Matthew B. Wallenstein

Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP): five years of screening with telemedicine.

BACKGROUND AND OBJECTIVE To report the 5-year results of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) telemedicine initiative. PATIENTS AND METHODS Infants requiring retinopathy of prematurity (ROP) screening at six neonatal intensive care units from December 1, 2005, to November 30, 2010, were evaluated with remote retinal photography by an ROP specialist. Every infant received outpatient binocular indirect ophthalmoscope examinations until termination criteria were achieved or until treatment. Outcomes were treatment-warranted ROP (TW-ROP, ETROP type 1) and adverse anatomical events. RESULTS Five hundred eleven infants (1,022 eyes) were screened. Fifteen infants had TW-ROP and underwent laser photocoagulation. The TW-ROP cohort had significantly lower birth weight and gestational age (both P < .001). No patient progressed to adverse anatomical outcomes and no case of TW-ROP was missed. Tele-medicine had 100% sensitivity, 99.8% specificity, 93.8% positive predictive value, and 100% negative predictive value for detection of TW-ROP. CONCLUSION Telemedicine demonstrates high diagnostic accuracy for detection of TW-ROP and can complement ROP screening.

SUNDROP: six years of screening for retinopathy of prematurity with telemedicine

OBJECTIVE To report the 6-year results of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative in the context of telemedicine screening initiatives for retinopathy of prematurity (ROP). DESIGN A retrospective analysis. PARTICIPANTS Premature newborns requiring ROP screening at 6 neonatal intensive care units from December 1, 2005, to November 30, 2011. METHODS Infants were evaluated via remote retinal photography by an ROP specialist. A total of 608 preterm infants meeting ROP examination criteria were screened with the RetCam II/III (Clarity Medical Systems, Pleasanton, Calif.). Primary outcomes were treatment-warranted ROP (TW-ROP) and adverse anatomical events. RESULTS During the 6 years, 1216 total eyes were screened during 2169 examinations, generating 26 970 retinal images, an average of 3.56 examinations and 44.28 images per patient. Twenty-two (3.6%) of the infants screened met criteria for TW-ROP. Compared with bedside binocular ophthalmoscopy, remote interpretation of RetCam II/III images had a sensitivity of 100%, specificity of 99.8%, positive predicative value of 95.5%, and negative predicative value of 100% for the detection of TW-ROP. No adverse anatomical outcomes were observed for any enrolled patient. CONCLUSIONS The 6-year results for the SUNDROP telemedicine initiative were highly favourable with respect to diagnostic accuracy. Telemedicine appears to be a safe, reliable, and cost-effective complement to the efforts of ROP specialists, capable of increasing patient access to screening and focusing the resources of the current ophthalmic community on infants with potentially vision-threatening disease.

Fever literacy and fever phobia.

Objective. To identify the percentage of parents who define the threshold for fever between 38.0°C and 38.3°C, which has not been reported previously, and to describe parental attitudes toward fever and antipyretic use. Study Design. Thirteen-question survey study of caregivers. Results. Overall, 81% of participants defined the threshold for fever as <38.0°C, 0% correctly defined fever between 38.0°C and 38.3°C, and 19% defined fever as >38.3°C. Twenty percent of children brought to clinic for a chief complaint of fever were never truly febrile. Ninety-three percent of participants believed that high fever can cause brain damage. For a comfortable-appearing child with fever, 89% of caregivers reported that they would give antipyretics and 86% would schedule a clinic visit. Conclusion. Our finding that 0% of parents correctly defined fever is both surprising and unsettling, and it should inform future discussions of fever between parents and clinicians.

A Randomized Clinical Trial of Therapeutic Hypothermia Mode during Transport for Neonatal Encephalopathy

OBJECTIVE To determine if temperature regulation is improved during neonatal transport using a servo-regulated cooling device when compared with standard practice. STUDY DESIGN We performed a multicenter, randomized, nonmasked clinical trial in newborns with neonatal encephalopathy cooled during transport to 9 neonatal intensive care units in California. Newborns who met institutional criteria for therapeutic hypothermia were randomly assigned to receive cooling according to usual center practices vs device servo-regulated cooling. The primary outcome was the percentage of temperatures in target range (33°-34°C) during transport. Secondary outcomes included percentage of newborns reaching target temperature any time during transport, time to target temperature, and percentage of newborns in target range 1 hour after cooling initiation. RESULTS One hundred newborns were enrolled: 49 to control arm and 51 to device arm. Baseline demographics did not differ with the exception of cord pH. For each subject, the percentage of temperatures in the target range was calculated. Infants cooled using the device had a higher percentage of temperatures in target range compared with control infants (median 73% [IQR 17-88] vs 0% [IQR 0-52], P < .001). More subjects reached target temperature during transport using the servo-regulated device (80% vs 49%, P <.001), and in a shorter time period (44 ± 31 minutes vs 63 ± 37 minutes, P = .04). Device-cooled infants reached target temperature by 1 hour with greater frequency than control infants (71% vs 20%, P < .001). CONCLUSIONS Cooling using a servo-regulated device provides more predictable temperature management during neonatal transport than does usual care for outborn newborns with neonatal encephalopathy.

RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome

Germline mutations in RASA1 are associated with capillary malformation‐arteriovenous malformation (CM‐AVM) syndrome. CM‐AVM syndrome is characterized by multi‐focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 “second hits” from vascular malformations associated with CM‐AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole‐exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR‐amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the probands mother was also obtained, and next‐generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic “second hits” are required for the development of vascular anomalies associated with CM‐AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1‐related disorders.

Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP): Four-years of Screening with Telemedicine

Abstract Purpose: To report the four-year experience of the Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) telemedicine initiative, which was developed to reduce the risk of blindness from retinopathy of prematurity (ROP). Materials and methods: A retrospective analysis of the SUNDROP archival data between 12/1/2005 and 11/30/2009. A total of 410 consecutively enrolled infants meeting ROP screening criteria had nurse-obtained fundoscopic images evaluated remotely by an ROP specialist. Every infant then received at least one dilated bedside binocular indirect ophthalmoscope (BIO) examination within one week of discharge. All infants were then followed with both telemedicine images and bedside evaluation in clinic according to recommended screening timelines. Primary outcomes were treatment-warranted ROP (TW-ROP), defined as Early Treatment of ROP Type 1, and adverse anatomical outcomes. Results: The SUNDROP telemedicine screening initiative has not missed any TW-ROP in its four-year evaluation period. A total of 410 infants (820 eyes) were imaged, resulting in 1486 examinations and 18,097 unique images. An average of 12.2 images were obtained per patient. Fourteen infants met TW-ROP criteria on telemedicine examination. After bedside evaluation, 13 infants required laser photocoagulation and one was followed until he spontaneously regressed. Infants with TW-ROP had a significantly lower gestational age (24.9 weeks), birth weight (658.7 grams), and were more likely to be male than the no TW-ROP cohort (all p values <0.00001). Telemedicine had a calculated sensitivity of 100%, specificity of 99.8%, positive predicative value of 92.9% and negative predictive value of 100% for the detection of TW-ROP. No patient progressed to retinal detachment or any adverse anatomical outcome. Conclusions: The SUNDROP initiative demonstrated a high degree of diagnostic reliability and was able to capture all infants with TW-ROP. Telemedicine offers a cost-effective, reliable and accurate screening methodology for identifying infants with TW-ROP without sacrificing quality of care.

Failed endotracheal intubation and adverse outcomes among extremely low birth weight infants.

Objective:To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.Study Design:A retrospective chart review was conducted for all ELBW infants ⩽1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first 5 min of life or if intubation was attempted during the first 10 min of life with heart rate <100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender and antenatal steroids.Results:The study sample included 88 ELBW infants. Forty percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared with 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 to 1.0), P<0.05.Conclusion:Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.

Periconceptional nutrient intakes and risks of orofacial clefts in California

Background:Evidence indicates that maternal nutrient intake may play a role in the development of birth defects. We investigated the association of maternal periconceptional intake of vitamin supplements and dietary nutrients with risk of developing cleft palate (CP) and cleft lip with or without cleft palate (CLP).Methods:Data were from a population-based, case–control study of fetuses and liveborn infants delivered in California in 1999–2003. Analyses included 170 cases with CP, 425 with CLP, and 534 nonmalformed controls. Dietary intake was estimated from a food frequency questionnaire.Results:Vitamin supplement intake was associated with a modestly decreased risk of clefts, but the confidence intervals (CIs) include 1.0. Among women who did not use vitamin supplements, dietary intake of several micronutrients was associated with risk of clefts. We found at least a twofold elevated risk of CP with low intake of riboflavin, magnesium, calcium, vitamin B12, and zinc; all CIs excluded 1.0. For CLP, we found at least a twofold elevated risk with low intake of niacin, riboflavin, vitamin B12, and calcium, and a decreased risk with high intake of folate and cryptoxanthin; all CIs excluded 1.0.Conclusion:The results suggest that periconceptional nutrient intake may be associated with risk of CP and CLP.

Heme Oxygenase-1 Expression Affects Murine Abdominal Aortic Aneurysm Progression

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is a cytoprotective enzyme upregulated in the vasculature by increased flow and inflammatory stimuli. Human genetic data suggest that a diminished HO-1 expression may predispose one to abdominal aortic aneurysm (AAA) development. In addition, heme is known to strongly induce HO-1 expression. Utilizing the porcine pancreatic elastase (PPE) model of AAA induction in HO-1 heterozygous (HO-1+/-, HO-1 Het) mice, we found that a deficiency in HO-1 leads to augmented AAA development. Peritoneal macrophages from HO-1+/- mice showed increased gene expression of pro-inflammatory cytokines, including MCP-1, TNF-alpha, IL-1-beta, and IL-6, but decreased expression of anti-inflammatory cytokines IL-10 and TGF-beta. Furthermore, treatment with heme returned AAA progression in HO-1 Het mice to a wild-type profile. Using a second murine AAA model (Ang II-ApoE-/-), we showed that low doses of the HMG-CoA reductase inhibitor rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression in the absence of lipid lowering. Our results support those studies that suggest that pleiotropic statin effects might be beneficial in AAA, possibly through the upregulation of HO-1. Specific targeted therapies designed to induce HO-1 could become an adjunctive therapeutic strategy for the prevention of AAA disease.

Mediastinal Kaposiform Hemangioendothelioma and Kasabach-Merritt Phenomenon in a Patient with no Skin Changes and a Normal Chest CT

A 16-month-old previously healthy boy was admitted to the hospital with respiratory distress and thrombocytopenia. Initial workup demonstrated large pleural and pericardial effusions. The patient had no cutaneous abnormality on physical examination, and his initial chest CT (computed tomography) was nondiagnostic. He required multiple platelet transfusions, chest tube placement, and pericardiocentesis. Sixteen days after admission, a chest MRI (magnetic resonance imaging) revealed a large infiltrative mass of the superior mediastinum, consistent with kaposiform hemangioendothelioma (KHE). The patients thrombocytopenia was due to associated Kasabach-Merritt phenomenon (KMP). The patient now has complete resolution of KMP after medical treatment with prednisolone, aminocaproic acid, vincristine, and aspirin.