Outpatient Utilization of the RAM Cannula for Nasal Noninvasive Ventilation in Children.

Background: The RAM cannula® consists of nasal prongs that can be used to administer oxygen, continuous, and bilevel positive airway pressure therapies. Studies have reported the efficacy and utility of the RAM cannula in inpatients requiring noninvasive ventilation (NIV); however, there is limited literature on the use of the RAM cannula to provide NIV in the outpatient setting. Objectives: This study aimed to describe the clinical features and outcomes of children who used NIV via RAM cannula in the outpatient setting. Design: Retrospective review. Methods: We conducted a retrospective review of children treated with outpatient NIV via RAM cannula at our institution between January 2010 and March 2023. The analyzed data included age, diagnoses, indications for NIV, duration of RAM cannula use, complications, and outcomes at 6 months. Results: We identified 20 patients who used outpatient NIV via RAM cannula during the study period. The median age at initiation of NIV via RAM cannula was 5.8 months (IQR 2.4-9.9 months). Indications for NIV included sleep-related hypoventilation (15%), restrictive lung disease (25%), obstructive sleep apnea (45%), and chronic respiratory failure (50%), with 6 patients having ⩾2 indications for NIV. RAM cannula was utilized for inability to tolerate conventional NIV interfaces (80%), to alleviate dyspnea (60%), and to avoid tracheostomy (55%). Patients used NIV via RAM cannula for a median duration of 7.7 months (IQR 3.7-20.6 months). Patient outcomes included ongoing usage of RAM cannula (55%), changing to conventional NIV interfaces (15%) or oxygen (10%), weaning off respiratory support (5%), and death (15%). There were no complications related to using the RAM cannula. Conclusion: Our study demonstrates the utility of outpatient NIV via RAM cannula in children with a variety of diagnoses until clinical improvement or tolerance of conventional interfaces, and for avoidance of tracheostomy.

Cryoextraction via flexible bronchoscopy in children with tracheobronchial obstruction.

BACKGROUND: Cryoextraction via flexible bronchoscopy (FB) can be used to alleviate airway obstruction due to blood clots, casts, mucus, and foreign bodies. There is limited literature regarding the utility of cryoextraction to restore airway patency in critically ill children, especially on extracorporeal membrane oxygenation (ECMO). The aims of this study were to describe the clinical course and outcomes of children who underwent cryoextraction via FB. METHODS: A singlecenter retrospective review of children who underwent cryoextraction via FB between 2017 and 2021 was conducted. The analyzed data included diagnoses, indications for cryoextraction, respiratory support modalities, FB and chest imaging results, and outcomes. RESULTS: Eleven patients aged 3-17 years underwent a total of 33 cryoextraction sessions via FB. Patients required ECMO (n = 9) or conventional mechanical ventilation (CMV) for pneumonia, pulmonary hemorrhage, pulmonary embolism, asthma exacerbation, and cardiorespiratory failure following cardiac surgery. One patient underwent elective FB and cryoextraction for plastic bronchitis. Indications for cryoextraction included airway obstruction due to tracheobronchial thrombi (n = 8), mucus plugs (n = 1), or plastic bronchitis (n = 2). Cryoextraction via FB was performed on patients on ECMO (n = 9) and CMV (n = 2) with 6 patients requiring ≥3 cryoextraction sessions for airway obstruction. There were no complications related to cryoextraction. Patient outcomes included partial (n = 5) or complete (n = 6) restoration of airway patency with ECMO decannulation (n = 5) and death (n = 4) due to critical illness. CONCLUSIONS: Cryoextraction via FB is an effective intervention that can be utilized in critically ill children with refractory tracheobronchial obstruction to restore airway patency and to facilitate liberation from ECMO.

External airway splint placement for severe pediatric tracheobronchomalacia.

OBJECTIVE: To present external airway splinting with bioabsorbable airway supportive devices (ASD) for severe, life-threatening cases of pediatric tracheomalacia (TM) or tracheobronchomalacia (TBM). METHODS: A retrospective cohort was performed for 5 pediatric patients with severe TM or TBM who underwent ASD placement. Devices were designed and 3D-printed from a bioabsorbable material, polycaprolactone (PCL). Pre-operative planning included 3-dimensional airway modeling of tracheal collapse and tracheal suture placement using nonlinear finite element (FE) methods. Pre-operative modeling revealed that triads along the ASD open edges and center were the most effective suture locations for optimizing airway patency. Pediatric cardiothoracic surgery and otolaryngology applied the ASDs by suspending the trachea to the ASD with synchronous bronchoscopy. Respiratory needs were trended for all cases. Data from pediatric patients with tracheostomy and diagnosis of TM or TBM, but without ASD, were included for discussion. RESULTS: Five patients (2 Females, 3 Males, ages 2-9 months at time of ASD) were included. Three patients were unable to wean from respiratory support after vascular ring division; all three weaned to room air post-ASD. Two patients received tracheostomies prior to ASD placement, but continued to experience apparent life-threatening events (ALTE) and required ventilation with supraphysiologic ventilator settings. One patient weaned respiratory support successfully after ASD placement. The last patient died post-ASD due to significant respiratory co-morbidity. CONCLUSION: ASD can significantly benefit patients with severe, unrelenting tracheomalacia or tracheobronchomalacia. Proper multidisciplinary case deliberation and selection are key to success with ASD. Pre-operative airway modeling allows proper suture placement to optimally address the underlying airway collapse.

Ventilator change in children on home mechanical ventilation affected by the Philips respironics trilogy ventilator recall.

The Philips Respironics recall notification issued in June 2021 affected many of their positive airway pressure devices and mechanical ventilators including the Trilogy 100 and 200 ventilators that are often utilized in children using home positive pressure ventilation via tracheostomy (PPV-T). Optimal strategies to replace ventilators in children using home PPV-T affected by the Philips recall are unknown. We conducted a retrospective study of children using home PPV-T with recalled Trilogy ventilators who underwent inpatient ventilator change to non-recalled portable home ventilators (PHV) using our collaborative institutional protocol. During the study period, there were 40 children using PPV-T with recalled Trilogy ventilators and 19 patients underwent inpatient ventilator change either during an elective hospitalization (n = 8) or during an unscheduled or postoperative hospitalization (n = 11). The median duration of hospitalization for ventilator change was 2 days (interquartile range: 6 days) and generally 1 day for patients admitted solely for ventilator change. In children using PPV-T with recalled Trilogy ventilators, a systematic protocol collaborating with the patients, physicians, and durable medical equipment companies may optimize transition to nonrecalled PHVs.

Bronchoscopic interventions for plastic bronchitis in children without structural heart disease.

Plastic bronchitis (PB) is a rare and life-threatening complication encountered in several disease states that leads to airway obstruction by branching casts. PB is most often reported in children with cyanotic congenital heart disease where recurrence is common, and mortality is high. There is limited data on optimal management strategies or recurrence of non-structural heart disease-related PB in children. We describe the clinical features, management, and outcomes in our cohort of children with non-structural heart disease-related PB. Among the 12 identified patients, asthma was the most common (67%) diagnosis. Ventilatory requirements ranged from room air to one patient who required extracorporeal membrane oxygenation (ECMO). Most patients (92%) required bronchoscopy, and cryotherapy was successfully utilized in two patients to relieve refractory obstructive airway casts. All patients received chest physiotherapy, and 11 patients were treated with two or more medications. There was one mortality despite ECMO, and one-third had recurrent PB, all of whom had asthma.Conclusion: Asthma is a risk factor for recurrent PB. Bronchoscopic interventions including cryotherapy are safe and effective treatment options in patients with refractory PB. What is Known: • Plastic bronchitis is a rare but life-threatening cause of airway obstruction caused by branching casts that are generally reported in patients with congenital heart disease. What is New: • In children without structural heart disease, asthma is a risk factor for recurrent plastic bronchitis. Cryotherapy via bronchoscopy is a safe and effective intervention in patients with refractory plastic bronchitis.

Mortality and Outcomes of Pediatric Tracheostomy Dependent Patients.

Objective: To describe clinical factors associated with mortality and causes of death in tracheostomy-dependent (TD) children. Methods: A retrospective study of patients with a new or established tracheostomy requiring hospitalization at a large tertiary children's hospital between 2009 and 2015 was conducted. Patient groups were developed based on indication for tracheostomy: pulmonary, anatomic/airway obstruction, and neurologic causes. The outcome measures were overall mortality rate, mortality risk factors, and causes of death. Results: A total of 187 patients were identified as TD with complete data available for 164 patients. Primary indications for tracheostomy included pulmonary (40%), anatomic/airway obstruction (36%), and neurologic (24%). The median age at tracheostomy and duration of follow up were 6.6 months (IQR 3.5-19.5 months) and 23.8 months (IQR 9.9-46.7 months), respectively. Overall, 45 (27%) patients died during the study period and the median time to death following tracheostomy was 9.8 months (IQR 6.1-29.7 months). Overall survival at 1- and 5-years following tracheostomy was 83% (95% CI: 76-88%) and 68% (95% CI: 57-76%), respectively. There was no significant difference in mortality based on indication for tracheostomy (p = 0.35), however pulmonary indication for tracheostomy was associated with a shorter time to death (HR: 1.9; 95% CI: 1.04-3.4; p = 0.04). Among the co-morbid medical conditions, children with seizure disorder had higher mortality (p = 0.04). Conclusion: In this study, TD children had a high mortality rate with no significant difference in mortality based on indication for tracheostomy. Pulmonary indication for tracheostomy was associated with a shorter time to death and neurologic indication was associated with lower decannulation rates.

Recurrent apnoea and respiratory failure in an infant: congenital central hypoventilation syndrome with a novel PHOX2B gene variant.

A 20-day-old term infant presented with recurrent apnoea, lethargy and respiratory failure. Examination revealed episodes of apnoea and desaturation to 85% without any signs of respiratory distress requiring initiation of non-invasive positive pressure ventilation (NPPV). Capillary blood gas was indicative of respiratory acidosis and serum bicarbonate was elevated at 35 mmol/L. Chest radiograph, echocardiogram and evaluations for infectious aetiologies resulted normal. Due to inability to wean off NPPV with ensuing apnoea and desaturation, polysomnogram was performed and showed central and obstructive sleep apnoea, hypoxaemia and hypoventilation. Central apnoeas and hypoventilation were worse in non-rapid eye movement sleep. Paired-like homeobox 2B genetic studies showed a novel non-polyalanine repeat mutation (c.429+1G>A) establishing the diagnosis of congenital central hypoventilation syndrome (CCHS). Our case highlights the utility of polysomnography in the evaluation of term infants with apnoea. Although rare, clinicians should consider a diagnosis of CCHS in the evaluation of infants with apnoea and hypoventilation.

Heterogeneous Pulmonary Phenotypes in Filamin A Mutation-Related Lung Disease.

Background: Interstitial lung disease (ILD) has been recently reported in a few patients with pathogenic variants in the Filamin A (FLNA) gene with variable presentation and prognosis. This study evaluated the respiratory manifestations and clinical features in children with FLNA disease. Methods: We conducted a retrospective review of pediatric patients with variants in FLNA in a tertiary children's hospital. The clinical features, genotype, management, and outcomes were analyzed. Results: We identified 9 patients with variants in FLNA aged 15 months to 24 years, 4 females and 5 males. Six patients had abnormal chest imaging ranging from mild interstitial prominence to atelectasis, interstitial densities, and hyperinflation. Three patients with ILD presented during the neonatal period or early infancy with respiratory distress or respiratory failure requiring supplemental oxygen or assisted ventilation via tracheostomy. We report male twins with the same FLNA variant and lung disease, but different ages and clinical features at presentation eventually culminating in respiratory failure requiring assisted ventilation. All patients had FLNA variants identified by FLNA sequencing, had abnormal echocardiograms, and none of the patients underwent lung biopsy or lung transplantation. The outcomes were variable and could be as severe as chronic respiratory failure. Conclusion: The wide spectrum of respiratory manifestations and abnormal chest imaging in our study highlights the importance of evaluation for lung disease in patients with variants in FLNA. FLNA sequencing in suspected cases with ILD may obviate the need for a lung biopsy, prompt surveillance for progressive lung disease, and evaluation for associated clinical features.

An instructional definition and assessment rubric for bioinformatics instruction.

The lack of an instructional definition of bioinformatics delays its effective integration into biology coursework. Using an iterative process, our team of biologists, a mathematician/computer scientist, and a bioinformatician together with an educational evaluation and assessment specialist, developed an instructional definition of the discipline: Bioinformatics is "an interdisciplinary field that is concerned with the development and application of algorithms that analyze biological data to investigate the structure and function of biological polymers and their relationships to living systems." The field is defined in terms of its two primary foundational disciplines, biology and computer science, and its interdisciplinary nature. At the same time, we also created a rubric for assessing open-ended responses to a prompt about what bioinformatics is and how it is used. The rubric has been shown to be reliable in successive rounds of testing using both common percent agreement (89.7%) and intraclass correlation coefficient (0.620) calculations. We offer the definition and rubric to life sciences instructors to help further integrate bioinformatics into biology instruction, as well as for fostering further educational research projects.

Hypoxaemia and interstitial lung disease in an infant with hypothyroidism and hypotonia.

A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1-14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain-thyroid-lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.

Simulation-based education to improve emergency management skills in caregivers of tracheostomy patients.

INTRODUCTION: Children with tracheostomies are medically complex and may be discharged with limited and variably trained home nursing support. When faced with emergencies at home, caregivers must often take the lead role in management, and many lack experience with troubleshooting these emergencies prior to initial discharge. METHODS: A high-fidelity simulation-based tracheostomy education program was designed using a programmable mannequin (Gaumard HAL S3004 one-year-old pediatric simulator). At the conclusion of our standard education program, caregivers completed three simulation scenarios: desaturation, mucus plugging, and dislodgement. A trained simulation facilitator graded performance. A self-assessment tool was used to analyze comfort with emergency management at the beginning of training, before and after simulation. Caregivers rated confidence using a 10 cm visual analog scale. All participants completed a post-simulation debriefing session. RESULTS: 39 caregivers completed all three scenarios and returned pre- and post-simulation self-assessments. Mean scores from the caregiver self-assessments increased for all three scenarios, with mean increases of 9 mm for desaturation, 16 mm for mucus plugging, and 10 mm for decannulation. Two patterns of responses emerged: caregivers with progressive increase in confidence through training, and caregivers who initially rated confidence highly, and had confidence decrease as the complexity of true emergency management became apparent. All participants found the simulations to be realistic and helpful. DISCUSSION: High-fidelity simulation training allows for realistic exposure to trach-related emergencies. Many caregivers overestimate their ability to handle emergencies and gain important insight through simulation. IMPLICATIONS FOR PRACTICE: Identification of skills and knowledge gaps prior to discharge allows for targeted re-education in emergency management.

Aicardi goutières syndrome is associated with pulmonary hypertension.

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

Patterns of Bird-Bacteria Associations.

Birds, with their broad geographic ranges and close association with humans, have historically played an important role as carriers of human disease and as reservoirs for drug-resistant bacteria. Here, we examine scientific literature over a 15-year timespan to identify reported avian-bacterial associations and factors that may impact zoonotic disease emergence by classifying traits of bird species and their bacteria. We find that the majority of wild birds studied were migratory, in temperate habitats, and in the order Passeriformes. The highest diversity of bacteria was found on birds in natural habitats. The most frequently reported bacteria were Escherichia coli, Salmonella enterica, and Campylobacter jejuni. Of the bacteria species reported, 54% have shown pathogenicity toward humans. Percentage-wise, more pathogens were found in tropical (vs. temperate) habitats and natural (vs. suburban, urban, or agricultural) habitats. Yet, only 22% were tested for antibiotic resistance, and of those tested, 75% of bacteria species were resistant to at least one antibiotic. There were no significant patterns of antibiotic resistance in migratory versus non-migratory birds, temperate versus tropical areas, or different habitats. We discuss biases in detection and representation, and suggest a need for increased sampling in non-temperate zones and in a wider range of avian species.

Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis.

OBJECTIVES: Preterm infants with bronchopulmonary dysplasia (BPD) are at increased risk for development of Pulmonary Hypertension (PHT). We performed a systematic review and meta-analysis to identify risk factors for development of PHT in infants with BPD. STUDY DESIGN: A systematic review identified risk factors for the development of PHT in infants with BPD. A meta-analysis of the pooled data was performed for each individual risk factor. RESULT: Of the 20 risk factors identified, 10 were repeated more than once in nine studies. Meta analysis showed that duration of mechanical ventilation, length of stay, oligohydramnios, use of high frequency ventilation, small for gestational age, sepsis and severity of BPD were significant risk factors; while birth weight and gestational age were inversely related. CONCLUSION: Several clinical variables are predictive of the development of PHT in infants with BPD. Prospective studies are needed to transform these risk factors into a risk-based scoring system.

Respiratory Difficulties in Children With Underlying Asthma During Immunotherapy for High-risk Neuroblastoma.

Treatment of high-risk neuroblastoma now includes antibody based antitumor immunotherapy as part of standard care. Although this therapy has resulted in dramatic improvements in survival, it is associated with significant side effects. Children with underlying respiratory issues, and in particular asthma, may be more susceptible to immunotherapy associated respiratory compromise and pulmonary complications. Early routine involvement of pulmonology care is warranted for these patients in an effort to allow maximal delivery of immunotherapy and minimize acute and long-term complications.

Inhaled treprostinil via the Tyvaso Inhalation System through a tracheostomy.

A 20-year-old man with pulmonary arterial hypertension secondary to systemic sclerosis was admitted to our hospital. Prior to admission, his PAH had been successfully managed with the use of tadalafil, ambrisentan and inhaled Tyvaso. Owing to respiratory failure from vocal cord paralysis, he underwent an emergent tracheotomy. The delivery of inhaled Tyvaso through a tracheostomy tube was explored. Post-tracheostomy, the patient continued his ability to self-administer the medication. His WHO functional classification, brain natriuretic peptide levels, and echocardiograms were not significantly different when Tyvaso was administered via tracheostomy compared with oral administration. This case report summarises the method used to deliver Tyvaso via a tracheostomy tube, which proved to be successful in this patient.

Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation.

Alternative splicing of a group II intron in a surface layer protein gene in Clostridium tetani.

Group II introns are ribozymes and retroelements found in bacteria, and are thought to have been the ancestors of nuclear pre-mRNA introns. Whereas nuclear introns undergo prolific alternative splicing in some species, group II introns are not known to carry out equivalent reactions. Here we report a group II intron in the human pathogen Clostridium tetani, which undergoes four alternative splicing reactions in vivo. Together with unspliced transcript, five mRNAs are produced, each encoding a distinct surface layer protein isoform. Correct fusion of exon reading frames requires a shifted 5' splice site located 8 nt upstream of the canonical boundary motif. The shifted junction is accomplished by an altered IBS1-EBS1 pairing between the intron and 5' exon. Growth of C. tetani under a variety of conditions did not result in large changes in alternative splicing levels, raising the possibility that alternative splicing is constitutive. This work demonstrates a novel type of gene organization and regulation in bacteria, and provides an additional parallel between group II and nuclear pre-mRNA introns.

Use of flexible bronchoscopy in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support.

INTRODUCTION: Critically ill children treated with extracorporeal membrane oxygenation (ECMO) support frequently have respiratory complications amenable to evaluation by flexible bronchoscopy (FB). The safety and efficacy of FB in this setting has not been well described in children. METHODS: Retrospective analysis of 153 FBs in 79 children treated with ECMO at a single institution from 2000 to 2008. Demographic data, clinical findings, and complications were obtained. Chest radiographs reports were evaluated prior to and following FB. Physiologic variables were compared prior to and following FB. RESULTS: Seventy-nine patients underwent FB on ECMO [58 veno-venous (VV) and 21 veno-arterial (VA) ECMO], with 153 total FBs performed. Indications for FB included clearance of tenacious airway secretions (n = 118, 77%), or evaluation of suspected secondary infections with bronchoalveolar lavage (n = 26, 17%). Two patients also had surfactant instillation following secretion removal. FB was performed a median 5 days following cannulation for ECMO (range 2-14 days). Most common findings included thick secretions (n = 77, 50.3%), mucoid secretions (n = 15, 9.8%), and mucopurulent secretions (n = 28, 18.3%). No deterioration in radiographic lung findings was described post-FB. FB was not associated with any significant change in heart rate, systemic blood pressure, or temperature. No significant changes in ECMO pump flow rate or sweep gas flow was seen during or after FB. Cannula dislodgement, inadvertent extubation, fever, pneumothorax, or intraprocedural hypoxemia was not reported. Fifty-three FBs (35%) resulted in blood-tinged secretions from the endotracheal tube post-FB, which resolved spontaneously. Three patients received high frequency oscillatory ventilation (HFOV) following FB in association with mild hemorrhage. CONCLUSIONS: FB is a well-tolerated and safe procedure in critically ill pediatric patients on ECMO. FB may have a diagnostic as well as therapeutic benefit in such patients.