Feeding and developmental outcomes after neonatal seizures-A prospective observational study.

Objective: Among neonates with acute symptomatic seizures, we evaluated whether inability to take full feeds at time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables. Methods: This prospective, 9-center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures including: evidence of brainstem injury on MRI, mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. Inability to take oral feeds was identified through review of medical records. Brainstem injury was identified through central review of neonatal MRIs. Developmental outcomes were assessed with the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 12, 18, and 24 months corrected age. Results: Among 276 infants, inability to achieve full oral feeds was associated with lower total WIDEA-FS scores (160.2±25.5 for full oral feeds vs. 121.8±42.9 for some/no oral feeds at 24 months, p<0.001). At 12 months, a G-tube was required for 23 of the 49 (47%) infants who did not achieve full oral feeds, compared with 2 of the 221 (1%) who took full feeds at discharge (p<0.001). Conclusions: Inability to take full oral feeds upon hospital discharge is an objective clinical sign that can identify infants with acute symptomatic neonatal seizures who are at high risk for impaired development at 24 months.

De-Prescribing Proton Pump Inhibitors in Patients With End Stage Kidney Disease: A Quality Improvement Project.

Background: Proton pump inhibitors (PPIs) are widely prescribed and may be associated with harm; hypomagnesemia and reduced effectiveness of calcium carbonate phosphate binders may be important in end-stage kidney disease (ESKD). Objectives: Our objectives included (1) discontinuing PPIs and H2 blockers and (2) assessing the impact on serum magnesium and markers of mineral metabolism. Design: Prospective cohort. Setting: Satellite hemodialysis unit of a tertiary care hospital. Patients: Incident and prevalent patients with ESKD treated with hemodialysis. Measurements: We assessed the impact of stopping PPI/H2 blockers in patients who did not have an absolute indication as per guidelines in the general population; serum magnesium, calcium, and phosphate were measured before and approximately 8 weeks later. Analysis of variance (ANOVA) test and Kruskal-Wallis was used to describe the population. Wilcoxon signed rank test for the paired change scores (from pre to post). Methods: The electronic medical record (EMR) was extensively searched for absolute indications for a PPI. Results were reviewed with the primary nephrology team before approaching patients about stopping the PPI. Basic demographic information and select medications were also collected. Results: Electronic medical records were reviewed for 179 patients, 74 had a PPI or H2 antagonist or both on their medication list (43%); 23 (31%) were assessed as appropriate. After primary team and patient review, 29 patients agreed to a trial of PPI withdrawal. Fourteen patients restarted their PPI, most for gastroesophageal reflux disease. Three patients had a GI bleed, 1 fatally. Serum calcium (P = .17) and the dose of phosphate binders (P = .075) did not change but serum phosphate increased (1.55 [0.29] to 1.85 [0.34] mmol/L; P = .0005). Serum magnesium also increased (1.01 [0.16] to 1.06 [0.14] mmol/L; P = .01). Limitations: Small patient numbers and observational nature of the study does not establish causation in this population at high risk to experience a gastrointestinal bleed. Conclusions: Our results suggest that PPI deprescribing as recommended in the general population may be associated with harm in patients with ESKD and requires further study. Trial Registration: Not registered.

Contexte: Les inhibiteurs de la pompe à protons (IPP) sont largement prescrits et peuvent être associés à une atteinte rénale; l'hypomagnésémie et la réduction de l'efficacité des chélateurs de phosphate à base de carbonate de calcium peuvent devenir significatifs chez les patients avec insuffisance rénale terminale (IRT). Objectifs: Nos objectifs comprenaient 1) l'arrêt des IPP et des antagonistes H2 et 2) l'évaluation des conséquences sur le taux de magnésium sérique et les marqueurs du métabolisme minéral. Conception: Étude de cohorte prospective. Cadre: L'unité d'hémodialyse satellite d'un hôpital de soins tertiaires. Sujets: Patients incidents et prévalents atteints d'IRT et traités par hémodialyse. Mesures: Nous avons évalué les conséquences de l'arrêt des IPP et antagonistes H2 chez les patients qui n'avaient pas d'indication absolue pour ces médicaments, conformément aux directives pour la population générale. Les taux sériques de magnésium, de calcium et de phosphate ont été mesurés avant l'arrêt et environ huit semaines plus tard. Les tests ANOVA et Kruskal-Wallis ont été utilisés pour décrire la population, et le test de rang de Wilcoxon pour les scores de changement appariés (de pré à post-intervention). Méthodologie: Les dossiers médicaux électroniques (DMÉ) ont été consultés rigoureusement à la recherche d'une indication absolue pour un IPP. Les résultats ont été revus avec l'équipe de néphrologie primaire avant d'approcher les patients quant à un arrêt des IPP. Les données démographiques initiales et les prescriptions pour certains médicaments ont également été recueillies. Résultats: Les DMÉ de 179 patients ont été consultés, révélant que 74 (43 %) d'entre eux prenaient soit un IPP, soit un antagoniste H2, soit les deux; chez 23 patients (31 %) la prescription était appropriée. Après évaluation par l'équipe médicale et discussion avec les patients, 29 patients ont accepté de cesser l'IPP. Quatorze patients ont recommencé les IPP, la plupart pour un reflux gastro-œsophagien. Trois patients ont souffert d'une hémorragie gastro-intestinale, dont une s'est avérée fatale. Le taux de calcium sérique (p=0,17) et la dose de chélateurs du phosphate (p=0,075) n'ont pas changé, mais le taux de phosphate sérique a augmenté (1,55 [0,29] à 1,85 [0,34] mmol/L; p=0,0005), tout comme le taux de magnésium sérique (1,01 [0,16] à 1,06 [0,14] mmol/L; p=0,01). Limites: Le faible échantillon de patients et la nature observationnelle de l'étude ne permettent pas d'établir un lien de causalité dans cette population présentant un risque élevé d'hémorragie gastro-intestinale. Conclusion: Nos résultats suggèrent que la déprescription des IPP recommandée dans la population générale pourrait être associée à un préjudice chez les patients atteints d'IRT. Des études plus approfondies sont nécessaires. Enregistrement de l'essai: Non enregistré.

New Pharmacologic Approaches to Bronchopulmonary Dysplasia.

Bronchopulmonary Dysplasia is the most common long-term respiratory morbidity of preterm infants, with the risk of development proportional to the degree of prematurity. While its pathophysiologic and histologic features have changed over time as neonatal demographics and respiratory therapies have evolved, it is now thought to be characterized by impaired distal lung growth and abnormal pulmonary microvascular development. Though the exact sequence of events leading to the development of BPD has not been fully elucidated and likely varies among patients, it is thought to result from inflammatory and mechanical/oxidative injury from chronic ventilatory support in fragile, premature lungs susceptible to injury from surfactant deficiency, structural abnormalities, inadequate antioxidant defenses, and a chest wall that is more compliant than the lung. In addition, non-pulmonary issues may adversely affect lung development, including systemic infections and insufficient nutrition. Once BPD has developed, its management focuses on providing adequate gas exchange while promoting optimal lung growth. Pharmacologic strategies to ameliorate or prevent BPD continue to be investigated. A variety of agents, to be reviewed henceforth, have been developed or re-purposed to target different points in the pathways that lead to BPD, including anti-inflammatories, diuretics, steroids, pulmonary vasodilators, antioxidants, and a number of molecules involved in the cell signaling cascade thought to be involved in the pathogenesis of BPD.

Safe Medication Disposal.

Safe disposal of expired or unused medications is essential for individual and environmental safety, yet many patients report not having received education on proper medication disposal. Unused medications in homes and improper medication disposal create various risks including intentional or accidental misuse, overdose, addiction in humans, as well as toxic effects in pets. As part of their community health clinical experience, senior nursing students from the University of Pennsylvania School of Nursing visited patients of a large home care and hospice agency in a Philadelphia suburb throughout the semester. A survey conducted with a small number (N = 15) of home care patients suggested the majority of patients had inadequate knowledge about safe medication disposal. The nursing students created and presented a tip sheet on safe medication disposal and a list of local prescription medication disposal sites to home care patients. They also obtained and provided medication disposal bags for patients and caregivers who were unable to get to medication disposal sites.

Severe Acute Kidney Injury Following Stage 1 Norwood Palliation: Effect on Outcomes and Risk of Severe Acute Kidney Injury at Subsequent Surgical Stages.

OBJECTIVES: To identify associations of severe acute kidney injury early after stage 1 (Norwood) operation with risk of severe acute kidney injury and comorbidities at subsequent palliative stages in patients with hypoplastic left heart syndrome and other single ventricle lesions with left-sided obstruction. DESIGN: Retrospective cohort study. Severe acute kidney injury defined as Kidney Disease Improving Global Outcomes stage 3. SETTING: Single pediatric cardiac center. PATIENTS: Infants less than or equal to 28 days old with single ventricle physiology and left-sided obstruction undergoing stage 1 operation between September 2007 and November 2012 (n = 136). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The occurrence rate of severe acute kidney injury was 21% (28/136) following stage 1, 12% (12/98) following stage 2 palliation (superior cavo-pulmonary anastomosis), and 10% (7/73) following stage 3 palliation (total cavo-pulmonary anastomosis). Severe acute kidney injury early after stage 1 operation was significantly associated with continuous intravenous loop diuretic infusion, need for extracorporeal membrane oxygenation, and in-hospital death (all p < 0.05). Gestational age at birth was associated with severe acute kidney injury at stage 2 (p = 0.04) and stage 3 (p = 0.01). Severe acute kidney injury at stage 1 was an independent risk factor for severe acute kidney injury at stage 2 (adjusted odds ratio, 4.3; 95% CI, 1.1-16.9; p = 0.04). Development of severe acute kidney injury after stage 1 was associated with longer mechanical ventilation time after stage 3 (p = 0.047). CONCLUSIONS: Severe acute kidney injury after stage 1 palliation was an independent risk factor for developing severe acute kidney injury at stage 2, and was associated with prolonged duration of mechanical ventilation following stage 3. Information on the incidence and associated risk factors for postoperative acute kidney injury in hypoplastic left heart syndrome patients from multiple congenital heart centers is a necessary next step to further understand the long-term burden of severe acute kidney injury after staged palliation.

A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci.

The rapid ubiquitination of chromatin surrounding DNA double-stranded breaks (DSB) drives the formation of large structures called ionizing radiation-induced foci (IRIF), comprising many DNA damage response (DDR) proteins. This process is regulated by RNF8 and RNF168 ubiquitin ligases and is thought to be necessary for DNA repair and activation of signaling pathways involved in regulating cell cycle checkpoints. Here we demonstrate that it is possible to interfere with ubiquitin-dependent recruitment of DDR factors by expressing proteins containing ubiquitin binding domains (UBDs) that bind to lysine 63-linked polyubiquitin chains. Expression of the E3 ubiquitin ligase RAD18 prevented chromatin spreading of 53BP1 at DSBs, and this phenomenon was dependent upon the integrity of the RAD18 UBD. An isolated RAD18 UBD interfered with 53BP1 chromatin spreading, as well as other important DDR mediators, including RAP80 and the BRCA1 tumor suppressor protein, consistent with the model that the RAD18 UBD is blocking access of proteins to ubiquitinated chromatin. Using the RAD18 UBD as a tool to impede localization of 53BP1 and BRCA1 to repair foci, we found that DDR signaling, DNA DSB repair, and radiosensitivity were unaffected. We did find that activated ATM (S1981P) and phosphorylated SMC1 (a specific target of ATM) were not detectable in DNA repair foci, in addition to upregulated homologous recombination repair, revealing 2 DDR responses that are dependent upon chromatin spreading of certain DDR factors at DSBs. These data demonstrate that select UBDs containing targeting motifs may be useful probes in determining the biological significance of protein-ubiquitin interactions.

DNA polymerase ζ is a major determinant of resistance to platinum-based chemotherapeutic agents.

Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA cross-links (ICLs). Replicative bypass of cisplatin DNA adducts requires the cooperative actions of at least three translesion DNA synthesis (TLS) polymerases: Polη, REV1, and Polζ. Because oxaliplatin, satraplatin, and picoplatin contain bulkier chemical groups attached to the platinum core compared with cisplatin, we hypothesized that these chemical additions may impede replicative bypass by TLS polymerases and reduce tolerance to platinum-containing adducts. We examined multiple responses of cancer cells to oxaliplatin, satraplatin, or picoplatin treatment under conditions where expression of a TLS polymerase was limited. Our studies revealed that, although Polη contributes to the tolerance of cisplatin adducts, it plays a lesser role in promoting replication through oxaliplatin, satraplatin, and picoplatin adducts. REV1 and Polζ were necessary for tolerance to all four platinum analogs and prevention of hyperactivation of the DNA damage response after treatment. In addition, REV1 and Polζ were important for the resolution of DNA double-stranded breaks created during replication-associated repair of platinum-containing ICLs. Consistent with ICLs being the predominant cytotoxic lesion, depletion of REV1 or Polζ rendered two different model cell systems extremely sensitive to all four drugs, whereas Polη depletion had little effect. Together, our data suggest that REV1 and Polζ are critical for promoting resistance to all four clinically relevant platinum-based drugs by promoting both translesion DNA synthesis and DNA repair.