Inova Children's Hospital

Alan L. Bisno, Michael A. Gerber, Jack M. Gwaltney, Jr., Edward L. Kaplan, and Richard H. Schwartz Department of Medicine, University of Miami School of Medicine and Veterans Affairs Medical Center, Miami, Florida; 2 Cincinnati Children’s Hospital Medical Center and University of Cincinnati School of Medicine, Ohio; University of Virginia School of Medicine, Charlottesville, Inova Fairfax Hospital for Children, Falls Church, Virginia; and Department of Pediatrics, University of Minnesota Medical School, Minneapolis

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Children's Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a children's primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were generally somewhat lower. PCV13 also elicited functional opsonophagocytic activity comparable with that elicited by PCV7. For the 6 additional serotypes in PCV13, PCV13 elicited binding and functional antibody levels notably greater than those in PCV7 recipients. After PCV13 immunization, concordance between antipolysaccharide and opsonophagocytic responses was noted for all 13 serotypes. The PCV13 toddler dose resulted in higher immune responses compared with infant-series doses. Safety and tolerability were comparable; reactogenicity was generally mild. CONCLUSIONS: PCV13 will be as effective as PCV7 in the prevention of pneumococcal disease caused by the 7 common serotypes and could provide expanded protection against the 6 additional serotypes. The PCV13 safety profile was comparable to that of PCV7.

We undertook a retrospective chart review of 37 neonates who received fentanyl by continuous infusion while undergoing extracorporeal membrane oxygenation (ECMO) between May 1986 and October 1988. We quantified the doses of all sedatives utilized, determined the incidence of neonatal abstinence syndrome (NAS), and identified risk factors associated with NAS. We determined peak fentanyl infusion rate, mean fentanyl infusion rate, total fentanyl dose, and duration of ECMO therapy. NAS was observed in 21 of 37 neonates (57%). In both the NAS and non-NAS neonates, mean infusion rate increased steadily during ECMO therapy, from a mean of 11.6 +/- 6.9 (SD) micrograms.kg-1.h-1 on day 1 to a mean of 52.5 +/- 19.4 (SD) micrograms.kg-1.h-1 by day 8. Total fentanyl dose and duration of ECMO were significantly greater in neonates with NAS. We found that neonates with a total dose greater than 1.6 mg/kg or an ECMO duration greater than 5 days had a significantly greater incidence of NAS (chi-squared test, P less than 0.01 and P less than 0.005; odds ratios = 7.0 and 13.9, respectively). With multiple logistic regression, ECMO duration was found to be the most powerful predictor of the occurrence of NAS. We also measured plasma fentanyl concentrations in a separate group of 5 neonates receiving fentanyl by continuous infusion for sedation. Fentanyl concentrations increased steadily during the period of infusion, suggesting the development of tolerance to the sedating effects. We conclude that continuous administration of fentanyl for sedation is associated with the uniform development of tolerance and a significant incidence of dependence. Alternative approaches to sedation should be investigated.

Germline mutations are the source of evolution and contribute substantially to many health-related processes. Here we use whole-genome deep sequencing data from 693 parents-offspring trios to examine the de novo point mutations (DNMs) in the offspring. Our estimate for the mutation rate per base pair per generation is 1.05 × 10(-8), well within the range of previous studies. We show that maternal age has a small but significant correlation with the total number of DNMs in the offspring after controlling for paternal age (0.51 additional mutations per year, 95% CI: 0.29, 0.73), which was not detectable in the smaller and younger parental cohorts of earlier studies. Furthermore, while the total number of DNMs increases at a constant rate for paternal age, the contribution from the mother increases at an accelerated rate with age.These observations have implications related to the incidence of de novo mutations relating to maternal age.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

In the past few years, drug-facilitated sexual assaults have received widespread media coverage. In addition to alcohol, the most frequently used date-rape drug, flunitrazepam (Rohypnol), a fast-acting benzodiazepine, and gamma-hydroxybutyrate (GHB) and its congeners are among the most popular drugs used for this purpose. The latter drug is easily procured at some gymnasiums, popular bars, discos, and rave clubs, as well as over the Internet. Perpetrators choose these drugs because they act rapidly, produce disinhibition and relaxation of voluntary muscles, and cause the victim to have lasting anterograde amnesia for events that occur under the influence of the drug. Alcoholic beverages potentiate the drug effects. We review several date-rape drugs, provide information on laboratory testing for them, and offer guidelines for preventing drug-facilitated sexual assault.

OBJECTIVES: Unintended variation in the care of patients with Crohn disease (CD) and ulcerative colitis (UC) may prevent achievement of optimal outcomes. We sought to improve chronic care delivery and outcomes for children with inflammatory bowel disease by using network-based quality improvement methods. METHODS: By using a modified Breakthrough Series collaborative structure, 6 ImproveCareNow Network care centers tested changes in chronic illness care and collected data monthly. We used an interrupted time series design to evaluate the impact of these changes. RESULTS: Data were available for 843 children with CD and 345 with UC. Changes in care delivery were associated with an increase in the proportion of visits with complete disease classification, measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, and patients receiving an initial thiopurine dose appropriate to their TPMT status. These were significant in both populations for all process variables (P < .01) except for measurement of TPMT in CD patients (P = .12). There were significant increases in the proportion of CD (55%-68%) and UC (61%-72%) patients with inactive disease. There was also a significant increase in the proportion of CD patients not taking prednisone (86%-90%). Participating centers varied in the success of achieving these changes. CONCLUSIONS: Improvements in the outcomes of patients with CD and UC were associated with improvements in the process of chronic illness care. Variation in the success of implementing changes suggests the importance of overcoming organizational factors related to quality improvement success.

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m(2) of doxorubicin in 30 mg/m(2) doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

OBJECTIVES: Selection of relevant patient safety interventions for the pediatric intensive care (PICU) requires identification of the types and severity of adverse events (AEs) and adverse drug events (ADEs) that occur in this setting. The study's objectives were to: 1) determine the rates of AEs/ADEs, including types, severity, and preventability, in PICU patients; 2) identify population characteristics associated with increased risk of AEs/ADEs; 3) develop and test a PICU specific trigger tool to facilitate identification of AEs/ADEs. DESIGN, SETTING, PATIENTS: Retrospective, cross-sectional, randomized review of 734 patient records who were discharged from 15 U.S. PICUs between September and December 2005. INTERVENTION: A novel PICU-focused trigger tool for AE/ADE detection. MEASUREMENTS AND RESULTS: Sixty-two percent of PICU patients had at least one AE. A total of 1488 AEs, including 256 ADEs, were identified. This translates to a rate of 28.6 AEs and 4.9 ADEs per 100 patient-days. The most common types of AEs were catheter complications, uncontrolled pain, and endotracheal tube malposition. Ten percent of AEs were classified as life-threatening or permanent; 45% were deemed preventable. Higher adjusted rates of AEs were found in surgical patients (p = .02), patients intubated at some point during their PICU stay (p = .002), and patients who died (p < .001). Surgical patients had higher preventable adjusted AE (p = .01) and ADE rates (p = .02). The adjusted cumulative risk of an AE per PICU day was 5.3% and 1.6% for an ADE alone. There was a 4% increase in adjusted ADEs rates for every year increase in age. CONCLUSIONS: AEs and ADEs occur frequently in the PICU setting. These data provide areas of focus for evidence-based prevention strategies to decrease the substantial risk to this vulnerable pediatric population.

BACKGROUND: Practical and objective instruments to assess pediatric Crohn's disease (CD) activity are required for observational research and quality improvement. The objectives were: 1) to determine the feasibility of completing the Pediatric Crohn's Disease Activity Index (PCDAI) and the Abbreviated PCDAI (APCDAI); and 2) to create a Short PCDAI by retaining and reweighting the most practical and informative components. METHODS: Physicians in the ImproveCareNow Collaborative for pediatric inflammatory bowel disease (IBD) were asked to record components of the PCDAI and assign a Physician Global Assessment (PGA) of disease severity at each patient encounter. We assessed the feasibility of the PCDAI, the APCDAI, and the individual index components by determining the proportion of visits in which data were recorded. We created a short index by retaining and reweighting components of the PCDAI completed in ≥80% of visits. The feasibility of the Short PCDAI and its ability to discriminate between PGA categories were evaluated using descriptive statistics. RESULTS: This study population included 1355 subjects with CD (6373 visits). The PCDAI and APCDAI were complete in 16.7% and 44.1% of visits, respectively. A Short PCDAI, including general well-being, abdominal pain, stools, weight, abdominal exam, and extraintestinal manifestations were completed in 66.5% of visits. The correlation between the Short PCDAI and PGA was similar to that of the PCDAI (r = 0.60, P < 0.001 versus 0.61, P < 0.001). CONCLUSIONS: The Short PCDAI is a practical and valid tool to measure pediatric CD activity. Its use should facilitate quality improvement and observational research.

BACKGROUND: Obesity and attention difficulties are known complications following surgical treatment for craniopharyngioma. Treatments to date have been largely disappointing. OBJECTIVE: To examine the use of the central nervous system stimulant dextroamphetamine sulfate to regulate appetite and subsequent weight gain in children treated for craniopharyngioma. SETTING: A multidisciplinary clinic specializing in pediatric brain tumors. PATIENTS: Five consecutive patients with significant weight gain and poor attention following surgical treatment for craniopharyngioma were selected for the study. INTERVENTION: Children enrolled in the study were treated with dextroamphetamine, and growth, laboratory, and behavioral assessments were conducted for 24 months. RESULTS: Mean +/- SD body mass index (weight in kilograms divided by height in meters squared) increased from 21 +/- 3.5 before the operation to 32 +/- 2.8 by the start of the protocol. Body mass indices remained stable throughout the protocol. No changes were observed in insulin levels or caloric intake, but the children were more active when taking dextroamphetamine. Parents noted a significant improvement in hyperactivity (mean +/- SD, 1.2 +/- 0.4 to 0.6 +/- 0.2; P =.05), scored with the Conners Parent and Teacher Rating Scales. Teachers noted a similar improvement. CONCLUSIONS: During dextroamphetamine treatment, weight gain stabilized in children who had experienced obesity following surgical resection for craniopharyngioma. In addition, parents and teachers noted significant improvements in children's overall activity and attention. Further studies are needed to determine if the improvements are stable and if earlier intervention can prevent the initial obesity.

PURPOSE: To assess the potential of whole-genome sequencing (WGS) to replicate and augment results from conventional blood-based newborn screening (NBS). METHODS: Research-generated WGS data from an ancestrally diverse cohort of 1,696 infants and both parents of each infant were analyzed for variants in 163 genes involved in disorders included or under discussion for inclusion in US NBS programs. WGS results were compared with results from state NBS and related follow-up testing. RESULTS: NBS genes are generally well covered by WGS. There is a median of one (range: 0-6) database-annotated pathogenic variant in the NBS genes per infant. Results of WGS and NBS in detecting 28 state-screened disorders and four hemoglobin traits were concordant for 88.6% of true positives (n = 35) and 98.9% of true negatives (n = 45,757). Of the five infants affected with a state-screened disorder, WGS identified two whereas NBS detected four. WGS yielded fewer false positives than NBS (0.037 vs. 0.17%) but more results of uncertain significance (0.90 vs. 0.013%). CONCLUSION: WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.

BACKGROUND: The tenet that children with acute purulent rhinitis need not be treated with antibiotics unless drainage persists for 7 to 10 days is taught to medical students and residents in primary care specialties but may not be adhered to in actual clinical practice. Because of the global increase in bacterial resistance stemming largely from the overuse of antibiotics, we sought to determine how acute purulent rhinitis is managed in the primary care setting. METHODS: We surveyed all 450 pediatricians (PD) and family practitioners (FP) in northern Virginia who were in active practice in 1994. The survey instrument was a questionnaire containing two clinical vignettes followed by a series of multiple choice or fill-in-the-blanks questions. Initial nonresponders received up to three additional mailings of the same questionnaire. RESULTS: There were 346 (77%) evaluable responses. Seventy-one percent of FP and 53% of PD (P = 0.001) immediately prescribed antibiotics for infants with scant, green nasal mucopurulent secretions of 1 day duration; fewer treated an older child immediately (50% FP vs. 24% PD, P < 0.00001). Only 15% of FP vs. 23% of PD (P = 0.07) waited for 7 to 10 days of persistent purulent nasal drainage in infants before prescribing antibiotics. Ninety-four percent of FP and 95% of PD (P = 0.8) indicated that they would prescribe antibiotics immediately for infants with acute purulent rhinitis who attended day care. For otitis-prone children who were not in day care, 86% of FP and 78% of PD (P = 0.02) would also treat without delay. The reasons given for prompt antibiotic therapy were (1) the belief that many untreated patients would develop persistent purulent nasal drainage, (2) concern that acute otitis media would develop, (3) pressure from mothers to prescribe an antibiotic and/or (4) the desire to allow employed parents to return to work earlier. Amoxicillin was the initial choice for 89% of FP vs. 76% of PD (P = 0.003). Most FP (89%) and PD (97%) were concerned about the increase in bacterial resistance rates arising from unnecessary antibiotic prescribing (P = 0.01). CONCLUSIONS: Most infants and children with acute purulent rhinitis of short duration were treated with antibiotics despite professed concerns over the spread of bacterial resistance; the practice was more prevalent among FP.

Phototherapy is the use of visible light for the treatment of hyperbilirubinemia in the newborn. This relatively common therapy lowers the serum bilirubin level by transforming bilirubin into water-soluble isomers that can be eliminated without conjugation in the liver. The dose of phototherapy is a key factor in how quickly it works; dose in turn is determined by the wavelength of the light, the intensity of the light (irradiance), the distance between the light and the baby, and the body surface area exposed to the light. Commercially available phototherapy systems include those that deliver light via fluorescent bulbs, halogen quartz lamps, light-emitting diodes, and fiberoptic mattresses. Proper nursing care enhances the effectiveness of phototherapy and minimizes complications. Caregiver responsibilities include ensuring effective irradiance delivery, maximizing skin exposure, providing eye protection and eye care, careful attention to thermoregulation, maintaining adequate hydration, promoting elimination, and supporting parent-infant interaction.

INTRODUCTION: Incorporation of clinical decision support systems (CDSSs) into computerized physician order entry assists prescribers with medication dosing, identification of duplicate therapies, drug-allergy alerts and drug-drug interactions (DDIs). The generation of DDI alerts is one aspect of CDSS that may improve patient safety and reduce adverse drug events. AREAS COVERED: Currents issues with the generation of DDI alerts, such as alert fatigue, unclear clinical significance and database inconsistencies are a few of the problems that have been identified with DDI alerting. Research has shown that DDI alerting may be improved through the tiering of alerts, generation of patient-specific alert and directing some alerts to clinicians other than physicians. More research in this area, such as how to decrease the variability of database rating systems, improve the identification of clinically significant alerts and increase the patient specificity of the generated DDI alerts, should be conducted. EXPERT OPINION: DDI knowledgebases need to take into account more patient-specific information. Strategies to avoid alert fatigue, such as DDI tiering and reducing signal:noise ratios, are important areas for future study. End-user participation and clinician feedback should be incorporated in the development of DDI knowledgebases to increase alert compliance.

OBJECTIVE: Our goal was to conduct a prospective, multicentered, comparative study that would objectively verify and explain observed differences in short-term neurodevelopmental outcomes after inflicted versus noninflicted head trauma. METHODS: Children <36 months of age who were hospitalized with acute head trauma confirmed by computed tomography imaging were recruited at multiple sites. Extensive clinical data were captured prospectively, subjects were examined, cranial imaging studies were blindly reviewed, and caregivers underwent scripted interviews. Follow-up neurodevelopmental evaluations were completed 6 months after injury. Head-trauma etiology and mechanisms were categorized by using objective a priori criteria. Thereafter, subject groups with inflicted versus noninflicted etiologies were compared. RESULTS: Fifty-four subjects who met the eligibility criteria were enrolled at 9 sites. Of 52 surviving subjects, 27 underwent follow-up assessment 6 months after injury. Etiology was categorized as noninflicted in 30 subjects, inflicted in 11, and undetermined in 13. Compared with subjects with noninflicted head trauma, subjects with inflicted head trauma (1) more frequently experienced noncontact injury mechanisms, (2) sustained greater injury depth, (3) more frequently manifested acute cardiorespiratory compromise, (4) had lower initial Glasgow Coma Scale scores, (5) experienced more frequent and prolonged impairments of consciousness, (6) more frequently demonstrated bilateral, hypoxic-ischemic brain injury, (7) had lower mental developmental index scores 6 months postinjury, and (8) had lower gross motor quotient scores 6 months postinjury. CONCLUSIONS: Compared with infants with noninflicted head trauma, young victims of inflicted head trauma experience more frequent noncontact injury mechanisms that result in deeper brain injuries, cardiorespiratory compromise, diffuse cerebral hypoxia-ischemia, and worse outcomes.

Key Points Childhood B-ALL patients, including those with VHR features, had favorable outcomes on DFCI 05-001 risk-stratified therapy. IKZF1 deletion was an independent predictor of inferior outcome, including among patients with low end-induction MRD.

OBJECTIVE: Although experts recommend routine screening of hepatic transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) in cases of potential child physical abuse, this practice is highly variable. Our objective was to determine the sensitivity and specificity of routine transaminase testing in young children who underwent consultation for physical abuse. PATIENTS AND METHODS: This was a prospective, multicenter, observational study of all children younger than 60 months referred for subspecialty evaluation of possible physical abuse. The child abuse team at each center recommended screening transaminases routinely as standard of care for all cases with a reasonable concern for physical abuse. Sensitivity and specificity for transaminases and clinical examination findings to detect identified abdominal injuries were determined, and receiver operating characteristic analysis was undertaken. RESULTS: Of 1676 consultations, 1272 (76%) patients underwent transaminase testing, and 54 (3.2% [95% confidence interval: 2.4-4.2]) had identified abdominal injuries. Area under the curve for the highest level of either transaminase was 0.85. Using a threshold level of 80 IU/L for either AST or ALT yielded a sensitivity of 77% and a specificity of 82% (positive likelihood ratio: 4.3; negative likelihood ratio: 0.3). Of injuries with elevated transaminase levels, 14 (26%) were clinically occult, lacking abdominal bruising, tenderness, and distention. Several clinical findings used to predict abdominal injury had high specificity but low sensitivity. CONCLUSIONS: In the population of children with concern for physical abuse, abdominal injury is an important cause of morbidity and mortality, but it is not so common as to warrant universal imaging. Abdominal imaging should be considered for potentially abused children when either the AST or ALT level is >80 IU/L or with abdominal bruising, distention, or tenderness.