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.

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.

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.

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.

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.

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.

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.

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.

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.

Pulmonary synovial sarcoma presenting as a pneumothorax during pregnancy.

BACKGROUND: Synovial sarcoma is a clinically rare, but morphologically well-defined neoplasm, which accounts for approximately 10% of all malignant soft-tissue tumors. The diagnosis can be established with clinical and imaging evaluations together with immunohistochemical, electron microscopy, and molecular genetic studies. CASE: We describe a case of primary pulmonary synovial sarcoma presenting as a pneumothorax in a young woman at 34 weeks of gestation. Her persistent symptomatology ultimately led to a video-assisted thoracoscopy and thorascopic decortication. The diagnosis was established by pathology and immunohistochemistry of the cells, which were consistent with primary pulmonary synovial sarcoma. CONCLUSION: Malignancies, even those as uncommon as primary synovial sarcoma, should be considered in the differential diagnosis of pneumothorax during pregnancy.

Technique of single-stage repair of coarctation of the aorta with ventricular septal defect.

The results of single-stage and two-stage repair of coarctation of the aorta (CoA) with ventricular septal defect (VSD) have improved, but the optimal treatment strategy remains controversial. This article emphasizes the technical details for performing the single-stage repair of CoA with VSD and compares the results of this technique with the two-stage approach. A retrospective analysis of 46 patients who underwent completed surgical repair of CoA with VSD at Children's Hospital of Michigan, either using the single-stage (N=23) or the two-stage (N=23) techniques, was performed. The postoperative complications, hospital mortality, freedom from cardiac re-interventions, and actuarial survival were the same in both groups. The advantages of single-stage over two-stage repair include an earlier age at completion of repair, fewer operations, and fewer incisions. The one disadvantage of a single-stage repair was the increased need for delayed sternal closure compared with the two-stage approach, but this disadvantage has been neutralized in the recent era.

Chorioamnionitis and ontogeny of circulating prostaglandin and thromboxane in preterm infants.

Our objective was to determine the effect of chorioamnionitis on plasma prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) during the first week in preterm infants. Plasma PGE2 and TxB2 were measured at 1, 3, and 7 days of age in preterm infants (birth weights 501 to 1500 g), with ( N = 26) and without ( N = 22) chorioamnionitis. Infants with maternal chorioamnionitis had significantly lower mean gestational age ( P = 0.0001) and birth weight ( P = 0.03) and a marginally higher rate of bronchopulmonary dysplasia (37% versus 12.5, P = 0.05), a result that may be related to the lower mean gestational age. Plasma PGE2 and TxB2 varied widely, more so on the first day but did not significantly differ between the two groups. TxB2 was lower among infants who died or developed morbidities. Circulating PGE2 and TxB2 concentrations in preterm infants in the first week vary considerably, are relatively unaltered by chorioamnionitis, and are lower in association with mortality and clinical morbidities. Further research on their role in the causation of adverse neonatal outcomes is necessary.

Nutritional supplementation in monochorionic diamniotic twin pregnancies: impact on twin-twin transfusion syndrome.

Twin-to-twin transfusion syndrome (TTTS) has been related to unbalanced unidirectional arteriovenous anastomoses in the placenta of monochorionic diamniotic (DiMo) twin gestations. As maternal malnutrition accounting for hypoproteinemia and anemia has been detected in severe cases of TTTS, the purpose of this study was to evaluate the impact of early diet supplementation on TTTS. Fifty-one DiMo twin pregnancies were given commercially available oral nutritional diet supplements and then compared in a retrospective cohort study to 52 twin gestations with the same chorionicity but not subjected to nutritional supplementation. Diet supplementation was associated with lower overall incidence of TTTS (20/52 versus 8/51, P = 0.02) and with lower prevalence of TTTS at delivery (18/52 versus 6/51, P = 0.012) when compared with no supplementation. Nutritional intervention also significantly prolonged the time between the diagnosis of TTTS and delivery (9.4 +/- 3.7 weeks versus 4.6 +/- 6.5 weeks; P = 0.014). The earlier nutritional regimen was introduced, the lesser chance of detecting TTTS ( P = 0.001). Although not statistically significant, dietary intervention was also associated with lower Quintero stage, fewer invasive treatments, and lower twin birth weight discordance. Diet supplementation appears to counter maternal metabolic abnormalities in DiMo twin pregnancies and improve perinatal outcomes in TTTS when combined with the standard therapeutic options.

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.

Pregnancy outcomes after laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Early reports described adverse perinatal outcomes of pregnancies after weight loss surgery (WLS), which subsequently raised concerns regarding safety. Our objective was to investigate, in a community-based, academic, tertiary care center, the safety of pregnancies after laparoscopic Roux-en-Y gastric bypass (LRYGB) and its potential effect on obesity-related perinatal complications. METHODS: The pregnancy outcomes of patients delivering infants after LRYGB at our institution were compared with those of control subjects (stratified by body mass index) who had not undergone WLS. The charts were retrospectively reviewed for demographics, delivery route, and perinatal complications. RESULTS: A total of 26 patients who delivered after LRYGB and 254 controls were identified. The mean interval from LRYGB to conception was 25.4 +/- 13.0 months. In general, the perinatal complications in the LRYGB patients were similar to those in the nonobese controls and lower than in the obese and severe obese controls, although statistical significance was not noted for all complications. No spontaneous abortions or stillbirths occurred in the LRYGB patients. No LRYGB patients required intravenous nutrition or hydration. The overall incidence of cesarean section in the LRYGB patients was similar to that in the obese and severely obese controls but significantly greater than that in the nonobese controls. The complication rates were similar in pregnancies occurring "early" (<12 mo) versus "late" (>18 mo) after LRYGB. CONCLUSION: The results of our study have shown that pregnancy after LRYGB is safe, with an incidence of perinatal complications similar to that of nonobese patients, and lower than that of obese and severely obese patients, who had not undergone WLS. Larger studies are required to demonstrate statistically significant improvements in outcome in patients treated with WLS.

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.

Improvement in infertility and pregnancy outcomes after weight loss surgery.

The majority of bariatric surgical procedures are performed in young women. There is a concern about safety and outcomes of pregnancies after weight loss surgery. Pregnancy after weight loss surgery is not only safe, but is associated with more favorable outcomes in comparison to obese populations who do not undergo weight loss surgery. An interval of 2 years is recommended from surgery to pregnancy. This delay helps avoid most of the potential nutritional complications. Optimal patient care is achieved in an experienced, multidisciplinary center. Early involvement of the bariatric surgeon in evaluating abdominal pain is critical because the underlying pathology may relate to the previous weight loss surgery. Although infertility is improved after weight loss surgery, reliable modes of contraception may be limited in this population.

Nitric oxide and prostaglandin response to group B streptococcal infection in the lung.

Group B streptococcus (GBS) causes a complex inflammatory process that involves prostaglandins (PG) and nitric oxide (NO). The goal of this study was to examine the inflammatory response to GBS in the lung and the co-regulation of the PG and NO pathways, if any, both in vitro and in vivo. Sprague Dawley rats were treated with various combinations of GBS, aminoguanidine (AG), a selective inducible nitric oxide synthase (iNOS) inhibitor, and L-arginine (LA), a NO donor. The mRNA expression of the COX 2 gene was studied by reverse transcriptase polymerase chain reaction (RTPCR) in rat lung tissue. The studies were confirmed in vitro using human lung epithelial (A549) cells treated with GBS, AG, and LA (in combinations similar to the rats) for 3 and 24 hr, after which PG E2 levels in the media were measured by enzyme linked immunosorbent assay (ELISA). COX 2 mRNA in rat lung tissue was significantly induced by GBS (p = 0.04), an effect that was suppressed by AG (p = 0.02). In the A549 cell line, PG E2 levels increased with GBS treatment at 3 and 24 hr (p <0.001). When AG was added, PG E2 levels were suppressed (p = 0.03) after 24 hr; LA partly reversed the suppression of PG E2 levels (p = 0.039). These data indicate that GBS infection causes significant COX 2 induction and PG E2 synthesis in lung tissue, regulated at least partly by the NO pathway. The interaction between the 2 pathways may play a pathogenic role in GBS lung infections and could be a potential target for pharmacological manipulation.