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Introduction: The rapid development of artificial intelligence (AI) in healthcare has exposed the unmet need for growing a multidisciplinary workforce that can collaborate effectively in the learning health systems. Maximizing the synergy among multiple teams is critical for Collaborative AI in Healthcare. Methods: We have developed a series of data, tools, and educational resources for cultivating the next generation of multidisciplinary workforce for Collaborative AI in Healthcare. We built bulk-natural language processing pipelines to extract structured information from clinical notes and stored them in common data models. We developed multimodal AI/machine learning (ML) tools and tutorials to enrich the toolbox of the multidisciplinary workforce to analyze multimodal healthcare data. We have created a fertile ground to cross-pollinate clinicians and AI scientists and train the next generation of AI health workforce to collaborate effectively. Results: Our work has democratized access to unstructured health information, AI/ML tools and resources for healthcare, and collaborative education resources. From 2017 to 2022, this has enabled studies in multiple clinical specialties resulting in 68 peer-reviewed publications. In 2022, our cross-discipline efforts converged and institutionalized into the Center for Collaborative AI in Healthcare. Conclusions: Our Collaborative AI in Healthcare initiatives has created valuable educational and practical resources. They have enabled more clinicians, scientists, and hospital administrators to successfully apply AI methods in their daily research and practice, develop closer collaborations, and advanced the institution-level learning health system.
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Cough is an important symptom in children with acute and chronic respiratory disease. Daily cough is common in Cystic Fibrosis (CF) and increased cough is a symptom of pulmonary exacerbation. To date, cough assessment is primarily subjective in clinical practice and research. Attempts to develop objective, automatic cough counting tools have faced reliability issues in noisy environments and practical barriers limiting long-term use. This single-center pilot study evaluated usability, acceptability and performance of a mechanoacoustic sensor (MAS), previously used for cough classification in adults, in 36 children with CF over brief and multi-day periods in four cohorts. Children whose health was at baseline and who had symptoms of pulmonary exacerbation were included. We trained, validated, and deployed custom deep learning algorithms for accurate cough detection and classification from other vocalization or artifacts with an overall area under the receiver-operator characteristic curve (AUROC) of 0.96 and average precision (AP) of 0.93. Child and parent feedback led to a redesign of the MAS towards a smaller, more discreet device acceptable for daily use in children. Additional improvements optimized power efficiency and data management. The MAS's ability to objectively measure cough and other physiologic signals across clinic, hospital, and home settings is demonstrated, particularly aided by an AUROC of 0.97 and AP of 0.96 for motion artifact rejection. Examples of cough frequency and physiologic parameter correlations with participant-reported outcomes and clinical measurements for individual patients are presented. The MAS is a promising tool in objective longitudinal evaluation of cough in children with CF.
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BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.
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Aminofenóis , Agonistas dos Canais de Cloreto , Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Quinolonas , Humanos , Fibrose Cística/tratamento farmacológico , Aminofenóis/administração & dosagem , Aminofenóis/farmacocinética , Aminofenóis/efeitos adversos , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Quinolonas/efeitos adversos , Lactente , Masculino , Feminino , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/farmacocinética , Agonistas dos Canais de Cloreto/efeitos adversos , Recém-Nascido , Resultado do TratamentoRESUMO
Eccrine sweat can serve as a source of biomarkers for assessing physiological health and nutritional balance, for tracking loss of essential species from the body and for evaluating exposure to hazardous substances. The growing interest in this relatively underexplored class of biofluid arises in part from its non-invasive ability for capture and analysis. The simplest devices, and the only ones that are commercially available, exploit soft microfluidic constructs and colorimetric assays with purely passive modes of operation. The most sophisticated platforms exploit batteries, electronic components and radio hardware for inducing sweat, for electrochemical evaluation of its content and for wireless transmission of this information. The work reported here introduces a technology that combines the advantages of these two different approaches, in the form of a cost-effective, easy-to-use device that supports on-demand evaluation of multiple biomarkers in sweat. This flexible, skin-interfaced, miniaturized system incorporates a hydrogel that contains an approved drug to activate eccrine sweat glands, electrodes and a simple circuit and battery to delivery this drug by iontophoresis through the surface of the skin, microfluidic channels and microreservoirs to capture the induced sweat, and multiple colorimetric assays to evaluate the concentrations of chloride, zinc, and iron. As demonstrated in healthy human participants monitored before and after a meal, such devices yield results that match those of traditional laboratory analysis techniques. Clinical studies that involve cystic fibrosis pediatric patients illustrate the use of this technology as a simple, painless, and reliable alternative to traditional hospital systems for measurements of sweat chloride.
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Técnicas Biossensoriais , Suor , Humanos , Criança , Cloretos , Colorimetria , BiomarcadoresRESUMO
BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. CLINICALTRIALS: GOV: NCT03219164.
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Fibrose Cística , Infecções por Pseudomonas , Adolescente , Humanos , Criança , Aztreonam/efeitos adversos , Pseudomonas aeruginosa , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Administração por Inalação , Antibacterianos/uso terapêutico , Infecções por Pseudomonas/diagnóstico , Infecções por Pseudomonas/tratamento farmacológico , Resultado do TratamentoRESUMO
Background: Insufficient recruitment of groups underrepresented in medical research threatens the generalizability of research findings and compounds inequity in research and medicine. In the present study, we examined barriers and facilitators to recruitment of underrepresented research participants from the perspective of clinical research coordinators (CRCs). Methods: CRCs from one adult and one pediatric academic medical centers completed an online survey in April-May 2022. Survey topics included: participant language and translations, cultural competency training, incentives for research participation, study location, and participant research literacy. CRCs also reported their success in recruiting individuals from various backgrounds and completed an implicit bias measure. Results: Surveys were completed by 220 CRCs. CRCs indicated that recruitment is improved by having translated study materials, providing incentives to compensate participants, and reducing the number of in-person study visits. Most CRCs had completed some form of cultural competency training, but most also felt that the training either had no effect or made them feel less confident in approaching prospective participants from backgrounds different than their own. In general, CRCs reported having greater success in recruiting prospective participants from groups that are not underrepresented in research. Results of the implicit bias measure did not indicate that bias was associated with intentions to approach a prospective participant. Conclusions: CRCs identified several strategies to improve recruitment of underrepresented research participants, and CRC insights aligned with insights from research participants in previous work. Further research is needed to understand the impact of cultural competency training on recruitment of underrepresented research participants.
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Newborn screening for cystic fibrosis was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive newborn screening tests persist. Through evaluation of national patient registry data, we determined that late initiation of cystic fibrosis care is associated with poorer long-term nutritional outcomes.
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Fibrose Cística , Recém-Nascido , Lactente , Humanos , Fibrose Cística/diagnóstico , Triagem Neonatal , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diagnóstico Tardio , Mutação , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2 [95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).
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Fibrose Cística , Adulto , Criança , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Alelos , Agonistas dos Canais de Cloreto/uso terapêutico , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and effective in people with cystic fibrosis (CF) aged ⩾6 years with at least one F508del-CFTR allele but has not been studied in younger children. Objectives: To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ELX/TEZ/IVA in children with CF aged 2-5 years. Methods: In this phase 3, open-label, two-part study (parts A and B), children weighing <14 kg (on Day 1) received ELX 80 mg once daily (qd), TEZ 40 mg qd, and IVA 60 mg each morning and 59.5 mg each evening; children weighing ⩾14 kg received ELX 100 mg qd, TEZ 50 mg qd, and IVA 75 mg every 12 hours. Measurements and Main Results: The primary endpoints for part A (15-d treatment period) were pharmacokinetics and safety and tolerability. For part B (24-wk treatment period), the primary endpoint was safety and tolerability; secondary endpoints included pharmacokinetics and absolute changes from baseline in sweat chloride concentration and lung clearance index2.5 (LCI2.5, defined as the number of lung turnovers required to reduce the end tidal N2 concentration to 2.5% of its starting value) through Week 24. Analysis of pharmacokinetic data from 18 children enrolled in part A confirmed the appropriateness of the part B dosing regimen. In part B, 75 children (F508del/minimal function genotypes, n = 52; F508del/F508del genotype, n = 23) were enrolled and dosed. Seventy-four children (98.7%) had adverse events, which were all mild (62.7%) or moderate (36.0%) in severity. The most common adverse events were cough, fever, and rhinorrhea. Decreases in sweat chloride concentration (-57.9 mmol/L; 95% confidence interval [CI], -61.3 to -54.6; n = 69) and LCI2.5 (-0.83 U; 95% CI, -1.01 to -0.66; n = 50) were observed from baseline through Week 24. Mean body mass index was within the normal range at baseline and remained stable at Week 24. Conclusions: In this open-label study in children 2-5 years of age, ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with that observed in older age groups, and led to clinically meaningful reductions in sweat chloride concentration and LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT04537793).
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Fibrose Cística , Humanos , Criança , Idoso , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Cloretos , Alelos , Agonistas dos Canais de Cloreto/uso terapêutico , Aminofenóis , Benzodioxóis , MutaçãoRESUMO
Translational research should examine racism and bias and improve health equity. We designed and implemented a course for the Master of Science in Clinical Investigation program of the Northwestern University Clinical and Translational Sciences Institute. We describe curriculum development, content, outcomes, and revisions involving 36 students in 2 years of "Anti-Racist Strategies for Clinical and Translational Science." Ninety-six percent of students reported they would recommend the course. Many reported changes in research approaches based on course content. A course designed to teach anti-racist research design is feasible and has a positive short-term impact on learners.
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Exclusion of special populations (older adults; pregnant women, children, and adolescents; individuals of lower socioeconomic status and/or who live in rural communities; people from racial and ethnic minority groups; individuals from sexual or gender minority groups; and individuals with disabilities) in research is a pervasive problem, despite efforts and policy changes by the National Institutes of Health and other organizations. These populations are adversely impacted by social determinants of health (SDOH) that reduce access and ability to participate in biomedical research. In March 2020, the Northwestern University Clinical and Translational Sciences Institute hosted the "Lifespan and Life Course Research: integrating strategies" "Un-Meeting" to discuss barriers and solutions to underrepresentation of special populations in biomedical research. The COVID-19 pandemic highlighted how exclusion of representative populations in research can increase health inequities. We applied findings of this meeting to perform a literature review of barriers and solutions to recruitment and retention of representative populations in research and to discuss how findings are important to research conducted during the ongoing COVID-19 pandemic. We highlight the role of SDOH, review barriers and solutions to underrepresentation, and discuss the importance of a structural competency framework to improve research participation and retention among special populations.
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During the year 2019, research and case reports or series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the second section, focusing specifically on new research related to pulmonary disease and infections. Additional sections will concentrate on CF transmembrane conductance regulator modulators and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews.
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Fibrose Cística , Humanos , Fibrose Cística/complicações , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Transdução de SinaisRESUMO
During the year 2019, numerous research studies and other reports were published that are interesting and instructive to professionals who care for people with cystic fibrosis (CF) and their families.⯠This report is the third of 3 CF year in review articles and focuses on the multisystem manifestations of CF care. Previous articles have addressed cystic fibrosis transmembrane regulator modulators and reports on CF pulmonary disease and airway infections. It is an exciting time to be involved in care and research that aims to improve care for people with CF and their families.
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Fibrose Cística , Humanos , Fibrose Cística/terapia , Regulador de Condutância Transmembrana em Fibrose Cística , TóraxRESUMO
BACKGROUND: Newborn screening (NBS) algorithms for cystic fibrosis (CF) vary in the United State of America and include different cystic fibrosis transmembrane conductance regulator (CFTR) variants. CFTR variant distribution varies among racial and ethnic groups. OBJECTIVE: Our objectives were to identify differences in detection rate by race and ethnicity for CFTR variant panels, identify each US state detection rate for CFTR variant panels, and describe the rate of false-negative NBS and delayed diagnoses by race and ethnicity. METHODS: This is a cross-sectional analysis of the detection rate of at least 1 CFTR variant for seven panels by race and ethnicity in genotyped people with CF (PwCF) or CFTR-related metabolic syndrome (CRMS)/CFTR-related disorders in CF Foundation Patient Registry (CFFPR) in 2020. We estimated the case detection rate of CFTR variant panels by applying the detection rate to Census data. Using data from CFFPR, we compared the rate of delayed diagnosis or false-negative NBS by race and ethnicity. RESULTS: For all panels, detection of at least 1 CFTR variant was highest in non-Hispanic White PwCF (87.5%-97.0%), and lowest in Black, Asian, and Hispanic PwCF (41.9%-93.1%). Detection of at least 1 CFTR variant was lowest in Black and Asian people with CRMS/CFTR-related disorders (48.4%-64.8%). States with increased racial and ethnic diversity have lower detection rates for all panels. Overall, 3.8% PwCF had a false-negative NBS and 11.8% had a delayed diagnosis; Black, Hispanic, and mixed-race PwCF were overrepresented. CONCLUSION: CFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false-negative NBS, delayed diagnosis, and likely health disparities.
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Fibrose Cística , Triagem Neonatal , Recém-Nascido , Humanos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Estudos Transversais , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Fibrose Cística/metabolismo , Genótipo , MutaçãoRESUMO
OBJECTIVE: We evaluated whether implementation of cystic fibrosis (CF) newborn screening (NBS) leads to equitable timeliness of initial evaluation. We compared age at first event (AFE, age at sweat test, encounter and/or care episode) between infants categorized as Black/African American, American Indian/ Native Alaskan, Asian, and/or Hispanic and/or other (Group 1) to White and not Hispanic infants (Group 2). METHODS: This retrospective cohort study from the Cystic Fibrosis Foundation Patient Registry (CFFPR) included infants born 2010-2018. Race and ethnicity categories followed US Census definitions. The primary outcome was AFE; the secondary outcome was weight for age (WFA) z-score averaged 12 to < 24 months. We compared distributions by Wilcoxon rank-sum test and proportions by Chi-square or Fisher's exact tests. A nested cohort study used a linear mixed effects model of variables that affect WFA, chosen a priori, to evaluate associations with 1-year WFA z-score. RESULTS: Among 6354 infants, 21% were in Group 1. Group 1 median AFE was 31 days (IQR 19, 49) and Group 2 was 22 days (IQR 14,36) (p< .001). Median WFA z-score at 1-2 years was lower in Group 1. In 3017 infants with complete data on variables of interest, AFE, Black race, CFTR variant class I-III, prematurity and public insurance were associated with lower 1-year WFA z-score. CONCLUSIONS: Differences in AFE for infants with CF from historically marginalized groups may exacerbate long standing health disparities. We speculate that inequitable identification of CFTR gene variants and/or bias may influence timeliness of evaluation after an out-of-range NBS.
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Fibrose Cística , Recém-Nascido , Lactente , Humanos , Fibrose Cística/diagnóstico , Triagem Neonatal , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Estudos Retrospectivos , Estudos de CoortesRESUMO
Cystic fibrosis (CF) newborn screening (NBS) was universally adopted in 2009 in the United States. Variations in NBS practices between states may impact the timing of diagnosis and intervention. Quantitative metrics can provide insight into NBS programs (NBSP), but the nuances cannot be elucidated without additional feedback from programs. This study was designed to determine facilitators and barriers to timely diagnosis and intervention following NBS for CF. The median age at the first CF event for infants with CF within each state was used to define early and late states (n = 15 per group); multiple CF centers were invited in states with more than two CF centers. Thirty states were eligible, and 61 NBSP and CF centers were invited to participate in structured interviews to determine facilitators and barriers. Once saturation of themes was reached, no other interviews were conducted. Forty-five interviews were conducted (n = 16 early CF center, n = 12 late CF center, n = 11 early NBSP, and n = 6 late NBSP). Most interviewees reported good communication between CF centers and NBSP. Communication between primary care providers (PCPs) and families was identified as a challenge, leading to delays in referral and subsequent diagnosis. The misperception of low clinical risk in infants from racial and ethnic minority groups was a barrier to early diagnostic evaluation for all groups. NBSP and CF centers have strong relationships. Early diagnosis may be facilitated through more engagement with PCPs. Quality improvement initiatives should focus on continuing strong partnerships between CF centers and NBS programs, improving education, communication strategies, and partnerships with PCPs, and improving CF NBS timeliness and accuracy.
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Rationale: Previous phase 3 trials showed that treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ⩾2 years with cystic fibrosis (CF) homozygous for the F508del mutation in CFTR (CF transmembrane conductance regulator) (F/F genotype). Objectives: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. Methods: This open-label, phase 3 study consisted of two parts (part A [n = 14] and part B [n = 46]) in which two cohorts were enrolled on the basis of age (cohort 1, 18 to <24 mo; cohort 2, 12 to <18 mo). For the 15-day treatment period in part A, the lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from part A were used to determine dose-based weight boundaries for part B (24-wk treatment period). Measurements and Main Results: The primary endpoint of part A was pharmacokinetics, and the primary endpoint for part B was safety and tolerability. Secondary endpoints for part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from part A confirmed the appropriateness of part B dosing. In part B, 44 children (95.7%) had adverse events, which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of CF, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was -29.1 mmol/L (95% confidence interval, -34.8 to -23.4 mmol/L). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation, such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin, were observed. Conclusions: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype, with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registered with www.clinicaltrials.gov (NCT03601637).
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Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Humanos , Aminofenóis , Aminopiridinas , Benzodioxóis , Agonistas dos Canais de Cloreto/uso terapêutico , Cloretos/análise , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Combinação de Medicamentos , Volume Expiratório Forçado , Mutação , LactenteRESUMO
PURPOSE: The electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements. METHODS: THEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items). RESULTS: Centers predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured VÌO2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., VÌO2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET. CONCLUSIONS: The survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application.