Caregivers' and providers' perspectives of social and medical care after pediatric liver transplant: Results from the multicenter SOCIAL-Tx study.

Disparities exist in pediatric liver transplant (LT). We characterized barriers and facilitators to providing transplant and social care within pediatric LT clinics. This was a multicenter qualitative study. We oversampled caregivers reporting household financial strain, material economic hardship, or demonstrating poor health literacy. We also enrolled transplant team members. We conducted semistructured interviews with participants. Caregiver interviews focused on challenges addressing transplant and household needs. Transplant provider interviews focused on barriers and facilitators to providing social care within transplant teams. Interviews were recorded, transcribed, and coded according to the Capability, Opportunity, Motivation-Behavior model. We interviewed 27 caregivers and 27 transplant team members. Fifty-two percent of caregivers reported a household income <$60,000, and 62% reported financial resource strain. Caregivers reported experiencing (1) high financial burdens after LT, (2) added caregiving labor that compounds the financial burden, (3) dependency on their social network's generosity for financial and logistical support, and (4) additional support being limited to the perioperative period. Transplant providers reported (1) relying on the pretransplant psychosocial assessment for identifying social risks, (2) discomfort initiating social risk discussions in the post-transplant period, (3) reliance on social workers to address new social risks, and (4) social workers feeling overburdened by quantity and quality of the social work referrals. We identified barriers to providing effective social care in pediatric LT, primarily a lack of comfort in assessing and addressing new social risks in the post-transplant period. Addressing these barriers should enhance social care delivery and improve outcomes for these children.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Early allograft dysfunction in a pediatric liver allograft with an occult pathogenic mutation in the urea cycle.

Liver transplantation risks transferring a genetic defect in metabolic pathways, including the urea cycle. We present a case of pediatric liver transplantation complicated by metabolic crisis and early allograft dysfunction (EAD) in a previously healthy unrelated deceased donor. Allograft function improved with supportive care, and retransplantation was avoided. Because hyperammonemia suggested an enzymatic defect in the allograft, genetic testing from donor-derived deoxyribonucleic acid revealed a heterozygous mutation in the ASL gene, which encodes the urea cycle enzyme argininosuccinate lyase. Homozygous ASL mutations precipitate metabolic crises during fasting or postoperative states, whereas heterozygous carriers retain sufficient enzyme activity and are asymptomatic. In the described case, postoperative ischemia/reperfusion injury created a metabolic demand that exceeded the enzymatic capacity of the allograft. To our knowledge, this is the first report of an acquired argininosuccinate lyase deficiency by liver transplantation and underscores the importance of considering occult metabolic variants in the allograft during EAD.

Recent Increase in Incidence of Severe Acute Hepatitis of Unknown Etiology in Children is Associated with Infection with Adenovirus and Other Nonhepatotropic Viruses.

OBJECTIVE: To evaluate whether the nature and severity of non-A-E severe acute hepatitis in children noted by the World Health Organization from late 2021 through early 2022 was indeed increased in 2021-2022 compared with prior years. STUDY DESIGN: We performed a single-center, retrospective study to track the etiology and outcomes of children with non-A-E severe acute hepatitis in 2021-2022 compared with the prior 3-year periods (2018-2019, 2019-2020, and 2020-2021). We queried electronic medical records of children ≤16 years of age with alanine or aspartate aminotransferase levels of >500 IU. Data were analyzed for the periods of October 1, 2021, to May 1, 2022, and compared with the same time periods in 2018-2021. RESULTS: Of 107 children meeting entry criteria, 82 cases occurred from October to May of 2018-2022. The average annual case number was 16.3 in 2018-2021 compared with a 2-fold increase (to 33) in 2021-2022 (P = .0054). Analyses of etiologies showed that this increase was associated with a higher number of children who tested positive for viruses (n = 16) when compared with the average of 3.7 for 2018-2021 (P = .018). Adenovirus (26.1%) and severe acute respiratory syndrome coronavirus-2 (10.3%) were the most frequently detected viruses in 2021-2022. Despite evidence of acute liver failure in 37.8% of children in the entire cohort and in 47% of those with viral infection, the overall survival rate was high at 91.4% and 88.9%, respectively. CONCLUSIONS: The number of children with severe acute hepatitis in our center increased from 2021 to May 2022, with a greater frequency of cases associated with adenovirus, yet transplant-free survival remains high.

D-methionine administered as late as 36 hours post-noise exposure rescues from permanent threshold shift and dose-dependently increases serum antioxidant levels.

OBJECTIVE: To elucidate D-methionine's (D-met) dose and time rescue parameters from steady-state or impulse noise-induced permanent threshold shift (PTS) and determine D-met rescue's influence on serum and cochlear antioxidant levels. DESIGN: Five D-met doses at 0, 50, 100, or 200 mg/kg/dose administered starting at 1, 24, or 36 hours post steady-state or impulse noise exposure. Auditory brainstem responses at baseline and 21 days post-noise measured PTS. Serum (superoxide dismutase [SOD], catalase [CAT],, glutathione reductaseand glutathione peroxidase [GPx]) and cochlear (Glutathione [GSH] and glutathione disulphide [GSSG]) antioxidant levels measured physiological impact. STUDY SAMPLE: Chinchillas (10/study group; 6-8/confirmatory groups). RESULTS: D-met significantly reduced PTS for impulse noise (100 mg [2, 6, 14 and 20 kHz]; 200 mg [2, 14 and 20 kHz]) and steady-state noise (all dosing groups, time parameters and tested frequencies). PTS reduction did not significantly vary by rescue time. D-met significantly increased serum SOD (100 and 200 mg for 24 hour rescue) and GPx (50 mg/kg at 24 hour rescue) at 21 days post-noise. Cochlear GSH and GSSG levels were unaffected relative to control. CONCLUSION: D-met rescues from steady-state and impulse noise-induced PTS even when administered up to 36 hours post-noise and dose-dependently influences serum antioxidant levels even 21 days post-noise. D-met's broad and effective dose/time window renders it a promising antioxidant rescue agent.

Abnormal infant neurobehavior and later neurodevelopmental delays in children with critical CHD.

Infants with critical CHD have abnormal neurobehavior assessed by the Neonatal ICU Network Neurobehavioral Scales. This retrospective cohort study hypothesized associations between abnormal infant neurobehavior in the first month of life and later neurodevelopmental outcomes at 1-2 years of age. Associations between abnormal infant attention (orienting to and tracking stimuli) on the Neonatal ICU Network Neurobehavioral Scales and later motor, cognitive, and language neurodevelopmental outcomes on the Bayley Scales of Infant Development-III at follow-up were examined with descriptive statistics and univariable and multivariable regression. Multiple imputation was used to account for missing outcome data. 189 infants with critical CHD were included, and 69% had abnormal neurobehavioral attention scores. 58 (31%) returned as toddlers for neurodevelopmental follow-up, of which 23% had motor delay. Abnormal infant attention had high sensitivity (92%, 95% CI 60-100%) but low specificity (36%, 95% CI 23-52%) for later motor delay. Higher infant attention scores were associated with higher later motor scores in univariable analysis (coefficient 3.49, 95% CI 0.52,6.46, p = 0.025), but not in multivariable analyses. Neither cognitive nor language scores were associated with infant attention scores. Lower birth weight and male sex were significantly associated with lower motor scores in multivariable analysis (p = 0.048, 0.007). Although impaired infant attention is interdependent with other clinical and demographic risk factors, it may be a sensitive clinical marker of risk for later motor delay. In children with critical CHD, impaired infant attention may be capturing early signs of abnormal visual-motor neurodevelopment.

Children undergoing early liver re-transplantation for primary non-function have improved survival.

BACKGROUND: Primary non-function (PNF) in the early post-LT period in children leads to prolonged hospitalization, high graft loss, and significant mortality. However, there is a paucity of data available on the natural history of children relisted for LT due to PNF, including those who recover graft function and survive with their original allograft. METHODS: We interrogated the United Network of Organ Sharing (UNOS) database for pediatric LT recipients who were relisted with a primary diagnosis of PNF from 2000 to 2020. Patients >21-year-old and multiple organ transplants were excluded. Logistic regression and Cox proportional hazard models were employed to identify risk factors for early re-transplantation (within 30 days of relisting) and mortality after adjusting for baseline clinical characteristics. RESULTS: One hundred and eight patients were relisted for LT for PNF during the study period. Twenty-five patients survived beyond 30 days from relisting with their original LT, 76 underwent early re-transplantation, and 7 did not survive. Having a high-risk EBV mismatch (OR 2.03, 95% CI 0.66-6.27) and an elevated donor serum creatinine (OR: 2.19, 95% CI 0.54-8.84) were associated with increased odds of a patient requiring early re-transplantation. Donor characteristics including age, final total bilirubin, final AST/ALT, and final serum sodium, as well as vasopressor use prior to procurement, were not associated with increased odds of early re-transplantation (p > 0.05). Operative characteristics including allograft type and cold-ischemia time were also not associated with early re-transplantation (p > 0.05). Patients undergoing early re-transplantation showed a trend toward improved 1-year graft survival (69% vs 55%, p = 0.24). On multivariable Cox proportional hazards modeling, early re-transplantation was associated with reduced risk of overall patient mortality compared to those who survived with their original LT (HR 0.27, 95% CI 0.12-0.67). CONCLUSION: Early re-transplantation for PNF is associated with improved patient survival compared with patients who survive with their original LT.

The audiogram: Detection of pure-tone stimuli in ototoxicity monitoring and assessments of investigational medicines for the inner ear.

Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided.

Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India.

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel double-blind placebo-controlled exploratory Phase 2 study.Study samples: Fifty adult cancer patients received oral D-met or placebo before each cisplatin dose. Physical examination, blood collection and audiometry occurred at baseline and subsequent visits plus post-treatment audiometry. After attrition, final analysis included 27 patients.Results: Significant treatment group by ear and time (baseline vs. post-treatment) interactions occurred at 10 kHz and 11.2 kHz. Placebo and D-met groups differed in threshold shift for left ear at 11.2 kHz (mean difference = 22.97 dB [9.59, 36.35]). Averaging across ears, placebo group showed significant threshold shifts from baseline to post-treatment at 10 kHz (mean shift= -13.65 dB [-21.32,-5.98]), 11.2 kHz (-16.15 dB [-25.19,-7.12]), and 12.5 kHz (-11.46 dB [-19.18,-3.74]) but not 8 kHz (-8.65 dB [-17.86, 0.55]). The D-met group showed no significant threshold shifts (8 kHz: -1.25 dB [-7.75, 5.25]; 10 kHz:-3.93 dB [-8.89, 1.03]; 11.2 kHz:-4.82 dB [-11.21, 1.57]; 12.5 kHz:-3.68 dB [-11.57, 4.21]). Side effects did not significantly differ between groups.Conclusion: Oral D-met reduces cisplatin-induced ototoxicity in humans.

D-methionine immediate and continued rescue after noise exposure does not prevent temporary threshold shift but alters cochlear and serum antioxidant levels.

OBJECTIVE: Determine if D-methionine (D-met) rescue prevents temporary threshold shift (TTS) from steady-state or impulse noise and determine D-met's impact on serum and cochlear antioxidant levels. DESIGN: D-met at 50, 100 or 200 mg/kg/doses were administered 0, 6 and 18 hours-post noise. ABRs at baseline and 24 hours post-noise measured TTS. Serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels measured physiological influence. Three control groups, with impulse or steady-state or without noise, were saline-injected. STUDY SAMPLE: Ten Chinchillas/group. RESULTS: D-met rescue did not significantly reduce TTS or impact serum CAT, SOD, GPx or GR levels vs. noise-exposed control groups, but TTS was greater in all groups relative to no-noise controls. D-met significantly elevated CAT at 50 mg/kg vs. steady-state controls and SOD at 200 mg/kg vs. impulse noise controls. D-met significantly reduced cochlear GSH/GSSG ratios in the 100 mg/kg D-met group vs. impulse noise controls. CONCLUSIONS: While D-met rescue has reduced permanent threshold shift in previous studies, it did not reduce TTS in this study. However, D-met rescue did alter selective serum and cochlear oxidative state changes 24 hours post-noise relative to controls. Results demonstrate TTS studies do not always predict PTS protection in otoprotectant experimental designs.

Anxiety symptoms and associated functional impairment in children with CHD in a neurodevelopmental follow-up clinic.

OBJECTIVES: To examine the prevalence of anxiety symptoms and associated functional impairment to adaptive skills among elementary-aged children with CHD and to determine the need for anxiety screening in this high-risk population. STUDY DESIGN: In a single-centre retrospective, cohort design, caregivers reported anxiety symptoms using Conner's scales and functional impairment to adaptive skills using the Adaptive Behavior Assessment System. A total of 194 children were stratified across two cohorts: early elementary (ages 3-6 years) and late elementary (ages 6-14 years). Descriptive statistics summarised the frequency of anxiety symptoms and functional impairment. Spearman's correlations compared anxiety symptoms to functional impairment of adaptive functioning. Univariable logistic regressions examined demographic and clinical characteristics associated with anxiety symptoms. RESULTS: The majority of patients presented with anxiety, early elementary (63%), and late elementary cohorts (78%). Functional impairment was moderately correlated with anxiety symptoms in the early elementary cohort (rs = -.42, 95% CI [-0.58, -0.21], p = <.001). Greater anxiety symptoms were associated with lower cardiac complexity at primary age of surgery in the late elementary cohort (OR = 12.15, p = 0.019). Lesser anxiety symptoms were associated with having private insurance (OR = 0.25, p = 0.014). CONCLUSION: This study demonstrates anxiety symptoms are common and associated with functional impairment to adaptive functioning in younger children with CHD. No clear clinical predictors exist for anxiety symptoms or functional impairment; therefore, screening for anxiety symptoms may need to be added to standard clinical assessment of all children with CHD participating in neurodevelopmental follow-up.

Sooty molds from the Jurassic of Patagonia, Argentina.

PREMISE: The sooty molds are a globally distributed ecological group of ascomycetes with epiphyllous, saprotrophic habit, comprising several phylogenetically distant taxa (i.e., members of the classes Dothideomycetes and Eurotiomycetes). Their fossil record extends almost continuously back to the early Cretaceous; however, they are hypothesized to have originated in the early Mesozoic. Here, we describe new specimens of sooty molds associated with conifer leaves from Jurassic hot spring deposits of Patagonia, Argentina. METHODS: Thin sections of chert samples from the La Matilde Formation, Deseado Massif (Santa Cruz, Argentina) were observed using light microscopy. RESULTS: The fungi occur on the surface and axils of leafy twigs with podocarpaceous affinities, forming dense subicula comprised by opaque moniliform hyphae. Additionally, several asexual and sexual reproductive structures are observed. On the basis of vegetative (i.e., dense subicula composed of moniliform hyphae; hyphae composed of opaque cells deeply constricted at the septa) and reproductive characters (i.e., poroconidial and sympodioconidial asexual stages and diverse spores), two morphotypes were identified with affinities within lineages of the subphylum Pezizomycotina that encompass the ecological group of sooty molds, and a third morphotype was within the phylum Ascomycota. CONCLUSIONS: This finding extends the fossil record of sooty molds to the Jurassic and their geographic fossil range to the South American continent. In particular, their association with podocarpaceous conifers is shown to be ancient, dating back to the Jurassic. This new record provides an additional reference point on the diversity of interactions that characterized Jurassic forests in Patagonia.

Health literacy and its association with adherence in pediatric liver transplant recipients and their parents.

OBJECTIVE: Non-adherence to pediatric regimens is a common concern. Low health literacy is correlated with poor outcomes in adults but is understudied in pediatrics. The current project aimed to determine the relationship between health literacy, adherence, and outcomes in pediatric liver transplant recipients. Hypotheses included a) parent and patient health literacy would be positively correlated; and b) low patient and/or parent health literacy would be negatively correlated with adherence and health outcomes. PATIENTS AND METHODS: Eligible participants were recruited during routine follow-up visits in a pediatric liver transplant clinic. Parents and patients (>13 years old) completed 2 measures of health literacy. Patients ≥18 years completed health literacy measures without corresponding parent surveys. Adherence variables and health outcomes were obtained from medical records. RESULTS: Seventy-nine patients across two sites completed the study. Variance in classification of health literacy between measures was observed; however, most parents (82%-100%) scored within an "adequate literacy" range. More adolescents scored in lower health literacy ranges relative to the parents. Markers of SES were positively correlated with health literacy. Parent health literacy was negatively associated with biopsy-proven rejection episodes and the number of hospitalizations; however, it was not associated with measures of tacrolimus adherence. There were no relationships observed between parent and adolescent health literacy. CONCLUSIONS: Health literacy is an important consideration in managing patient care; however, available measures demonstrate variability in capturing the skills of patients. Effective communication strategies may ameliorate admittedly small, but negative, impacts of limited health literacy on outcomes.

Congenital Portosystemic Shunts in Children: Associations, Complications, and Outcomes.

BACKGROUND: Congenital portosystemic shunt (CPSS) is a rare malformation in which splanchnic venous flow bypasses the liver. CPSS is associated with other congenital anomalies and syndromes and can be associated with life-threatening complications. CPSS and their management remain underreported in the literature. Here, we review the clinical characteristics, management, and outcomes of a cohort of children and young adults with CPSS from two pediatric centers. METHODS: Cases of CPSS from Cincinnati Children's Hospital Medical Center and C.S. Mott Children's Hospital were reviewed to define CPSS anatomy, associated anomalies, complications, interventions, and outcomes. The imaging features and histopathology of liver lesions were characterized in detail. RESULTS: A total of 11 cases were identified. Median age was 10 years (range 0-26); 8 (73%) cases were female. Associated anomalies included six patients with heterotaxy (55%), five patients with congenital heart disease (45%), three patients with Turner syndrome (27%), and two patients with omphalocele, exstrophy, imperforate anus, spinal defects (OEIS) complex (18%). Eight (73%) cases had hyperammonemia ± encephalopathy. A 4-month-old presented with hepatopulmonary syndrome, and 12-year-old presented with pulmonary hypertension. Eight patients (73%) had liver lesions including five with premalignant adenomas and three with well-differentiated hepatocellular carcinoma (HCC). Four children underwent successful CPSS occlusion/ligation. Three children underwent liver transplant (2) or resection (1) for HCC without recurrence at extended follow-up. CONCLUSIONS: CPSS is associated with multiple anomalies (heterotaxy, congenital heart disease) and syndromes (Turner syndrome). CPSS liver lesions should be very carefully evaluated due to risk of premalignant adenomas and HCC. Serious complications of CPSS can occur at a young age but can be managed endovascularly or with open surgery.

Prospective Assessment of Ultrasound Shear Wave Elastography for Discriminating Biliary Atresia from other Causes of Neonatal Cholestasis.

OBJECTIVE: To prospectively assess the diagnostic performance of ultrasound shear wave elastography (SWE) and hepatobiliary laboratory biomarkers for discriminating biliary atresia from other causes of neonatal cholestasis. STUDY DESIGN: Forty-one patients <3 months of age with neonatal cholestasis (direct bilirubin >2 mg/dL) and possible biliary atresia were prospectively enrolled. Both 2-dimensional (2D) and point ultrasound SWE were performed prior to knowing the final diagnosis. Median 2D (8) and point (10) shear wave speed measurements were calculated for each subject and used for analyses. The Mann-Whitney U test was used to compare shear wave speed and laboratory measurements between patients with and without biliary atresia. Receiver operating characteristic curve analyses and multivariable logistic regression were used to evaluate diagnostic performance. RESULTS: Thirteen subjects (31.7%) were diagnosed with biliary atresia, and 28 subjects (68.3%) were diagnosed with other causes of neonatal cholestasis. Median age at the time of ultrasound SWE was 37 days. Median 2D (2.08 vs 1.49 m/s, P = .0001) and point (1.95 vs 1.21 m/s, P = .0014) ultrasound SWE measurements were significantly different between subjects with and without biliary atresia. Using a cut-off value of >1.84 m/s, 2D ultrasound SWE had a sensitivity = 92.3%, specificity = 78.6%, and area under the receiver operating characteristic curve (AuROC) of 0.89 (P < .0001). Using a cut-off value of >320 (U/L), gamma-glutamyl transferase (GGT) had a sensitivity = 100.0%, specificity = 77.8%, and AuROC of 0.85 (P < .0001). Multivariable logistic regression demonstrated an AuROC of 0.93 (P < .0001), with 2 significant covariates (2D ultrasound SWE [OR = 23.06, P = .01]; GGT [OR = 1.003, P = .036]). CONCLUSIONS: Ultrasound SWE and GGT can help discriminate biliary atresia from other causes of neonatal cholestasis.

Protection for medication-induced hearing loss: the state of the science.

OBJECTIVE: This review will summarise the current state of development of pharmaceutical interventions (prevention or treatment) for medication-induced ototoxicity. DESIGN: Currently published literature was reviewed using PubMed and ClinicalTrials.gov to summarise the current state of the science. Details on the stage of development in the market pipeline are provided, along with evidence for clinical safety and efficacy reported. STUDY SAMPLE: This review includes reports from 44 articles and clinical trial reports regarding agents in clinical or preclinical trials, having reached approved Investigational New Drug status with the Federal Drug Administration. RESULTS: Vitamins and antioxidants are the most common agents currently evaluated for drug-induced ototoxicity intervention by targeting the oxidative stress pathway that leads to cochlear cell death and hearing loss. However, other strategies, including steroid treatment and reduction of ototoxic properties of the primary drugs, are discussed. CONCLUSIONS: Retention of hearing during and after a life threatening illness is a major quality-of-life issue for patients receiving ototoxic drugs and their families. The agents discussed herein, while not mature enough at this point, offer great promise towards that goal. This review will provide a knowledge base for hearing providers to inquiries about such options from patients and interdisciplinary care teams alike.

Use of a Digital Modified Checklist for Autism in Toddlers - Revised with Follow-up to Improve Quality of Screening for Autism.

OBJECTIVES: To assess changes in quality of care for children at risk for autism spectrum disorders (ASD) due to process improvement and implementation of a digital screening form. STUDY DESIGN: The process of screening for ASD was studied in an academic primary care pediatrics clinic before and after implementation of a digital version of the Modified Checklist for Autism in Toddlers - Revised with Follow-up with automated risk assessment. Quality metrics included accuracy of documentation of screening results and appropriate action for positive screens (secondary screening or referral). Participating physicians completed pre- and postintervention surveys to measure changes in attitudes toward feasibility and value of screening for ASD. Evidence of change was evaluated with statistical process control charts and χ2 tests. RESULTS: Accurate documentation in the electronic health record of screening results increased from 54% to 92% (38% increase, 95% CI 14%-64%) and appropriate action for children screening positive increased from 25% to 85% (60% increase, 95% CI 35%-85%). A total of 90% of participating physicians agreed that the transition to a digital screening form improved their clinical assessment of autism risk. CONCLUSIONS: Implementation of a tablet-based digital version of the Modified Checklist for Autism in Toddlers - Revised with Follow-up led to improved quality of care for children at risk for ASD and increased acceptability of screening for ASD. Continued efforts towards improving the process of screening for ASD could facilitate rapid, early diagnosis of ASD and advance the accuracy of studies of the impact of screening.

Abnormalities in serum biomarkers correlate with lower cardiac index in the Fontan population.

BACKGROUND: Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients. Methods and results This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman's Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6-33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (-0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (-0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63-0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)]. CONCLUSIONS: Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers.

Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.

D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs.

OBJECTIVE: Test D-methionine (D-met) as an otoprotectant from kanamycin-induced ototoxicity and determine the lowest maximally protective D-met dose. DESIGN: Auditory brainstem responses (ABR) were measured at 4, 8, 14, and 20 kHz at baseline and two, four, and six weeks after kanamycin and D-met administration initiation. ABR threshold shifts assessed auditory function. Following six-week ABR testing, animals were decapitated and cochleae collected for outer hair cell (OHC) quantification. STUDY SAMPLE: Eight groups of 10 male pigmented guinea pigs were administered a subcutaneous kanamycin (250 mg/kg/dose) injection once per day and an intraperitoneal D-met injection (0 (saline), 120, 180, 240, 300, 360, 420, or 480 mg/kg/day) twice per day for 23 days. RESULTS: Significant ABR threshold shift reductions and increased OHC counts (p ≤ 0.01) were measured at multiple D-met-dosed groups starting at two-week ABR assessments. A 300 mg/kg/day optimal otoprotective D-met dose provided 34-41 dB ABR threshold shift reductions and OHC protection. Lesser, but significant, D-met otoprotection was measured at lower and higher D-met doses. CONCLUSIONS: D-met significantly reduced ABR threshold shifts and increased OHC percentages compared to kanamycin-treated controls. Results may be clinically significant particularly for multidrug-resistant tuberculosis patients who frequently suffer from kanamycin-induced hearing loss in developing countries.