This study aimed to establish the time of initiation and the determinants of renal function decline in type 1 diabetes. Until now, such decline has been assumed to be a late-occurring event ...associated with proteinuria. A total of 267 patients with normoalbuminuria and 301 patients with microalbuminuria were followed for 8 to 12 yr. Linear trends (slopes) in GFR were estimated by serial measurement of serum cystatin C. Cases of early renal function decline were defined by loss in cystatin C GFR that exceeded -3.3%/yr, a threshold that corresponds to the 2.5th percentile of the distribution of GFR slopes in an independent nondiabetic normotensive population. Cases of early renal function decline occurred in 9% (mean slope -4.4; range -5.9 to -3.3%/yr) of the normoalbuminuria group and 31% (mean slope -7.1; range -23.8 to -3.3%/yr) of the microalbuminuria group (P < 0.001). Risk for early renal function decline depended on whether microalbuminuria regressed, remained stable, or progressed, rising from 16 to 32 and 68%, respectively (P < 0.001). In multivariate analysis, risk for decline was higher after age 35 yr or when glycosylated hemoglobin exceeded 9% but did not vary with diabetes duration, smoking, BP, or angiotensin-converting enzyme inhibitor treatment. Contrary to the existing paradigm of diabetic nephropathy, progressive renal function decline in type 1 diabetes is an early event that occurs in a large proportion of patients with microalbuminuria. Together with testing for microalbuminuria, clinical protocols using cystatin C to diagnose early renal function decline and track response to therapeutic interventions should be developed.
Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, ...current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.
Research on early renal function decline in diabetes is hampered by lack of simple tools for detecting trends (particularly systematic decreases) in renal function over time when GFR is normal or ...elevated. This study sought to assess how well serum cystatin C meets that need. Thirty participants with type 2 diabetes in the Diabetic Renal Disease Study met these three eligibility criteria: GFR >20 ml/min per 1.73 m2 at baseline (based on cold iothalamate clearance), 4 yr of follow-up, and yearly measurements of iothalamate clearance and serum cystatin C. With the use of linear regression, each individual's trend in renal function over time, expressed as annual percentage change in iothalamate clearance, was determined. Serum cystatin C in mg/L was transformed to its reciprocal (100/cystatin C), and linear regression was used to determine each individual's trend over time, expressed as annual percentage change. In paired comparisons of 100/cystatin C with iothalamate clearance at each examination, the two measures were numerically similar. More important, the trends in 100/cystatin C and iothalamate clearance were strongly correlated (Spearman r = 0.77). All 20 participants with negative trends in iothalamate clearance (declining renal function) also had negative trends for 100/cystatin C. Results were discordant for only three participants. In contrast, the trends for three commonly used creatinine-based estimates of GFR compared poorly with trends in iothalamate clearance (Spearman r < 0.35). Serial measures of serum cystatin C accurately detect trends in renal function in patients with normal or elevated GFR and provide means for studying early renal function decline in diabetes.
In 2013, Utah enacted legislation requiring that infants failing newborn hearing screening be tested for cytomegalovirus infection. As a result, cytomegalovirus-infected infants are being identified ...because of hearing deficits. The neuroimaging findings in this population have not been characterized.
Retrospective medical record review was used to identify patients seen at the University of Utah and Primary Children’s Hospitals in Salt Lake City, Utah, who failed newborn hearing screening. A cohort of patients with congenital cytomegalovirus infection, brain magnetic resonance imaging (MRI), and sedated auditory brainstem response testing was studied.
Seventeen patients were identified; 11 (65%) were female. Confirmatory auditory brainstem response testing, performed at a median age 29 days, showed profound hearing loss in 8 (47%) subjects, severe loss in two (12%), moderate loss in two (12%), and mild loss in three (18%); two (12%) subjects had normal hearing. The diagnosis of cytomegalovirus infection was made at a median age 23 days. Brain imaging was performed at a median age 65 days. Ten (59%) subjects had one or more neuroimaging abnormality. White matter lesions were found in eight (47%) subjects, cysts in three (18%), and stroke in two (12%). Polymicrogyria was identified in two (12%) subjects. Seven (41%) subjects had normal brain MRIs.
These results indicate that most infants whose cytomegalovirus infections were identified after failing newborn hearing screening had abnormal brain MRIs. Our results suggest that brain MRIs should be considered in infants with congenital cytomegalovirus infections who are identified through hearing screening programs.
Neonatal hypoxia-ischemia encephalopathy (HIE) is the leading cause of neonatal death and poor neurodevelopmental outcomes worldwide. Therapeutic hypothermia (TH), while beneficial, still leaves many ...HIE treated infants with lifelong disabilities. Furthermore, infants undergoing TH often require treatment for pain and agitation which may lead to further brain injury. For instance, morphine use in animal models has been shown to induce neuronal apoptosis. Dexmedetomidine is a potent α
-adrenergic receptor agonist that may be a better alternative to morphine for newborns with HIE treated with TH. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress ventilation. Importantly, there is increasing evidence that dexmedetomidine has neuroprotective properties. Even though there are limited data on pharmacokinetics (PK), safety and efficacy of dexmedetomidine in infants with HIE, it has been increasingly administered in many centers.
To review the current approach to treatment of pain, sedation and shivering in infants with HIE undergoing TH, and to describe a new phase II safety and pharmacokinetics randomized controlled trial that proposes the use of dexmedetomidine vs. morphine in this population.
This article presents an overview of the current management of pain and sedation in critically ill infants diagnosed with HIE and undergoing TH for 72 h. The article describes the design and methodology of a randomized, controlled, unmasked multicenter trial of dexmedetomidine vs. morphine administration enrolling 50 (25 per arm) neonates ≥36 weeks of gestation with moderate or severe HIE undergoing TH and that require pain/sedation treatment.
Dexmedetomidine may be a better alternative to morphine for the treatment of pain and sedation in newborns with HIE treated with TH. There is increasing evidence that dexmedetomidine has neuroprotective properties in several preclinical studies of injury models including ischemia-reperfusion, inflammation, and traumatic brain injury as well as adult clinical trials of brain trauma. The Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE) trial will evaluate whether administration of dexmedetomidine vs. morphine is safe, establish dexmedetomidine optimal dosing by collecting opportunistic PK data, and obtain preliminary neurodevelopmental data to inform a large Phase III efficacy trial with long term neurodevelopment impairment as the primary outcome.
Background
Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the ...effectiveness of targeted gene panels for these purposes remains unknown.
Methods
RapSeq, a newly developed panel targeting 4,503 disease‐causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences.
Results
A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control.
Conclusions
This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.
This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants in the NICU/PICU/CICU. This study shows for the first time that rapid sequencing of a panel that includes the majority of known disease‐causing genes has a diagnostic yield similar to previously published rates for rapid exome and genome sequencing. Early diagnosis appeared to have a positive impact on clinical management.
Abstract Objective Elevated rates of epilepsy and motor impairments including cerebral palsy are seen in children who were born prematurely. Maternal antenatal magnesium supplementation has been ...associated with decreased rates of cerebral palsy in infants born prematurely. Our objective was to determine whether the neonatal serum magnesium level between 24 and 48 hours following birth is associated with better long-term neurodevelopmental outcomes (epilepsy, motor impairment) in premature infants. Methods We performed a retrospective cohort analysis in infants born <37 weeks gestation over a 10-year period. Prenatal, perinatal, and postnatal clinical and demographic information was collected. Crude and adjusted odds ratios were estimated under generalized linear models with generalized estimating equations to examine the association of the neonatal serum magnesium level between 24 and 48 hours following birth with the risk of epilepsy and/or motor impairment (spasticity; hypotonia; cerebral palsy). Results The final cohort included 5,461 infants born <37 weeks gestation from 2002-2011. The adjusted relative risk ratio (RR) for the combined outcomes of epilepsy and/or motor impairment, controlling for gestational age, current age, maternal magnesium supplementation, maternal steroid administration, five minute Apgar score, neonatal infection, need for vasopressor use, and birth weight; and with serum magnesium level as the main independent variable, was 0.85 ( p 0.24). Stratified analyses by gestational age <32 weeks or >32 weeks were not significantly associated with adverse neurodevelopmental outcome (respectively RR 0.79 and 1.2, p 0.12 and 0.49). A multivariate analysis for the risk of motor impairment alone had a RR of 0.94 ( p 0.72). Conclusion This study shows that the neonatal magnesium level between 24 and 48 hours of life in premature infants is not significantly associated with the risk for developing epilepsy or motor impairment.
Patients admitted to the neonatal intensive care unit (NICU) have higher association for neurodevelopment deficits, specifically cerebral palsy (CP). We identified patients with risk for CP using ...abnormal Pretchl's General Movement Assessment (GMA) and sub-category of cramped synchronized movements (CSM) and reported their feeding outcomes at discharge. Over 75 % of these patients required either nasogastric (NGT) or gastrostomy tube (GT) at discharge. Of these, 57 % weaned off their NGT or GT at home and 43 % of patients still needed a GT one year after discharge. Of those that could not wean off their NGT or GT, these patients had longer hospital stay, took lower percentage by mouth, and an older post-menstrual age at discharge. We did not find a difference in NGT or GT use between patients with IVH, ELBW, nor between their birthweight or gestation age at birth. This study provides further clinical characteristics in NICU patients who have higher risk of CP, and supports the need for skilled feeding therapy and resources both during and after NICU admission.
•Neonates admitted to a neonatal-intensive care unit have higher association for cerebral palsy•Cerebral palsy can be predicted in neonates using Pretchl’s General Movement Assessments (GMA) exam, specifically (+) cramped synchronized movement (CSM)•Neonates with CSMs are highly likely to need enteral feeding tube upon discharge•Majority of infants will overcome their feeding dysfunction at home, but some may have severe features of feeding dysfunction that will require a g-tube
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