concentration, increasing BMI and improving quality of their life. Its role in cystic fibrosis-related diabetes (CFRD) is not yet clear. It was found that this new CFTR modulator has an overall favorable safety profile, with mild to moderate adverse events. Further studies are needed for a deeper understanding of the impact of CFTR modulators on other CF manifestations, or the possibility of treating with ELX/TEZ/IVA CF patients with rare CFTR mutations.

PMID:36980112 | DOI:10.3390/children10030554

Biomolecules. 2023 Feb 24;13(3):425. doi: 10.3390/biom13030425.

ABSTRACT

Cystic fibrosis is a monogenic disease with a multisystemic phenotype, ranging from predisposition to chronic lung infection and inflammation to reduced bone mass. The exact mechanisms unbalancing the maintenance of an optimal bone mass in cystic fibrosis patients remain unknown. Multiple factors may contribute to severe bone mass reduction that, in turn, have devastating consequences in the patients' quality of life and longevity. Here, we will review the existing evidence linking the CFTR dysfunction and cell-intrinsic bone defects. Additionally, we will also address how the proinflammatory environment due to CFTR dysfunction in immune cells and chronic infection impairs the maintenance of an adequate bone mass in CF patients.

PMID:36979360 | DOI:10.3390/biom13030425

Antibiotics (Basel). 2023 Mar 16;12(3):593. doi: 10.3390/antibiotics12030593.

ABSTRACT

Bacteriophages (phages) are antimicrobials with resurgent interest that are being investigated for the treatment of antibiotic refractory infection, including for Pseudomonas aeruginosa (Pa) lung infection in cystic fibrosis (CF). In vitro work supports the use of this therapy in planktonic and biofilm culture models; however, consistent data are lacking for efficacy across different clinical Pa strains, culture models, and in combination with antibiotics in clinical use. We first examined the efficacy of a 4-phage cocktail as an adjunct to our CF centre's first-line systemic combination antibiotic therapy (ceftazidime + tobramycin) for 16 different clinical Pa strains and then determined subinhibitory interactions for a subset of these strains with each antibiotic in planktonic and biofilm culture. When a 4-phage cocktail (4 × 108 PFU/mL) was added to a ceftazidime-tobramycin combination (ceftazidime 16 mg/mL + tobramycin 8 mg/mL), we observed a 1.7-fold and 1.3-fold reduction in biofilm biomass and cell viability, respectively. The four most antibiotic resistant strains in biofilm were very susceptible to phage treatment. When subinhibitory concentrations of antibiotics and phages were investigated, we observed additivity/synergy as well as antagonism/inhibition of effect that varied across the clinical strains and culture model. In general, more additivity was seen with the phage-ceftazidime combination than with phage-tobramycin, particularly in biofilm culture, where no instances of additivity were seen when phages were combined with tobramycin. The fact that different bacterial strains were susceptible to phage treatment when compared to standard antibiotics is promising and these results may be relevant to ongoing clinical trials exploring the use of phages, in particular in the selection of subjects for clinical trials.

PMID:36978460 | DOI:10.3390/antibiotics12030593

Antibiotics (Basel). 2023 Feb 28;12(3):484. doi: 10.3390/antibiotics12030484.

ABSTRACT

Characterized by impaired mucus transport and subsequent enhanced colonization of bacteria, pulmonary infection causes major morbidity and mortality in patients with cystic fibrosis (CF). Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) are the two most common types of bacteria detected in CF lungs, which undergo multiple adaptational mechanisms such as biofilm formation resulting in chronic pulmonary infections. With the advantages of greater airway concentration and minimized systemic toxicity, inhaled antibiotics are introduced to treat chronic pulmonary infection in CF. Inhaled tobramycin, aztreonam, levofloxacin, and colistin are the four most common discussed inhaled antibiotics targeting P. aeruginosa. Additionally, inhaled liposomal amikacin and murepavadin are also in development. This review will discuss the virulence factors and adaptational mechanisms of P. aeruginosa and S. aureus in CF. The mechanism of action, efficacy and safety, current status, and indications of corresponding inhaled antibiotics will be summarized. Combination therapy and the strategies to select an optimal inhaled antibiotic protocol will also be discussed.

PMID:36978351 | DOI:10.3390/antibiotics12030484

Respirology. 2023 Mar 28. doi: 10.1111/resp.14498. Online ahead of print.

NO ABSTRACT

PMID:36978257 | DOI:10.1111/resp.14498

Ital J Pediatr. 2023 Mar 28;49(1):39. doi: 10.1186/s13052-023-01440-9.

ABSTRACT

Invasive pulmonary aspergillosis (IPA) is a severe condition in immunocompromised children, but the optimal management is still under debate. In order to better clarify this issue, a literature search was performed through MEDLINE/PubMed database to describe current risk factors and diagnostic, therapeutic and prophylactic tools for invasive pulmonary aspergillosis (IPA) in the paediatric age. Observational studies and clinical trials regarding diagnosis, treatment and prophylaxis were considered, and results were summarised. Five clinical trials and 25 observational studies (4453 patients) were included.Haematological malignancies, previous organ transplant and other primary or acquired immunodeficiency were identified as risk factors for IPA in children.Current diagnostic criteria distinguish between "proven", "probable" and "possible" disease. Consecutive galactomannan assays have good sensitivity and specificity, especially when performed on broncho-alveolar lavage. At the same time, β-D-glucan should not be used since cut-off in children is unclear. PCR assays cannot currently be recommended for routine use.Voriconazole is the recommended first-line agent for IPA in children older than 2 years of age. Liposomal amphotericin B is preferred in younger patients or cases of intolerance to voriconazole. Its plasma concentrations should be monitored throughout the treatment. The optimal duration of therapy has yet to be determined. Posaconazole is the preferred prophylactic agent in children older than 13 years old, whereas oral voriconazole or itraconazole are the drugs of choice for those between 2-12 years. Further good-quality studies are warranted to improve clinical practice.

PMID:36978151 | DOI:10.1186/s13052-023-01440-9

J Clin Invest. 2023 Mar 28:e167957. doi: 10.1172/JCI167957. Online ahead of print.

ABSTRACT

BACKGROUND: Lung infections are among the most consequential manifestations of cystic fibrosis (CF) and are associated with reduced lung function and shortened survival. Drugs called CFTR modulators improve activity of dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channels, which is the physiological defect causing CF. However, it is unclear how improved CFTR activity affects CF lung infections.

METHODS: We performed a prospective, multicenter, observational study to measure the effect of the newest and most effective CFTR modulator, elexacaftor/tezacaftor/ivacaftor (ETI) on CF lung infections. We studied sputum from 236 people with CF during their first 6 months of ETI using bacterial cultures, PCR and sequencing.

RESULTS: Mean sputum densities of Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Achromobacter and Burkholderia spp. decreased by 2-3 log10 CFU/ml after 1 month of ETI. However, most participants remained culture-positive for the pathogens cultured from their sputum before starting ETI. In those becoming culture-negative after ETI, the pathogens present before treatment were often still detectable by PCR months after sputum converted to culture-negative. Sequence-based analyses confirmed large reductions in CF pathogen genera, but other bacteria detected in sputum were largely unchanged. ETI treatment increased average sputum bacterial diversity and produced consistent shifts in sputum bacterial composition. However, these changes were caused by ETI-mediated decreases in CF pathogen abundance rather than changes in other bacteria.

CONCLUSIONS: Treatment with the most effective CFTR modulator currently available produced large and rapid reductions in traditional CF pathogens in sputum, but most participants remain infected with the pathogens present before modulator treatment.

TRIAL REGISTRATION: The trial registered at www.

CLINICALTRIALS: gov as NCT04038047.

FUNDING: This study was funded by the Cystic Fibtosis Foundation (PROMISE-MICRO18K1 and SINGH19R0) and NIH (R01HL148274).

PMID:36976651 | DOI:10.1172/JCI167957

J Pediatr Gastroenterol Nutr. 2023 Mar 29. doi: 10.1097/MPG.0000000000003783. Online ahead of print.

ABSTRACT

OBJECTIVE/BACKGROUND: Endoscopic balloon dilatation (EBD) has been shown to be effective and safe in adults with stricturing Crohn's disease (CD) yet pediatric data is sparse. We aimed to assess efficacy and safety of EBD in stricturing pediatric CD.

METHODS: International collaboration included 11 centers from Europe, Canada and Israel. Recorded data included patient demographics, stricture features, clinical outcomes, procedural adverse events and need for surgery. Primary outcome was surgery-free over 12 months, secondary outcomes were clinical response and adverse events.

RESULTS: 88 dilatations were performed over 64 dilatation series in 53 patients. Mean age at CD diagnosis 11.1 (±4.0) years, stricture length 4cm (IQR 2.8-5) and bowel wall thickness 7mm (IQR 5.3-8). 12/64 (19%) patients underwent surgery in the year following the dilatation series, at a median of 89 days (IQR 24-120; range 0-264) following EBD. 7/64 (11%) had subsequent unplanned EBD over the year, of whom two eventually underwent surgical resection. 2/88 (2%) perforations were recorded, one of whom was managed surgically, and 5 patients had minor adverse events managed conservatively.There was a significant improvement in all clinical measures following EBD with wPCDAI-defined remission increasing from 13% at baseline to 44%, 46% and 61%, and absence of obstructive symptoms in 55%, 53% and 64% of patients at week 2, 8 and 24 respectively.

CONCLUSIONS: In this largest study of EBD in pediatric stricturing CD to date, we demonstrated that EBD is effective in relieving symptoms and avoiding surgery. Adverse events rates were low and consistent with adult data.

PMID:36976584 | DOI:10.1097/MPG.0000000000003783

J Leukoc Biol. 2023 Mar 20:qiad033. doi: 10.1093/jleuko/qiad033. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a life-threatening genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator (CFTR) chloride channel. Clinically, over 90% of CF patients succumb to pulmonary complications precipitated by chronic bacterial infections, predominantly by Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA). Despite the well-characterized gene defect and clearly defined clinical sequelae of CF, the critical link between the chloride channel defect and the host defense failure against these specific pathogens has not been established. Previous research from us and others has uncovered that neutrophils from CF patients are defective in phagosomal production of hypochlorous acid (HOCl), a potent microbicidal oxidant. Here we report our studies to investigate if this defect in HOCl production provides PA and SA with a selective advantage in CF lungs. A polymicrobial mixture of CF pathogens (PA and SA) and non-CF pathogens (Streptococcus pneumoniae (SP), Klebsiella pneumoniae (KP), and Escherichia coli (EC)) was exposed to varied concentrations of HOCl. The CF pathogens withstood higher concentrations of HOCl than did the non-CF pathogens. Neutrophils derived from F508del-CFTR HL-60 cells killed PA less efficiently than did the wild-type counterparts in the polymicrobial setting. After intratracheal challenge in wild-type and CF mice, the CF pathogens outcompeted the non-CF pathogens and exhibited greater survival in the CF lungs. Taken together, these data indicate that reduced HOCl production due to the absence of CFTR function creates an environment in CF neutrophils that provides a survival advantage to specific microbes, namely SA and PA, in the CF lungs.

PMID:36976023 | DOI:10.1093/jleuko/qiad033

Microbiol Spectr. 2023 Mar 28:e0020923. doi: 10.1128/spectrum.00209-23. Online ahead of print.

ABSTRACT

COVID-19 has significantly affected hospital infection prevention and control (IPC) practices, especially in intensive care units (ICUs). This frequently caused dissemination of multidrug-resistant organisms (MDROs), including carbapenem-resistant Acinetobacter baumannii (CRAB). Here, we report the management of a CRAB outbreak in a large ICU COVID-19 hub Hospital in Italy, together with retrospective genotypic analysis by whole-genome sequencing (WGS). Bacterial strains obtained from severe COVID-19 mechanically ventilated patients diagnosed with CRAB infection or colonization between October 2020 and May 2021 were analyzed by WGS to assess antimicrobial resistance and virulence genes, along with mobile genetic elements. Phylogenetic analysis in combination with epidemiological data was used to identify putative transmission chains. CRAB infections and colonization were diagnosed in 14/40 (35%) and 26/40 (65%) cases, respectively, with isolation within 48 h from admission in 7 cases (17.5%). All CRAB strains belonged to Pasteur sequence type 2 (ST2) and 5 different Oxford STs and presented blaOXA-23 gene-carrying Tn2006 transposons. Phylogenetic analysis revealed the existence of four transmission chains inside and among ICUs, circulating mainly between November and January 2021. A tailored IPC strategy was composed of a 5-point bundle, including ICU modules' temporary conversion to CRAB-ICUs and dynamic reopening, with limited impact on ICU admission rate. After its implementation, no CRAB transmission chains were detected. Our study underlies the potentiality of integrating classical epidemiological studies with genomic investigation to identify transmission routes during outbreaks, which could represent a valuable tool to ensure IPC strategies and prevent the spread of MDROs. IMPORTANCE Infection prevention and control (IPC) practices are of paramount importance for preventing the spread of multidrug-resistant organisms (MDROs) in hospitals, especially in the intensive care unit (ICU). Whole-genome sequencing (WGS) is seen as a promising tool for IPC, but its employment is currently still limited. COVID-19 pandemics have posed dramatic challenges in IPC practices, causing worldwide several outbreaks of MDROs, including carbapenem-resistant Acinetobacter baumannii (CRAB). We present the management of a CRAB outbreak in a large ICU COVID-19 hub hospital in Italy using a tailored IPC strategy that allowed us to contain CRAB transmission while preventing ICU closure during a critical pandemic period. The analysis of clinical and epidemiological data coupled with retrospective genotypic analysis by WGS identified different putative transmission chains and confirmed the effectiveness of the IPC strategy implemented. This could be a promising approach for future IPC strategies.

PMID:36976013 | DOI:10.1128/spectrum.00209-23

Int J Neonatal Screen. 2023 Mar 17;9(1):15. doi: 10.3390/ijns9010015.

ABSTRACT

In 1963, Robert Guthrie's pioneering work developing a bacterial inhibition assay to measure phenylalanine in dried blood spots, provided the means for whole-population screening to detect phenylketonuria in the USA. In the following decades, NBS became firmly established as a part of public health in developed countries. Technological advances allowed for the addition of new disorders into routine programmes and thereby resulted in a paradigm shift. Today, technological advances in immunological methods, tandem mass spectrometry, PCR techniques, DNA sequencing for mutational variant analysis, ultra-high performance liquid chromatography (UPLC), iso-electric focusing, and digital microfluidics are employed in the NBS laboratory to detect more than 60 disorders. In this review, we will provide the current state of methodological advances that have been introduced into NBS. Particularly, 'second-tier' methods have significantly improved both the specificity and sensitivity of testing. We will also present how proteomic and metabolomic techniques can potentially improve screening strategies to reduce the number of false-positive results and improve the prediction of pathogenicity. Additionally, we discuss the application of complex, multiparameter statistical procedures that use large datasets and statistical algorithms to improve the predictive outcomes of tests. Future developments, utilizing genomic techniques, are also likely to play an increasingly important role, possibly combined with artificial intelligence (AI)-driven software. We will consider the balance required to harness the potential of these new advances whilst maintaining the benefits and reducing the risks for harm associated with all screening.

PMID:36975853 | DOI:10.3390/ijns9010015

Int J Neonatal Screen. 2023 Feb 21;9(1):10. doi: 10.3390/ijns9010010.

ABSTRACT

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor-tezacaftor-ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF (n = 51), CRMS/CFSPID (n = 21), and CF carriers (n = 489), ETI-exposed infants (n = 19) had lower IRT values (p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants.

PMID:36975847 | DOI:10.3390/ijns9010010