Mol Divers. 2022 Dec 26. doi: 10.1007/s11030-022-10584-5. Online ahead of print.

ABSTRACT

Burkholderia cepacia complex (BCC) is a group of gram-negative bacteria composed of at least 20 different species that cause diseases in plants, animals as well as humans (cystic fibrosis and airway infection). Here, we analyzed the proteomic data of 47 BCC strains by classifying them in three groups. Phylogenetic analyses were performed followed by individual core region identification for each group. Comparative analysis of the three individual core protein fractions resulted in 1766 ortholog/proteins. Non-human homologous proteins from the core region gave 1680 proteins. Essential protein analyses reduced the target list to 37 proteins, which were further compared to a closely related out-group, Burkholderia gladioli ATCC 10,248 strain, resulting in 21 proteins. 3D structure modeling, validation, and druggability step gave six targets that were subjected to further target prioritization parameters which ultimately resulted in two BCC targets. A library of 12,000 ZINC drug-like compounds was screened, where only the top hits were selected for docking orientations. These included ZINC01405842 (against Chorismate synthase aroC) and ZINC06055530 (against Bifunctional N-acetylglucosamine-1-phosphate uridyltransferase/Glucosamine-1-phosphate acetyltransferase glmU). Finally, dynamics simulation (200 ns) was performed for each ligand-receptor complex, followed by ADMET profiling. Of these targets, details of their applicability as drug targets have not yet been elucidated experimentally, hence making our predictions novel and it is suggested that further wet-lab experimentations should be conducted to test the identified BCC targets and ZINC scaffolds to inhibit them.

PMID:36567421 | DOI:10.1007/s11030-022-10584-5

Folia Microbiol (Praha). 2022 Dec 26. doi: 10.1007/s12223-022-01026-8. Online ahead of print.

ABSTRACT

Trimethoprim-sulfamethoxazole (SXT) is the preferable treatment option of the infections caused by Achromobacter spp. Our study aimed to analyze the SXT resistance of 98 Achromobacter spp. isolates from pediatric patients, among which 33 isolates were SXT-resistant. The presence of intI1 was screened by PCR and genome sequence analyses. The intI1 gene was detected in 10 of SXT-resistant isolates that had shorter intI1 PCR fragments named intI1S. Structural changes in intI1S were confirmed by genome sequencing and analyses which revealed 86 amino acids deletion in IntI1S protein compared to canonical IntI1 protein. All IntI1S isolates were of non-CF origin. Pan-genome analysis of intI1S bearing A. xylosoxidans isolates comprised 9052 genes, with the core genome consisting of 5455 protein-coding genes. Results in this study indicate that IntI1S isolates were derived from clinical settings and that cystic fibrosis (CF) patients were potential reservoirs for healthcare-associated infections that occurred in non-CF patients.

PMID:36567375 | DOI:10.1007/s12223-022-01026-8

J Mol Biol. 2022 Dec 22:167929. doi: 10.1016/j.jmb.2022.167929. Online ahead of print.

ABSTRACT

We have previously shown that the CBb subunit of crotoxin, a β-neurotoxin with phospholipase A2 (PLA2) activity, targets the human ΔF508CFTR chloride channel implicated in cystic fibrosis (CF). By direct binding to the nucleotide binding domain 1 (NBD1) of ΔF508CFTR, this neurotoxic PLA2 acts as a potentiator increasing chloride channel current and corrects the trafficking defect of misfolded ΔF508CFTR inside the cell. Here, for a therapeutics development of new anti-cystic fibrosis agents, we use a structure-based in silico approach to design peptides mimicking the CBb-ΔF508NBD1 interface. Combining biophysical and electrophysiological methods, we identify several peptides that interact with the ΔF508NBD1 domain and reveal their effects as potentiators on phosphorylated ΔF508CFTR. Moreover, protein-peptide interactions and electrophysiological studies allowed us to identify key residues of ΔF508NBD1 governing the interactions with the novel potentiators. The designed peptides bind to the same region as CBb phospholipase A2 on ΔF508NBD1 and potentiate chloride channel activity. Certain peptides also show an additive effect towards the clinically approved VX-770 potentiator. The identified CF therapeutics peptides represent a novel class of CFTR potentiators and illustrate a strategy leading to reproducing the effect of specific protein-protein interactions.

PMID:36566799 | DOI:10.1016/j.jmb.2022.167929

Lancet Infect Dis. 2022 Dec 22:S1473-3099(22)00726-5. doi: 10.1016/S1473-3099(22)00726-5. Online ahead of print.

ABSTRACT

Children are entitled to receive antibiotic therapy that is based on evidence and best practice, but might be overlooked in hospital programmes designed to achieve antimicrobial stewardship [AMS]. This failure to include children could be because children make up small proportion of patients in most hospitals, and are cared for by specialised paediatric staff. We reviewed the evidence and consulted experts in three global regions to develop ten recommendations for good-practice in hospital AMS programmes for children. We performed a review of scientific research, published between Jan 1, 2007, and Oct 17, 2019, concerning AMS, and formed a multinational expert group comprising members from the USA, Canada, the UK, Belgium, Switzerland, Australia, and Aotearoa New Zealand to develop the recommendations. These recommendations aim to help health-care workers who care for children in these regions to deliver best-practice care. We surveyed health-care workers with expertise in antibiotic therapy for children across these regions, and found that the recommendations were considered both very important and generally feasible. These recommendations should be implemented in hospitals to improve antibiotic therapy for children and to stimulate research into future improvements in care.

PMID:36566768 | DOI:10.1016/S1473-3099(22)00726-5

Respir Med Res. 2022 Nov 28;83:100981. doi: 10.1016/j.resmer.2022.100981. Online ahead of print.

ABSTRACT

Lung transplantation (LTx) is a steadily expanding field. The considerable developments have been driven over the years by indefatigable work conducted at LTx centers to improve donor and recipient selection, combined with multifaceted efforts to overcome challenges raised by the surgical procedure, perioperative care, and long-term medical complications. One consequence has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. The Francophone Pulmonology Society (Société de Pneumology de Langue Française, SPLF) set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force examined the most recent literature and evaluated the risk factors that limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while also improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

PMID:36565563 | DOI:10.1016/j.resmer.2022.100981

Eur J Pediatr. 2022 Dec 24. doi: 10.1007/s00431-022-04766-4. Online ahead of print.

ABSTRACT

We aimed to evaluate cutoff values of immunoreactive trypsinogen (IRT)/IRT and determine relationship between IRT values and clinical characteristics of children with cystic fibrosis (CF). This study is cross-sectional study. Data of children with positive newborn screening (NBS) between 2015 and 2021 were evaluated in three pediatric pulmonology centers. Age at admission, sex, gestational age, presence of history of meconium ileus, parental consanguinity, sibling with CF, and doll-like face appearance, first and second IRT values, sweat chloride test, fecal elastase, fecal fat, biochemistry results, and age at CF diagnosis were recorded. Sensitivity and specificity of IRT cutoff values were evaluated. Of 815 children with positive NBS, 58 (7.1%) children were diagnosed with CF. Median values of first and second IRT were 157.2 (103.7-247.6) and 113.0 (84.0-201.5) μg/L. IRT values used in current protocol, sensitivity was determined as 96.6%, specificity as 17.2% for first IRT, and 96.6% sensitivity, 20.5% specificity for second IRT. Positive predictive value (PPV) was determined as 7.1%. When cutoff value for first IRT was estimated as 116.7 μg/L, sensitivity was 69.0% and specificity was 69.6%, and when cutoff value was set to 88.7 μg/L for second IRT, sensitivity was 69.0% and specificity was 69.0%. Area under curve was 0.757 for first and 0.763 for second IRT (p < 0.001, p < 0.001, respectively). PPV was calculated as 4.3%. Conclusion: Although sensitivity of CF NBS is high in our country, its PPV is significantly lower than expected from CF NBS programs. False-positive NBS results could have been overcome by revising NBS strategy. What is Known: • Although immunoreactive trypsinogen elevation is a sensitive test used in cystic fibrosis newborn screening, its specificity is low. • In countries although different algorithms are used, all strategies begin with the measurement of immunoreactive trypsinogen in dried blood spots. What is New: • In our study, it was shown that use of the IRT/IRT protocol for cystic fibrosis newborn screening is not sufficient for the cut-off values determined by the high number of patients. • Newborn screening strategy should be reviewed to reduce false positive newborn screening results.

PMID:36565324 | DOI:10.1007/s00431-022-04766-4

Pulmonology. 2022 Dec 21:S2531-0437(22)00281-1. doi: 10.1016/j.pulmoe.2022.11.007. Online ahead of print.

NO ABSTRACT

PMID:36564238 | DOI:10.1016/j.pulmoe.2022.11.007

J Pediatr (Rio J). 2022 Dec 20:S0021-7557(22)00133-4. doi: 10.1016/j.jped.2022.11.007. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the prevalence of GERD exclusively by means of multichannel intraluminal impedanciometry associated with pH monitoring (MIIpH) and compare it with respiratory symptoms in children with CF. To compare MIIpH with pHmetry alone to perform GERD diagnosis.

METHODS: An analytical cross-sectional study was conducted with children diagnosed with CF who underwent MIIpH. Clinical and laboratory markers, including respiratory and digestive symptoms, were used for comparative analyses. High-resolution chest computed tomography was performed on patients with symptoms of chronic lung disease. Severity was classified according to the Bhalla score.

RESULTS: A total of 29 children < 10 yo (18 girls) were evaluated; 19 of whom with physiological GER and 10 with GERD. Of the children with GERD, seven had predominantly acid GER, two acid+non-acid GER, and one non-acid GER. Three patients had GERD diagnosed only by MIIpH. Bhalla scores ranged from seven to 17.75 with no significant relationship with GERD. The number of pulmonary exacerbations was associated with a decrease in esophageal clearance regardless of the position in pHmetry and MIIpH.

CONCLUSIONS: The prevalence of GERD was 34% in children with CF. There was no association between respiratory disease severity and GER types. MIIpH detected 30% more patients with GERD than pHmetry.

PMID:36564006 | DOI:10.1016/j.jped.2022.11.007

Respir Med Res. 2022 Sep 6;83:100953. doi: 10.1016/j.resmer.2022.100953. Online ahead of print.

NO ABSTRACT

PMID:36563551 | DOI:10.1016/j.resmer.2022.100953

Respir Med Res. 2022 Oct 9;83:100962. doi: 10.1016/j.resmer.2022.100962. Online ahead of print.

ABSTRACT

BACKGROUND: Patient-reported outcomes (PROs) are increasingly used in randomized controlled trials (RCTs) to foster patient-centered healthcare. The aim of this investigation was to assess the completeness of reporting of PROs in RCTs pertaining to cystic fibrosis (CF).

METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for RCTs concerning CF that included PROs as a primary or secondary outcome. The RCTs were assessed by 2 independent investigators using an adaptation of the Consolidated Standards of Reporting Trials for Patient-Reported Outcomes (CONSORT-PRO) and the Cochrane Risk of Bias (RoB) 2.0 assessment. We calculated the mean completion percentage of adherence to the CONSORT-PRO adaptation and used bivariate regression models to evaluate for associations with particular trial characteristics.

RESULTS: Our systematic search returned 2302 potential studies. Fifty-nine eligible RCTs were included after full-text screening. The RCT mean completeness of reporting was 38.38% (SD = 12.74). We found the following associations between trial characteristics and completeness of PRO reporting: (1) significantly higher reporting completeness for RCTs published in journals requiring adherence to the CONSORT guideline (p-value = 0.049), (2) improved reporting completeness in studies with 'some concerns' of RoB versus 'high' RoB (p-value = 0.042), and (3) significantly better reporting completeness when the PRO is the primary outcome of a RCT (p-value = 0.006).

CONCLUSION: Inadequate PRO reporting exists within RCTs focused on CF. Given that CF has substantial effects on quality of life, PROs are imperative to understand patients' experiences. We believe greater adherence to CONSORT-PRO will promote the standardization of PRO reporting and will facilitate comprehension of PROs by stakeholders, patients, and clinicians.

PMID:36563550 | DOI:10.1016/j.resmer.2022.100962

J Med Chem. 2022 Dec 23. doi: 10.1021/acs.jmedchem.2c00352. Online ahead of print.

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.

PMID:36563291 | DOI:10.1021/acs.jmedchem.2c00352

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221144211. doi: 10.1177/17534666221144211.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is associated with worsening of depression and anxiety symptoms. Elexacaftor/tezacaftor/ivacaftor (Trikafta®), a cystic fibrosis transmembrane regulator (CFTR) modulator approved in 2019, significantly improves lung function, decreases pulmonary exacerbations, and improves quality of life. Studies are needed to evaluate the effects of Trikafta on symptoms of anxiety and depression.

RESEARCH QUESTION: Do adults with CF report a change in depression and anxiety symptoms after Trikafta initiation?

STUDY DESIGN AND METHODS: A retrospective chart review was conducted of patients with CF (n = 127) receiving care from January 2015 through February 2022. Data collected included demographics, annual PHQ-9 and GAD-7 scores, FEV1 percent predicted at each visit, BMI, consistency and timeline of Trikafta use, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of psychiatric medications, number of psychiatric emergency department visits and psychiatric hospital admissions, and sleep disturbances.

RESULTS: Of the 127 patients screened for eligibility, 100 patients were included. Data collected yielded 563 PHQ-9, 563 GAD-7, and 560 ppFEV1 data points. No significant changes in average PHQ-9 or GAD-7 scores were found after Trikafta initiation or due to the COVID-19 pandemic. However, 22% of patients initiated or had a change in psychiatric medications, and patients with changes in psychiatric medications had significantly higher PHQ-9 and GAD-7 scores than patients not prescribed psychiatric medications. Trikafta use improved lung function by an average of 5.23% (p = 8.56e-08). Around a quarter (23%) of all patients reported sleep issues after initiating Trikafta.

INTERPRETATION: No significant changes in average PHQ-9 and GAD-7 scores were found after Trikafta initiation. A quarter of patients required a change in psychiatric medications, and significant differences in depression and anxiety scores were found between patients with a change in psychiatric medications and those not prescribed medication. Twenty-three percent of patients reported a prevalence of sleep issues after Trikafta initiation.

PMID:36562554 | DOI:10.1177/17534666221144211

Expert Opin Drug Discov. 2022 Dec 23. doi: 10.1080/17460441.2023.2160439. Online ahead of print.

ABSTRACT

INTRODUCTION: Fibrotic lung diseases represent a large subset of diseases with an unmet clinical need. Oligonucleotide therapies (ONT) are a promising therapeutic approach for treatment of pulmonary disease as they can inhibit pathways which are otherwise difficult to target. Additionally, targeting the lung specifically with ONT is advantageous because it reduces the possibilities of systemic side effects and tolerability concerns.

AREAS COVERED: This review presents the chemical basis of designing various ONTs currently known to treat fibrotic lung diseases. Further, the authors have also discussed the delivery vehicle, routes of administration, physiological barriers of the lung, and toxicity concerns with ONTs.

EXPERT OPINION: : ONTs provide a promising therapeutic approach for treatment of fibrotic diseases of the lung, particularly because ONTs directly delivered to the lung show little systemic side effects compared to current therapeutic strategies. Dry powder aerosolized inhalers may be a good strategy for getting ONTs into the lung in humans. However, as of now, no dry powder ONTs have been approved for use in the clinical setting, and this challenge must be overcome for future therapies. Various delivery methods that can aid in direct targeting may also improve the use of ONTs for lung fibrotic diseases.

PMID:36562410 | DOI:10.1080/17460441.2023.2160439

Ochsner J. 2022 Winter;22(4):349-352. doi: 10.31486/toj.22.0002.

NO ABSTRACT

PMID:36561098 | PMC:PMC9753951 | DOI:10.31486/toj.22.0002

Pharmaceutics. 2022 Nov 30;14(12):2667. doi: 10.3390/pharmaceutics14122667.

NO ABSTRACT

PMID:36559160 | DOI:10.3390/pharmaceutics14122667

Life (Basel). 2022 Dec 13;12(12):2087. doi: 10.3390/life12122087.

NO ABSTRACT

PMID:36556452 | DOI:10.3390/life12122087

J Clin Med. 2022 Dec 9;11(24):7323. doi: 10.3390/jcm11247323.

NO ABSTRACT

PMID:36555939 | DOI:10.3390/jcm11247323

Int J Mol Sci. 2022 Dec 19;23(24):16225. doi: 10.3390/ijms232416225.

NO ABSTRACT

PMID:36555865 | DOI:10.3390/ijms232416225

Int J Mol Sci. 2022 Dec 19;23(24):16194. doi: 10.3390/ijms232416194.

NO ABSTRACT

PMID:36555839 | DOI:10.3390/ijms232416194

Healthcare (Basel). 2022 Dec 13;10(12):2520. doi: 10.3390/healthcare10122520.

NO ABSTRACT

PMID:36554044 | DOI:10.3390/healthcare10122520