Effect of docosahexaenoic acid and olive oil supplementation on pup weight in alcohol-exposed pregnant rats.

Background: Low birth weight has been observed in offspring of alcoholic mothers due likely to unresolved inflammation and oxidative injury. Dietary lipids play a role in inflammation and its resolution. The primary objective was to investigate the effect of DHA and olive oil on the birth weight of pups born to alcohol-exposed dams. Methods: Pregnant rats were randomized to the control or three treatment (alcohol) groups. From gestational days (GD) 8-19, the control group received daily olive oil and malto/dextrose, whereas groups 2 and 3 received olive oil and low-dose alcohol or high-dose alcohol, respectively. Group 4 received daily DHA and high-dose alcohol. The dam's blood was collected on GD 15 and 20 for cytokine analysis. Dams were sacrificed on GD 20. The mean birth weight of pups was compared by one-way ANOVA with post hoc Duncan's test. Results: There was a significant increase in the pups' mean birth weight in the high-dose alcohol/DHA and high-dose alcohol/olive oil. Higher pro-inflammatory cytokines (IL-1ß and IL-12p70) were noted in the alcohol-exposed dams. Conclusions: DHA and olive oil supplementation in alcohol-exposed pregnant rats significantly increased their pups' birth weight despite having high pro-inflammatory cytokines. The mechanism of this effect remains to be determined.

Acute Kidney Injury in Pediatric Acute SARS-CoV-2 Infection and Multisystem Inflammatory Syndrome in Children (MIS-C): Is There a Difference?

Objective: To evaluate the prevalence and factors associated with the risk of acute kidney injury (AKI) in pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and multisystem inflammatory syndrome in children (MIS-C). Study Design: We performed a retrospective chart review of 113 patients with SARS-CoV-2 infection with or without MIS-C admitted at Children's Hospital of Michigan (CHM) from March to August 2020. Patient demographic details, laboratory data, imaging studies, echocardiography reports, and treatment data were collected. Results: Of the 92 patients included in the final analysis, 22 (24%) developed AKI with 8/22 (36%) developing stage 3 AKI. The prevalence of AKI was much higher in patients with MIS-C 15/28 (54%) vs. those with acute SARS-CoV-2 infection 7/64 (11%), (p < 0.001). Overall, when compared to patients without AKI, patients with AKI were older in age (11 vs. 6.5 years, p = 0.007), African American (86 vs. 58%, p = 0.028), had MIS-C diagnosis (68 vs. 19%, p < 0.001), required ICU admission (91 vs. 20%, p < 0.001), had cardiac dysfunction (63 vs. 16%, p < 0.001), required inotropic support (59 vs. 6%, p < 0.001) and had a greater elevation in inflammatory markers. In a multivariate analysis, requirement of inotropes [Odds Ratio (OR)-22.8, p < 0.001], African American race (OR-8.8, p = 0.023) and MIS-C diagnosis (OR-5.3, p = 0.013) were the most significant predictors for AKI. All patients had recovery of kidney function, and none required kidney replacement therapy. Conclusion: Children with acute SARS-CoV-2 infection and MIS-C are at risk for AKI, with the risk being significantly greater with MIS-C. The pathogenesis of AKI in acute SARS-CoV-2 infection appears to be a combination of both renal hypo-perfusion and direct renal parenchymal damage whereas in MIS-C, the renal injury appears to be predominantly pre-renal from cardiac dysfunction and capillary leak from a hyperinflammatory state. These factors should be considered by clinicians caring for these children with a special focus on renal protective strategies to aid in recovery and prevent additional injury to this high-risk subgroup.

Fatty acid ethyl esters in meconium: A biomarker of fetal alcohol exposure and effect.

To determine if meconium fatty acid ethyl esters (FAEE) in rat pups is a good biomarker of prenatal exposure and effect to alcohol, three groups of pregnant rats were studied: one control (pair fed) and two treatment groups given 25% alcohol at 2.2 or 5.5 g-1 kg-1 d-1. The pups were delivered on day 20 and, for each dam, were separated into a male and female group. The body, brain, intestines, and placenta of the pups were obtained, weighed, and stored at -20°C. The pups' intestines (as surrogate of meconium) from each group were pooled, and meconium was analyzed by gas chromatography/mass spectroscopy for FAEE. The meconium showed the following FAEE: ethyl palmitate, ethyl stearate, and ethyl linolenate and were only found in the alcohol-treated group and with high specificity but low sensitivity. Mean body weight of the pups was lower in the treatment groups compared to the control groups. Ethyl palmitate concentration correlated negatively to the pups' mean body and brain weights. Therefore, ethyl palmitate, stearate, and linolenate, in meconium of rat pups prenatally exposed to alcohol, are useful biomarkers of prenatal alcohol exposure, with ethyl palmitate a good biomarker of adverse effect on the pups' body and brain weight.

Retrospective Analysis of Pediatric and Adult Populations Using an LC-MS/MS Method for Oxcarbazepine/Eslicarbazepine Metabolite.

BACKGROUND: Therapeutic drug monitoring of anti-epileptic drugs is important to manage seizure control in patients with epilepsy. Oxcarbazepine is a second-generation anti-epileptic drug approved for use in pediatric patients, and eslicarbazepine acetate is a newer generation drug used as adjunctive therapy and monotherapy for partial-onset (focal) seizures. While several second and third generation anti-epileptic drugs have broader therapeutic efficacy in patients, these drugs can still have severe side effects and variable interpatient pharmacokinetics. Consequently, there is a need for accurate and sensitive analytical methods to support therapeutic drug monitoring. METHODS: An assay improvement for a LC-MS/MS method was developed for the major metabolite of oxcarbazepine and eslicarbazepine, licarbazepine (MHD), using a 13C-labeled form of the compound as the internal standard. Additionally, retrospective data analysis was used to compare the distribution of results observed in adult vs pediatric patients. RESULTS: Accuracy and linearity across the analytical measuring range of 1 to 60 µg/mL was acceptable. Inter- and intra-run precision was less than 6% at 3 concentrations tested. The limit of detection was determined to be 0.5 µg/mL. Significant interference from hemolysis, icterus, lipemia, or 187 other potential interferences was not detected. CONCLUSIONS: The improved assay for MHD was appropriate for clinical use. Retrospective data analysis showed that pediatric and adult patients had a similar distribution of oxcarbazepine/eslicarbazepine metabolite concentrations in serum.

Clinical Trial Enrollment is Associated With Improved Follow-up Rates Among Survivors of Childhood Cancer.

Fortunately >80% of children diagnosed with cancer become long-term survivors; however, this population is at a significantly increased risk of morbidity and mortality as a result of their previous cancer therapy, and long-term follow-up (LTFU) is critical. Multiple barriers to receiving adequate LTFU care have been studied. We investigated whether lack of enrollment in a therapeutic clinical trial may be a barrier to receiving LTFU care. We conducted a review of 353 patient records at the Children's Hospital of Michigan enrolled in our Children's Oncology Group registry between January 1, 2005 and December 31, 2010. In total, 71 patients were excluded (death before follow-up, n=61; currently receiving therapy, n=5; known transfer of care, n=4; insufficient information, n=1). In total, 158 (56%) patients were enrolled in a therapeutic clinical trial. Follow-up rates at 1-, 2- and 5-years following completion of therapy for patients enrolled in a therapeutic clinical trial were 96.8% (153/158), 93.7% (148/158), and 81.7% (103/126), respectively, compared with 83.1% (103/124; P<0.001), 74.2% (92/124; P<0.001), and 66.7% (72/108; P=0.001) for patients not enrolled. Our findings suggest patients enrolled in a therapeutic clinical trial have better LTFU rates and supports the importance of patient enrollment in therapeutic clinical trials when possible. Additional resources may be warranted to improve LTFU for patients not enrolled.

Pharmacists' knowledge, support, and perceived roles associated with providing naloxone in the community.

INTRODUCTION: Prior to the Michigan naloxone standing order legislation, a sample of Michigan pharmacists was surveyed to (1) identify gaps in knowledge regarding naloxone: (2) assess supportive attitudes towards the standing order and; (3) determine perceived pharmacist roles when providing naloxone. METHODS: A 37-item survey was emailed to Michigan Pharmacist Association members (n = 2757), July to August 2016. Responses to knowledge, supportive attitude, and perceived roles items were analyzed using descriptive statistics and logistic regression. Significance set at p < 0.05. RESULTS: The useable response was 8% (n = 211), 92% white, 54% female, aged 46.5 ± 14.6 years. Knowledge: Eighty-five percent (179/211) agreed laypersons can administer naloxone. Sixty-four percent could identify an opioid overdose and 74% agreed with required pharmacist naloxone education; yet 20% had education. Supportive attitude: Eighty-seven percent (184/211) supported the standing order. Perceived role: Fifty-six percent agreed with responsibility for following patients after providing naloxone. Predictors of agreement were rural practice location (OR = 2.5; 95% CI 1.2-5.0, p = 0.01), and requiring naloxone education (OR = 3.0; 95% CI 1.3-6.8, p = 0.007). Having a Doctor of Pharmacy versus a Bachelor of Science Pharmacy degree decreased odds of agreement by 43.5% (OR = 0.435; 95% CI 0.221-0.857, p = 0.016). DISCUSSION: Timing of survey may explain the low number of trained respondents. The increased willingness of BS Pharmacists to follow patients may reflect longer practice and closer community ties. Limitations include low generalizability and small sample. CONCLUSION: A small representative sample of Michigan pharmacists is knowledgeable regarding naloxone and has supportive attitudes towards the standing order.

The Effects of Residual Air and Viscosity on the Rate of Heat Penetration of Retort Food Simulant in Pouch When Using Static and Oscillating Motions.

The objectives of this work were to determine the effect of 3 levels of residual air and 2 different retort motions on the value of the average heating slope of the rate of heat penetration of 3 different viscosities of a food simulant in flexible retort pouches. Pouches were thermally processed in a water spray automated batch retort system using 2 different methods of motion: static and oscillating continuously at a speed of 10.5 rotations per min (RPM) with an angle of 15°. Nine residual air and viscosity combinations were processed during each experimental run: low viscosity with no residual air (LV-NRA), medium viscosity with no residual air (MV-NRA), high viscosity with no residual air (HV-NRA), low viscosity with medium residual air (LV-MRA), medium viscosity with medium residual air (MV-MRA), high viscosity with medium residual air (HV-MRA), low viscosity with high residual air (LV-HRA), medium viscosity with high residual air (MV-HRA), and high viscosity with high residual air (HV-HRA). As the amount of residual air in the pouches increased, the average heating slope value decreased in both static and oscillating motions. As the viscosity of the product increased the amount of residual air affected the average heating slope less in static and oscillating motions. Overall, the oscillating motion resulted in faster rates of heat penetration in all viscosities compared to static mode. The oscillating motion reduced processing times up to 27% compared to static mode. PRACTICAL APPLICATION: This research can be applied to food manufacturers that are retorting foods in pouches. Residual air in pouches has been studied previously; however, with the development of new retort motions, more research needs to be conducted about the effect of residual air in a pouch using the different motions. Food manufacturers can use this information to optimize their amount of residual air based on their product viscosity and retort motion. This could dramatically lower processing time which would save money and increase output as well as potentially increases product quality. This research is aimed at influencing food manufacturers, process authorities, and product developers.

Comments on Meta-Analyses in General and in Stem Cell Research: An Overview and Cautionary Advice.

Meta-analysis, a tool for contrasting and combining results from different research studies, has been around now for over 40 years. Journal editors are eager to publish the results from meta-analyses, as they propose to represent the integration of best research evidence with clinical expertise and patient values. There are guidelines available, most notably through the Cochrane Collaborative, for investigators to follow in conducting a responsible and, therefore publishable, meta-analysis. Despite the burgeoning popularity of this powerful analytical tool, the procedure is not without its pitfalls. In this study, we advise the readership to familiarize themselves with the most common shortcomings in an effort to help elevate our ability to critically appraise the results of these analyses.

What you need to know about statistics, part II: reliability of diagnostic and screening tests.

The foundation for the usefulness of any diagnostic test should be that it is both reliable and accurate in its clinical diagnosis. In this article we present the second of a two-part series on validity and reliability, discussing the assessment of reliability among raters of diagnostic tests and between diagnostics tests themselves. To examine reproducibility (reliability) among raters of diagnostic tests we present the calculation of two statistical procedures: (1) the kappa coefficient statistic when presented with categorical data for the presence or absence of a clinical diagnosis and (2) the intraclass correlation coefficient (ICC) for continuously scaled data among raters. The accuracy among diagnostic tests (i.e. their interchangeability) can be evaluated by application of (1) a Bland-Altman plot procedure (with its 95% limits of agreement) and (2) the Passing-Bablok regression procedure (for the identification and evaluation of systematic and proportional differences). When deciding whether to select a diagnostic test one must evaluate its ability to provide more precise information than a gold standard test, and whether in clinical practice it would be more beneficial for patients to adopt it.

What you need to know about statistics Part I: validity of diagnostic and screening tests.

The intent of this manuscript is to provide guidance and support to clinicians and investigators for reporting the results of screening and diagnostic tests. This article is the first of two parts addressing statistics in imaging research. In this part validity measures are discussed. In part II reliability measures will be discussed. In discussing validity, the following concepts will be introduced: (1) functions of diagnostic tests, (2) statistical characteristics of diagnostic tests and application of validity measures, (3) power and sample size for testing the sensitivity and specificity of the diagnostic test, (4) statistical versus clinical significance and (5) characteristics of a useful diagnostic test.

Post tonsillectomy hemorrhage: who needs intervention?

BACKGROUND: Post-tonsillectomy hemorrhage (PTH) remains a significant complication. There are no guidelines for Pediatric Emergency Department (PED) disposition of children with secondary PTH. OBJECTIVES: To describe the incidence, clinical characteristics and interventions required by children presenting to a PED with secondary PTH. To identify patient and clinical characteristics associated with need for operative/inpatient intervention. METHODS: Retrospective chart review of healthy children 1-18 years with secondary PTH from 2005 to 2012. Demographics, clinical and oropharynx findings, laboratory data, intervention type and ED disposition were recorded. RESULTS: We encountered 181 children with 193 episodes of PTH. One hundred and twenty one patients were included in the final analysis. Secondary PTH rate was 2.3%. Only a minority of patients were hypotensive (3.3%) or had hemoglobin<10g/dl (9.5%) at presentation. 65.3% Children had positive oropharyngeal exam: clot 39 (49.4%) patients; ooze 17 (21.5%) patients; ooze+clot in 5 (6.3%) patients or active bleeder in 18 (22.8%) patients. Eighty seven (71.9%) patients were admitted; 74 (61.1%) patients required active intervention: medical 14.8%, surgical 74.4% or both 10.8%. Thirty seven children needed immediate operative intervention. Only positive oropharyngeal exam and age ≥6 years were significantly associated with need for intervention. None of the patients with a confirmed normal oropharyngeal exam at the initial visit required any intervention either medical or surgical. The rate of return visit for recurrent PTH was found to be similar for both the admitted and the discharged group. No patient returned with a life threatening hemorrhage. CONCLUSIONS: Majority of children with secondary PTH were admitted and nearly 3/5th of them required an intervention. Our data suggests that healthy children <6 years with a confirmed normal oropharyngeal exam are less likely to require an intervention and may be candidates for safe discharge from the ED provided reliability of return for recurrence can be assured.

Impact of small-for-gestational age (SGA) status on gentamicin pharmacokinetics in neonates.

We compared gentamicin pharmacokinetics among neonates born small-for-gestational age (SGA) and appropriate for gestational age (AGA). We further compared gentamicin pharmacokinetics in subgroups of AGA and SGA neonates born preterm and term and treated within and after the initial week of age. Steady state peak and trough serum gentamicin concentrations were used to calculate clearance (Cl), elimination constant (Kel), volume of distribution (Vd), and half-life (t1/2 ) in infants (n = 236) who received ≥48 hours therapy. Statistical analyses (SPSS 17.0) included chi-square and the non-parametric Mann-Whitney U-test. SGA infants treated early (≤7days) (n = 29) and at postmenstrual ages ≤32 weeks (n = 23) had significantly lower median Kel (0.069/h vs. 0.081/h and 0.067/h vs. 0.075/h) and clearance (0.58 mL/kg/min vs. 0.68 mL/kg/min and 0.46 mL/kg/min vs. 0.65 mL/kg/min), compared to those born AGA. There were no significant differences in pharmacokinetic profiles with later therapy or at more mature ages. The prolonged half-life of gentamicin may need to be considered in dosing regimens for preterm SGA infants in the initial week of life.

Outcomes of tracheostomy in the neonatal intensive care unit: is there an optimal time?

OBJECTIVE: To compare short-term outcomes of infants who underwent early versus late tracheostomy during their initial hospitalization after birth and determine the association, if any, between tracheostomy timing and outcomes. STUDY DESIGN: Retrospective chart review of infants who underwent a tracheostomy during their initial hospitalization at a single site. RESULTS: The median (range) gestational age of our cohort (n = 127) was 28 (23-42) weeks and birth weight was 988 (390-4030) g. Tracheostomy indications included airway lesions (47%), bronchopulmonary dysplasia (25%), both (22%) and others (6%). Median postmenstrual age (PMA) at tracheostomy was 45 (35-75) weeks. Death occurred in 27 (21%) infants and 65 (51%) infants were mechanically ventilated. G-tube was present at discharge in 42 (33%) infants. Infants who underwent early tracheostomy (<45 weeks PMA) (n = 66) had significantly lower gestational ages, weights and respiratory support than the late (≥45 weeks PMA) (n = 61) group. Death (29.5% versus 14%), home ventilation (41% versus 21%) and G tube (44% versus 14%) were significantly more frequent in the late tracheostomy group. On bivariate regression, outcomes were not independently associated with tracheostomy timing, after adjustment for gestational age and respiratory support. CONCLUSIONS: Of infants who underwent tracheostomy during the initial hospitalization after birth, 21% died. On adjusted analysis, tracheostomy timing was not independently associated with outcomes.

An evaluation of supracondylar humerus fractures: is there a correlation between postponing treatment and the need for open surgical intervention?

PURPOSE: The goal of this study was to evaluate the treatment and recovery of patients treated for Gartland type III supracondylar humerus fractures in order to determine if postponing treatment leads to a higher rate of open surgical treatment or complications. METHODS: A retrospective study was conducted examining the medical records of children with Gartland type III supracondylar humerus fractures at our institution for a two-year period. The patients included in the study were treated with closed reduction and percutaneous pinning (CRPP) or open reduction and internal fixation (ORIF). RESULTS: After exclusions, 134 patients were included in the study, with an average age of 5.6 years. The patients were grouped according to whether their treatment was postponed (39.6 %) or immediate (60.4 %). The majority of all patients were treated using CRPP: 46 (86.8 %) of the postponed patients and 75 (92.6 %) of the immediate patients. Very few postsurgical complications occurred in the patients; there was only one (1.6 %) case of iatrogenic nerve injury in a postponed patient as well as four (3.8 %) cases of loss of carrying angle: one (2.3 %) in postponed patients and three (4.8 %) in immediate patients. CONCLUSIONS: Postponing treatment of type III supracondylar humerus fractures in children did not lead to an increase in open surgical treatment; nor did it lead to an increase in complications.

Postoperative pain management after spinal fusion surgery: an analysis of the efficacy of continuous infusion of local anesthetics.

Spinal fusion surgery is a major surgery that results in severe postoperative pain, therefore pain reduction is a primary concern. New strategies for pain management are currently under investigation and include multimodal treatment. A 3-year retrospective analysis of patients with idiopathic scoliosis undergoing spinal fusion surgery was performed at our hospital, assessing patient pain scores, opioid use, and recovery. We evaluated the effect of adding continuous infusion of local anesthetics (CILA) to a postoperative pain management protocol that includes intraoperative intrathecal morphine, as well as postoperative patient-controlled analgesia and oral opioid/acetaminophen combination. The study compared 25 patients treated according to the standard protocol, with 62 patients treated with CILA in addition to the pain management protocol. Patients in the CILA group used nearly 0.5 mg/kg less opioid analgesics during the first 24 hours after surgery.

Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may be due to mutations in genes associated with non-syndromic HPE. Mutations in ZIC2, located on chromosome 13q32, are a common cause of non-syndromic, non-chromosomal HPE. OBJECTIVE: To characterise genetic and clinical findings in patients with ZIC2 mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 1200 individuals with HPE spectrum disorders was analysed for sequence variations in ZIC2. Clinical details were examined and all other known cases of mutations in ZIC2 were included through a literature search. RESULTS: By direct sequencing of DNA samples of an unselected group of unrelated patients with HPE in our NIH laboratory, ZIC2 mutations were found in 8.4% (49/582) of probands. A total of 157 individuals from 119 unrelated kindreds are described, including 141 patients with intragenic sequence determined mutations in ZIC2. Only 39/157 patients have previously been clinically described. Unlike HPE due to mutations in other genes, most mutations occur de novo and the distribution of HPE types differs significantly from that of non-ZIC2 related HPE. Evidence is presented for the presence of a novel facial phenotype which includes bitemporal narrowing, upslanting palpebral fissures, a short nose with anteverted nares, a broad and well demarcated philtrum, and large ears. CONCLUSIONS: HPE due to ZIC2 mutations is distinct from that due to mutations in other genes. This may shed light on the mechanisms involved in formation of the forebrain and face and will help direct genetic counselling and diagnostic strategies.

A maternal and perinatal mortality in pregnancy complicated by the kyphoscoliotic form of Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos syndrome is a group of inherited connective tissue diseases demonstrating autosomal-dominant, autosomal-recessive, and X-linked inheritance patterns. The diagnosis can be established by clinical, biochemical, and genetic findings. CASE: Our nulliparous patient presented with an unspecified diagnosis of Ehlers-Danlos syndrome. Laboratory testing confirmed the kyphoscoliotic type. Based on clinical and phenotypic similarities with the vascular type of Ehlers-Danlos syndrome, termination was advised. Minor trauma in the third trimester led to delivery of a stillborn fetus, which was followed by disseminated intravascular coagulopathy and death of the mother. Maternal autopsy revealed that there had been a spontaneous rupture of the right iliac artery. CONCLUSION: Practitioners should be aggressive in recommending effective birth control in patients with the kyphoscoliotic form of Ehlers-Danlos syndrome. In cases of established pregnancy, patients should be made fully aware of their risks of death and severe complications.

An epidemiologic study comparing fetal exposure to tobacco smoke in three Southeast Asian countries.

The high prevalence of smoking in Southeast Asia (SEA) means pregnant women face exposure to tobacco smoke that may affect the health of their fetus. This study determined fetal exposure to tobacco smoke by meconium analysis for cotinine in 3 locations in SEA: Bulacan Province, Philippines (N=316), Bangkok, Thailand (N=106) and Singapore City (N=61). Maternal exposure to tobacco smoke was 71.1% (1.3% active; 69.8% passive) in Bulacan, 57.5% (0.9% active; 58.6% passive) in Bangkok and 54.1% (11.5% active; 42.0% passive) in Singapore. Fetal exposure to tobacco smoke (by meconium analysis) was 1.3% (Bulacan), 4.7% (Bangkok) and 13.1% (Singapore); however, a large proportion of infants who tested positive for cotinine (65%) were born to mothers who gave no history of either active or passive exposure to environmental tobacco smoke. Fetal exposure to tobacco smoke is a major health problem.