J Cyst Fibros. 2023 Jul 1:S1569-1993(23)00827-5. doi: 10.1016/j.jcf.2023.06.013. Online ahead of print.

NO ABSTRACT

PMID:37400299 | DOI:10.1016/j.jcf.2023.06.013

Lancet Infect Dis. 2023 Jun 30:S1473-3099(23)00271-2. doi: 10.1016/S1473-3099(23)00271-2. Online ahead of print.

ABSTRACT

BACKGROUND: Previous SARS-CoV-2 infection and vaccination, coupled with the rapid evolution of SARS-CoV-2 variants, have modified COVID-19 clinical manifestations. We aimed to characterise the clinical symptoms of COVID-19 individuals in omicron BA.2 and BA.5 Japanese pandemic periods to identify omicron and subvariant associations between symptoms, immune status, and clinical outcomes.

METHODS: In this registry-based observational study, individuals registered in Sapporo's web-based COVID-19 information system entered 12 pre-selected symptoms, days since symptom onset, vaccination history, SARS-CoV-2 infection history, and background. Eligibility criteria included symptomatic individuals who tested positive for SARS-CoV-2 (PCR or antigen test), and individuals who were not tested for SARS-CoV-2 but developed new symptoms after a household member tested positive for SARS-CoV-2. Symptom prevalence, variables associated with symptoms, and symptoms associated with progression to severe disease were analysed.

FINDINGS: Data were collected and analysed between April 25 and Sept 25, 2022. For 157 861 omicron-infected symptomatic individuals, cough was the most common symptom (99 032 [62·7%] patients), followed by sore throat (95 838 [60·7%] patients), nasal discharge (69 968 [44·3%] patients), and fever (61 218 [38·8%] patients). Omicron BA.5 infection was associated with a higher prevalence of systemic symptoms than BA.2 in vaccinated and unvaccinated individuals (adjusted odds ratio [OR] for fever: 2·18 [95% CI 2·12-2·25]). Omicron breakthrough-infected individuals with three or more vaccinations or previous infection were less likely to exhibit systemic symptoms (fever 0·50 [0·49-0·51]), but more likely to exhibit upper respiratory symptoms (sore throat 1·33 [1·29-1·36]; nasal discharge 1·84 [1·80-1·89]). Infected older individuals (≥65 years) had lower odds for all symptoms. However, when symptoms were manifest, systemic symptoms were associated with increased odds for severe disease (dyspnoea 3·01 [1·84-4·91]; fever 2·93 [1·89-4·52]), whereas upper respiratory symptoms were associated with decreased odds (sore throat 0·38 [0·24-0·63]; nasal discharge 0·48 [0·28-0·81]).

INTERPRETATION: Host immunological status, omicron subvariant, and age were associated with a spectrum of COVID-19 symptoms and outcomes. BA.5 produced a higher systemic symptom prevalence than BA.2. Vaccination and previous infection reduced systemic symptom prevalence and improved outcomes but increased upper respiratory tract symptom prevalence. Systemic, but not upper respiratory, symptoms in older people heralded severe disease. Our findings could serve as a practical guide to use COVID-19 symptoms to appropriately modify health-care strategies and predict clinical outcomes for older patients with omicron infections.

FUNDING: Japan Agency for Medical Research and Development.

PMID:37399831 | DOI:10.1016/S1473-3099(23)00271-2

Biochem J. 2023 Jul 3:BCJ20220552. doi: 10.1042/BCJ20220552. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a common cause of serious hospital-acquired infections, the leading proven cause of mortality in people with cystic fibrosis and is associated with high levels of antimicrobial resistance. Pyocins are narrow spectrum protein antibiotics produced by P. aeruginosa that kill strains of the same species and have the potential to be developed as therapeutics targeting multi-drug resistant isolates. We have identified two novel pyocins designated SX1 and SX2. Pyocin SX1 is a metal-dependent DNase while pyocin SX2 kills cells through inhibition of protein synthesis. Mapping the uptake pathways of SX1 and SX2 shows these pyocins utilize a combination of the common polysaccharide antigen (CPA) and a previously uncharacterized TonB-dependent transporter (TBDT) PA0434 to traverse the outer membrane. In addition, TonB1 and FtsH are required by both pyocins to energise their transport into cells and catalyse their translocation across the inner membrane, respectively. Expression of PA0434 was found to be specifically regulated by copper availability and we have designated PA0434 as Copper Responsive Transporter A, or CrtA. To our knowledge these are the first S-type pyocins described that utilize a TBDT that is not involved in iron uptake.

PMID:37399084 | DOI:10.1042/BCJ20220552

bioRxiv. 2023 Jun 15:2023.06.14.544983. doi: 10.1101/2023.06.14.544983. Preprint.

ABSTRACT

Pseudomonas aeruginosa is the predominant bacterial pathogen in the cystic fibrosis (CF) lung, establishing a chronic, drug-resistant infection often via a single adapting and diversifying strain. In this study, we collected a bio-repository of 300 isolates of P. aeruginosa from four CF patients to unravel the extent of within-patient genomic diversity in CF lung infection; elucidate the evolutionary processes by which this diversity is generated; and understand how diversification impacts antimicrobial resistance. We found that populations of P. aeruginosa in the CF lung displayed patient specific genomic diversity ranging from 1 to 199 median pairwise SNPs, and 31 to 4,592 total SNPs within a population. Diversification was driven by a combination of de novo mutations, recombination, and variations in gene content, with the highest levels of population diversity associated with the presence of DNA mismatch repair mutants. Populations with higher levels of genomic diversity displayed increased variation in antibiotic resistance phenotypes; however, even populations with lower genomic diversity displayed substantial diversity in resistance profiles. Intriguingly, we found evidence that mutations in DNA mismatch repair can facilitate the evolution of seemingly undesirable traits in vivo , such as increased sensitivity to certain antimicrobials. Overall, our findings highlight that (i) P. aeruginosa genomic population diversity in chronic CF lung infection is highly variable between patients; (ii) hypermutator populations can evolve increased sensitivity to antimicrobials even under apparent antibiotic selection; and that (iii) current methods of single-isolate sampling and susceptibility testing should be re-evaluated in the study of chronic P. aeruginosa infection.

SIGNIFICANCE: Chronic lung infection with Pseudomonas aeruginosa is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Upon infection, P. aeruginosa rapidly acquires mutations, which can result in diverse, treatment-resistant populations. However, within-patient diversity is largely overlooked by clinicians and researchers. We sequenced the genomes of 300 CF lung-derived isolates of P. aeruginosa to investigate genomic diversity and its role in the evolution of antimicrobial resistance (AMR). Genomic diversity was variable, with higher levels of diversity correlating with increased variation in AMR. In two patients, mutations in DNA mismatch repair genes drove the evolution of increased susceptibility to multiple antimicrobials. Based on these findings, we advocate for deeper population sampling to improve our understanding of CF lung infection.

PMID:37398156 | PMC:PMC10312765 | DOI:10.1101/2023.06.14.544983

bioRxiv. 2023 May 30:2023.05.30.542968. doi: 10.1101/2023.05.30.542968. Preprint.

ABSTRACT

Antagonistic behaviors between bacterial cells can have profound effects on microbial populations and disease outcomes. Polymicrobial interactions may be mediated by contact-dependent proteins with antibacterial properties. The Type VI Secretion System (T6SS) is a macromolecular weapon used by Gram-negative bacteria to translocate proteins into adjacent cells. The T6SS is used by pathogens to escape immune cells, eliminate commensal bacteria, and facilitate infection. Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that causes a wide range of infections in immunocompromised patients and infects the lungs of patients with cystic fibrosis. Infections with the bacterium can be deadly and are challenging to treat because many isolates are multidrug-resistant. We found that globally dispersed S. maltophilia clinical and environmental strains possess T6SS genes. We demonstrate that the T6SS of an S. maltophilia patient isolate is active and can eliminate other bacteria. Furthermore, we provide evidence that the T6SS contributes to the competitive fitness of S. maltophilia against a co-infecting Pseudomonas aeruginosa isolate, and that the T6SS alters the cellular organization of S. maltophilia and P. aeruginosa co-cultures. This study expands our knowledge of the mechanisms employed by S. maltophilia to secrete antibacterial proteins and compete against other bacteria.

IMPORTANCE: Infections with the opportunistic pathogen Stenotrophomonas maltophilia can be fatal for immunocompromised patients. The mechanisms used by the bacterium to compete against other prokaryotes are not well understood. We found that the T6SS allows S. maltophilia to eliminate other bacteria and contributes to the competitive fitness against a co-infecting isolate. The presence of T6SS genes in isolates across the globe highlights the importance of this apparatus as a weapon in the antibacterial arsenal of S. maltophilia . The T6SS may confer survival advantages to S. maltophilia isolates in polymicrobial communities in both environmental settings and during infections.

PMID:37398041 | PMC:PMC10312562 | DOI:10.1101/2023.05.30.542968

Clin Case Rep. 2023 Jun 28;11(7):e7489. doi: 10.1002/ccr3.7489. eCollection 2023 Jul.

ABSTRACT

KEY CLINICAL MESSAGE: Primary lung cancer was reported by a bilateral lung transplant patient without any risk factors. Single lung transplantation should be contemplated instead of double lung transplantation as it has been shown to increase the risk of lung cancers.

ABSTRACT: This is a case report of a 37-year-old woman, with no history of smoking, who developed adenocarcinoma in her transplanted lung 17 years post transplantation. The development of lung cancer 17 years after transplantation is considered as a rare finding in this case report. According to the Annual Report on Cardiothoracic Organ Transplantation 2019-2020, the NHS Blood and Transplant Data, approximately 156 lung transplants were performed in the UK during 2019-2020. The third most common primary disease group recipient was cystic fibrosis and bronchiectasis. There are several medical complications described in the recipients' post-lung transplantation, and the increased risk of lung malignancy due to immunosuppression is well-established in comparison to the general population. Most cancers, however, develop in the native lung following a single lung transplant. Several cases of lymphoproliferative malignancies in the transplanted lung have been reported following bilateral lung transplantation. This is a case report of a 37-year-old woman with no history of smoking who developed adenocarcinoma in her transplanted lung 17 years later. This patient underwent lobectomy via thoracotomy and was discharged home in good condition. Only a few cases of patients developing primary lung cancer in the transplanted lung with no recipient risk factor have been reported in the literature to date. The development of lung cancer 17 years after transplantation was a rare finding in this case report.

PMID:37397580 | PMC:PMC10307987 | DOI:10.1002/ccr3.7489

Oncoimmunology. 2023 Jun 28;12(1):2224679. doi: 10.1080/2162402X.2023.2224679. eCollection 2023.

ABSTRACT

In a recent paper in Nature, Park et al. propose a mechanism through which intestinal dysbiosis compromises the efficacy of immunotherapy targeting the PD-L1/PD-1 interaction. Dysbiosis may upregulate a pair of checkpoint molecules, i.e. PD-L2 interacting with RGMb. Antibodies targeting PD-L2/RGMb can restore responses to PD-1 blockade in the context of dysbiosis.

PMID:37396957 | PMC:PMC10308862 | DOI:10.1080/2162402X.2023.2224679

Biofilm. 2023 Jun 3;5:100133. doi: 10.1016/j.bioflm.2023.100133. eCollection 2023 Dec.

ABSTRACT

Pseudomonas aeruginosa biofilms are relevant for a variety of disease settings, including pulmonary infections in people with cystic fibrosis. Biofilms are initiated by individual bacteria that undergo a phenotypic switch and produce an extracellular polymeric slime (EPS). However, the viscoelastic characteristics of biofilms at different stages of formation and the contributions of different EPS constituents have not been fully explored. For this purpose, we develop and parameterize a mathematical model to study the rheological behavior of three biofilms - P. aeruginosa wild type PAO1, isogenic rugose small colony variant (RSCV), and mucoid variant biofilms against a range of experimental data. Using Bayesian inference to estimate these viscoelastic properties, we quantify the rheological characteristics of the biofilm EPS. We employ a Monte Carlo Markov Chain algorithm to estimate these properties of P. aeruginosa variant biofilms in comparison to those of wild type. This information helps us understand the rheological behavior of biofilms at different stages of their development. The mechanical properties of wild type biofilms change significantly over time and are more sensitive to small changes in their composition than the other two mutants.

PMID:37396464 | PMC:PMC10313507 | DOI:10.1016/j.bioflm.2023.100133

Biofilm. 2023 Mar 24;5:100113. doi: 10.1016/j.bioflm.2023.100113. eCollection 2023 Dec.

ABSTRACT

The biofilm lifestyle of bacterial pathogens is a hallmark of chronic lung infections such as in cystic fibrosis (CF) patients. Bacterial adaptation to the complex conditions in CF-affected lungs and repeated antibiotherapies lead to increasingly tolerant and hard-to-treat biofilms. In the context of growing antimicrobial resistance and restricted therapeutic options, antimicrobial photodynamic therapy (aPDT) shows great promise as an alternative to conventional antimicrobial modalities. Typically, aPDT consists in irradiating a non-toxic photosensitizer (PS) to generate reactive oxygen species (ROS), which kill pathogens in the surrounding environment. In a previous study, we reported that some ruthenium (II) complexes ([Ru(II)]) can mediate potent photodynamic inactivation (PDI) against planktonic cultures of Pseudomonas aeruginosa and Staphylococcus aureus clinical isolates. In the present work, [Ru(II)] were further assayed to evaluate their ability to photo-inactivate such bacteria under more complex experimental conditions better recapitulating the microenvironment in lung infected airways. Bacterial PDI was tentatively correlated with the properties of [Ru(II)] in biofilms, in mucus, and following diffusion across the latter. Altogether, the results obtained demonstrate the negative impacting role of mucus and biofilm components on [Ru(II)]-mediated PDT, following different possible mechanisms of action. Technical limitations were also identified that may be overcome, making this report a pilot for other similar studies. In conclusion, [Ru(II)] may be subjected to specific chemical engineering and/or drug formulation to adapt their properties to the harsh micro-environmental conditions of the infected respiratory tract.

PMID:37396462 | PMC:PMC10313506 | DOI:10.1016/j.bioflm.2023.100113

Front Microbiol. 2023 Jun 15;14:1205389. doi: 10.3389/fmicb.2023.1205389. eCollection 2023.

ABSTRACT

INTRODUCTION: Stenotrophomonas maltophilia is an opportunistic pathogen infecting persons with cystic fibrosis (pwCF) and portends a worse prognosis. Studies of S. maltophilia infection dynamics have been limited by cohort size and follow-up. We investigated the natural history, transmission potential, and evolution of S. maltophilia in a large Canadian cohort of 321 pwCF over a 37-year period.

METHODS: One-hundred sixty-two isolates from 74 pwCF (23%) were typed by pulsed-field gel electrophoresis, and shared pulsotypes underwent whole-genome sequencing.

RESULTS: S. maltophilia was recovered at least once in 82 pwCF (25.5%). Sixty-four pwCF were infected by unique pulsotypes, but shared pulsotypes were observed between 10 pwCF. In chronic carriage, longer time periods between positive sputum cultures increased the likelihood that subsequent isolates were unrelated. Isolates from individual pwCF were largely clonal, with differences in gene content being the primary source of genetic diversity objectified by gene content differences. Disproportionate progression of CF lung disease was not observed amongst those infected with multiple strains over time (versus a single) or amongst those with shared clones (versus strains only infecting one patient). We did not observe evidence of patient-to-patient transmission despite relatedness between isolates. Twenty-four genes with ≥ 2 mutations accumulated over time were identified across 42 sequenced isolates from all 11 pwCF with ≥ 2 sequenced isolates, suggesting a potential role for these genes in adaptation of S. maltophilia to the CF lung.

DISCUSSION: Genomic analyses suggested common, indirect sources as the origins of S. maltophilia infections in the clinic population. The information derived from a genomics-based understanding of the natural history of S. maltophilia infection within CF provides unique insight into its potential for in-host evolution.

PMID:37396351 | PMC:PMC10308010 | DOI:10.3389/fmicb.2023.1205389

Arch Pediatr. 2023 Jun 30:S0929-693X(23)00098-2. doi: 10.1016/j.arcped.2023.06.008. Online ahead of print.

ABSTRACT

The aim of our study was to assess the nutritional status of hospitalized children with cystic fibrosis. We extracted data from the ePINUT surveys. Undernutrition was defined as a body mass index (BMI) of <18.5 according to the International Obesity Task Force cut-off, and the nutritional status goal was defined as a BMI z-score ≥0 SD for children older than 2 years and a weight-for-height z-score ≥0 SD for those younger than 2 years. Undernutrition frequency in the 114 patients with cystic fibrosis was 46% and was higher than in children with other chronic diseases (n = 5863; 30.5%; p = 0.001); 81% of children were below the nutritional status goal. Undernutrition frequency in cystic fibrosis is higher than in other chronic diseases.

PMID:37394365 | DOI:10.1016/j.arcped.2023.06.008

J Cyst Fibros. 2023 Jun 30:S1569-1993(23)00825-1. doi: 10.1016/j.jcf.2023.06.011. Online ahead of print.

ABSTRACT

BACKGROUND: Hyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations.

METHODS: The STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables.

RESULTS: Glucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL.

CONCLUSIONS: Hyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations.

PMID:37394317 | DOI:10.1016/j.jcf.2023.06.011

Respir Med. 2023 Jun 30:107309. doi: 10.1016/j.rmed.2023.107309. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Few questionnaires are available for routine assessment of dyspnea. The study aimed to design a self-administered questionnaire assessing the impact of chronic dyspnea on daily activities, named DYSLIM (Dyspnea-induced Limitation).

METHODS: The development followed 4 steps: 1: selection of relevant activities and related questions (focus groups); 2: clinical study: internal and concurrent validity vs. modified Medical Research Council (mMRC), Baseline Dyspnea Index (BDI) and Saint George Respiratory Questionnaire (SGRQ); 3: item reduction; 4: responsiveness. Eighteen activities (from eating to climbing stairs) were considered with 5 modalities for each: doing the task slowly, taking breaks, seeking assistance, changing habits, and activity avoidance. Each modality was graded from 5 (never) to 1 (very often). Validation study included 194 patients: COPD (FEV1 ≥ 50% pred: n = 40; FEV1 < 50% pred: n = 65); cystic fibrosis (n = 30), interstitial lung disease (n = 30), pulmonary hypertension (n = 29). Responsiveness was evaluated by post-pulmonary rehabilitation data in 52 COPD patients.

RESULTS: Acceptability was high and short term (7 days) reproducibility was satisfactory (Kappa mostly above 0.7). Concurrent validity was high vs. mMRC (Spearman correlation coefficient, r = 0.71), BDI (r = - 0.75) and SGRQ (r = - 0.79). The reduced questionnaire with 8 activities (from cleaning to climbing stairs) and 3 modalities (slowly, seeking help, changing habits) showed a comparable validity and was chosen as the final short version. Effect size of rehabilitation was good for both the full (0.57) and short (0.51) versions. A significant correlation was also found between changes of SGRQ and DYSLIM post rehabilitation: r = - 0.68 and r = - 0.60 for full and reduced questionnaires, respectively.

CONCLUSION: The DYSLIM questionnaire appears promising for the evaluation of dyspnea-induced limitations in chronic respiratory diseases and seems suitable for use in various contexts.

PMID:37394196 | DOI:10.1016/j.rmed.2023.107309

J Cyst Fibros. 2023 Jun 29:S1569-1993(23)00823-8. doi: 10.1016/j.jcf.2023.06.009. Online ahead of print.

ABSTRACT

BACKGROUND: Mental health screening in accordance with consensus guidelines became routine clinical practice in our cystic fibrosis (CF) Center in 2015. We hypothesized improvement in anxiety and depression symptoms over time and associations between elevated screening scores and disease severity. We aimed to observe the impact of the COVID-19 pandemic and modulator use on mental health symptoms.

METHODS: Retrospective chart reviews were conducted for people 12 years and older with at least one Generalized Anxiety Disorder-7 (GAD-7) or Patient Health Questionnaire-9 (PHQ-9) screening for six years. Descriptive statistics were used to summarize demographic variables and logistic regression and linear mixed models were used to evaluate the relationship between screening scores and clinical variables.

RESULTS: Analyses included 150 participants (ages 12-22 years). The percentage of minimal to no symptom scores increased over time for anxiety and depression. Increased mental health visits and CFRD were associated with higher PHQ-9 and GAD-7 scores. Higher FEV1pp was associated with lower GAD-7 and PHQ-9 scores. More effective modulator use was associated with lower PHQ-9 scores. Mean PHQ-9 and GAD-7 scores were not significantly different when comparing pre-pandemic and pandemic scores.

CONCLUSION: Disruptions in screening during the pandemic were minimal and symptom scores remained stable. Individuals with higher mental health screening scores were more likely to have CFRD and utilization of mental health services. Consistent mental health monitoring and support is needed so individuals with CF can endure anticipated and unanticipated stressors including changes in physical health, healthcare, and societal stressors such as COVID-19 pandemic.

PMID:37393160 | DOI:10.1016/j.jcf.2023.06.009

J Crohns Colitis. 2023 Jul 1:jjad111. doi: 10.1093/ecco-jcc/jjad111. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Ulcerative proctitis (UP) is an uncommon presentation in paediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of UP in children, and identify predictors of poor outcomes.

METHODS: Retrospective study involving 37 sites affiliated with the IBD Porto Group of ESPGHAN. Data were collected from patients aged<18 years diagnosed with UP between 01/01/2016-31/12/2020.

RESULTS: We identified 196 patients with UP (median age at diagnosis 14.6 [IQR 12.5-16.0] years), with a median follow-up of 2.7 (IQR 1.7-3.8) years. The most common presenting symptoms were bloody stools (95%), abdominal pain (61%) and diarrhea )47%). At diagnosis, the median paediatric ulcerative colitis activity index (PUCAI) score was 25 (IQR 20-35), but most patients exhibited moderate-severe endoscopic inflammation. By the end-of-induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 48%, 48% and 73%, respectively. The rates of treatment escalation to biologics at 1, 3 and 5 years were 10%, 22% and 43%, respectively. In multivariate analysis, the PUCAI score at diagnosis was significantly associated with initiation of systemic steroids, or biologics, and subsequent acute severe colitis events and IBD-associated admission, with a score≥35 providing increased risk for poor outcomes. By the end of follow-up, 3.1% of patients underwent colectomy. Patients with proximal disease progression (48%) had significantly higher rates of cecal patch at diagnosis and higher PUCAI score by end-of-induction, compared to those without progression.

CONCLUSION: Paediatric patients with UP exhibit high rates of treatment escalation and proximal disease extension.

PMID:37392064 | DOI:10.1093/ecco-jcc/jjad111

Sovrem Tekhnologii Med. 2023;15(2):60-70. doi: 10.17691/stm2023.15.2.06. Epub 2023 Mar 29.

ABSTRACT

The aim of the study was to define the spectrum of genetic risk factors of chronic pancreatitis (CP) development in patients living in the European part of the Russian Federation.

MATERIALS AND METHODS: The study group included 105 patients with CP, with the age of the disease onset under 40 years old (the average age of onset was 26.9 years). The control group consisted of 76 persons without clinical signs of pancreatitis. The diagnosis of chronic pancreatitis in patients was made on the basis of clinical manifestations and the results of laboratory and instrumental investigations. Genetic examination of patients was conducted using the next-generation sequencing (NGS) technology and included targeted sequencing of all exons and exon-intron boundaries of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes. The genotyping of the rs61734659 locus of the PRSS2 gene was also conducted.

RESULTS: Genetic risk factors of the CP development were found in 61% of patients. Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). The frequent gene variants in Russian patients with CP were as follows: CTRC gene - c.180C>T (rs497078), c.760C>T (rs121909293), c.738_761del24 (rs746224507); cumulative odds ratio (OR) for all risk alleles was 1.848 (95% CI: 1.054-3.243); CFTR gene - c.3485G>T (rs1800120), c.1521_1523delCTT (p.Phe508del, rs113993960), and c.650A>G (rs121909046); OR=2.432 (95% CI: 1.066-5.553). In the SPINK1, PRSS1, and CPA1 genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the SPINK1 gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the PRSS1 gene - c.86A>T (p.Asn29Ile, rs111033566); of the CPA1 gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) CTRC according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the CTRC gene, the variant c.493+49G>C (rs6679763) appeared to be benign, the c.493+51C>A (rs10803384) variant was frequently detected among both the diseased and healthy persons and did not demonstrate a protective effect. The protective factor c.571G>A (p.Gly191Arg, rs61734659) of the PRSS2 gene was detected only in the group of healthy individuals and confirmed its protective role. 12.4% of the patients with CP had risk factors in 2 or 3 genes.

CONCLUSION: Sequencing of the coding regions of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes allowed to identify genetic risk factors of the CP development in 61% of cases. Determining the genetic cause of CP helps to predict the disease course, perform preventive measures in the proband's relatives, and facilitate a personalized treatment of the patient in future.

PMID:37389024 | PMC:PMC10306969 | DOI:10.17691/stm2023.15.2.06

BMC Cancer. 2023 Jun 30;23(1):607. doi: 10.1186/s12885-023-11052-5.

ABSTRACT

BACKGROUND: Single nucleotide polymorphism (SNP) is a genetic variation that occurs when a single nucleotide base in the DNA sequence varies between individuals and is present in at least 1% of the population. Genetic variants in FAM13A are associated with different types of chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and lung cancer. However, there is little literature on the association of FAM13A genotypes with oral cancer. Therefore, this project will explore the correlation between the FAM13A genotype and the formation of oral cancer.

METHODS: In this project, we will examine the presence of gene polymorphisms gene polymorphisms of rs1059122, rs3017895, rs3756050, and rs7657817 in the FAM13A gene exon, and combine the expression of these genes to try to clarify the impact of the FAM13A gene polymorphism on oral cancer. First, four loci (rs1059122, rs3017895, rs3756050, and rs7657817) of the FAM13A SNP were genotyped using TaqMan allelic discrimination.

RESULTS: By estimating OR and AOR, FAM13A exhibited different genotypic variables in four SNPs that were not statistically significant between controls and patients with oral cancer. The results of the general analysis showed that different distributions of allelic types did not affect clinical stage, tumour size, lymph node invasion, distant metastasis, and pathological differentiation status. However, in the alcohol drinking group specifically, patients with the rs3017895 SNP G genotype had a 3.17-fold (95% CI, 1.102-9.116; p = 0.032) increase in the well differentiated state of cells compared to patients with the A allele.

CONCLUSIONS: Our results suggested that the SNP rs3017895 FAM13A could contribute to oral cancer. More sample studies are needed in the future to confirm our results and more functional studies are needed to investigate their relevant roles in the development of oral cancer.

PMID:37391706 | DOI:10.1186/s12885-023-11052-5

Neoreviews. 2023 Jul 1;24(7):e414-e430. doi: 10.1542/neo.24-6-e414.

ABSTRACT

See Bonus NeoBriefs videos and downloadable teaching slides Gastrointestinal complications of cystic fibrosis (CF) are often the earliest manifestations of disease and contribute to significant morbidity and mortality. Early diagnosis of CF is paramount, as early intervention has been associated with improved long-term pulmonary and nutritional outcomes. In this review, we describe common gastrointestinal, pancreatic, hepatic, and nutritional manifestations of CF in neonates to aid clinicians in diagnosing and managing the earliest gastrointestinal manifestations of CF. Furthermore, we discuss how the use of CFTR-targeted therapies by pregnant and/or breastfeeding persons may affect CF diagnosis in newborns and their potential impact on halting or reversing CF disease progression.

PMID:37391660 | DOI:10.1542/neo.24-6-e414

Bone. 2023 Jun 28:116835. doi: 10.1016/j.bone.2023.116835. Online ahead of print.

ABSTRACT

In people with cystic fibrosis (CF), chronic inflammation and infection increase the risk for low bone mineral density and CF-related bone disease. During acute pulmonary exacerbations (APE), people with CF have increases in markers of bone resorption. Vitamin D has been proposed as a potential nutrient to lower inflammation. In this ancillary analysis of the Vitamin D for the Immune System in CF study, we hypothesized that vitamin D administered at the time of APE would have favorable changes on bone turnover markers compared to placebo. Participants with CF were randomized to receive a single dose of 250,000 IU of vitamin D or placebo during an APE and followed for 1 year for the primary outcome of APE or death after randomization. Bone turnover markers: C-terminal telopeptide (CTX-1) and procollagen type 1 intact N-terminal propetide (P1NP) were assessed at randomization (during APE) and after recovery from the APE in 45 participants. Participants randomized to vitamin D had significant decreases in markers of bone turnover; participants who received placebo had non-significant increases in markers of bone turnover. Vitamin D supplementation during an APE may help reduce the risk for CF-related bone disease.

PMID:37390941 | DOI:10.1016/j.bone.2023.116835

ACS Biomater Sci Eng. 2023 Jun 30. doi: 10.1021/acsbiomaterials.3c00481. Online ahead of print.

ABSTRACT

Microbes entrenched within biofilms can withstand 1000-fold higher concentrations of antibiotics, in part due to the viscous extracellular matrix that sequesters and attenuates antimicrobial activity. Nanoparticle (NP)-based therapeutics can aid in delivering higher local concentrations throughout biofilms as compared to free drugs alone, thereby enhancing the efficacy. Canonical design criteria dictate that positively charged nanoparticles can multivalently bind to anionic biofilm components and increase biofilm penetration. However, cationic particles are toxic and are rapidly cleared from circulation in vivo, limiting their use. Therefore, we sought to design pH-responsive NPs that change their surface charge from negative to positive in response to the reduced biofilm pH microenvironment. We synthesized a family of pH-dependent, hydrolyzable polymers and employed the layer-by-layer (LbL) electrostatic assembly method to fabricate biocompatible NPs with these polymers as the outermost surface. The NP charge conversion rate, dictated by polymer hydrophilicity and the side-chain structure, ranged from hours to undetectable within the experimental timeframe. LbL NPs with an increasingly fast charge conversion rate more effectively penetrated through, and accumulated throughout, wildtype (PAO1) and mutant overexpressing biomass (ΔwspF) Pseudomonas aeruginosa biofilms. Finally, tobramycin, an antibiotic known to be trapped by anionic biofilm components, was loaded into the final layer of the LbL NP. There was a 3.2-fold reduction in ΔwspF colony forming units for the fastest charge-converting NP as compared to both the slowest charge converter and free tobramycin. These studies provide a framework for the design of biofilm-penetrating NPs that respond to matrix interactions, ultimately increasing the efficacious delivery of antimicrobials.

PMID:37390118 | DOI:10.1021/acsbiomaterials.3c00481