Official American Thoracic Society Clinical Practice Guidelines: Diagnostic Evaluation of Infants with Recurrent or Persistent Wheezing.

BACKGROUND: Infantile wheezing is a common problem, but there are no guidelines for the evaluation of infants with recurrent or persistent wheezing that is not relieved or prevented by standard therapies. METHODS: An American Thoracic Society-sanctioned guideline development committee selected clinical questions related to uncertainties or controversies in the diagnostic evaluation of wheezing infants. Members of the committee conducted pragmatic evidence syntheses, which followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The evidence syntheses were used to inform the formulation and grading of recommendations. RESULTS: The pragmatic evidence syntheses identified few studies that addressed the clinical questions. The studies that were identified constituted very low-quality evidence, consisting almost exclusively of case series with risk of selection bias, indirect patient populations, and imprecise estimates. The committee made conditional recommendations to perform bronchoscopic airway survey, bronchoalveolar lavage, esophageal pH monitoring, and a swallowing study. It also made conditional recommendations against empiric food avoidance, upper gastrointestinal radiography, and gastrointestinal scintigraphy. Finally, the committee recommended additional research about the roles of infant pulmonary function testing and food avoidance or dietary changes, based on allergy testing. CONCLUSIONS: Although infantile wheezing is common, there is a paucity of evidence to guide clinicians in selecting diagnostic tests for recurrent or persistent wheezing. Our committee made several conditional recommendations to guide clinicians; however, additional research that measures clinical outcomes is needed to improve our confidence in the effects of various diagnostic interventions and to allow advice to be provided with greater confidence.

Standardizing Care and Parental Training to Improve Training Duration, Referral Frequency, and Length of Stay: Our Quality Improvement Project Experience.

OBJECTIVES: At our institution, there is a six bed Pediatric Respiratory Care Unit for technology dependent infants and children with a tracheostomy tube. A lack of consistency in patient care and parent/guardian education prompted our group to critically evaluate the services we provided by revisiting our teaching protocol and instituting a new model of care in the Unit. The aims of this quality improvement (QI) project were to standardize care and skills proficiency training to parents of infants with a tracheostomy tube in preparation for discharge to home. METHODS: After conducting a current state survey of key unit stakeholders, we initiated a multidisciplinary, QI project to answer the question: 'could a standardized approach to care and training lead to a decrease in parental/guardian training time, a decrease in length of stay, and/or an increase in developmental interventions for infants with tracheostomy tubes'? A convenience sample of infants with a tracheostomy tube admitted to the Pediatric Respiratory Care Unit were included in the study. Descriptive statistics were used to analyze the results. RESULTS: Through this QI approach, we were able to decrease the time required by parents to achieve proficiency in the care of a technology dependent infant, the length of stay for these infants, and increase referral of the infants for developmental assessment. CONCLUSIONS: These outcomes have implications for how to approach deficiencies in patient care and make changes that lead to sustained improvements.

Heparin binding VEGF isoforms attenuate hyperoxic embryonic lung growth retardation via a FLK1-neuropilin-1-PKC dependent pathway.

BACKGROUND: Previous work in our laboratory demonstrated that hyperoxia suppressed the expression of vascular endothelial growth factor (VEGF) by the embryonic lung, leading to increased epithelial cell apoptosis and failure of explant airway growth and branching that was rescued by the addition of Vegf165. The aims of this study were to determine protective pathways by which VEGF isoforms attenuate hyperoxic lung growth retardation and to identify the target cell for VEGF action. METHODS: Timed pregnant CD-1 or fetal liver kinase (FLK1)-eGFP lung explants cultured in 3% or 50% oxygen were treated ± Vegf121, VEGF164/Vegf165 or VEGF188 in the presence or absence of anti-rat neuropilin-1 (NRP1) antibody or GO6983 (protein kinase C (PKC) pan-inhibitor) and lung growth and branching quantified. Immunofluorescence studies were performed to determine apoptosis index and location of FLK1 phosphorylation and western blot studies of lung explants were performed to define the signaling pathways that mediate the protective effects of VEGF. RESULTS: Heparin-binding VEGF isoforms (VEGF164/Vegf165 and VEGF188) but not Vegf121 selectively reduced epithelial apoptosis and partially rescued lung bud branching and growth. These protective effects required NRP1-dependent FLK1 activation in endothelial cells. Analysis of downstream signaling pathways demonstrated that the VEGF-mediated anti-apoptotic effects were dependent on PKC activation. CONCLUSIONS: Vegf165 activates FLK1-NRP1 signaling in endothelial cells, leading to a PKC-dependent paracrine signal that in turn inhibits epithelial cell apoptosis.

Effect of vitamin D-binding protein genotype on the development of asthma in children.

BACKGROUND: Potential vitamin D-related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D-binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D-binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers. OBJECTIVE: To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children. METHODS: A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D-binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded. RESULTS: GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant. CONCLUSION: In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D-binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).

Association between right ventricular dysfunction and restrictive lung disease in childhood cancer survivors as measured by quantitative echocardiography.

BACKGROUND: Restrictive lung disease is a complication in childhood cancer survivors who received lung-toxic chemotherapy and/or thoracic radiation. Left ventricular dysfunction is documented in these survivors, but less is known about right ventricular (RV) function. Quantitative echocardiography may help detect subclinical RV dysfunction. The aim of this study was to assess RV function quantitatively in childhood cancer survivors after lung-toxic therapy. PROCEDURES: We identified records of 33 childhood cancer survivors who (1) were treated with lung-toxic therapy and/or radiation, (2) were cancer-free for ≥ one year after therapy, and (3) had pulmonary function tests and echocardiograms from their most recent follow-up visit. RESULTS: Participants' mean age was 11.6 ± 4.5 years at cancer diagnosis and 23 ± 8.6 years at evaluation. The most common diagnosis was lymphoma/leukemia (n = 27). Twenty-nine subjects had anthracycline exposure. Eleven of the 33 subjects demonstrated restrictive pulmonary impairment (total lung capacity 3.69 ± 1.5 L [69.3 ± 22.4% predicted]). Among quantitative measures of RV function, isovolumetric acceleration (IVA), a measure of contractility, was significantly lower in the group with restrictive lung disease (2.42 ± 0.56 vs. 1.83 ± 0.78 m/sec(2); P < 0.05). There was a trend towards lower tissue Doppler derived S' and tricuspid annular plane systolic excursion in the group with restrictive lung disease. Subjects with restrictive lung disease were found to have ≥ 2 abnormal parameters (P < 0.01). CONCLUSION: IVA may detect early RV dysfunction in childhood cancer survivors with restrictive lung disease. Our findings require confirmation in a larger study population and validation by cardiac MRI.

Pediatric unilobar resection in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) causes chronic infections and progressive bronchiectasis that can lead to severe lung disease. Because there are no cures or regenerative therapy options for PCD, treatment of severe lung disease in PCD is focused on managing symptoms, including aggressive administration of antibiotics and diligent airway clearance. The Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) does not recommend routine lobectomy, reserving its use for "rare cases of PCD with severe, localized bronchiectasis" and warns that a lobectomy should be treated with caution. However, if aggressive medical management fails, selective surgical removal of severely defective lung may result in maintenance or improvement of pulmonary function. Certainly, the decision to recommend lung resection in the face of chronic bronchiectasis from PCD requires an extensive discussion before it is considered as an alternative treatment. The purpose of this manuscript was to demonstrate that in selected cases of unilobar disease with bronchiectasis that are not responsive to other therapies (antibiotics and airway clearance), removal of localized necrotic areas of the lung along with prophylactic antibiotics can improve the quality of life of children with PCD associated bronchiectasis and improve growth and nutritional status, and pulmonary function.

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease.

Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sbeta(0) thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) > or =2.5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19-31 months). Patients with initial TRV > or = 3 or TRV > or = 2.5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow-up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram (P = 0.01), lower haemoglobin (P = 0.003) and lower oxygen saturation (P = 0.03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40.16 to 29.26 (P = 0.017) after 3-6 months and to 23.6 mmHg (P = 0.002) after 9-12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea.

A novel presentation of diffuse lung disease caused by congenital hypothyroidism.

A term infant was born with respiratory distress, and subsequent imaging, histopathologic, and hormonal studies confirmed congenital hypothyroidism. This report is intended to alert pediatricians to the possibility of congenital hypothyroidism as a cause of respiratory symptoms of unknown cause in neonates with respiratory distress.

Predictors of asthma-related pediatric emergency department visits and hospitalizations.

OBJECTIVE: Asthma is a leading cause of emergency department visits and hospitalizations for children in the United States. As part of a larger study, the purpose of this analysis was to determine which variables were most effective at predicting subsequent pediatric asthma-related emergency department visits and hospitalizations. METHODS: A retrospective, descriptive study was conducted. Subjects consisted of a convenience sample of 298 children admitted to a New England Children's Hospital in 2006 with a primary diagnosis of asthma. Data from two hospital databases were collected for 12 months before and 12 months after the 2006 admission. Basic descriptive statistics were followed by chi-square tests to determine which variables were associated with emergency department visits and hospitalizations. Logistic regression analysis was used to determine which variables were significant predictors of asthma-related emergency department visits and hospitalizations. RESULTS: Sixty-percent of all subjects were male. Ninety subjects experienced a total of 145 emergency department visits and 54 experienced a total of 70 hospitalizations. A previous emergency department visit was a significant predictor of both subsequent emergency department visits and subsequent hospitalizations. Age was also an independent risk factor for subsequent hospitalizations. In this sample, the risk of a hospitalization increased with each year increase in age. CONCLUSION: These findings support the importance of early identification of children with asthma so that appropriate asthma management can be instituted before an emergency department visit occurs. Furthermore, results suggest involving school-age and preadolescent children in the care of their asthma so that they can be equipped and encouraged to self-manage their own asthma.

Activation of DOR attenuates anoxic K+ derangement via inhibition of Na+ entry in mouse cortex.

We have recently found that in the mouse cortex, activation of delta-opioid receptor (DOR) attenuates the disruption of K(+) homeostasis induced by hypoxia or oxygen-glucose deprivation. This novel observation suggests that DOR may protect neurons from hypoxic/ischemic insults via the regulation of K(+) homeostasis because the disruption of K(+) homeostasis plays a critical role in neuronal injury under hypoxic/ischemic stress. The present study was performed to explore the ionic mechanism underlying the DOR-induced neuroprotection. Because anoxia causes Na(+) influx and thus stimulates K(+) leakage, we investigated whether DOR protects the cortex from anoxic K(+) derangement by targeting the Na(+)-based K(+) leakage. By using K(+)-sensitive microelectrodes in mouse cortical slices, we showed that 1) lowering Na(+) concentration and substituting with impermeable N-methyl-D-glucamine caused a concentration-dependent attenuation of anoxic K(+) derangement; 2) lowering Na(+) concentration by substituting with permeable Li(+) tended to potentiate the anoxic K(+) derangement; and 3) the DOR-induced protection against the anoxic K(+) responses was largely abolished by low-Na(+) perfusion irrespective of the substituted cation. We conclude that external Na(+) concentration greatly influences anoxic K(+) derangement and that DOR activation likely attenuates anoxic K(+) derangement induced by the Na(+)-activated mechanisms in the cortex.

Opportunities on the road to value-based payment for children with chronic respiratory disease.

The transition from a fee-for-service payment system to value-based payment system gained momentum in the US in 2010 with the passage of the Affordable Care Act and continues to progress rapidly. Market research estimates that value-based payment models will surpass fee-for-service by 2020. This change offers both great opportunity and great risk to the medical care of the heterogeneous populations of children with chronic respiratory disease. The fee-for-service model has driven the emergence of a healthcare delivery infrastructure markedly misaligned with the medical needs of children with chronic respiratory disease. A change to value-based payment models offers the opportunity to create systems better aligned with the complex and varied care needs of these children. However, rapid change without input from the relevant stakeholders could yield an infrastructure even more misaligned with the needs of children with chronic respiratory disease than the current one and threaten access to high quality medical care for these populations. Through the lens offered by three fictional case studies, this review: (1) illustrates current and evolving payment models; (2) describes limitations of these payment models; and (3) suggests a novel way to envision and evaluate value-based payment models for children with chronic respiratory disease.

Electronic medical records in a sub-specialty practice: one asthma center's experience.

There are numerous known benefits associated with the use of an electronic medical record (EMR). In October of 2004, a pediatric respiratory medicine practice at a major academic institution began the process of implementing an EMR system. Through this process, another benefit was realized, improved coordination between out-patient and in-patient care in relation to asthma education. The process began with the formation of an implementation team. The team consisted of technical as well as clinical experts from various disciplines. Together the team developed templates, decision support tools and standardized patient care letters. The team also determined workflow and provided training on the EMR system. A major benefit associated with EMR implementation was the increase in the number of children who were hospitalized with an asthma exacerbation and received an asthma action plan upon discharge. Prior to the EMR system, 4% received an asthma action plan upon discharge. After implementation of the EMR system, 58% received an asthma action plan upon discharge.

Risk factors for tracheostomy requirement in extremely low birth weight infants.

AIM: To identify variables that affect the risk of tracheostomy in a population of extremely low birth weight (ELBW) infants. METHODS: A retrospective matched case-control study was conducted. ELBW infants with a tracheostomy were compared with controls without tracheostomy. Data collection included demographics, detailed information about each intubation and extubation attempt, the use of steroids and the presence of comorbidities. Statistical analyses include conditional logistic regression and Poisson regression for clustered observations. RESULTS: Twenty-eight ELBW infants with a tracheostomy were identified. Mean gestational age for both cases and controls was 25 weeks (22-29) and 67.9% were males. Tracheostomy was performed on average on day of life 118 (95%CI: 107-128) and weight at tracheostomy was 2877 g (95%CI: 2657-3098). In the final model, cumulative days with an endotracheal tube (ETT) and total number of intubation episodes were associated with a tracheostomy. For each additional day of intubation, odds of tracheostomy increased by 11% (OR = 1.11, 95%CI: 1.01, 1.23) and with each new intubation episode/failed extubation episode, odds of tracheostomy increased by 150% from the previous episode (OR = 2.5, 95%CI: 1.2, 5.2). CONCLUSIONS: Greater cumulative exposure to ETT ventilation and number of intubations is associated with having a tracheostomy.

Cortical delta-opioid receptors potentiate K+ homeostasis during anoxia and oxygen-glucose deprivation.

Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that delta-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K(+), which plays a role in neuronal death, we asked whether DOR activation preserves K(+) homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K(+)-sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala(2), D-Leu(5)]-enkephalinamide attenuated the anoxia- and OGD-induced increase in extracellular K(+) and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K(+) and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K(+) homeostasis. These data suggest that activation of DOR protects the cortex against anoxia- or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K(+) homeostasis during anoxia or ischemia.

Anisomycin protects cortical neurons from prolonged hypoxia with differential regulation of p38 and ERK.

MAP kinase is associated with delta-opioid receptor (DOR) signaling and plays a role in cell survival/death. Since anisomycin may alter MAP kinase activity and affect neuronal survival, we investigated whether anisomycin alters neuronal response to hypoxic stress and DOR inhibition. The experiments were performed in cultured cortical neurons. MAP kinase activities were determined by immunoblotting and neuronal viability was assessed by LDH leakage and live/dead morphological study. DOR inhibition with naltrindole (10 microM) led to significant injury in normoxic neurons after 24 h of treatment and exacerbated hypoxia-induced injury. Along with the injury, either by hypoxia or naltrindole, phosphorylated p38 increased in a major way, while phosphorylated ERK and JNK had no significant change or slightly decreased. Anisomycin (50 ng/ml) prevented the increase in phosphorylated p38 immunoreactivity induced by naltrindole and reduced the neuronal injury. The results suggest that (1) MAP kinases are differentially involved in neuronal response to hypoxia and DOR inhibition in cortical neurons with phosphorylated p38 immunoreactivity being upregulated and (2) anisomycin attenuates the increase in phosphorylated p38 immunoreactivity and reduces neuronal injury induced by hypoxia and DOR inhibition.

Biochemical Screening for Pulmonary Hypertension in Preterm Infants with Bronchopulmonary Dysplasia.

BACKGROUND: Pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD) is associated with increased morbidity and mortality. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and decreased levels of amino acid precursors of nitric oxide (NO) have been associated with PH, but have not been studied in infants with PH secondary to BPD. OBJECTIVE: The aim of this study was to identify a biochemical marker for PH in infants with BPD. METHODS: Twenty infants, born at <27 weeks' gestational age (GA) and/or with a birth weight (BW) ≤750 g, who met the criteria for BPD at 36 weeks' corrected GA (CGA) were enrolled in this cross-sectional pilot study. A screening echocardiogram was conducted at 36-38 weeks' CGA and plasma NT-proBNP and amino acid levels were obtained within 1 week of the screening echocardiogram. RESULTS: Five infants (25%) had echocardiographic evidence of PH. GA and BW were not significantly different between the 2 groups (a PH group and a No PH group). NT-proBNP was significantly elevated in the PH group (median 1,650 vs. 520 pg/ml; p = 0.001) but citrulline levels were significantly lower (median 21 vs. 36 µmol/l; p = 0.005). Arginine levels were not significantly different between the groups (median 78 vs. 79 µmol/l; p = 1). CONCLUSION: NT-proBNP and the NO precursor citrulline may be cost-effective biochemical markers for screening for the presence of PH in preterm infants who have BPD. If validated in a larger study, such biochemical markers may, in part, replace PH screening echocardiograms in these patients.

Unusual pulmonary findings in mucolipidosis II.

We report undescribed pulmonary findings in a child with mucolipidosis II (ML-II). Children with ML-II bear significant pulmonary morbidity that may include extensive pulmonary fibrosis, persistent hemosiderosis as well as pulmonary airway excrescences as they reach preschool age.

DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex.

Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na(+) influx through TTX-sensitive voltage-gated Na(+) channels may be a main mechanism for hypoxia-induced disruption of K(+) homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na(+) channels. In the present study we examined the role of DOR in the regulation of Na(+) influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na(+) influx induced by a Na(+) channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na(+) activity in mouse cortical slices with Na(+) selective electrodes and found that (1) anoxia-induced Na(+) influx occurred mainly through TTX-sensitive Na(+) channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na(+) influx; (3) veratridine, a Na(+) channel opener, enhanced the anoxia-induced Na(+) influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na(+) influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCßII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na(+) influx through Na(+) channels via PKC (especially PKCßII and PKCθ isoforms) dependent mechanisms in the cortex.

Secure web messaging in a pediatric chronic care clinic: a slow takeoff of "kids' airmail".

BACKGROUND: Although e-mail may be an efficient clinician-patient communication tool, standard e-mail is not adequately secure to meet Health Insurance Portability and Accountability Act (HIPAA) guidelines. For this reason, firewall-secured electronic messaging systems have been developed for use in health care. Impact and usability of these secure systems have not been broadly assessed. OBJECTIVE: To evaluate the impact of a secure electronic messaging system implemented for a pediatric subspecialty clinic. METHODS: This study was performed in an outpatient, academic pediatric respiratory clinic in spring 2009 in New Haven, Connecticut. Patients were surveyed prior to implementation regarding internet usage. The Kryptiq messaging system was implemented and messages were monitored continuously and tracked. Open-ended qualitative interviews with 28 users and nonusers were conducted, and we described the process of implementation. RESULTS: All of the 127 patients/families surveyed expressed interest in using the Internet to contact their clinic providers, and they all reported having the ability to access the Internet. In the 8 months after implementation, only 5 messages were initiated by patients in contrast to 2363 phone calls. Themes emerged from the open-ended interviews that indicated promoters, barriers, and potential uses. Prominent barriers included the lack of convenience and personal touch and being technically difficult to use. CONCLUSIONS: Although these patients/families expressed strong interest in e-mailing, secure Web messaging was less convenient than using the phone, too technically cumbersome, lacked a personal touch, and was used only by a handful of patients.