Cystic Fibrosis Research Articles

Spirituality and religious coping in patients with cystic fibrosis and their parents

In this article, we reviewed spirituality and religiouscoping in patients with cystic fibrosis (CF) and theirparents to draw attention to the importance ofspiritual and religious dimensions of CF patients.Coping styles seem to have a large effect upon thequality of life of CF patients. In CF, all phasesincluding past, present and future were permeatedwith the search for the meaning of the disease andsocial support, the importance of religion andspirituality, and child's socialization. Children withCF reported a variety of religious/spiritual copingstrategies they nearly always associated withadaptive health outcomes. Persons with late-life CFdiagnoses used spirituality to make meaning,understanding themselves in a collaborativepartnership with their pulmonologist and Allah.Most parents of children with CF reported prayer as helpful and multi-faceted, including individual andgroup prayer. Parents imagined Allah as active,benevolent, and interventionist; found hope in theirbeliefs; felt supported by Allah; and related religionto their motivation to adhere to their child's treatmentplan. Conclusion – We would like to emphasize thatspirituality and religious coping have a large effectupon the quality of life of CF patients and theirparents. Given religion's importance to many peoplein the world, we believe that using religious copingis the right of patients with CF and their parents.Spiritual care for patients with CF and their parentsneeds to be integrated into the curriculum of nursesand health care professionals in collaboration withpastoral caregivers.

Effects of Several Bile Acids on the Production of Virulence Factors by Pseudomonas aeruginosa

The presence of bile acids in the cystic fibrosis patient’s lungs contributes to an increase in the inflammatory response, in the dominance of pathogens, as well as in the decline in lung function, increasing morbidity. The aim of this study is to determine the effects of exposure of Pseudomonas aeruginosa to primary and secondary bile acids on the production of several virulence factors which are involved in its pathogenic power. The presence of bile acids in the bacterial culture medium had no effect on growth up to a concentration of 1 mM. However, a slight decrease in the adhesion index as well as a reduction in the virulence of the bacteria on the HT29 cell line could be observed. In this model, exposure of P. aeruginosa to bile acids showed a significant decrease in the production of LasB and AprA proteases due to the reduction in the expression of their genes. A decrease in pyocyanin production was also observed in relation to the effects of bile acids on the quorum sensing regulators. In order to have an effect on gene expression, it is necessary for bile acids to enter the bacteria. P. aeruginosa harbors two potential homologs of the eukaryotic genes encoding the bile acid transporters NTCP1 and NTCP2 that are expressed in hepatocytes and enterocytes, respectively. By carrying out a comparative BLAST-P between the amino acid sequences of the PAO1 proteins and those of NTCP1 and NTCP2, we identified the products of the PA1650 and PA3264 genes as the unique homologs of the two eukaryotic genes. Exposure of the mutant in the PA1650 gene to chenodeoxycholic acid (CDCA) and lithocholic acid (LCA) showed a less significant effect on pyocyanin production than with the isogenic PAO1 strain. Also, no effect of CDCA on the PA3264 gene mutant was observed. This result indicated that CDCA should enter the bacteria by the transporter produced by this gene. The entry of LCA into bacteria seemed more complex and rather responded to a multifactorial system involving the product of the PA1650 gene but also the products of other genes encoding potential transporters.

Influence of Fungal Colonization on Exacerbations in Patients with Cystic Fibrosis

The importance of fungal pathogens in cystic fibrosis (CF) patients and their diagnosis remains a challenge, so our aim was to analyze the influence of the detection of fungi in sputum by using conventional culture and molecular techniques, polymerase chain reaction (PCR), lateral flow devices (LFDs), and galactomannan (GM) on exacerbations in patients with cystic fibrosis. A prospective study was conducted in patients via follow-up in the CF Unit of the Central University Hospital of Asturias from January 2021 to April 2022. Adult patients with at least one documented exacerbation were included. A complete fungal analysis of sputum samples was performed both in a period of clinical stability and in the exacerbation period. The microbiological study included conventional cultures for fungi, qPCR (polymerase chain reaction), LFDs (lateral flow devices), and galactomannan (GM) in sputum. We found that there were changes in their detection according to whether the patient is in a period of clinical stability or exacerbation; the positivity of the molecular tests and biomarkers in the period of exacerbation increased by 14%, 25%, and 21% for the analysis by qPCR, GM, and LFDs for Aspergillus and by 15% for the sputum culture for Aspergillus, which may mean that fungal isolates may play a role in the exacerbations of these patients.

Lentiviral Gene Therapy for Cystic Fibrosis: A Promising Approach and First-in-Human Trial.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Although CF is a multiorgan disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with CF (estimated at 10-15% of the global CF population) who are genetically ineligible for, or intolerant of, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with CF, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides, and gene editing, being explored. Various nonviral and viral vectors have been investigated for CF gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively redosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of CF. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024.

Exploring aggregation genes in a P. aeruginosa chronic infection model.

This study identifies genes essential for the formation of Pseudomonas aeruginosa (Pa) aggregates in cystic fibrosis (CF) sputum, filling a critical gap in understanding their specific biology. Using a synthetic CF sputum model (SCFM2) and RNA sequencing, 13 key genes were identified, whose disruption led to distinct spatial phenotypes observed through high-resolution microscopy. The addition of wild-type cells either rescued the mutant phenotype or increased spatial heterogeneity, suggesting cooperative interactions are involved in aggregate formation. This research advances our knowledge of Pa aggregate biology, particularly the unique genes and pathways involved in CF-like environments, offering valuable insights for developing targeted therapeutic strategies against aggregate-specific pathways.

Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy—Assessment of Patient’s Primary Myotubes

Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy—Assessment of Patient’s Primary Myotubes

Nutrient conditions affect antimicrobial pharmacodynamics in Pseudomonas aeruginosa.

The infectious microenvironment in chronic respiratory tract infections is characterized by substantial variability in nutrient conditions, which may impact colonization and treatment response of pathogens. Metabolic adaptation of the cystic fibrosis (CF)-associated pathogen Pseudomonas aeruginosa has been shown to lead to changes in antibiotic sensitivity. The impact of specific nutrients on the response to antibiotics is, however, poorly characterized. Here, we investigated how different carbon sources impact the antimicrobial pharmacodynamic responses in P. aeruginosa. We evaluated the effect of six antibiotics (aztreonam, ceftazidime, ciprofloxacin, colistin, imipenem, and tobramycin) on P. aeruginosa cultured in a basal medium enriched for seven different carbon sources (alanine, arginine, aspartate, glucose, glutamate, lactate, and proline). Pharmacodynamic responses were characterized by measuring time-kill profiles for a bioluminescent P. aeruginosa PAO1 Xen41 strain. We show that single-nutrient modifications minimally affected bacterial growth rate. For specific nutrient-antibiotic combinations, we find relevant alterations in antibiotic sensitivity (i.e., EC50) and the maximum drug effect (Emax), in particular for ciprofloxacin, colistin, imipenem, and tobramycin. The most pronounced effect was observed for tobramycin, where glucose was found to reduce the EC50 (0.5-fold), whereas lactate-enriched conditions led to a 4.3-fold increase in EC50. Using pharmacokinetic-pharmacodynamic simulations, we illustrate that the magnitude of the nutrient-driven pharmacodynamic changes impact treatment for clinical dosing strategies of tobramycin. In summary, this study underscores the impact of nutrient composition on antimicrobial pharmacodynamics, which could potentially contribute to observed variability of antimicrobial treatment responses in CF patients.IMPORTANCEChronic respiratory tract infections in cystic fibrosis patients present significant challenges for antibiotic treatment due to the complexity of the respiratory environment. This study investigated how variations in nutrient levels, altered during chronic infections, affect pathogen response to antibiotics in an experimental setting. By simulating different nutrient conditions, we aimed to uncover interactions between nutrient availability and antibiotic sensitivity. Our findings provide critical insights that could lead to more effective treatment strategies for managing chronic respiratory tract infections in cystic fibrosis patients while also guiding future research in improving treatment methodologies.

Cefiderocol pharmacokinetics during acute pulmonary exacerbations in hospitalized adult persons with cystic fibrosis.

Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h-1. Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC (fT >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC24h of 1,191 (781-1,496) mg/L*h. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% fT >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC24h of 1,279 (1,054-1,590) mg/L*h. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal fT >MIC exposure for pathogens up to MICs of 8 mg/L and AUC24h estimates similar to previously reported estimates in non-CF patients.

Role of the two-component system AmgRS in early resistance of Pseudomonas aeruginosa to cinnamaldehyde.

Exposure of Pseudomonas aeruginosa to cinnamaldehyde (CNA), a natural electrophilic antimicrobial often used as self-medication to treat mild infections, triggers overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. In this study, we demonstrate that CNA exposure induces expression of genes regulated by the two-component system AmgRS. AmgRS activates MexAB-OprM production, independent of repressors MexR and NalD. In addition to the essential role played by the NalC-ArmR pathway in this adaptive process, AmgRS is critical for the survival of P. aeruginosa challenged with CNA. Altogether, these data suggest that efflux-dependent and -independent mechanisms are activated in the early phase of CNA exposure, allowing for progressive enzymatic reduction of the biocide to non-toxic cinnamic alcohol.IMPORTANCEExposure of Pseudomonas aeruginosa to cinnamaldehyde (CNA), an antimicrobial used in self-medication, induces overproduction of the MexAB-OprM efflux system, leading to multidrug resistance. Our study demonstrates that the AmgRS two-component system aids in the survival of P. aeruginosa strain PA14 under CNA exposure through both MexAB-OprM-dependent and -independent mechanisms until the enzymatic reduction of CNA into the less toxic cinnamic alcohol. This discovery highlights the pivotal role of AmgRS in mediating defense against aldehyde biocides, emphasizing its significance in the persistence of P. aeruginosa, a pathogen associated with hospital-acquired infections and cystic fibrosis, and underscores the potential impact on clinical treatment strategies.

Mechanistic Insights into Succinic Acid as an Adjuvant for Ciprofloxacin in Treating Pseudomonas aeruginosa Growing Within Cystic Fibrosis Airway Mucus

Pseudomonas aeruginosa is a major cause of chronic respiratory infections in patients with cystic fibrosis (CF), with biofilm formation contributing to its persistence and antibiotic resistance. This study aimed to gain insights into the mechanistic action of succinic acid as a ciprofloxacin adjuvant against clinically relevant CF isolates, including small colony variants and mucoid strains, and a ciprofloxacin-resistant strain grown within CF dense mucus. Time-kill assays in artificial CF mucus, along with planktonic and surface-attached biofilm experiments, were used to assess the activity of succinic acid alone and in combination with sublethal ciprofloxacin concentrations. Succinic acid demonstrated an adjuvant effect of ciprofloxacin against P. aeruginosa grown within CF mucus at pH levels below pKa1 during the early bacterial growth stages. In examining planktonic growth and biofilms under these conditions, we found that succinic acid demonstrated strong antibacterial and antibiofilm properties. Conversely, succinic acid activity decreased at later growth stages, though it enhanced the ciprofloxacin effect, especially against mucoid biofilms. Moreover, we noted that, in dense CF mucus, succinic acid activity was attenuated compared to a non-CF environment, indicating diffusion challenges. These findings underscore the potential of succinic acid as a therapeutic adjuvant for improving antibiotic treatment outcomes and overcoming biofilm-associated resistance in CF.

Congenital absence of vas deferens: Anatomical and embryological inputs from a series of autopsies reported in Europe throughout the 18th and 19th century.

Congenital absence of the vas deferens (CAVD) is a syndrome with a heterogeneous presentation: bilateral (CBAVD) or unilateral (CUAVD), complete or partial and associated or not with other anomalies of the male urogenital system. A turning point came in 1968 when CBAVD was associated with cystic fibrosis and its CFTR gene mutations. Genetic studies then revealed that a minority of CBAVD but a majority of CUAVD are CFTR-independent. In the literature, reference is classically made to two sources from the 18th and 19th century: Hunter and Reverdin. This scarcity prompted us to look for additional observations of CAVD. By a meticulous bibliographical search, we identified a corpus of 10 European observations (8 CUAVD and 2 CBAVD) some of them richly illustrated. They were collected between 1755 and 1876 throughout adult men autopsies. We also provided their primary and unambiguous sources. Analysis of the reported data revealed some interesting facts: both CBAVD cases were unlikely linked to cystic fibrosis and half of CUAVD cases were associated with an ipsilateral kidney absence, suggesting a CFTR-independent pathophysiology. Moreover, the anatomical details of the anomalies raise interesting embryological questions we have tried to address in the light of current data. This work made it possible to identify new historical sources dealing with male genital tract pathologies. It sheds light on the origins of andrology and opens up interesting prospects for research and education in the field.

Dupilumab in chronic rhinosinusitis with nasal polyposis and concomitant cystic fibrosis: a real-life experience.

Chronic rhinosinusitis (CRS) has been distinguished in primary CRS, a primary inflammatory disorder limited to airways and secondary CRS, in which the sinonasal pathology is caused by a systemic disease or a local pathologic condition. Primary CRS is in turn classified in Type 2 and Non-type 2 on the basis of the endotype and of the pattern of the immune response. Advance in the knowledge of CRS has led to new therapeutic options, among which Dupilumab (anti-IL4R). We report the clinical response to Dupilumab in two patients with cystic fibrosis and nasal polyposis, in which the coexistence of a primary and secondary CRS could not be excluded. Nasal endoscopy, smell and quality of life of the patients were evaluated at each follow-up. In the first case, increased blood eosinophils, allergy to inhalants and NSAIDs intolerance supported the suspect of primary CRS with type 2 inflammatory pattern, in addition to cystic fibrosis and the therapy was effective. In the second case the patient did not show atopy or peculiar blood test and even if the phenotype could suggest a primary CRS combined with a secondary one, the treatment was ineffective and it was suspended. Even though classifications can be helpful, they can be reductive in cases where different aetiologies overlap. The presence of a concomitant primary CRS must not be excluded a priori in patients affected by secondary CRS. Each patient must be investigated to identify endotype characteristics and select the most appropriate therapeutic option.

Bronchiectasis in African children: Prevalence, etiology, and clinical spectrum at a pediatric tertiary hospital in Cape Town, South Africa

Objectives: The objective of the study was to describe the disease burden, etiology, and clinical spectrum of bronchiectasis in children attending a tertiary hospital in Cape Town, South Africa. Materials and Methods: Data were collected by chart review of all patients aged 3 months to 15 years attending the respiratory clinic at Red Cross War Memorial Children’s Hospital between January 2019 and December 2019. We included children who had a diagnosis of bronchiectasis based on a history of a recurrent (>3 episodes/year) or persistent (>4 weeks) wet or productive cough and a clinical phenotype characterized by any of the following: Exertion dyspnea, recurrent chest infections, growth failure, finger clubbing, and chest deformity associated with radiographic features of bronchiectasis on chest radiograph or chest tomography reported by a pediatric radiologist. Patients with cystic fibrosis were excluded from the study. Results: Of 337 children seen at the respiratory clinic during the study period, 58 (17.2%) had bronchiectasis that was diagnosed at a mean age of 34 months (standard deviation 26), and 32 (55.0%) were female. The most common causes of bronchiectasis were post-infectious 25 (43.1%), and underlying immunodeficiencies 19 (32.8%), including 16/58 (27.6%) who were living with human immunodeficiency virus (HIV) and 3 (5.1%) with primary immunodeficiency. Other causes included aspiration syndrome 8 (13.8%) and anatomical abnormalities 4 (6.9%). Of the participants with post-infectious bronchiectasis, tuberculosis (TB) was the most common organism isolated 16 (64.0%), and most common in children living with HIV (11/16, 68.8%). Cough was common in 48 (82.8%), with wet cough being predominant in 41 (85.4%), course crepitations were found in 37 (63.8%), hyperinflation in 24 (41.4%), finger clubbing in 21 (36.2%), wheeze in 16 (29.3%), and exertional dyspnea in 7 (12.0%). Conclusion: Bronchiectasis is common in South African children, usually resulting from previous pneumonia episodes, with TB being the most common infective cause. The importance of early diagnosis and treatment of underlying causes, especially infectious diseases in low-middle-income settings, to prevent bronchiectasis is highlighted.

A Global Perspective on Transition Models for Pediatric to Adult Cystic Fibrosis Care: What Has Been Made So Far?

Interest in the transition of care for cystic fibrosis (CF) patients has grown significantly over time, driven by advancements in treatment that have extended life expectancy. As more CF patients survive into adulthood, the need for structured transition strategies has become a priority for healthcare systems worldwide. Transition programs for CF differ globally, reflecting varying resources and healthcare systems. In North America, the US CF Foundation has fostered adult care since the 1990s, with accreditation standards mandating adult programs and structured transition guidelines, exemplified by the CF RISE program for gradual responsibility shifts. Canada integrates US-inspired models, emphasizing national advocacy and outcomes evaluation. In Europe, approaches varies widely; the UK leads with structured programs like the Liverpool model and robust registry support, while France and Germany adopt multidisciplinary methods. In Australia and New Zealand, youth-centered policies prioritize early planning and access via telemedicine. In Asia, where CF is rare, transitions are less formalized, with some progress in countries like Japan and Turkey, though resource gaps and limited data tracking remain significant challenges. Despite varied approaches across countries, common barriers like resource limitations and psychological readiness continue to challenge successful transitions. Highlighting the importance of centralized, well-coordinated transition programs, recent initiatives have focused on the implementation of national and international CF registries to enhance health outcomes and quality of life. This narrative review provides a global perspective on transition strategies developed across various healthcare systems for CF patients, identifying best practices, common challenges, and outcomes related to the continuity of care.

Pulmonary MRI in Newborns and Children.

Lung MRI is an important tool in the assessment and monitoring of pediatric and neonatal lung disorders. MRI can provide both similar and complementary image contrast to computed tomography for imaging the lung macrostructure, and beyond this, a number of techniques have been developed for imaging the key functions of the lungs, namely ventilation, perfusion, and gas exchange, through the use of free-breathing proton and hyperpolarized gas MRI. Here, we review the state-of-the-art in MRI methods that have found utility in pediatric and neonatal lung imaging, the structural and physiological information that can be gleaned from such images, and strategies that have been developed to deal with respiratory (and cardiac) motion, and other technological challenges. The application of lung MRI in neonatal and pediatric lung conditions, in particular bronchopulmonary dysplasia, cystic fibrosis, and asthma, is reviewed, highlighting our collective experiences in the clinical translation of these methods and technology, and the key current and future potential avenues for clinical utility of this methodology. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Changes in immunofluorescence staining during islet regeneration in a cystic fibrosis-related diabetes (CFRD) ferret model

ABSTRACT Background Knockout (KO) ferrets with the cystic fibrosis transmembrane conductance regulator (CFTR) exhibit distinct phases of dysglycemia and pancreatic remodeling prior to cystic fibrosis-related diabetes (CFRD) development. Following normoglycemia during the first month of life (Phase l), hyperglycemia occurs during the subsequent 2 months (Phase Il) with decreased islet mass, followed by a period of near normoglycemia (Phase Ill) in which the islets regenerate. We aimed to characterize islet hormone expression patterns across these Phases. Methods Immunofluorescence staining per islet area was performed to characterize islet hormone expression patterns in age matched CFTR KO and wild type (WT) ferrets, focusing on the first three phases. Results In Phase I, insulin staining intensity was higher in CF (p < 0.01) than WT but decreased in Phase III (p < 0.0001). Glucagon was lower in CF during Phases I and increased in Phase III, while proinsulin decreased (p < 0.0001) Phases II and III. CF sections showed lower proinsulin-to-insulin ratio in Phase I (p < 0.01) and in Phase III (p < 0.05) compared to WT. Conversely, glucagon-to-insulin ratio was lower in CF in Phase I (p < 0.0001) but increased in Phase III (p < 0.0001). Mender’s coefficient overlap showed higher overlap of insulin over proinsulin in CF sections in Phase II (p < 0.001) and Phase III (p < 0.0001) compared to WT. Mender’s coefficient rate was higher in CF sections during Phase II (p < 0.001). Conclusion CF ferret islets revealed significant immunofluorescent staining changes compared to WT during various phases of disease, providing insights into CRFD pathophysiology.

EMC3 is critical for CFTR function and calcium mobilization in the mouse intestinal epithelium.

Membrane proteins, such as the Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), play a crucial role in gastrointestinal functions and heath. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins' processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3ΔIEC). EMC3ΔIEC mice were viable but notable smaller compared to their wildtype littermates. While intestinal structure was generally maintained, EMC3ΔIEC crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3ΔIEC enteroids. CFTR-mediated organoid swelling in EMC3ΔIEC mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC.

The New Model of Prioritizing Orphan Drugs: The Case Study for Hemophilia, SMA, CF and MS

Background: Rare diseases, characterized by low prevalence and high complexity, pose significant challenges to health systems due to the uncertainty surrounding the best diagnostic methods and availability of effective treatments. Objectives: This study aimed to introduce new methods for prioritizing orphan drugs, with a pilot application to hemophilia, spinal muscular atrophy (SMA), cystic fibrosis (CF), and multiple sclerosis (MS). Methods: This quantitative research, conducted at Iran’s National Institute for Health Research from 2021 to 2023, employs multi-criteria decision-making models (MCDA) to evaluate the efficacy of health care technologies for "rare and hard to cure" diseases. A preliminary model was developed based on a pilot selection of seven medications, for which comprehensive data was extracted. The clinical efficacy was assessed using quality adjusted life years (QALY) as a metric. The model design was grounded on three critical factors: The annual cost of intervention per individual, the annual number of eligible patients for intervention, and the Proportion of expenses covered by the governmental budget. Additionally, the model incorporated various constraints and a regulatory coefficient, denoted as “w,” to enhance its robustness. Results: By running the model, the coverage of selected medications through model optimization, revealing the following percentages: Alemtuzumab (30%), ocrelizumab (30%), emicizumab (6%), dornase alfa (29%), tobramycin (2%), and spinraza (0.02%). Additionally, the corresponding monetary coverage in Iranian Rials is reported as follows: Alemtuzumab (27,144,000,000 IRR), ocrelizumab (109,645,200,000 IRR), emicizumab (17,360,490,000 IRR), dornase alfa (43,350,930,000 IRR), tobramycin (1,268,505,000 IRR), and spinraza (350,000,000 IRR). Conclusions: This model has tried to solve the shortcomings of the existing models regarding the prioritization of orphan drugs by combining different factors to improve access to essential treatments for rare diseases, although it can be generally asserted that no unique model can answer all policymakers’ questions regarding budget allocation of rare diseases and orphan products.

Newborn Screening for Six Primary Conditions in a Clinical Setting in Morocco

Newborn screening (NBS) represents an important public health measure for the early detection of specified disorders; such screening can prevent disability and death, not only from metabolic disorders but also from endocrine, hematologic, immune, and cardiac disorders. Screening for critical congenital conditions affecting newborns’ health is a great challenge, especially in developing countries such as Morocco, where NBS program infrastructure is lacking. In addition, the consanguinity rate is high in Morocco. This study aimed to demonstrate the feasibility of integrating NBS into a diagnostic laboratory for routine analysis. Six primary severe conditions were included: congenital hypothyroidism (CH), cystic fibrosis (CF), phenylketonuria (PKU), glucose-6-phosphate dehydrogenase deficiency (G6PD), congenital adrenal hyperplasia (CAH), and hemoglobinopathies. Methods: A retrospective investigation was carried out to examine the outcomes of NBS in Casablanca, Morocco. A total of 5511 newborn blood samples were collected via heel-prick sampling and tested for the above disorders. Most of the samples were collected within the third and sixth days of birth. The dried blood spots were analyzed via a quantitative immunofluorescence technique and isoelectric focusing. Results: A total of 72 newborns had one of the six pathological conditions. The most prevalent disorders were hemoglobinopathies, which were identified in 47 newborns (0.9%), with 29 having HbC carrier status (0.5%), 15 having Hb S carrier status (0.3%), and 3 having an Hb Bart’s carrier profile (0.05%). This was followed by G6PD deficiency, which was found to affect 16 newborns (0.32% of cases). CF was found in one case (0.02%), whereas five newborns (0.09%) tested positive for CAH. Additionally, two newborns (0.04%) tested positive for CH, and one newborn tested positive for PKU (0.02%). Conclusion: Our findings underscore the importance and success of NBS programs in preventing morbidity and mortality and improving the quality of life of affected neonates. The significant gap in data and research on these disorders within the Moroccan population highlights the urgent need to integrate NBS into routine practice in diagnostic laboratories across Morocco. This integration is crucial for enhancing the health and well-being of Moroccan newborns.

Ethical challenges of multiple organ transplant in cystic fibrosis.

Ethical challenges of multiple organ transplant in cystic fibrosis.