bioRxiv [Preprint]. 2024 Nov 8:2024.11.06.622340. doi: 10.1101/2024.11.06.622340.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a chronic systemic disease caused by dysfunctional or absent cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is expressed in human immune cells and plays a role in regulating innate immunity both directly and indirectly. Besides CFTR, research indicates that the epithelial sodium channel (ENaC) also contributes to dysfunction in CF airway epithelial cells. However, the impact of non-CFTR ion channel dysfunction on CF immune responses is not yet fully understood. A precise understanding of how CF immune function is regulated by ion channels may allow antibiotic-and mutation-agnostic treatment approaches to chronic bacterial infection and inflammation. Therefore, we hypothesized that ENaC is aberrantly expressed in CF macrophages and directly contributes to impaired phagocytic and inflammatory functions.

METHODS: ENaC expression was characterized in human immune cells isolated from CF and non-CF blood donors. Monocyte-derived macrophage (MDM) function and bacterial killing was tested in the setting of ENaC modulation.

RESULTS: Baseline expression of ENaC in human CF MDMs, lymphocytes, and granulocytes was increased at both the transcript and protein level relative to non-CF controls and persisted after exposure to bacteria. Inhibition of CFTR in non-CF MDMs resulted in ENaC overexpression.CFTR modulator treatment reduced but did not eliminate ENaC overexpression in CF MDMs. Interestingly, ENaC inhibition with Amiloride increased CFTR expression. Amiloride-treated CF MDMs also showed normalized ROS production, improved autophagy, and decreased pro-inflammatory cytokine production. Finally, results from an ion channel microarray indicated that sodium channel expression in CF MDMs normalized after Amiloride treatment with minimal effect on other ion channels.

DISCUSSION: ENaC is overexpressed in CF immune cells and is associated with abnormal macrophage function. ENaC modulation in immune cells is a novel potential therapeutic target for infection control in CF, either in combination with CFTR modulators, or as a sole agent for patients not currently eligible for CFTR modulators.

PMID:39574739 | PMC:PMC11580935 | DOI:10.1101/2024.11.06.622340

Balkan Med J. 2024 Nov 22. doi: 10.4274/balkanmedj.galenos.2024.2024-7-144. Online ahead of print.

ABSTRACT

BACKGROUND: Since January 2015, the Cystic Fibrosis National Newborn Bloodspot Screening (CF-NBS) program has been implemented in Turkey with two samples of immune reactive trypsinogen (IRT-1/IRT-2) testing.

AIMS: This study aimed to evaluate the Turkish national CF screening program, which included patients referred to a tertiary pediatric pulmonology center, to ascertain the optimal cut-off values for IRT-1/IRT-2 and to identify alternative strategies for mitigating the number of late-diagnosed false-negative patients (FNPs) who initially exhibited screen negative results but were diagnosed subsequently based on clinical suspicion. The study also compared NBS-positive patients to FNPs to determine the influence of delayed diagnosis.

STUDY DESIGN: A retrospective cohort study.

METHODS: Screening for CF was conducted in accordance with the national CF-NBS program within 48-72 hours of birth by collecting a few drops of heel blood on Guthrie paper. A cut-off value of 90 μg/l was accepted for the first IRT, while 70 μg/l was accepted for the second sample. Infants with elevated IRT values in both samples were referred to the CF centers for a sweat test (ST). Based on the diagnosis, the NBS-positive infants referred to our CF center for ST analysis were divided into three groups: CF; cystic fibrosis-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID); and false-positive NBS. In addition, the study included NBS-negative patients who initially received negative screen results but were subsequently diagnosed with CF based on clinical suspicion.

RESULTS: Of the 227 NBS-positive infants referred within the study period, 53 (23.34%) were diagnosed with CF (true-positive NBS), 11 were classified as CRMS/CFSPID (4.84%), and 163 were classified as falsepositive NBS (71.8%). CF was diagnosed in 66 infants, 53 (80.3%) of whom were confirmed using the NBS test, while the 13 (19.7%) patients who were missed on the NBS test were diagnosed based on clinical suspicion (FNP). The study findings indicate that the IRT/IRT approach exhibited a sensitivity of 80.3% and a positive predictive value (PPV) of 23.3%.

CONCLUSION: The current study is the first to analyze the NBS program for CF using data from the Western Anatolian Region of Türkiye. Due to the low sensitivity and PPV of the IRT/IRT protocol and the high proportion of false-positive infants and FNPs, the current national program is not practicable for Türkiye. False-negative results significantly delay the diagnosis and invalidate the screening objectives. It is essential to establish optimal cut-off values for IRT-1/IRT-2 or revise existing strategies to reduce the number of FNPs missed by the screening program.

PMID:39574132 | DOI:10.4274/balkanmedj.galenos.2024.2024-7-144

Sci Rep. 2024 Nov 21;14(1):28832. doi: 10.1038/s41598-024-80108-8.

ABSTRACT

The mucociliary clearance (MC) system is a vital host defense against infection in the lung. MC system function is dependent on ciliary density, structure, and function and airway surface liquid (ASL) composition and hydration. Animal and human studies indicate that MC rate decreases with age which may contribute to the increased rates of pulmonary infection experienced by older people. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encodes an anion channel on epithelial surfaces that plays a key role in maintaining ASL hydration. Failure or dysfunction of CFTR could result in the dehydration of airway mucus, depressing MC. Here we use two available databases including bulk (GTEx) and single-cell (CELLxGENE) sequencing data from the lung to determine if CFTR expression decreases with age. Bulk expression data and single-cell expression data from goblet, club, and respiratory basal cells all demonstrated patterns of decreasing CFTR expression with age. Ciliated airway cells did not. Secretory cells (including club and goblet cells) and basal cells are the largest source of CFTR expression in the airway. This indicates that changes in CFTR expression and ASL dehydration may contribute to the decreasing MC associated with aging.

PMID:39572772 | DOI:10.1038/s41598-024-80108-8

Rev Argent Microbiol. 2024 Nov 20:S0325-7541(24)00123-8. doi: 10.1016/j.ram.2024.10.002. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a Gram-negative bacillus capable of developing in humid environments and animal tissue. The interest in this bacterium lies in its ability to cause opportunistic diseases in patients with cystic fibrosis and healthcare-associated infections (HAIs). The objective of our study was to characterize the resistance profile of strains causing HAIs isolated in hospitals within our community, from January 2019 to December 2021. This descriptive, prospective, and cross-sectional study involved the isolation of strains from January 2019 to December 2021 at the Autonomous University of Baja California (UABC). The identification of the strains was carried out using Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrometry, and the detection of beta-lactam resistance was performed according to the criteria of the Clinical and Laboratory Standards Institute as stipulated in the CLSI M100-S27 document. A total of 649 samples were obtained from January 2019 to December 2021, including sputum (335 samples), urine (119 samples), and wounds (91 samples). Resistance to carbapenems was 38.94% for meropenem and 21.97% for imipenem. For cephalosporins, there was a 21.05% resistance rate for cefepime, 22.9% for ceftazidime, and 24.78% for ceftolozane-tazobactam. The prevalence of antimicrobial resistance has increased over time, which is attributable to both selective pressure and the evolution of the microorganisms themselves.

PMID:39572364 | DOI:10.1016/j.ram.2024.10.002

Arch Bronconeumol. 2024 Nov 2:S0300-2896(24)00412-5. doi: 10.1016/j.arbres.2024.10.009. Online ahead of print.

ABSTRACT

Respiratory diseases exhibit diverse patterns in prevalence, clinical presentations, and outcomes between men and women. Historically, certain conditions were more prevalent in men, but trends have shifted, highlighting the need to understand sex disparities in respiratory health. Social, environmental, and healthcare changes have reshaped the landscape of respiratory diseases, complicating diagnosis and treatment. Moreover, the underrepresentation of women in clinical trials has limited our understanding of their specific needs. In this review, we explore the sex differences in the prevalence, clinical characteristics, and presentation of respiratory diseases, emphasizing the importance of tailored approaches to diagnosis and management. By recognizing and addressing these disparities, we can advance toward more equitable and effective respiratory healthcare for all individuals.

PMID:39572362 | DOI:10.1016/j.arbres.2024.10.009

J Clin Invest. 2024 Nov 21:e183219. doi: 10.1172/JCI183219. Online ahead of print.

ABSTRACT

Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes which initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis and renal failure. Focusing on psoriasis as a disease model, we used high-resolution mass spectrometry imaging and identified keratin 14 (K14)-expressing keratinocytes executing a ferroptotic death program in human psoriatic skin. Psoriatic phenotype with characteristic Th1/Th17 skin and extracutaneous immune responses was initiated and maintained in a murine model designed to actuate ferroptosis in a fraction of K14+ glutathione peroxidase 4 (Gpx4)-deficient epidermal keratinocytes. Importantly, an anti-ferroptotic agent, Liproxstatin-1, was as effective as clinically relevant biologic IL-12/IL-23/TNFα-targeting therapies or the depletion of T cells in completely abrogating molecular, biochemical and morphologic features of psoriasis. As ferroptosis in select epidermal keratinocytes triggers and sustains a pathologic psoriatic multi-organ inflammatory circuit, we suggest that strategies targeting ferroptosis, or its causes, may be effective in preventing or ameliorating a variety of chronic inflammatory diseases.

PMID:39570671 | DOI:10.1172/JCI183219

Eur J Pediatr. 2024 Nov 21;184(1):38. doi: 10.1007/s00431-024-05845-4.

ABSTRACT

Newborn screening for cystic fibrosis (CF-NBS) using an IRT-DNA algorithm with a 12 CFTR-variant panel and an IRT/IRT failsafe was officially implemented in the French-speaking Community of Belgium in January 2020. This screening protocol was evaluated after 4 years according to the criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. Immunoreactive trypsinogen concentration (IRT) was measured on dried blood spots collected between the second and the fourth day of life. CFTR variants genotyping was initiated when IRT ≥ 99th percentile (P99). If at least 1 variant was identified, the child was referred to a CF center for a sweat test (ST). If IRT ≥ 99.9th percentile with no variant identified, a failsafe was provided with IRT repeated on day 21 and subsequent ST in case of persistent IRT > P99. Extensive Gene Analysis was initiated if sweat chloride level was ≥ 30 mmol/L. Over a period of 4 years, 212.979 newborns were screened. Forty-two were diagnosed with CF: 34 by CF-NBS, 3 following a meconium ileus, 3 by family history and 2 missed cases. Additionally, 112 healthy carriers and 14 CFSPID were identified. The median age at the first consultation was 23 days. The sensitivity of our CF-NBS is 95% (target ≥ 95%), the positive predictive value 18% (target ≥ 30%) and CF/CFSPID ratio 2.8.

CONCLUSION: Although follow-up is limited, this first evaluation demonstrates encouraging sensitivity and early management before one month of age.

WHAT IS KNOWN: • Newborn screening for cystic fibrosis improves the prognosis of patients.

WHAT IS NEW: • This article presents an initial assessment of our screening after 4 years.

PMID:39570414 | DOI:10.1007/s00431-024-05845-4

Nucleic Acids Res. 2024 Nov 21:gkae1069. doi: 10.1093/nar/gkae1069. Online ahead of print.

ABSTRACT

Single-stranded DNA (ssDNA) templates along with Cas9 have been used for knocking-in exogenous sequences in the genome but suffer from low efficiency. Here, we show that ssDNA with chemical modifications in 12-19% of internal bases, which we denote as enhanced ssDNA (esDNA), improve knock-in (KI) by 2-3-fold compared to end-modified ssDNA in airway basal stem cells (ABCs), CD34 + hematopoietic cells (CD34 + cells), T-cells and endothelial cells. Over 50% of alleles showed KI in three clinically relevant loci (CFTR, HBB and CCR5) in ABCs using esDNA and up to 70% of alleles showed KI in the HBB locus in CD34 + cells in the presence of a DNA-PKcs inhibitor. This level of correction is therapeutically relevant and is comparable to adeno-associated virus-based templates. The esDNA templates did not improve KI in induced pluripotent stem cells (iPSCs). This may be due to the absence of the nuclease TREX1 in iPSCs. Indeed, knocking out TREX1 in other cells improved KI using unmodified ssDNA. esDNA can be used to modify 20-30 bp regions in primary cells for therapeutic applications and biological modeling. The use of this approach for gene length insertions will require new methods to produce long chemically modified ssDNA in scalable quantities.

PMID:39569586 | DOI:10.1093/nar/gkae1069

BMC Pediatr. 2024 Nov 20;24(1):752. doi: 10.1186/s12887-024-05154-7.

ABSTRACT

While Cystic Fibrosis is characterized by a high phenotypic variability, a correlation is reported between the pancreatic status and the CFTR genotype. Here we report an unusual case of a child with Cystic Fibrosis (F508del-duplication of exons 1-3 genotype) diagnosed at 8 years old for pancreatic insufficiency and non-pathological sweat test, in absence of respiratory symptoms and acute episodes of pancreatitis. Nasal potential differences and intestinal current measurements were normal, while the short-circuit current measured on patient-derived colonoids grown on Transwell® indicated the presence of a reduced CFTR-dependent current relative to non-CF colonoids with, a modest improvement of CFTR activity record following treatment with elexacaftor/tezacaftor/ivacaftor.This case opens the discussion on the importance of performing CFTR sequencing and the search for large gene rearrangements in cases of pancreatic insufficiency of unclear etiology, also in the presence of non-pathological sweat test. Children with CF and non-pathological sweat chloride are likely to develop higher concentrations if they truly have CF.

PMID:39567905 | DOI:10.1186/s12887-024-05154-7

J Cyst Fibros. 2024 Nov 19:S1569-1993(24)01805-8. doi: 10.1016/j.jcf.2024.10.012. Online ahead of print.

ABSTRACT

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) provides valuable clinical and demographic data but includes limited information on health services and medications provided outside of CF Care Centers. Linking CFFPR to claims databases such as national Medicaid data could address these data gaps.

METHODS: Linkage algorithms based on state of residence, gender, and date of birth were utilized to match individuals with CF diagnostic codes in national Medicaid databases (2016) to individuals in the CFFPR (2015-2016). Subsets of individuals with partial social security numbers or residing in the state of North Carolina were utilized to validate the accuracy of linkages and perform exploratory analyses on care utilization and costs.

RESULTS: Of the 32,152 individuals in CFFPR, 10,616 were uniquely linked to national Medicaid databases. The 372 linked individuals within the NC extract had 8.0 ± 7.6 visits to outpatient providers, substantially higher than the 4.2 ± 2.4 CF Care Center outpatient visits documented within CFFPR. Similarly, linked individuals had 2.1 ± 1.7 oral antibiotic prescriptions within CMS pharmacy databases versus 0.5 ± 1.9 oral antibiotic prescriptions in CFFPR. Total pharmacy costs for the linked individuals in NC were $16.4 million, with pancrealipase (19 %), dornase alfa (24 %), and CFTR modulators (29 %) the largest expenditures. Total non-pharmacy costs were $7.5 million, with inpatient hospitalization representing 53 % of costs.

CONCLUSION: Linkage of data from Medicaid and CFFPR can produce valid comprehensive data on low-income people with CF and provide opportunities to examine utilization/adherence or comparative effectiveness and safety of medications as well as conduct economic analyses in the low-income CF population.

PMID:39567301 | DOI:10.1016/j.jcf.2024.10.012

BMJ Case Rep. 2024 Nov 19;17(11):e261989. doi: 10.1136/bcr-2024-261989.

ABSTRACT

We present the case of a patient with cystic fibrosis on long-term oral linezolid treatment for Mycobacteria abscessus lung infection who developed severe linezolid-induced lactic acidosis (LILA) resulting in deranged clotting and pancytopenia. The lactic acidosis was resistant to treatment with intravenous fluid but resolved within 20 hours of initiating continuous veno-venous haemofiltration. An unintended consequence of haemofiltration was that vascular access interfered with effective chest physiotherapy, resulting in worsened lung consolidation requiring prolonged intravenous antibiotic therapy for coexisting Pseudomonas aeruginosa infection. Given the potential mortality and morbidity of LILA, monitoring lactate levels may be clinically important but the optimum timing of monitoring is currently unclear.

PMID:39566923 | DOI:10.1136/bcr-2024-261989

Respir Med. 2024 Nov 18:107868. doi: 10.1016/j.rmed.2024.107868. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved health and increased life expectancy in many patients with cystic fibrosis (pwCF). Family planning issues have become more important since then. Many women decide to remain on modulator therapy during pregnancy despite insufficient evidence-based recommendations for continuing ETI during pregnancy and lactation.

METHODS: In this retrospective observational report, we present data on maternal serum concentrations of ETI, assessed via a therapeutic drug monitoring (TDM) program established at our CF center for adults. Blood was taken during routine visits. We retrospectively analysed the corresponding predicted forced expiratory volume in 1 second (ppFEV1), at five time points before, during, and after pregnancy.

RESULTS: Of seven ETI-exposed pregnancies in six women between February 2021 and September 2023, the intake of ETI resulted in no maternal complications and healthy offspring. The dose was reduced in all women, 71.4 % before and 28.6 % during pregnancy, primarily as a result of side effects and/or increased ETI concentrations. Despite dose reductions, serum concentrations showed a broad distribution, with values below, within, and above the Cmax range according to the pharmacokinetic data in the manufacturer's product characteristics. Pulmonary function largely remained stable without pulmonary exacerbations requiring intravenous antibiotic treatment.

CONCLUSION: This observational report shows the most extensive dataset for ETI concentrations during pregnancy. Individualized dose adjustments could help to resolve adverse side effects while continuing CFTR therapy. Specific populations, such as pregnant women, might benefit from a TDM. However, future research with more pharmacokinetic data from pregnant pwCF is needed.

PMID:39566645 | DOI:10.1016/j.rmed.2024.107868

Cell Rep Med. 2024 Nov 19;5(11):101819. doi: 10.1016/j.xcrm.2024.101819.

ABSTRACT

Non-cystic fibrosis bronchiectasis is a progressive respiratory disease with limited treatment options, prompting the exploration of regenerative therapies. This study investigates the safety and efficacy of autologous P63+ progenitor cell transplantation in a randomized, single-blind, controlled, phase 1/2 trial. Thirty-seven patients receive bronchoscopic airway clearance (B-ACT) (n = 19) or B-ACT plus P63+ progenitor cells (n = 18). Results show that compared to the control group, the change in DLCO levels from baseline to 24 weeks post therapy is significantly higher in the cell treatment group (p value = 0.039). Furthermore, the patients in the cell treatment group demonstrate significantly reduced lung damaged area, improved SGRQ score, and ameliorated BSI and FACED scores within 4-12 weeks post therapy. Transcriptomic analysis reveals that progenitor cells with higher expression of P63 gene have better therapeutic efficacy. These findings suggest that P63+ progenitor cells may offer a promising therapeutic approach for bronchiectasis. This study was registered at ClinicalTrials.gov(NCT03655808).

PMID:39566467 | DOI:10.1016/j.xcrm.2024.101819

Cureus. 2024 Oct 19;16(10):e71888. doi: 10.7759/cureus.71888. eCollection 2024 Oct.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare lung disease that causes chronic oto-sino-pulmonary disease with irreversible lung damage. Several diagnostic methods exist, but electron microscopy (EM) is the most accurate tool, as it visualizes alterations in the axonemal ultrastructure; however, some patients may present a normal ciliary structure. Therefore, other diagnostic methods have been promoted, such as genetic studies or immunofluorescence of specific markers; nonetheless, they are not very accessible and expensive and even present a high level of false negatives. The quantification of nasal nitric oxide (nNO) has been a well-known tool for decades for the screening of this pathology, and recent studies have highlighted its high predictive value in the diagnosis of PCD, as it is a rapid tool in its processing, execution, and accessibility, especially in countries with limited health resources. We present the case of a patient with respiratory symptoms since childhood and extensive lung damage (cystic bronchiectasis); due to lack of access to EM or immunofluorescence, determinations of nNO were performed and found to be compatible with PCD.

PMID:39564026 | PMC:PMC11576054 | DOI:10.7759/cureus.71888

Cureus. 2024 Oct 20;16(10):e71913. doi: 10.7759/cureus.71913. eCollection 2024 Oct.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder that profoundly affects the respiratory and digestive systems, particularly in pediatric patients. This comprehensive review aims to conduct a comparative analysis of various treatment modalities employed in the management of CF in children. We systematically evaluated current literature focusing on pharmacological interventions, airway clearance techniques, nutritional management, and emerging therapies, including gene therapy and personalized medicine. Our analysis highlights the efficacy, safety, and accessibility of these treatments through a comparative lens, examining performance across diverse patient populations. Key comparisons include standard therapies, such as CF transmembrane conductance regulator (CFTR) modulators, versus traditional treatments and the effectiveness of airway clearance techniques in relation to lung function outcomes. We explore variations in treatment adherence and outcomes based on socioeconomic factors and healthcare systems. The review underscores the importance of individualized care plans tailored to the unique needs of pediatric patients. By synthesizing findings from clinical studies, meta-analyses, and expert guidelines, this review serves as a valuable resource for healthcare providers and researchers. Our goal is to optimize therapeutic strategies for pediatric patients with CF and ultimately improve their clinical outcomes.

PMID:39564025 | PMC:PMC11576056 | DOI:10.7759/cureus.71913

Respirology. 2024 Nov 19. doi: 10.1111/resp.14857. Online ahead of print.

NO ABSTRACT

PMID:39562851 | DOI:10.1111/resp.14857

Eur J Med Chem. 2024 Nov 8;282:117040. doi: 10.1016/j.ejmech.2024.117040. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) results from the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel of key importance in the airway epithelia. CFTR helps control optimal hydration of the airways, a crucial requirement for healthy lungs. CFTR modulators have recently been approved as an effective treatment option for many genetic variants of CF. The epithelial sodium channel (ENaC), unlike CFTR which is secretory, is an absorptive pathway, and therefore its inhibition is an alternative and potentially complementary approach to aid hydration of the airways. Due to the adverse effect of ENaC inhibition in the kidney we, as have several others, focused on the design and synthesis of novel ENaC inhibitors for direct delivery to the airways via inhalation. A new series of ENaC inhibitors is described, wherein the well-established pyrazine core of first-generation inhibitors was replaced with a pyrrolopyrazine. Aiming for high retention at the surface of the lung following inhalation, optimisation of this template focused on significantly increasing polarity to minimize passive cellular permeability. The resulting optimized clinical candidate ETD001 demonstrates potent inhibition of ENaC (59 nM) prolonged retention in the airways of rats (13 % of the delivered dose retained after 6h) following intratracheal administration and a potent and long-acting effect in a sheep model of mucociliary clearance following inhalation (ED100 (4-6h) = 9 μg/kg). ETD001 entered a phase II study in CF patients in July 2024.

PMID:39561495 | DOI:10.1016/j.ejmech.2024.117040

Diabetologia. 2024 Nov 19. doi: 10.1007/s00125-024-06323-0. Online ahead of print.

ABSTRACT

AIMS/HYPOTHESIS: We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.

METHODS: OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or ≤ 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8+ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.

RESULTS: Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1+ CD8+ T effector memory cells.

CONCLUSIONS/INTERPRETATION: OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

PMID:39560746 | DOI:10.1007/s00125-024-06323-0

Kidney360. 2024 Nov 19. doi: 10.34067/KID.0000000652. Online ahead of print.

ABSTRACT

The Autosomal Dominant Polycystic Kidney Disease (ADPKD) Centers of Excellence Program, launched by the Polycystic Kidney Disease Foundation in 2022, aims to bridge the gap in specialized care for individuals with ADPKD. This program seeks to enhance the availability of specialized clinicians and simplify the process for patients seeking expert care. It is founded on three pillars: improving care for all individuals with ADPKD, educating and empowering the community, and advancing PKD research. The program draws inspiration from successful models in other diseases, such as cystic fibrosis and muscular dystrophy, which have demonstrated the effectiveness of standardized care centers in improving patient outcomes. Patient and clinician stakeholder interviews have identified key areas where a national program could make a significant impact, including the need for a core care team with defined referral processes, mentorship and shared care models, patient navigation services, and education around expert consensus and care guidelines. The program introduces two designations: "Center of Excellence" and "Partner Clinic" to accommodate diverse care settings and enhance patient access to specialists. The Partner Clinic designation ensures that patients in smaller community practices have access to specialized care through mentorship and guidance from experts at Centers of Excellence. The program also emphasizes the importance of specialized services, especially in underserved communities experiencing health disparities, to manage the complexities of ADPKD care. Patient focus groups have highlighted the need for care navigation services, centralized sources of knowledge, and access to local care. The program aims to address these needs by providing a structured framework for care coordination, enhancing patient self-advocacy, and improving overall outcomes for individuals with ADPKD.

PMID:39560608 | DOI:10.34067/KID.0000000652

Pediatr Allergy Immunol. 2024 Nov;35(11):e14276. doi: 10.1111/pai.14276.

ABSTRACT

This common statement of the American Academy of Allergy, Asthma and Immunology (AAAAI) and The European Academy of Allergy and Clinical Immunology (EAACI) provides an update of the 2012 published guidelines on food challenges. The guidelines equally address food challenges in the research and the clinical settings. They first address the diagnostic tests which can guide the decision to conduct a challenge. Safety of food challenges is prime, and the various procedures and safety issues as well as medications potentially involved in challenges are extensively discussed. Challenges are suggested to be conducted with semi-logarithmic incremental doses based on the protein content, typically for IgE-mediated food allergy with intervals of 20-30 min between doses. Specific protocols for other types of reactions such atopic dermatitis or gastrointestinal food allergy are detailed separately. Proper stopping criteria are essential in order to reduce the risk of false-positive diagnoses, but also severe reactions. The guidelines recommend criteria based on "go on," "stop," or "observation." These revised guidelines will clearly provide much needed guidance for food challenges in the research and clinical settings. They will continue to evolve with new diagnostic tests or new needs in the field of food allergy.

PMID:39560049 | DOI:10.1111/pai.14276