Rain may improve survival from direct lightning strikes to the human head.

There is evidence that humans can survive a direct lightning strike to the head. Our question is: could water (rain) on the skin contribute to an increase in the survival rate? We measure the influence of rain during high-energy direct lightning strikes on a realistic three-compartment human head phantom. We find a lower number of perforations and eroded areas near the lightning strike impact points on the head phantom when rain was applied compared to no rain. Current amplitudes in the brain were lower with rain compared to no rain before a fully formed flashover. We conclude that rain on the scalp potentially contributes to the survival rate of 70-90% due to: (1) lower current exposition in the brain before a fully formed flashover, and (2) reduced mechanical and thermal damage.

Refinement of newborn screening for cystic fibrosis with next generation sequencing.

BACKGROUND: Newborn screening for cystic fibrosis (CF) has been underway universally in the United States for more than a decade, as well in most European countries, and algorithms have been evolving throughout this period with quality improvement projects as immunoreactive trypsinogen (IRT) determinations alone have been transformed to a 2-tier strategy with DNA analyses. OBJECTIVE: To apply next generation sequencing (NGS) as a screening method to expand the DNA tier and identify substantially more variants in the CF transmembrane conductance regulator (CFTR) gene to enhance sensitivity and equity while minimizing incidental findings. DESIGN: Sequential evaluation and improvement plan in three phases using algorithm modifications coupled to statewide follow up and analysis of screening outcomes. RESULTS: After demonstrating feasibility in the first phase, we studied an IRT/NGS algorithm that included CFTR Variants with Varying Clinical Consequences (VVCCs). This revealed a high identification of CF patients with 2-variants detected through screening, but for every CF case there were 1.4 with CF metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID). This led us to a third phase of improvement in which the VVCCs were eliminated except for R117H, resulting in 94% 2-variant detection of patients and 0.44:1 ratio of CRMS/CFSPID to CF. CONCLUSION: NGS can be used with IRT as an effective method of identifying infants at risk for CF without an appreciable increase in detection of carriers. Its potential added value includes facilitating equity, enhancing sensitivity and detecting more CF patients with 2-variants during the screening process.

Defining and identifying early-onset lung disease in cystic fibrosis with cumulative clinical characteristics.

BACKGROUND: Because of the heterogeneity in cystic fibrosis (CF) lung disease among young children, a clinical method to identify early-onset lung disease is needed. OBJECTIVE: To develop a CF early-onset lung disease (CFELD) scoring system by utilizing prospectively collected longitudinal data on manifestations in the first 3 years of life. DESIGN: We studied 145 infants born during 2012-2017, diagnosed through newborn screening by age 3 months, and followed to 36 months of age. Cough severity, pulmonary exacerbations (PEx), respiratory cultures, and hospitalizations were collected at each CF center visit (every 1-2 months in infancy and quarterly thereafter). These data were used to construct the CFELD system and to classify lung disease into five categories: asymptomatic, minimal, mild, moderate, and severe. RESULTS: The most frequent manifestation of CF early lung disease was MD-reported PEx episodes, PEx hospitalizations, and positive Pseudomonas aeruginosa cultures. Parent-reported cough severity was correlated with the number of respiratory hospitalizations (r = 0.48, p < 0.0001). The distribution of CFELD categories was 10% asymptomatic, 17% minimal, 29% mild, 33% moderate, and 12% severe. The moderate and severe categories occurred threefold higher in pancreatic insufficient (PI, 49%) versus sufficient subjects (16%), p < 0.0001. In addition to PI, gastrointestinal and nutrition-related hospitalizations, plasma cytokines interleukin (IL)-6 and IL-10, duration of CFTR modulator therapy, and type of health insurance were significant predictors of CFELD scores. CONCLUSION: The CFELD scoring system is novel, allows systematic evaluation of lung disease prognosis early, and may aid in therapeutic decision-making particularly in the initiation of CFTR modulator therapy.

F1099L-CFTR (c.3297C>G) has Impaired Channel Function and Associates with Mild Disease Phenotypes in Two Pediatric Patients.

(1) Background: many rare cystic fibrosistransmembrane conductance regulator (CFTR) mutations remain poorly characterized with regard to functional consequences of the mutation. We present the clinical features of two pediatric cystic fibrosis (CF) subjects who are heterozygous for F1099L (c.3297C>G), one with G551D (a class III mutation) and one with 3849 + 10kbC->T (a class V mutation). We also identified the molecular defect(s) that are associated with F1099L mutation to correlate with the clinical features that we observed; (2) Methods: clinical findings and history were extracted from the electronic medical record and de-identified. F1099L-CFTR protein expression level and maturation status, channel function, and the effects of CFTR modulation on these characteristics were investigated using western blotting and iodide efflux assay; (3) Results: these two subjects have mild CF phenotypes when F1099L is combined with two known disease-causing mutations. F1099L-CFTR has a moderate defect in processing and maturation, causing fewer CFTR channels at the cell surface and, therefore, impaired channel activities. These defects could be effectively corrected using VX-809 (lumacaftor); and, (4) Conclusions: our biochemical data correlate with the disease manifestations and suggest that F1099L is potentially a CF-causing mutation. The study expands our knowledge of rare CFTR mutations and may help in developing effective therapies for subjects with F1099L mutation.

Newborn screening alone insufficient to improve pulmonary outcomes for cystic fibrosis.

BACKGROUND: The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes. METHODS: Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV1) and mortality. A random intercept model was used to compare the ppFEV1 decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method. RESULTS: Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV1 decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups. CONCLUSIONS: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy.

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

Joint Outcomes Following Surgery for Superior Tibiofibular Joint-Associated Peroneal Intraneural Ganglion Cysts.

BACKGROUND: Intraneural ganglion cysts are joint-connected, with the primary pathology residing in the associated joint. For peroneal intraneural ganglion cysts, the surgical strategy can include resection of the synovial surface of the superior tibiofibular joint (STFJ). However, the rate of instability postoperatively is unclear. OBJECTIVE: To evaluate the rate of STFJ instability, following surgery for peroneal intraneural ganglion cysts. The second goal of the study was to assess the relationship between volume of resection of the STFJ and risk of extraneural recurrence. METHODS: We performed a retrospective analysis of a cohort of patients with peroneal intraneural ganglion cysts. We analyzed clinical factors, including recurrence, and assessed the rate of postoperative STFJ instability. We created 3-dimensional models of the STFJ pre- and postoperatively to compare the volume of resection in recurrent cases and nonrecurrent cases using a case-control design. RESULTS: The total cohort consisted of 65 subjects. No patient had evidence of radiological or clinical instability of the STFJ postoperatively. Extraneural radiological recurrence occurred in 6 (9%) patients. No intraneural recurrences were observed. The average volume of resection for patients with recurrence was 1349 mm3 (SD = 1027 mm3) vs 3018 mm3 (SD = 1433 mm3) in controls that did not have a recurrence (P = .018). CONCLUSION: This study supports performing an aggressive STFJ resection to minimize the risk of extraneural recurrence. Superior tibiofibular joint resection is not associated with postoperative joint instability. A smaller volume resection is correlated with recurrence risk.

Measurement and analysis of partial lightning currents in a head phantom.

Direct lightning strikes to the human head can lead to various effects, ranging from burnings to death. The biological and physical mechanisms of a direct lightning strike in the human head are not well understood. The aim of this paper is to design an experimental setup to measure the spatial and temporal current distribution during a direct lightning strike to physical head phantoms to establish normative values for personal lightning protection equipment design and testing. We created head phantoms made of agarose, replicating the geometric and dielectric properties of scalp, skull, and intracranial volume. The bases of the three compartments were galvanically contacted via copper electrodes to measure the current per compartment. We used pulse generators to apply aperiodic voltage and current signals that modelled lightning components. Our experiments indicated that the scalp compartment was exposed to the current with a fraction of 80-90%. The brain and skull compartments were exposed between 6-13% and 3-6% of the total measured current respectively. In case of a flashover, most of the current (98-99%) flowed through the discharge channel. Unlike previous theoretical estimates and measurements in technical setups, we observed considerably longer times for the flashover to build up. In our experiments, the time to build up a fully formed flashover varied from approximately 30-700 µs. The observed current patterns in cases without and with flashover provided information on regions of possible damage in the human head. Consequently, we identified the phenomenon of a flashover as a potential mechanism for humans to survive a lightning strike. Our measured current distributions and amplitudes formed the base for normative values, which can be used in later experimental investigations regarding the possibilities of individual lightning protection equipment for humans.

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .05) from the psychological model showed I-group and CF-group parents perceived their children to be more vulnerable than H-group parents but reported lower levels of protectiveness than H-group parents. Perceptions of vulnerability mediated protectiveness for CF- and I-groups. The biological model showed I-group children had significantly less severe genotype and phenotype, and lower sweat chloride levels than the CF-group; I-group parents had lower expectations about children developing CF symptoms. Both models showed negative associations between children's ages and protectiveness. Psychological factors explained perceptions of child vulnerability and protectiveness; biological factors explained protectiveness. Parent perceptions of vulnerability and protectiveness are separate, independent constructs.

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Intraoperative intravenous fluorescein as an adjunct during surgery for peroneal intraneural ganglion cysts.

The intraoperative use of intravenous fluorescein is presented in a case of peroneal intraneural ganglion cyst. When illuminated with the operative microscope and yellow filter, this fluorophore provided excellent visualization of the abnormal cystic peroneal nerve and its articular branch connection. The articular (synovial) theory for the pathogenesis of intraneural cysts is further supported by this pattern of fluorescence. Further, our report presents a novel use of fluorescein in peripheral nerve surgery.

Outcomes following surgery for peroneal intraneural ganglion cysts.

INTRODUCTION: The objective of this study was to answer the typical questions from patients regarding the likely neurologic outcome and likelihood of recurrence when discussing peroneal intraneural ganglion cysts preoperatively. METHODS: Retrospective analysis of all patients who underwent surgery for a peroneal intraneural ganglion cyst between January 1, 2000, and April 1, 2017, was performed. Postoperative neurologic outcomes and radiologic recurrences are reported. RESULTS: There were 65 patients. Average clinical follow-up was 14 months. Median dorsiflexion and eversion preoperatively were 2/5 and 4/5, respectively. Median dorsiflexion and eversion at last follow-up postoperatively were 5/5. Radiologic recurrence occurred in 6 (9%) patients, all extraneural. DISCUSSION: The data support excellent postoperative motor outcomes, despite frequent dense weakness of peroneal-innervated musculature preoperatively. The surgical approach appears to eliminate risk of intraneural recurrence and minimizes risk of extraneural recurrence. Muscle Nerve 57: 989-993, 2018.

Diagnosis of Cystic Fibrosis in Screened Populations.

OBJECTIVE: Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. STUDY DESIGN: To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. RESULTS: After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. CONCLUSIONS: It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.

Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation.

OBJECTIVE: Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. STUDY DESIGN: To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. RESULTS: After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. CONCLUSIONS: It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.

Redesigning Care Delivery.

This Hospitals in Pursuit of Excellence column considers innovative care and payment models to help hospitals and health systems achieve the Triple Aim.

H7N9 influenza virus neutralizing antibodies that possess few somatic mutations.

Avian H7N9 influenza viruses are group 2 influenza A viruses that have been identified as the etiologic agent for a current major outbreak that began in China in 2013 and may pose a pandemic threat. Here, we examined the human H7-reactive antibody response in 75 recipients of a monovalent inactivated A/Shanghai/02/2013 H7N9 vaccine. After 2 doses of vaccine, the majority of donors had memory B cells that secreted IgGs specific for H7 HA, with dominant responses against single HA subtypes, although frequencies of H7-reactive B cells ranged widely between donors. We isolated 12 naturally occurring mAbs with low half-maximal effective concentrations for binding, 5 of which possessed neutralizing and HA-inhibiting activities. The 5 neutralizing mAbs exhibited narrow breadth of reactivity with influenza H7 strains. Epitope-mapping studies using neutralization escape mutant analysis, deuterium exchange mass spectrometry, and x-ray crystallography revealed that these neutralizing mAbs bind near the receptor-binding pocket on HA. All 5 neutralizing mAbs possessed low numbers of somatic mutations, suggesting the clones arose from naive B cells. The most potent mAb, H7.167, was tested as a prophylactic treatment in a mouse intranasal virus challenge study, and systemic administration of the mAb markedly reduced viral lung titers.