Pediatric Annals

Special Issue Article 

Review of Cystic Fibrosis

Danielle Goetz, MD; Clement L. Ren, MD, MBA

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF. CF is a lifelong, life-limiting disease, but an organized care center network with multidisciplinary approach, quality improvement initiatives, and research has led to markedly increased survival and development of adult CF care programs. In the past few years, medications that directly target the underlying CF defect have been developed, which should result in even greater survival benefits. [Pediatr Ann. 2019;48(4):e154–e161.]

Abstract

Cystic fibrosis (CF) is an autosomal recessive disease characterized by pancreatic insufficiency and chronic endobronchial airway infection. This latter feature results in progressive bronchiectasis and ultimately respiratory failure, which is the leading cause of death in patients with CF. Other complications include sinusitis, diabetes mellitus, bowel obstruction, hepatobiliary disease, hyponatremic dehydration, and infertility. Diagnosis of CF is confirmed by demonstration of elevated sweat chloride. Most cases of CF are identified through newborn screening (NBS). There are also infants with positive NBS but inconclusive diagnostic testing; a small proportion of these infants may go on to develop CF. CF is a lifelong, life-limiting disease, but an organized care center network with multidisciplinary approach, quality improvement initiatives, and research has led to markedly increased survival and development of adult CF care programs. In the past few years, medications that directly target the underlying CF defect have been developed, which should result in even greater survival benefits. [Pediatr Ann. 2019;48(4):e154–e161.]

Cystic fibrosis (CF) is the most common life-limiting genetic disease in the white population. There are approximately 30,000 people with CF living in the United States,1 and there are approximately 70,000 people with CF worldwide.1 CF predominantly affects people of white descent, but it can occur in people of all races and ethnicities (Table 1). When first described in the 1930s, most children with CF died in infancy, but due to therapeutic gains the median predicted age of survival increased from age 28 years in 1986 to age 47.7 years in 2016 (Figure 1), and now 52.7% of people with CF are adults.1

Cystic Fibrosis Incidence and Carrier Frequency by Race

Table 1.

Cystic Fibrosis Incidence and Carrier Frequency by Race

Predicted median survival age for cystic fibrosis, from 1986 to 2016, in 5-year increments. Reprinted with permission from the Cystic Fibrosis Foundation Patient Registry. ©2017 Cystic Fibrosis Foundation.

Figure 1.

Predicted median survival age for cystic fibrosis, from 1986 to 2016, in 5-year increments. Reprinted with permission from the Cystic Fibrosis Foundation Patient Registry. ©2017 Cystic Fibrosis Foundation.

Pathophysiology

Cystic fibrosis transmembrane conductance regulator (CFTR) plays a critical role in regulation of ion flow across cell membranes. Loss of CFTR expression or function affects multiple organ systems.2 Although CF is a multisystem disease, the primary organ systems affected are the pancreas and the lungs. Mucus obstruction of pancreatic ducts results in pancreatic insufficiency and malabsorption. In the lungs, loss of CFTR function results in abnormal mucus detachment, loss of the airway surface liquid layer, and impaired innate immunity. Other complications are shown in Table 2.

Clinical Manifestations of Cystic Fibrosis

Table 2.

Clinical Manifestations of Cystic Fibrosis

Genetics

CF is an autosomal recessive disease caused by mutations in the CFTR gene, which is located on chromosome 7q. More than 2,000 CFTR mutations has associated with a CF phenotype are known, but they are not all associated with disease liability. The Clinical and Functional Translation of CFTR project (known as CFTR2) is a worldwide effort to assign the disease liability to CFTR sequence variants.3 CFTR2 classifies mutations into four categories: (1) CF-causing, (2) mutations with varying clinical consequences (MVCC), (3) not CF-causing, and (4) unknown. Parents of children with CF are asymptomatic carriers. If both parents are carriers for a CFTR gene mutation, with each pregnancy there is a 25% chance of having a child with CF and a 50% chance of having a child who is a carrier. People who are carriers of CF have no manifestations of CF and no known survival benefit.

Diagnosis and Newborn Screening

Diagnosis of CF requires the presence of two known CF-causing mutations in addition to clinical symptoms or evidence of CFTR dysfunction.4 The CF Foundation diagnosis guidelines.4 recommend measurement of sweat chloride using quantitative pilocarpine iontophoresis testing (QPIT) as the first choice for assessment of CFTR function. Loss of CFTR function results in failure to resorb chloride from the sweat duct and elevated sweat chloride. A sweat chloride concentration of <30 mmol/L is normal; a concentration of ≥60 mmol/L is consistent with CF. Patients with intermediate concentrations (between 30 and 59 mmol/L) may have CF and should be evaluated at a specialized CF care center. Genetic testing identifies patients for mutation-specific therapies, but due to the aforementioned issues regarding assigning disease liability to CFTR mutations, it is not the preferred method of diagnostic testing. There are other methods to assess sweat electrolytes, such as sweat conductivity, but these tests are not as accurate as QPIT and should not be used to diagnosis CF.

Historically, the diagnosis of CF was considered based on suggestive clinical manifestations (Table 2). However, in recent years newborn screening (NBS) for CF has increasingly supplanted clinical diagnosis as the method by which CF is identified. Early diagnosis of CF through NBS is associated with improved nutritional status,5 pulmonary status, and survival.6 As of 2010, all states have been performing NBS for CF; in 2016, 62.4% of all US cases of CF were diagnosed by NBS.1 NBS algorithms differ by state, but all begin with measurement of immunoreactive trypsinogen (IRT), a pancreatic pro-enzyme increased in newborns with CF. Some newborns without CF can also have an elevated IRT, so a second step is required to increase NBS specificity. This consists of either a repeat IRT test 2 to 4 weeks later, genetic testing on the NBS bloodspot, or combined repeat IRT and DNA testing.7 Infants with persistently elevated IRT or one or more CFTR mutations are referred for sweat testing. Although CF can be presumptively diagnosed in NBS-positive infants with two CF-causing mutations, confirmation by sweat testing is still recommended.4 NBS infants with one identified mutation and a normal sweat test are CF carriers. DNA-based NBS algorithms detect many more CF carriers than affected people. Although some states (California and New York) perform sequencing of the entire CFTR coding region, most states only test for a panel of CFTR mutations. Because sequencing cannot detect deep intronic mutations or large deletions in the CFTR gene, a negative NBS or CFTR gene sequencing test does not rule out CF. A sweat test should be performed on any child who develops clinical findings concerning for CF (Table 2), even if NBS was normal.

In some cases, NBS for CF can result in the identification of infants with CFTR-related metabolic syndrome (CRMS), which is called CF screen positive, inconclusive diagnosis (CFSPID) in Europe. Infants with CRMS/CFSPID have an abnormal CF NBS but inconclusive diagnostic testing. This occurs because one of the two mutations is an MVCC, or because sweat chloride concentration is intermediate.8 The prevalence of CRMS/CFSPID depends on the NBS algorithm, but in the US approximately one infant with CRMS/CFSPID is identified for every five or six infants diagnosed with CF. Most people with CRMS/CFSPID will not develop CF. However, 10% to 20% develop Pseudomonas aeruginosa-positive throat cultures8 and 10% are subsequently diagnosed with CF.9 Pediatricians need to counsel patients and families after positive NBS and refer for sweat testing and evaluation at an accredited CF center. Children with CF are followed in their CF care center monthly during the first 6 months, every 2 months from age 6 to 12 months, and ≤3 months thereafter.10 Patients with CRMS/CFSPID should be seen at least once yearly to assess for symptoms or new CFTR variant information.11

Respiratory System Disease

Airway Microbiology

Chronic airway infection is the hallmark of CF lung disease. Bacterial colonization of the respiratory tract occurs within the first few days of life in CF infants. The most common organisms infecting infants and young children with CF are Staphylococcus aureus and Haemophilus influenzae (Figure 2). The prevalence of infection with P. aeruginosa increases with age, most notably by age 6 to 10 years.1 Over time, P. aeruginosa forms a biofilm leading to chronic infection and worse outcomes.12 For this reason, the standard of care at CF centers is to perform quarterly surveillance for P. aeruginosa acquisition and eradicate it before biofilm formation.13 Methicillin-resistant Staphylococcus aureus (MRSA) is found in 30% of CF patients, similar to community carrier rates. MRSA acquisition has also been associated with worse clinical outcomes, although the data surrounding this issue are not as robust as for P. aeruginosa.14 Eradication therapy for MRSA is currently not recommended. Other organisms cultured from CF sputum include gram-negative bacteria such as Stenotrophomonas maltophila, Achromobacter species, and Burkholderia cepacia (which can rarely be associated with B. cepacia syndrome with severe, rapid decline in pulmonary status). Other organisms include atypical Mycobacterium (non-tuberculous mycobacteria such as M. abscessus)15 and Aspergillus fumigatus, which does not usually cause primary infection but is associated with allergic bronchopulmonary aspergillosis (ABPA). ABPA is characterized by elevated serum immunoglobulin E, reduced lung function, and increased respiratory symptoms.13

Prevalence of respiratory microorganisms by age cohort in 2016. MDR-PA, multidrug-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus. Reprinted with permission from the Cystic Fibrosis Foundation Patient Registry. ©2017 Cystic Fibrosis Foundation.

Figure 2.

Prevalence of respiratory microorganisms by age cohort in 2016. MDR-PA, multidrug-resistant Pseudomonas aeruginosa; MRSA, methicillin-resistant Staphylococcus aureus. Reprinted with permission from the Cystic Fibrosis Foundation Patient Registry. ©2017 Cystic Fibrosis Foundation.

Lung Disease

The CFTR protein defect leads to defective secretion of chloride and bicarbonate across the CFTR channel and excessive sodium absorption through the epithelial sodium channel, which results in thick viscous mucus, impaired mucociliary clearance, and airway obstruction.16 Small airway obstruction causes hyperinflation, and decreased mucus clearance results in inflammation, infection, and ultimately bronchiectasis (dilated airways).16 Although bronchiectasis and the extent of disease may not be evident on plain chest radiograph, they are readily detected on chest computed tomography (Figure 3). Signs of pulmonary involvement are present early in CF. Infant pulmonary function tests are abnormal by age 6 months and bronchiectasis is present in 29% of children with CF by age 3 years.17,18 These lung findings have occurred despite NBS diagnosis, suggesting that traditional pulmonary therapies are inadequate in preventing progression of CF lung disease.

Chest imaging in cystic fibrosis. (A) Chest radiograph showing hyperinflation, bronchial wall thickening, and mucus plugging in a child with cystic fibrosis. (B) Chest computed tomography in a different child with cystic fibrosis demonstrating bronchiectasis bilaterally (although worse on the right side), with signet-ring signs (cross-section of airways are bigger than associated bronchial ateries) (black arrows) as well as tram-tracking (white arrows).

Figure 3.

Chest imaging in cystic fibrosis. (A) Chest radiograph showing hyperinflation, bronchial wall thickening, and mucus plugging in a child with cystic fibrosis. (B) Chest computed tomography in a different child with cystic fibrosis demonstrating bronchiectasis bilaterally (although worse on the right side), with signet-ring signs (cross-section of airways are bigger than associated bronchial ateries) (black arrows) as well as tram-tracking (white arrows).

CF pulmonary exacerbations (PEx) are episodes of worsening respiratory status and are characterized by increased respiratory rate, cough, sputum, hypoxemia, chest radiograph changes (infiltrates, mucus plugging, atelectasis) or chest examination findings (crackles, reduced breath sounds), decreased pulmonary function, work/school absenteeism, fatigue, and weight loss.19 PEx are negatively correlated with survival, quality-of-life outcomes, and lung function.19 CF patients are treated with oral or intravenous antibiotics and aggressive airway clearance for 10 to 21 days (or more) in the hospital or home.19

The cornerstones of CF lung disease treatment are airway clearance therapy (ACT), treatments to affect mucus/sputum rheology, and antibiotics. ACT options include manual chest percussion (chest physiotherapy), extrathoracic oscillatory vest compression, or intraluminal positive expiratory pressure devices. According to CFF recommendations, one type of ACT is not superior to another, but some type of ACT should be performed every day.20 The CF Foundation has published recommendations for use of chronic pulmonary therapies in CF (Table 3).21 Dornase alfa (recombinant human DNase) is an endonuclease; inhaled daily it reduces sputum viscosity. Inhaled hypertonic saline helps rehydrate the airway surface liquid layer and airway mucus. Both therapies improve lung function and reduce PEx rates. Antibiotics are used acutely to treat PEx or chronically in patients with chronic P. aeruginosa infection. For the latter, formulations of tobramycin and aztreonam have been specifically developed for inhalation. Chronic inhaled-antibiotic therapy improves lung function and reduces PEx rates. Tobramycin and aztreonam are inhaled on alternate months to reduce treatment-emergent drug resistance. Low-dose azithromycin has anti-inflammatory effects and improves lung function in patients with CF chronically infected with P. aeruginosa. High-dose ibuprofen is another anti-inflammatory therapy, but concerns about side effects have limited its use.

Chronic Pulmonary Therapy Recommendationsa

Table 3.

Chronic Pulmonary Therapy Recommendations

Advanced Lung Disease and Transplantation

Patients with CF progress to having bronchiectasis and respiratory failure. Hemoptysis occurs in 9% of patients with CF each year due to rupture of bronchial vessels accompanying bronchiectatic airways, which may require urgent bronchial artery embolization if massive.7,22 Pneumothorax is another recognized complication of CF, and it is best managed with chest thoracostomy, or more rarely with surgery.22 Bilateral lung transplantation is a potentially lifesaving procedure for chronic respiratory failure but it carries significant long-term risk.23 Decisions regarding lung transplantation are based on an assessment of a patient's severity of lung disease, social supports, and psychological assessment. Transplantation is not an ultimate cure for CF and patients require lifelong immunosuppressive therapy afterwards. The transplanted lungs are also subject to graft failure, usually due to bronchiolitis obliterans syndrome. Guidelines for consideration of lung transplantation are available.24

Pancreatic Insufficiency and Nutrition

Pancreatic insufficiency occurs in 85% of patients with CF and is the other major focus of CF care. The CFTR defect in the pancreatic ducts leads to enzymatic ductal destruction starting in-utero.25 Pancreatic insufficiency is diagnosed by decreased fecal pancreatic elastase. Historically, nutritional failure was the cause of death in infants with CF until pancreatic enzyme replacement therapy (PERT) and nutritional supplementation became available.26 The dose of PERT is usually empirically determined, but high doses (>3,000 IU/kg per meal) should be avoided because of the risk of fibrosing colonopathy. Although weight for age can usually be normalized in infants with CF using PERT, length remains lower than in unaffected infants;27 this may be due to reduced insulin-like growth factor-1 secretion in infants with CF.

There is a strong association between nutritional status and clinical outcomes in CF. Patients who have weight-for-length ≥50th percentile as infants or toddlers have improved lung function compared to those with weight-for-length <50th percentile.28 Nutritional status at age 3 years predicts lung function at age 6 years.29 Better nutritional status in childhood is associated with improved survival.30 For these reasons, the CF Foundation has set a goal that the body mass index (BMI) of every patient with CF should be ≥50th percentile.27 Nutritional supplementation via oral or gastrostomy tube feedings may be needed in patients who fail to maintain adequate growth near or above the 50%th percentile of weight for length or BMI.13 Vitamin deficiency (especially for the fat-soluble vitamins A, D, E, and K) can also occur (Table 4), and patients with CF need additional fat-soluble vitamin supplementation.

Fat-Soluble Vitamin Deficiencies in Cystic Fibrosis

Table 4.

Fat-Soluble Vitamin Deficiencies in Cystic Fibrosis

Gastrointestinal Disease

Gastrointestinal complications are extremely common in patient with CF.25,26 Meconium ileus occurs in 10% to 20% of newborns with CF. Although mild cases of MI can be treated conservatively, most cases require surgery. Distal intestinal obstructive syndrome due to intestinal dysmotility and inflammation can lead to bowel obstruction in the CF ileocecum, with colicky abdominal pain, distension, and palpable mass in the right lower quadrant. Medical management includes intravenous hydration, oral polyethylene glycol, or enema with diatrizoate meglumine and diatrizoate sodium solution. Surgery is a last resort. Constipation, which occurs in the colon and not the ileum, is also common in CF and can be treated with osmotic laxatives. Rectal prolapse is associated with constipation. Recurrent pancreatitis occurs in 10% of pancreatic-sufficient patients. Hepatobiliary disease occurs with increased incidence in patients with CF. Cirrhosis, with portal hypertension leading to esophageal varices and splenomegaly, is present in 5% to 15% patients, and may necessitate liver transplant. Other gastrointestinal conditions that occur more frequently in the CF population include intussusception, fatty liver disease, cholelithiasis, and colon cancer (in adults with CF).

Cystic Fibrosis-Related Diabetes

CF-related diabetes occurs in 30% of people with CF who are age 25 years or older but can also be present in younger patients with CF.13 Obstruction of the pancreatic ducts leads to fatty infiltration and destruction of the pancreas; those with pancreatic insufficiency are more likely to have islet cell malfunction. Annual screening for diabetes with an oral glucose tolerance test is recommended in all people with CF age 10 years or older, or in those with unexplained weight loss or pulmonary decline.13

Other Complications

Most CF patients have pansinusitis. Nasal polyposis occurs in children (18%) and adolescents (45%).7 Medical management includes saline irrigation and nasal steroids; sinus surgery may be indicated as well. Hyponatremic hypochloremic metabolic alkalosis and dehydration occur due to excessive loss of sodium chloride in sweat. CF causes infertility in 98% of men due to azoospermia and congenital bilateral absence of the vas deferens.13 Women are generally fertile, but men with one mutation (carriers) may have infertility.13

Unique Challenges

Psychosocial and Mental Health

Because CF is a chronic, life-shortening disease, depression and anxiety are more prevalent in both patients and caregivers. The CFF has recommended annual screening for these disorders in patients and caregivers.31 Screening and treatment are facilitated by mental health coordinators on the CF multidisciplinary team, who may be social workers, psychologists, or other professionals.

Transition to Adult Programs

Patients with CF are living longer and the availability of adult programs at which adults can receive their CF care is essential. It is helpful if the pediatric center and adult center have a transition process for young adults.

Recent Advances in CF Treatment and Precision Medicine

The most significant advance in CF therapeutics in the past several years has been the development of CFTR modulators, which are small molecules taken orally that partially restore CFTR function.32 Currently available CFTR modulators include potentiators (which increase function of CFTR expressed on the cell surface) and correctors (which increase CFTR surface expression). Ivacaftor is a potentiator approved by the US Food and Drug Administration that improves CFTR function and is effective in patients whose mutations result in surface protein expression but no ion conductance.21 Approximately 10% of patients with CF in the US have an ivacaftor-responsive CFTR mutation. The most common CFTR mutation in the CF population in the US is F508del; approximately 46% of patients with CF in the US are F508del homozygous and another 41% are compound heterozygous. The F508del mutation results in protein misfolding and decreased ion conductance. Because of the misfolding, F508del-CFTR is not expressed on the cell surface, so ivacaftor alone is insufficient to restore CFTR function in patients with CF with the F508del mutation. Lumacaftor and tezacaftor are correctors, which partially “correct” the folding defect in F508del, resulting in a small amount of surface protein expression. Combining either of these compounds with ivacaftor improves lung function and reduces PEx rates in F508del homozygous patients. Other potentiator/corrector combinations are currently under investigation. If proven effective, these newer compounds will lead to availability of CFTR modulator therapy for 90% to 95% of patients with CF in the US by 2021.

Care Center Network

The CFF established a Care Center Network in 1961 that now consists of more than 150 accredited CF centers in the US.33 The model of care is a multidisciplinary team that coordinates care. CF centers have regular site visits and oversight by the CF Foundation. To maintain accreditation, CF centers must meet specific standards based on the size of their patient population for the numbers of physicians, program coordinators (nurse practitioners, physician assistants, or nurses), social workers, nutritionists, and respiratory therapists and adhere to quality standards for sweat test collection and analysis and CF microbiology. The CF center must have a full spectrum of specialists with CF expertise (eg, otolaryngology). An active quality improvement program is also required.33

Summary

CF is an autosomal recessive disease whose main clinical features are pancreatic insufficiency and chronic endobronchial infection. Most CF patients are diagnosed via NBS, which also identifies many CF carriers and patients with CRMS/CFSPID. Current CF treatment focuses on nutrition support, PERT, ACT, and management of CF airway infections. CFTR modulators treat the underlying defect in CF and are revolutionizing CF care. There is the potential that in the next few years, early diagnosis of CF through NBS and treatment with CFTR modulators will prevent the progression of CF lung disease.

References

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Cystic Fibrosis Incidence and Carrier Frequency by Race

Race Incidence Carrier Frequencya
White 1:3,200 1/29
Black 1:15,000 1/65
Hispanic 1:10,000–1:14,000 1/46
Asian 1: 35,000 1/90

Clinical Manifestations of Cystic Fibrosis

Ears, Nose, Throat Lungs/Airways Pancreas Gastrointestinal Genitourinary Other
Pansinusitis Chronic sinusitis Polyps Cough ± sputum production Recurrent bronchitis or pneumonia Airway obstruction Bronchial reactivity Bronchiectasis Hemoptysis Pneumothorax Steatorrhea (pancreatic insufficiency) Cystic fibrosis-related diabetes Pancreatitis (in pancreatic-sufficient patients) Fat-soluble vitamin deficiency Constipation (rectal prolapse) Increase gastroesophageal reflux, intussusception, cholelithiasis, appendicitis Distal intestinal obstructive syndrome Meconium ileus Cirrhosis/portal hypertension/liver failure/prolonged neonatal jaundice Meconium ileus Male infertility (may be present in carriers) Congenital bilateral absence of the vas deferens Nephrolithiasis Digital clubbing Hyponatremic, hypochloremic dehydration (metabolic alkalosis) Sweat chloride ≥60 mmol/L Early aquagenic wrinkling of the skin Osteoporosis (vitamin D deficiency) Arthritis Vasculitis Hemolysis (vitamin E deficiency) Anxiety and depression

Chronic Pulmonary Therapy Recommendationsa

Therapy Recommendation and Goal
High-dose ibuprofen (anti-inflammatory) (need adequate serum levels) Recommended for children age ≥6 years (insufficient evidence for adults)   To slow progression of lung disease and prevent decline in lung function
Azithromycin (anti-inflammatory) (do not use if sputum is positive for atypical mycobacteria) With chronic Pseudomonas aeruginosa: recommended age ≥6 years   To improve lung function and decrease exacerbations Without chronic P. aeruginosa: consider if age ≥6 years   To decrease exacerbations
Inhaled tobramycin (anti-infective) Inhaled aztreonam (anti-infective) With chronic P. aeruginosa: recommended age ≥6 years To improve lung function and quality of life, and decrease exacerbations Without chronic P. aeruginosa: recommended age ≥6 years To improve lung function and quality of life
DNAse (mucolytic) Recommended age ≥6 years To improve lung function and decrease exacerbations
Hypertonic saline (mucolytic) Recommended age ≥6 years To improve lung function and quality of life, and decrease exacerbations
Ivacaftor (cystic fibrosis transmembrane potentiator) Recommended age ≥6 years if at least one copy of G551D mutation To improve lung function and quality of life, and decrease exacerbations

Fat-Soluble Vitamin Deficiencies in Cystic Fibrosis

Vitamin Manifestations of Deficiency
A Night blindness Conjunctival and corneal xerosis Follicular hyperkeratosis
D Nutritional rickets Osteopenia leads to predisposition to fractures Osteoporosis
E Peripheral neuropathy Myopathy Hemolysis
K Coagulopathy (increased prothrombin time) Petechiae or purpura
Authors

Danielle Goetz, MD, is a Clinical Associate Professor of Pediatrics, Division of Pediatric Pulmonology, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo. Clement L. Ren, MD, MBA, is a Professor of Clinical Pediatrics, Division of Pediatric Pulmonology, Department of Pediatrics, Indiana University School of Medicine.

Address correspondence to Danielle Goetz, MD, UBMD Pediatrics, 1001 Main Street, 5th Floor Conventus Building, Buffalo, NY 14203; email: dgoetz@upa.chob.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20190327-01

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