Crowdsourcing to Assess Speech Quality Associated With Velopharyngeal Dysfunction.

OBJECTIVE: To assess crowdsourced responses in the evaluation of speech outcomes in children with velopharyngeal dysfunction (VPD). DESIGN: Fifty deidentified speech samples were compiled. Multiple pairwise comparisons obtained by crowdsourcing were used to produce a rank order of speech quality. Ratings of overall and specific speech characteristics were also collected. Twelve speech-language pathologists (SLPs) who specialize in VPD were asked to complete the same tasks. Crowds and experts completed each task on 2 separate occasions at least 1 week apart. SETTING: On-line crowdsourcing platform. PARTICIPANTS: Crowdsource raters were anonymous and at least 18 years of age, North American English speakers with self-reported normal hearing. Speech-language pathologists were recruited from multiple cleft/craniofacial teams. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Correlation of repeated assessments and comparison of crowd and SLP assessments. RESULTS: We obtained 6331 lay person assessments that met inclusion criteria via crowdsourcing within 8 hours. The crowds provided reproducible Elo rankings of speech quality, ρ(48) = .89; P <.0001, and consistent ratings of intelligibility and acceptability (intraclass correlation coefficient [ICC] = .87 and .92) on repeated assessments. There was a significant correlation of those crowd rankings, ρ(10) = .86; P = .0003, and ratings (ICC = .75 and .79) with those of SLPs. The correlation of more specific speech characteristics by the crowds and SLPs was moderate to weak (ICC < 0.65). CONCLUSIONS: Crowdsourcing shows promise as a rapid way to obtain large numbers of speech assessments. Reliability of repeated assessments was acceptable. Large groups of naive raters yield comparable evaluations of overall speech acceptability, intelligibility, and quality, but are not consistent with expert raters for specific speech characteristics such as resonance and nasal air emission.

Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

BACKGROUND: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures. METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation. FINDINGS: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung. INTERPRETATION: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure. FUNDING: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

Perceptions of risk of infertility among male survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

BACKGROUND: The objective of the current study was to characterize and identify factors associated with perceptions of risk of infertility among adult male survivors of childhood cancer. METHODS: A total of 1233 adult male survivors from the Childhood Cancer Survivor Study who were without a history of disease recurrence or subsequent malignancy reported their perceptions of their risk of infertility compared with men never diagnosed with cancer. Survivors were a median age of 37.8 years (range, 22.0-58.7 years) and were 28.4 years from their diagnosis (range, 21.4-39.2 years). Multivariable logistic regression evaluated factors associated with perceptions of risk. RESULTS: Overall, 35.9% of the survivors (443 of 1233 survivors) reported perceptions of their risk of infertility that were discordant with their actual risk based on previous cancer treatment exposures. Discordant perceptions were equally common among men exposed to gonadotoxic therapies (36.3%; 311 of 857 men) and those with no history of gonadotoxic exposure (35.1%; 132 of 376 men). Survivors who fathered children (odds ratio [OR], 4.14; 95% confidence interval [95% CI], 2.74-6.24), had no survivor-focused health care (OR, 3.07; 95% CI, 1.57-5.99), were nonwhite (OR, 2.28; 95% CI, 1.10-4.75), and were of lower income were more likely to report no increased risk of infertility after gonadotoxic treatment. Perceptions of increased risk of infertility among men with no history of gonadotoxic treatment were predicted by never having fathered a child (OR, 1.88; 95% CI, 1.17-3.03), recent participation in survivor-focused health care (OR, 2.11; 95% CI, 1.01-4.42), and higher educational achievement. CONCLUSIONS: Many male survivors of childhood cancer are unaware of how their cancer treatments could impact their reproductive health, underscoring the need for all patients to receive education regarding their risk of infertility throughout the continuum of cancer care. Cancer 2018;124:2447-55. © 2018 American Cancer Society.

Erectile Dysfunction in Male Survivors of Childhood Cancer-A Report From the Childhood Cancer Survivor Study.

INTRODUCTION: With survival rates higher than 80%, the number of survivors from pediatric cancer continues to increase. Late effects resulting from cancer and cancer therapy are being characterized, but little information exists on sexual health for men who have survived childhood cancer. AIM: To assess erectile dysfunction (ED) in men who survived childhood and adolescent cancers and to identify potential risk factors for ED. METHODS: In total, 1,622 men and 271 eligible brothers in the Childhood Cancer Survivor Study cohort completed the Male Health Questionnaire, which provided information on sexual practices and sexual function. Combined with demographic, cancer, and treatment information from medical record abstraction, results of the Male Health Questionnaire were analyzed using multivariable modeling. The International Index of Erectile Function was used to identify ED in subjects. MAIN OUTCOME MEASURE: International Index of Erectile Function. RESULTS: Survivors (mean age = 37.4 years, SD = 7.3 years) reported significantly lower sexual activity in the year before the survey than the brothers (mean age = 38.8 years, SD = 8.5 years) without cancer. ED was reported by 12.3% (95% CI = 10.4-14.3) of survivors and 4.2% (95% CI = 2.0-7.9) of brothers. Survivors showed significantly higher relative risk (RR) for ED (RR = 2.63, 95% CI = 1.40-4.97). In addition to older age, survivors who were exposed to higher-dose (≥10 Gy) testicular radiation (RR = 3.55, 95% CI = 1.53-8.24), had surgery on the spinal cord or nerves (RR = 2.87, 95% CI = 1.36-6.05), prostate surgery (RR = 6.56, 95% CI = 3.84-11.20), or pelvic surgery (RR = 2.28, 95% CI = 1.04-4.98) were at higher risk for ED. CONCLUSION: Men who have survived childhood cancer have a greater than 2.6-fold increased risk for ED and certain cancer-specific treatments are associated with increased risk. Attention to sexual health, with its physical and emotional implications, and opportunities for early detection and intervention in these individuals could be important.

Transmission of nevirapine-resistant HIV type 1 via breast milk to infants after single-dose nevirapine in Beira, Mozambique.

Acquisition of nevirapine (NVP)-resistant human immunodeficiency virus type 1 (HIV-1) by breast-feeding infants after receipt of single-dose NVP to prevent mother-to-child transmission is not well defined. A prospective observational study of 307 infants evaluated the rate of breast milk transmission of NVP-resistant HIV and the concentrations of mutants over time. NVP resistance was detected in 9 of 24 infants (37.5%; 95% confidence interval, 18.8%-59.4%) infected via breast milk. Eight had a pure mutant HIV population at the time infection was first detected, and majority mutant populations persisted in all 6 infants with follow-up specimens. Infection of breast-feeding infants with NVP-resistant HIV resulted in mutants persisting as the dominant virus, which may indefinitely compromise treatment with NVP-based antiretroviral regimens.

Feasibility and Favorable Responses Following Investigational CAR T-Cell Therapy for Relapsed and Refractory Infant ALL.

Infants with B-cell acute lymphoblastic leukemia (B-ALL) continue to have significantly worse outcomes compared to older children with B-ALL, and those with relapsed or refractory (R/R) infant ALL have especially dismal outcomes with conventional treatment. CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable success in the treatment of R/R childhood B-ALL, though the majority of reports have been in non-infant patients. Barriers to the successful implementation of CAR T-cell therapy in infant B-ALL include challenges related to apheresis, product manufacturing and disease-specific considerations such as lineage switch. We describe our experience utilizing two experimental CD19-CAR T-cell products, SCRI-CAR19 or SCRI-CAR19x22, for 19 patients with R/R infant B-ALL enrolled on three clinical trials. CAR T-cell products were successfully manufactured in 18/19 (94.7%) patients, with a median age of 22.5 months at enrollment (range, 14.5-40.1 months). Sixteen of 17 (94.1%) treated patients achieved a complete remission without detectable minimal residual disease. The 1-year leukemia free survival was 75% and 1-year overall survival was 76.5%, with a median follow up time of 35.8 months (range, 1.7-83.6 months). Cytokine release syndrome (CRS) occurred in 14/17 (82.4%) patients, with only 1 patient experiencing Grade 3 CRS. Neurotoxicity occurred in 2/17 (11.8%) patients with all events ≤ Grade 2. With the successful early clinical experience of CAR T-cell therapy in this population, more systematic evaluation specific to infant ALL is warranted.

STRIvE-02: A First-in-Human Phase I Study of Systemically Administered B7-H3 Chimeric Antigen Receptor T Cells for Patients With Relapsed/Refractory Solid Tumors.

PURPOSE: B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors. PATIENTS AND METHODS: Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design. RESULTS: Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 106 CAR T cells/kg; n = 3) or DL2 (1 × 106 CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/µL (range, 0-4.98 cells/µL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/µL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1. CONCLUSION: B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).

Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine.

Single-dose nevirapine (sdNVP) given to prevent mother-to-child-transmission of HIV-1 selects NVP-resistance. Short-course zidovudine (ZDV) was hypothesized to lower rates of NVP-resistance. HIV-1 infected pregnant women administered sdNVP with or without short-course ZDV were assessed for HIV-1 mutations (K103N, Y181C, G190A, and V106M) prior to delivery and postpartum. Postpartum NVP-resistance was lower among 31 taking ZDV+sdNVP compared to 33 taking only sdNVP (35.5% vs. 72.7%; χ2 P = .003). NVP mutants decayed to <2% in 24/35 (68.6%) at a median 6 months postpartum, with no differences based on ZDV use (logrank P = .99). Short-course ZDV was associated with reduced NVP-resistance mutations among women taking sdNVP.

GFAP and NfL increase during neurotoxicity from high baseline levels in pediatric CD19-CAR T-cell patients.

There is a need for biomarkers to predict and measure the severity of immune effector cell-associated neurotoxicity syndrome (ICANS). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are well-validated biomarkers of astroglial and neuronal injury, respectively. We hypothesized that pretreatment GFAP and NfL levels can predict the risk of subsequent ICANS and that increases in GFAP and NfL levels during treatment reflect ICANS severity. We measured cerebrospinal fluid GFAP (cGFAP) and NfL (cNfL) along with serum NfL (sNfL) levels at pretreatment and day 7 to 10 after chimeric antigen receptor (CAR) T-cell infusion in 3 pediatric cohorts treated with CD19- or CD19/CD22-directed CAR T cells. cGFAP and cNfL levels increased during grade ≥1 ICANS in patients treated with CD19-directed CAR T cells but not in those who received CD19/CD22-directed CAR T cells. The sNfL levels did not increase during ICANS. Prelymphodepletion cGFAP, cNfL, and sNfL levels were not predictive of subsequent ICANS. Elevated baseline cGFAP levels were associated with a history of transplantation. Patients with prior central nervous system (CNS) radiation had higher cNfL levels, and elevated baseline sNfL levels were associated with a history of peripheral neuropathy. Thus, cGFAP and cNfL may be useful biomarkers for measuring the severity of CNS injury during ICANS in children. Elevated baseline levels of cGFAP, cNfL, and sNfL likely reflect the cumulative injury to the central and peripheral nervous systems from prior treatment. However, levels of any of the 3 biomarkers before CAR T-cell infusion did not predict the risk of ICANS.

Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation. SIGNIFICANCE: This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.

Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy.

OBJECTIVES/AIMS: To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. BACKGROUND: Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. METHODS: Prospective cohort study in L and NL children, 3-17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6- and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed. RESULTS: We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. CONCLUSIONS: We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.

Modified Manufacturing Process Modulates CD19CAR T-cell Engraftment Fitness and Leukemia-Free Survival in Pediatric and Young Adult Subjects.

T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 can induce potent and sustained responses in children with relapsed/refractory acute lymphoblastic leukemia (ALL). The durability of remission is related to the length of time the CAR T cells persist. Efforts to understand differences in persistence have focused on the CAR construct, in particular the costimulatory signaling module of the chimeric receptor. We previously reported a robust intent-to-treat product manufacturing success rate and remission induction rate in children and young adults with recurrent/refractory B-ALL using the SCRI-CAR19v1 product, a second-generation CD19-specific CAR with 4-1BB costimulation coexpressed with the EGFRt cell-surface tag (NCT02028455). Following completion of the phase I study, two changes to CAR T-cell manufacturing were introduced: switching the T-cell activation reagent and omitting midculture EGFRt immunomagnetic selection. We tested the modified manufacturing process and resulting product, designated SCRI-CAR19v2, in a cohort of 21 subjects on the phase II arm of the trial. Here, we describe the unanticipated enhancement in product performance resulting in prolonged persistence and B-cell aplasia and improved leukemia-free survival with SCRI-CAR19v2 as compared with SCRI-CAR19v1.

Body mass index (BMI) at diagnosis is associated with surgical wound complications in patients with localized osteosarcoma: a report from the Children's Oncology Group.

BACKGROUND: Malnutrition is common at diagnosis and during treatment for sarcoma patients. Poor nutritional status is associated with increased risk of complications, particularly infections. We investigated the role of body mass index (BMI) on the incidence of surgical wound complications in patients with localized osteosarcoma treated on the Children's Oncology Group (COG) legacy trial, INT-0133. PROCEDURE: Patients considered in this report had localized osteosarcoma, enrolled on COG trial INT-0133, remained on protocol therapy to have definitive surgery 6-16 weeks after study entry, and had adequate height, weight, and surgical complication data for analysis. By protocol design, definitive surgical resection was planned for 10 weeks after induction chemotherapy. Wound complications within 30 days after definitive surgery were considered post-operative. BMI was calculated at the start of neoadjuvant chemotherapy and expressed as age- and gender-adjusted percentile. The incidence of wound complications was evaluated by logistic regression or Fisher's exact test. RESULTS: A total of 498 patients met criteria for analysis. Low BMI (≤10th percentile) was seen in 73 (14.7%), middle BMI (11th-94th percentile) in 382 (76.7%), and high BMI (≥95th percentile) in 43 (8.6%) patients. Wound infection or slough was seen in low BMI patients (OR = 2.0, P = 0.07) although the results did not reach statistical significance. Arterial thrombosis was more common in high BMI patients (OR = 9.4, P = 0.03). CONCLUSIONS: Abnormal BMI at the start of treatment for localized osteosarcoma is associated with increased risk of post-operative wound complications such as arterial thrombosis. Future studies should evaluate whether maintenance of age-appropriate BMI reduces the risk of surgical complications.

A randomized clinical trial comparing oral, aerosolized intranasal, and aerosolized buccal midazolam.

STUDY OBJECTIVE: We determine whether aerosolized intranasal or buccal midazolam reduces the distress of pediatric laceration repair compared with oral midazolam. METHODS: Children aged 0.5 to 7 years and needing nonparenteral sedation for laceration repair were randomized to receive oral, aerosolized intranasal, or aerosolized buccal midazolam. Patient distress was rated by blinded review of videotapes, using the Children's Hospital of Eastern Ontario Pain Score. Secondary outcomes included activity scores, sedation adequacy, sedation onset, satisfaction, and adverse events. RESULTS: For the 169 subjects (median age 3.1 years) evaluated for the primary outcome, we found significantly less distress in the buccal midazolam group compared with the oral route group (P=.04; difference -2; 95% confidence interval -4 to 0) and a corresponding nonsignificant trend for the intranasal route (P=.08; difference -1; 95% confidence interval -3 to 1). Secondary outcomes (177 subjects) favored the intranasal group, including a greater proportion of patients with an optimal activity score (74%), a greater proportion of parents wanting this sedation in the future, and faster sedation onset. Intranasal was the route least tolerated at administration. Adverse events were similar between groups. CONCLUSION: When comparing the administration of midazolam by 3 routes to facilitate pediatric laceration repair, we observed slightly less distress in the aerosolized buccal group. The intranasal route demonstrated a greater proportion of patients with optimal activity scores, greater proportions of parents wanting similar sedation in the future, and faster onset but was also the most poorly tolerated at administration. Aerosolized buccal or intranasal midazolam represents an effective and useful alternative to oral midazolam for sedation for laceration repair.

Rising prevalence of gastroschisis in Washington State.

The aim of this study was to assess gastroschisis prevalence in Washington (WA) State in relation to putative risk factors. Gastroschisis prevalence was calculated from the WA State birth cohort during 1987-2006 using an administrative database with birth certificate data linked with hospital discharge records and the ICD-9 procedure code 54.71, which specifies gastroschisis repair. Poisson regression analysis was used to evaluate time trends while adjusting for risk factors. Birth year was included as a linear term. Maternal age, smoking, race, residence in urban versus rural area, geographic region (eastern versus western Washington), paternal age, and infant gender were included as categorical factors. Prevalence ratios were adjusted for birth year and all of the preceding factors. Two hundred and eighty-two infants with gastroschisis were identified. In the adjusted analysis, the prevalence ratio for gastroschisis was 1.1 per year (95% CI 1.08-1.13), indicating an average 10% increase per birth year. Teen mothers were at a higher risk compared to mothers≥25 yr old (adjusted rate ratio [aRR] 8.02; 95% CI 5.30-12.13), as were teen fathers (aRR 2.35; 95% CI 1.48-3.74) compared to fathers≥25 years old. Maternal smoking was associated with a higher risk compared to those who were nonsmokers (aRR 1.58; 95% CI 1.19-2.09). Black mothers had a lower risk compared with white mothers. There was no association with geographic classification of mother's residence. Gastroschisis prevalence has increased in WA, particularly in teen mothers and in smokers. This is not explained by a rise in teenage pregnancies or maternal smoking. Further investigation of factors specific to teenage lifestyle is warranted.

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis.

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.

Nevirapine resistance by timing of HIV type 1 infection in infants treated with single-dose nevirapine.

BACKGROUND: In women, single-dose nevirapine for prophylaxis against mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) selects for nevirapine-resistant HIV-1, which subsequently decays rapidly. We hypothesized that the selection, acquisition, and decay of nevirapine-resistant HIV-1 differs in infants, varying by the timing of HIV-1 infection. METHODS: We conducted a prospective, observational study of 740 Mozambican infants receiving single-dose nevirapine prophylaxis and determined the timing of infection and concentrations of nevirapine-resistant HIV-1 over time. RESULTS: Infants with established in utero infection had a high rate (87.0%) of selection of nevirapine-resistant HIV-1 mutants, which rapidly decayed to undetectable levels. The few without nevirapine resistance received zidovudine with single-dose nevirapine and/or their mothers took alternative antiretroviral drugs. Infants with acute in utero infection had a lower rate of nevirapine-resistant HIV-1 (33.3%; P = .006, compared with established in utero infection), but mutants persisted over time. Infants with peripartum infection also had a lower rate of nevirapine-resistant HIV-1 (38.1%; P = .001, compared with established in utero infection) but often acquired 100% mutant virus that persisted over time (P = .017, compared with established in utero infection). CONCLUSIONS: The detection and persistence of nevirapine-resistant HIV-1 in infants after single-dose nevirapine therapy vary by the timing of infection and the antiretroviral regimen. In infants with persistent high-level nevirapine-resistant HIV-1, nevirapine-based antiretroviral therapy is unlikely to ever be efficacious because of concentrations in long-lived viral reservoirs. However, the absence or decay of nevirapine-resistant HIV-1 in many infants suggests that nevirapine antiretroviral therapy may be effective if testing can identify these individuals.

Fibroblast growth factor-10 signals development of von Brunn's nests in the exstrophic bladder.

von Brunn's nests have long been recognized as precursors of benign lesions of the urinary bladder mucosa. We report here that von Brunn's nests are especially prevalent in the exstrophic bladder, a birth defect that predisposes the patient to formation of bladder cancer. Cells of von Brunn's nest were found to coalesce into a stratified, polarized epithelium which surrounds itself with a capsule-like structure rich in types I, III, and IV collagen. Histocytochemical analysis and keratin profiling demonstrated that nested cells exhibited a phenotype similar, but not identical, to that of urothelial cells of transitional epithelium. Immunostaining and in situ hybridization analysis of exstrophic tissue demonstrated that the FGF-10 receptor is synthesized and retained by cells of von Brunn's nest. In contrast, FGF-10 is synthesized and secreted by mesenchymal fibroblasts via a paracrine pathway that targets basal epithelial cells of von Brunn's nests. Small clusters of 10pRp cells, positive for both FGF-10 and its receptor, were observed both proximal to and inside blood vessels in the lamina propria. The collective evidence points to a mechanism where von Brunn's nests develop under the control of the FGF-10 signal transduction system and suggests that 10pRp cells may be the original source of nested cells.

Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery.

OBJECTIVES: The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen. AIM: To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T). BACKGROUND: Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe. METHODS/MATERIALS: A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg·kg(-1) rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg·kg(-1) of intranasal fentanyl, and group 3 received acetaminophen and 1 mg·kg(-1) of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined. RESULTS: There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported. CONCLUSIONS: We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.

Gastric contents in pediatric patients following bone marrow transplantation.

BACKGROUND: Graft versus host disease (GVHD) of the gut is thought to delay gastric emptying and so may increase the risk of aspirating retained contents while under anesthesia. Knowing that gastric emptying is delayed in patients with GVHD might lead one to choose to intubate the trachea for all patients with suspected GVHD, who present for diagnostic esophagogastricduodenoscopy (EGD). We are not aware of published data that gives specific guidance as to the need for intubation in the pediatric bone marrow or stem cell transplantation (BMT) population. This review was intended to evaluate the gastric contents (pH and volume) in this group of patients, to provide anesthesiologists with data that would inform their decisions about airway management for these patients. METHODS: Retrospective chart review of patients