Ari J. Wassner

Rates of Medical Errors and Preventable Adverse Events Among Hospitalized Children Following Implementation of a Resident Handoff Bundle

IMPORTANCE Handoff miscommunications are a leading cause of medical errors. Studies comprehensively assessing handoff improvement programs are lacking. OBJECTIVE To determine whether introduction of a multifaceted handoff program was associated with reduced rates of medical errors and preventable adverse events, fewer omissions of key data in written handoffs, improved verbal handoffs, and changes in resident-physician workflow. DESIGN, SETTING, AND PARTICIPANTS Prospective intervention study of 1255 patient admissions (642 before and 613 after the intervention) involving 84 resident physicians (42 before and 42 after the intervention) from July-September 2009 and November 2009-January 2010 on 2 inpatient units at Boston Childrens Hospital. INTERVENTIONS Resident handoff bundle, consisting of standardized communication and handoff training, a verbal mnemonic, and a new team handoff structure. On one unit, a computerized handoff tool linked to the electronic medical record was introduced. MAIN OUTCOMES AND MEASURES The primary outcomes were the rates of medical errors and preventable adverse events measured by daily systematic surveillance. The secondary outcomes were omissions in the printed handoff document and resident time-motion activity. RESULTS Medical errors decreased from 33.8 per 100 admissions (95% CI, 27.3-40.3) to 18.3 per 100 admissions (95% CI, 14.7-21.9; P < .001), and preventable adverse events decreased from 3.3 per 100 admissions (95% CI, 1.7-4.8) to 1.5 (95% CI, 0.51-2.4) per 100 admissions (P = .04) following the intervention. There were fewer omissions of key handoff elements on printed handoff documents, especially on the unit that received the computerized handoff tool (significant reductions of omissions in 11 of 14 categories with computerized tool; significant reductions in 2 of 14 categories without computerized tool). Physicians spent a greater percentage of time in a 24-hour period at the patient bedside after the intervention (8.3%; 95% CI 7.1%-9.8%) vs 10.6% (95% CI, 9.2%-12.2%; P = .03). The average duration of verbal handoffs per patient did not change. Verbal handoffs were more likely to occur in a quiet location (33.3%; 95% CI, 14.5%-52.2% vs 67.9%; 95% CI, 50.6%-85.2%; P = .03) and private location (50.0%; 95% CI, 30%-70% vs 85.7%; 95% CI, 72.8%-98.7%; P = .007) after the intervention. CONCLUSIONS AND RELEVANCE Implementation of a handoff bundle was associated with a significant reduction in medical errors and preventable adverse events among hospitalized children. Improvements in verbal and written handoff processes occurred, and resident workflow did not change adversely.

A Standardized Assessment of Thyroid Nodules in Children Confirms Higher Cancer Prevalence Than in Adults

CONTEXT Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated. OBJECTIVE The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan. DESIGN AND SETTING Boston Childrens Hospital and Brigham and Womens Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) ≥ 1 cm, ultrasound-guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods. PATIENTS AND RESULTS Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02). CONCLUSIONS Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules ≥ 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted.

Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

Nephrolithiasis is a prevalent condition with a high morbidity. Although dozens of monogenic causes have been identified, the fraction of single-gene disease has not been well studied. To determine the percentage of cases that can be molecularly explained by mutations in 1 of 30 known kidney stone genes, we conducted a high-throughput mutation analysis in a cohort of consecutively recruited patients from typical kidney stone clinics. The cohort comprised 272 genetically unresolved individuals (106 children and 166 adults) from 268 families with nephrolithiasis (n=256) or isolated nephrocalcinosis (n=16). We detected 50 likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 14.9% (40 of 268) of all cases; 20 of 50 detected mutations were novel (40%). The cystinuria gene SLC7A9 (n=19) was most frequently mutated. The percentage of monogenic cases was notably high in both the adult (11.4%) and pediatric cohorts (20.8%). Recessive causes were more frequent among children, whereas dominant disease occurred more abundantly in adults. Our study provides an in-depth analysis of monogenic causes of kidney stone disease. We suggest that knowledge of the molecular cause of nephrolithiasis and nephrocalcinosis may have practical implications and might facilitate personalized treatment.

Congenital hypothyroidism: recent advances.

Purpose of reviewThis review summarizes significant recent advances in the epidemiology, pathophysiology, and treatment of congenital hypothyroidism. Recent findingsThe apparent incidence of congenital hypothyroidism has more than doubled in recent years because of several factors, including more inclusive diagnostic criteria, shifting demographics, and increasing survival of preterm infants. The greatest increase has occurred in mildly affected patients, many of whom have a eutopic thyroid gland. Congenital hypothyroidism may be transient or persistent, but the natural history cannot be predicted by severity at diagnosis. In premature infants, who are especially vulnerable to hypothyroidism, the rise in thyroid-stimulating hormone may be delayed and therefore detected only by routine follow-up screening. Recent studies of defects in thyroid hormone synthesis have focused on the role of mutations in the dual oxidase system and of a novel apical iodide transporter, anoctamin 1. Finally, emerging data suggest that exposure to excess thyroid hormone may be as harmful as hypothyroidism to long-term cognitive development. SummaryAlthough newborn screening has virtually eradicated mental retardation due to congenital hypothyroidism in parts of the world, new information continues to accumulate and new questions to arise about the diagnosis, physiology, and optimal management of this disorder.

Prevalence of Monogenic Causes in Pediatric Patients with Nephrolithiasis or Nephrocalcinosis

BACKGROUND AND OBJECTIVES Nephrolithiasis is a prevalent condition that affects 10%-15% of adults in their lifetime. It is associated with high morbidity due to colicky pain, the necessity for surgical intervention, and sometimes progression to CKD. In recent years, multiple monogenic causes of nephrolithiasis and nephrocalcinosis have been identified. However, the prevalence of each monogenic gene in a pediatric renal stone cohort has not yet been extensively studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS To determine the percentage of cases that can be explained molecularly by mutations in one of 30 known nephrolithiasis/nephrocalcinosis genes, we conducted a high-throughput exon sequencing analysis in an international cohort of 143 individuals <18 years of age, with nephrolithiasis (n=123) or isolated nephrocalcinosis (n=20). Over 7 months, all eligible individuals at three renal stone clinics in the United States and Europe were approached for study participation. RESULTS We detected likely causative mutations in 14 of 30 analyzed genes, leading to a molecular diagnosis in 16.8% (24 of 143) of affected individuals; 12 of the 27 detected mutations were not previously described as disease causing (44.4%). We observed that in our cohort all individuals with infantile manifestation of nephrolithiasis or nephrocalcinosis had causative mutations in recessive rather than dominant monogenic genes. In individuals who manifested later in life, causative mutations in dominant genes were more frequent. CONCLUSIONS We present the first exclusively pediatric cohort examined for monogenic causes of nephrolithiasis/nephrocalcinosis, and suggest that important therapeutic and preventative measures may result from mutational analysis in individuals with early manifestation of nephrolithiasis or nephrocalcinosis.

Hypothyroidism in the newborn period.

Purpose of reviewThis review summarizes significant advances in the epidemiology, pathophysiology and treatment of congenital hypothyroidism, with a focus on thyroid dysfunction in preterm infants. Recent findingsCongenital hypothyroidism appears to be increasing in incidence, primarily due to increased stringency of screening strategies, with smaller contributions from changing demographics and improved survival of increasingly premature infants. The greatest increase has been in mildly affected infants. Although many such cases are transient, some eventually prove to be severe and/or permanent. In preterm infants, transient hypothyroidism is common and may be delayed in onset. The cause is probably multifactorial, and inadequate iodine intake may contribute to some cases. Transient hypothyroxinemia of prematurity, also common in premature infants, is correlated with markers of inflammation. Despite concern about the potential morbidity of transient hypothyroxinemia of prematurity, the benefits and safety of treatment have not been established. Novel genetic causes of congenital hypothyroidism continue to be identified, and accumulating data support the sensitivity of infants with severe congenital hypothyroidism to small changes in levothyroxine formulation. SummaryChanges in newborn screening strategies have increasingly identified thyroid function abnormalities of unclear clinical significance. Novel causes of congenital hypothyroidism continue to be identified, and new data continue to emerge regarding optimal therapy.

Severe hypercalcaemia due to subcutaneous fat necrosis: presentation, management and complications

Objective Subcutaneous fat necrosis (SCFN) is a rare form of panniculitis in infants that generally occurs following birth trauma, meconium aspiration, or therapeutic cooling. Severe hypercalcaemia occurs in a subset of patients, but data on its presentation, management and outcomes are limited. This report details the clinical course and complications of infants treated for severe hypercalcaemia (peak serum calcium ≥3.0 mmol/L) due to SCFN. Design Chart review of all infants with SCFN seen at a single paediatric centre over a 13-year period. Patients Seven infants with SCFN developed severe hypercalcaemia, with median peak serum calcium 4.1 mmol/L (range 3.3–5.1). Results Severe hypercalcaemia occurred before 6 weeks of age, and was asymptomatic in 3/7 patients (43%). Most patients were treated with intravenous hydration, furosemide, glucocorticoids and low-calcium formula, which restored normocalcaemia in a median of 9 days (range 2–42). Fever developed during treatment in 4/7 infants (57%): two patients had bacterial infections and two had no infectious source identified. Nephrocalcinosis was present in 5/6 patients (83%) who were evaluated by renal ultrasound. Nephrocalcinosis failed to resolve in all cases over a median follow-up of 20 months (range 8–48), but no renal dysfunction was observed. Eosinophilia, which has not been reported previously in SCFN, was present in 6/7 patients (86%). Conclusions In this largest series to date of infants with severe hypercalcaemia due to SCFN, novel findings include the common occurrence of fever and a high incidence of persistent nephrocalcinosis without evidence of adverse renal outcomes.

Mutations in SLC26A1 Cause Nephrolithiasis

Nephrolithiasis, a condition in which urinary supersaturation leads to stone formation in the urinary system, affects about 5%-10% of individuals worldwide at some point in their lifetime and results in significant medical costs and morbidity. To date, mutations in more than 30 genes have been described as being associated with nephrolithiasis, and these mutations explain about 15% of kidney stone cases, suggesting that additional nephrolithiasis-associated genes remain to be discovered. To identify additional genes whose mutations are linked to nephrolithiasis, we performed targeted next-generation sequencing of 18 hypothesized candidate genes in 348 unrelated individuals with kidney stones. We detected biallelic mutations in SLC26A1 (solute carrier family 26 member 1) in two unrelated individuals with calcium oxalate kidney stones. We show by immunofluorescence, immunoblotting, and glycosylation analysis that the variant protein mimicking p.Thr185Met has defects in protein folding or trafficking. In addition, by measuring anion exchange activity of SLC26A1, we demonstrate that all the identified mutations in SLC26A1 result in decreased transporter activity. Our data identify SLC26A1 mutations as causing a recessive Mendelian form of nephrolithiasis.

Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and nephrocalcinosis

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Isolated Central Hypothyroidism in Young Siblings as a Manifestation of PROP1 Deficiency: Clinical Impact of Whole Exome Sequencing

Background/Aims: Central hypothyroidism (CH) in children is rare and may be due to a variety of genetic defects. Most of these defects, but not all, are associated with additional pituitary hormone deficits. In a young child presenting with CH, it is important to determine whether additional pituitary hormone deficiencies are present, but this may be difficult to establish clinically. Methods: We describe the clinical characteristics of two young siblings, aged 6 months and 2 years, presenting with isolated CH. Whole exome sequencing was performed to determine the genetic basis of isolated CH. Results: A homozygous frameshift mutation of PROP1 (296delGA) was identified in both probands. Defects in PROP1 cause progressive deficiency of multiple pituitary hormones. Based on this genetic diagnosis, further clinical testing was performed that demonstrated growth hormone deficiency in one sibling. Conclusions: PROP1 deficiency may present as isolated CH at a very young age. In disorders with multiple potential causative genes, whole exome sequencing may facilitate rapid genetic diagnosis and lead to important changes in clinical management.