Lifelong Sequelae Research Articles

Neonatal Cerebellar Hemorrhage and Facial Nerve Palsy: An Unusual Association

Cerebellar hemorrhage is rare in term newborns and is most often seen after traumatic birth. Lifelong sequelae include motor and cognitive impairment. We report the uncommon case of a late preterm infant born by spontaneous delivery who showed right peripheral facial palsy at 24 hours of life. Cranial ultrasound showed lateral ventricles dilatation and a diffuse hyperechoic round lesion in the right cerebellar hemisphere. The computed tomography scan confirmed a hemorrhagic lesion in the right cerebellar hemisphere and in the vermis with midline shift and intraventricular bleeding. Ommaya reservoir was inserted and used for a few days. The facial palsy gradually recovered to a complete remission after 6 weeks. Follow-up examinations at 12 and 18 months evidenced infant's delayed motor function, hyperreflexia, tremors, and speech delay.

MON-029 Polycystic Ovary Syndrome (PCOS) in Adolescent Girls:Toward a Simple On-Treatment Predictor of Post-Treatment Ovulation Rate

There is no approved treatment for adolescent girls with PCOS. The vast majority of these patients are guided into a trajectory that starts with oral contraceptive (OC) treatment, leads into oligo-anovulatory subfertility, then into the use of assisted reproductive techniques, and ultimately into pregnancies with a double-to-triple risk for complications (such as gestational diabetes, preeclampsia and preterm birth) potentially with lifelong sequelae in the offspring.Evidence is converging into the insight that adolescent PCOS is frequently driven by hepato-visceral fat excess (“central obesity”) ensuing from a mismatch between (rather restrictive) prenatal and (rather abundant) postnatal nutrition, on a background of genetic susceptibility (Trends Endocrinol Metab 2018;29:815). This insight has prompted the exploration of an alternative PCOS treatment that aims at reducing the central-fat excess (without causing weight loss in non-obese girls) in order to normalize the entire phenotype, including ovulation rate.So far, this alternative approach has been tested in two randomized controlled pilot studies that were performed in non-obese girls with PCOS and with no need for contraception (total N=62; age 16 yr; BMI 24 Kg/m2; treatment for 1 year; ovulation assessment during the post-treatment year). In these studies, the effects of an OC were compared to those of SPIOMET, which is a low-dose combination of spironolactone (= a mixed anti-androgen and -mineralocorticoid, also activating brown adipose tissue; Diab Ob Metab 2019;21:509), pioglitazone and metformin (= two insulin sensitizers acting through different mechanisms).Pooled results of the pilot studies confirm the first report (J Adolesc Health 2017;61:446) that SPIOMET has more normalizing effects than OC; there were approximately 3-fold more ovulations post-SPIOMET than post-OC; normovulation occurred only post-SPIOMET; anovulation was >10-fold more frequent post-OC.Pooled results also disclosed two new features of adolescent PCOS: low concentrations of circulating CXCL14 (= a brown adipokine, signaling activity in brown adipose tissue; Cell Metab 2018;28:750) and miR-451a (= an inhibitor of THRSP-mediated hepatic lipogenesis; Mol Cell Endocrinol 2018;474:260), both of which remain abnormally low on OC, but normalize on SPIOMET treatment. The on-treatment Z-scores of fasting insulin and miR-451a explained together approximately 50% of the variation in post-treatment ovulation rates. This simple duo, if validated in larger and more diverse PCOS populations, may become a first on-treatment predictor of post-treatment ovulation rate.

A Case of Vaping-associated Acute Lung Injury

Although vaping has been promoted by manufacturers as a safe alternative to traditional smoking, the dangers of vaping and e-cigarette use have come to the forefront of the medical community, particularly the risks associated with tetrahydrocannabinol-containing products. Although many patterns of vaping-associated lung injuries have been reported in the literature, one of the most concerning is that of diffuse alveolar damage. As e-cigarette and vaping use is becoming increasingly popular, particularly in the younger population, it is important to become familiar with this entity to ensure proper and timely diagnosis to prevent lifelong sequelae.

Lifelong pulmonary sequelae of bronchopulmonary dysplasia.

To summarize the current literature evaluating long-term pulmonary morbidity among surviving very preterm infants with bronchopulmonary dysplasia (BPD). BPD predisposes very preterm infants to adverse respiratory signs and symptoms, greater respiratory medication use, and more frequent need for rehospitalization throughout early childhood. Reassuringly, studies also indicate that older children and adolescents with BPD experience, on average, similar functional status and quality of life when compared to former very preterm infants without BPD. However, measured deficits in pulmonary function may persist in those with BPD and indicate an increased susceptibility to early-onset chronic obstructive pulmonary disease during adulthood. Moreover, subtle differences in exercise tolerance and activity may put survivors with BPD at further risk of future morbidity in later life. Despite advances in neonatal respiratory care, a diagnosis of BPD continues to be associated with significant pulmonary morbidity over the first two decades of life. Long-term longitudinal studies are needed to determine if recent survivors of BPD will also be at increased risk of debilitating pulmonary disease in adulthood.

754 Social Determinants Associated with Paediatric Burn Injury: A Population Based, Case-control Study

Abstract Introduction Children are disproportionately represented as victims of burn injury compared to adults. Life-long sequelae post-burn manifest as increased rates of mental and physical illness, substance abuse, and suicide. Social determinants of health (SDoH) influence risk of injury, however the extent and influence of SDoH on burn injury is less clear. To determine which social determinants influence burn injury in children, a retrospective case-control study was conducted. Methods Children (< 17 years of age) admitted to a regional burn centre between January 1 1999 and March 30 2017 were matched based on age, sex and geographic location 1:5 with an uninjured cohort. Population level administrative data describing the SDoH, at the regional administrative multifaceted data repository were compared between the cohorts. Thirteen SDoH were chosen based on a systematic review conducted by the research team. Results No significant differences existed in descriptive statistics between the burn and control cohorts. Mean age at burn injury = 5.46 (± 5.23), average TBSA (%) = 10.5 (± 13.4). The most common mechanism of burn injury was scald (42.03%) Upon multivariable logistic regression, children: from a low-income household (O.R. 1.97 (1.46, 2.65)); in foster care (O.R. 1.57 (1.11, 2.21)); from a family that received income assistance (O.R. 1.71 (1.33, 2.19)); or born to a teen mother (O.R. 1.43 (1.13, 1.81)) were associated with an increased risk of burn injury. Conclusions This study identified SDoH associated with an increased risk of burn injury. This case-control study supports the finding that children from a low-income household, children in care, from a family that received income assistance, and children born to a teen mother are at an elevated risk of burn injury. Applicability of Research to Practice Identifying children at increased potential risk provides an opportunity to prevent burn injuries, bypassing the associated long-term physical disfigurement, life-long mental health consequences and mortality. This study also has merit in maximizing the efficiency of a burn prevention budget through targeted burn safety and risk reduction programs.

Abstract A23: Proteogenomic discovery of novel tumor proteins as neoantigens for personalized T-cell immunotherapy in pediatric medulloblastoma

Abstract Medulloblastoma is a common childhood brain tumor for which current therapies fail to cure high-risk subgroups, including metastatic and recurrent disease. Toxicity limits further intensification of conventional chemo-radiation therapy, and most survivors endure significant lifelong sequelae from treatment. There is an urgent need to develop new tools to combat this cancer without increasing the late effects burden. Neoantigens, which are exclusively expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. The ideal target antigen is abundantly expressed by tumor cells but not by normal tissues, in order to limit off-target effects. Tumors translate a host of highly novel transcripts that are the result of aberrations in tumor DNA and the unmasking of alternative or novel exons. We used a novel proteogenomic approach to identify tumor-restricted peptides and used them to select and expand T cells capable of mounting a tumor-specific cytotoxic immune response, with no off-target effects for patients with MB. Using RNA-seq and WGS data, we created personalized custom searchable databases containing predicted novel proteins from somatic mutations, novel isoforms, and fusion proteins from 56 medulloblastoma tumors. By searching this database with raw mass spectrometry data from the paired medulloblastoma tumor, we have identified tens of peptides arising from the translation of tumor-specific transcripts; these peptides are potential neoantigens. Our data indicate that in cases of tumors with low mutation rates, such as pediatric brain tumors, novel isoforms are the main source of neoantigens. In a pilot study, we have tested these peptides for their ability to select and expand polyclonal populations of T cells from the same patient whose tumor was the source of the peptides. The immunogenicity of each individual peptide was then determined. Flow cytometry cellular characterization reveals populations of both CD4+ and CD8+ cells with an activation profile marked by IFN-γ and TNF-α production. Immunosuppressive marker profiles have also been characterized for these cells. Using cytotoxicity assays, we demonstrated that tumor-specific T cells can eliminate neoantigen-bearing tumor cells. These findings demonstrate an initial proof of principle that proteogenomics can be used to identify immunogenic tumor specific peptides and lay the groundwork for a personalized, targeted T-cell therapy for children with high-risk medulloblastoma. Citation Format: Samuel Rivero-Hinojosa, Melanie Grant, Aswini Panigrahi, Huizhen Zhang, Veronika Caisova, Catherine Bollard, Brian Rood. Proteogenomic discovery of novel tumor proteins as neoantigens for personalized T-cell immunotherapy in pediatric medulloblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A23.

The Effect of Intensive Phototherapy Treatment on CD4 and CD8 T-Lymphocyte subsets in Neonatal Jaundice

Introduction: Jaundice is the most common condition that requires medical attention and hospital readmission in neonates. Serum bilirubin levels may rise excessively, which can be cause lifelong neurologic sequelae (kernicterus). Objectives: To investigate the effect of intensive phototherapy on the expression of CD4 and CD8 lymphocyte subsets in neonates with indirect hyperbilirubinemia. Patients and Methods: This is a prospective study included 30 full term neonates admitted to neonatal intensive care unit, Minia university hospital and 20 full term healthy neonates during the period from October 2016 to October 2017. Results: There were no significant differences regarding CD4%, CD8% and CD4/CD8 ratios in neonates with indirect hyperbilirubinemia either before or after phototherapy. After phototherapy there were no significant differences between cases and controls as regarding CD4% and CD4/CD8 ratio while there was a significant decrease in CD% in cases compared to controls (p value 0.03). A significant positive correlation between CD4% and age (r- value 0.39, p-value 0.02) was present in cases. Conclusions: The results demonstrated that in addition to the well-known positive effect of phototherapy on neonatal serum bilirubin level, this treatment have no effect on the function of the immune system in neonates as regards CD4 and CD8 subsets as well as CD4/CD8 ratio .

Characteristics of Open Globe Injuries in the United States From 2006 to 2014

Open globe injuries can lead to substantial visual morbidity and lifelong sequelae. Interventions to reduce the burden of open globe injuries in the United States require a better understanding of these injuries through well-designed epidemiologic investigations. To examine the incidence, common injury mechanisms, and economic burden of open globe injuries in the United States. This retrospective, cross-sectional study of US nationwide emergency department (ED) data assessed all ED visits of patients with a primary diagnosis of open globe injury in the Nationwide Emergency Department Sample (NEDS) from January 1, 2006, to December 31, 2014. Data analysis was performed from August 29, 2018, to November 11, 2019. Annual incidence of open globe injuries by age, sex, mechanism of injury, and concomitant diagnosis, as well as median charges associated with open globe injuries and variables associated with hospitalization. A total of 124 989 ED visits for open globe injuries were assessed, with an incidence of 4.49 per 100 000 population in the United States from 2006 to 2014 (mean [SD] age of study participants, 37.7 [22.5] years; 94 078 [75.3%] male). The incidence was highest in 2006 (5.88 per 100 000 population) and decreased by 0.3% per month between 2006 and 2014 (incidence rate ratio, 0.99; 95% CI, 0.99-0.99; P < .001). Open globe injuries occurred in 37 060 individuals (30.6%) of low socioeconomic status. The most common injury mechanism was being struck by or against an object or person (40 119 of all 124 989 injury mechanisms [32.1%]). Open globe injuries associated with falls increased 6.6% between 2006-2010 and 2011-2015 (95% CI, 1.04-1.08; P < .001) and were the most common injury mechanism in individuals older than 70 years. The total cost associated with open globe injuries was $793 million. The cost of ED visits increased from $865 during 2006-2010 to $1557 during 2011-2015. Inpatient costs similarly increased from $21 527 during 2006-2010 to $30 243 during 2011-2015. The incidence of open globe injuries in the United States decreased from 2006 to 2014. Although the data are from 5 to 13 years ago, these findings appear to provide valuable information for targeting preventive measures toward individuals at highest risk; targeting young men with lower socioeconomic status and individuals 70 years or older at an increased risk of falls may help lower the incidence of open globe injuries.

Neurodevelopmental outcome of healthy term newborn with serum bilirubin >15 mg/dl at one year.

Neonatal hyperbilirubinemia is a common medical emergency in early neonatal period. Unconjugated bilirubin is neurotoxic and can lead to lifelong neurological sequelae in survivors. To find out the association between serum bilirubin and neurodevelopmental outcome at 1 year of age using Development Assessment Scale for Indian Infants (DASII). A prospective cohort study was conducted in the Department of Pediatrics of a tertiary care institution of Central India between January 2018 and August 2019. Total 108 term healthy neonates, with at least one serum bilirubin value of >15 mg/dl, were included. Subjects were divided into three groups based on the serum bilirubin; group 1: (15-20 mg/dl) -85(78.7%) cases, group 2: (20-25 mg/dl) -17(15.7%), and group 3: (>25 mg/dl) -6(5.5%). Developmental assessment was done using DASII at 3, 6, 9, 12 months of age. Out of 108 cases, 101(93.5%) received phototherapy, and 7(6.5%) received double volume exchange transfusion. Severe delay was observed in 5(4.6%) and mild delay in 2(1.9%) cases in the motor domain of DASII at one year. Severe delay in the motor domain was associated with mean TSB of 27.940±2.89 mg/dl and mild delay with mean TSB of 22.75±1.76 mg/dl (p = 0.001). On cluster analysis, delay was observed in locomotion 1 score in 11(13%) cases (p = 0.003) and manipulation score in 6(7.1%) cases in group 1. Increased serum bilirubin was a significant risk factor for the delayed neurodevelopment in babies with neonatal jaundice. Even a moderate level of bilirubin significantly affects the developmental outcome.

A Sexually Dimorphic Role for STAT3 in Sonic Hedgehog Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma.

NPI-0052 and gamma-radiation induce a synergistic apoptotic effect in the most aggressive medulloblastoma subgroup

Abstract Group 3 medulloblastoma (MB) is the most aggressive and least characterised of all MB subgroups. These tumours are highly metastatic and patients undergo aggressive treatments leaving survivors with severe side effects. The standard of care for these patients consists of surgical resection followed by gamma-radiation and chemotherapy. Whilst this conventional therapy is successful in the majority of cases, however, many survivors are left with lifelong severe neurocognitive and physical sequelae. Interestingly, the proteasome plays a vital role in the pathogenesis of different tumours, therefore proteasome inhibition can be used as a new strategy for treating MB. NPI-0052 is a proteasome inhibitor that can penetrate the blood-brain barrier with a good safety profile, making it an appealing treatment for brain tumors. In the present study, we evaluate the anticancer activity of NPI-0052 in a range of MB patient derived MB cells and cell lines. Our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. We also show that the p53-family plays a substantial role in NPI-0052’s mechanism of action. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with gamma-radiation, a component of the current MB therapy, in both cells and tumour organoids. Our work underscores the use of NPI-0052 as a novel therapy for reducing the doses of gamma-radiation in G3-MB patients.

Bullying Victimization Among School-Going Adolescents in Malaysia: Prevalence and Associated Factors.

This study aimed to assess the prevalence and factors associated with bullying victimization from a nationwide school-based survey among 27 458 students aged 13 to 17 years. The overall prevalence of having been bullied in the past 30 days was 16.2%; this decreased with age. Multivariate logistic regression analysis revealed that factors most strongly associated with bullying victimization were exposure to physical attacks (adjusted odds ratio [aOR] = 2.46, 95% confidence interval [CI] = 2.17-2.79), illicit drug use (aOR = 2.44, 95% CI = 1.78-3.34), involvement in physical fights (aOR = 1.97, 95% CI = 1.74-2.23), being younger than 14 years (aOR =1.95, 95% CI = 1.59-2.38), and having ever attempted suicide (aOR = 1.83, 95% CI = 1.51-2.21). Other significantly associated factors include loneliness, truancy, making suicidal plans, and symptoms of depression, anxiety, and stress. Exposure to bullying victimization can result in negative lifelong sequelae and important associated factors should be considered in planning effective school-based anti-bullying interventions.

Exercise Overrides Blunted Hypoxic Ventilatory Response in Prematurely Born Men.

PurposePre-term birth provokes life-long anatomical and functional respiratory system sequelae. Although blunted hypoxic ventilatory response (HVR) is consistently observed in pre-term infants, it remains unclear if it persists with aging and, moreover, if it influences hypoxic exercise capacity. In addition, it remains unresolved whether the previously observed prematurity-related alterations in redox balance could contribute to HVR modulation.MethodsTwenty-one prematurely born adult males (gestational age = 29 ± 4 weeks], and 14 age matched controls born at full term (gestational age = 39 ± 2 weeks) underwent three tests in a randomized manner: (1) hypoxia chemo-sensitivity test to determine the resting and exercise poikilocapnic HVR and a graded exercise test to volitional exhaustion in (2) normoxia (FiO2 = 0.21), and (3) normobaric hypoxia (FiO2 = 0.13) to compare the hypoxia-related effects on maximal aerobic power (MAP). Selected prooxidant and antioxidant markers were analyzed from venous samples obtained before and after the HVR tests.ResultsResting HVR was lower in the pre-term (0.21 ± 0.21 L ⋅ min-1 ⋅ kg-1) compared to full-term born individuals (0.47 ± 0.23 L ⋅ min-1 ⋅ kg-1; p < 0.05). No differences were noted in the exercise HVR or in any of the measured oxidative stress markers before or after the HVR test. Hypoxia-related reduction of MAP was comparable between the groups.ConclusionThese findings indicate that blunted resting HVR in prematurely born men persists into adulthood. Also, active adults born prematurely seem to tolerate hypoxic exercise well and should, hence, not be discouraged to engage in physical activities in hypoxic environments. Nevertheless, the blunted resting HVR and greater desaturation observed in the pre-term born individuals warrant caution especially during prolonged hypoxic exposures.

Targeting Glucose Metabolism in Medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood. Although current treatment approaches for this cancer have improved overall survival, they leave devastating and lifelong sequelae and the mortality remains high. Novel targeted therapies are therefore crucial to improve survival in these children and decrease treatment‐related toxicity.Medulloblastoma development is largely driven by deregulation of normal cerebellar proliferation wherein the sonic hedgehog (Shh) pathway plays a critical role. Activating mutations of Shh genes are frequent in medulloblastoma and promote their rapid growth. In addition, highly aggressive Shh‐active medulloblastomas also exhibit mutations of the Ras/MAPK pathway and increased HIF‐1α, which are observed to stimulate glycolysis by activating the 6‐phosphofructo‐2‐kinase/fructose‐2,6 bisphosphatase family of enzymes (PFKFB1‐4). The PFKFBs produce fructose‐2,6‐bisphosphate (F26BP), a potent activator of 6‐phosphofructo‐1‐kinase, a rate‐limiting step in glycolysis. Recent data indicate that the PFKFB4 family member is increased in multiple human tumors and cancer lines, required for cell survival in aggressive brain tumors and strongly induced by hypoxia. We have found that the PFKFB4 enzyme was highly expressed in a series of patient‐derived medulloblastomas and correlated significantly with expression of the Shh pathway effector Smoothened (SMO) and GLI1. Through HIF‐1α upregulation, hypoxia was observed to strongly induce PFKFB4 expression in Shh‐active medulloblastoma cells and silencing PFKFB4 in these cells markedly suppressed F26BP and glycolytic flux to lactate and significantly decreased cell survival and proliferation, more prominently in hypoxia, indicating that PFKFB4 may be preferentially required for survival and growth under hypoxia. In addition, we found that co‐silencing PFKFB4 with SMO or GLI1 markedly decreased cell survival. We have recently developed a novel selective small molecule inhibitor of PFKFB4 and examined the effects of inhibiting PFKFB4 and the Shh pathway simultaneously. We found that simultaneous administration of the PFKFB4 inhibitor and inhibitors of the Shh pathway synergistically decreased Shh‐active medulloblastoma cell viability. Taken together, our data indicate that targeting PFKFB4 may be a valid therapeutic option against medulloblastoma and strongly support the further examination of simultaneous inhibition of PFKFB4 and the Shh pathway as a treatment strategy in medulloblastoma.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Trajectories of sexual identity development and psychological well-being for highly sexually active gay and bisexual men: A latent growth curve analysis.

Examining sexual identity development-the process through which sexual minorities discover and disclose their sexual orientations-within a minority stress framework may help to contextualize sexual and mental health disparities among gay and bisexual men. Research on sexual identity development has typically focused on ages of achieving specific milestones (i.e., awareness, identification, sexual experience, and disclosure), though differences in onset and speed of the process and impact of these trajectories on healthy functioning in adulthood are understudied. We analyzed cross-sectional data from 374 highly sexually active gay and bisexual men in NYC. Using latent growth curve modelling, we examined trajectories of sexual identity development through the four primary milestones. We next examined their associations with childhood and background characteristics, adult experiences of sexual minority stress, and adult mental health. Gay sexual identity and greater childhood gender nonconformity were associated with earlier reported onset of sexual identity development and younger age was significantly associated with faster progression through the developmental process. The model showed that faster progression through sexual identity development was associated with higher levels of sexual orientation-based discrimination, emotion dysregulation, sexual compulsivity, and anxiety and depression in adulthood. These findings support the need for a comprehensive and developmentally-informed model of adulthood functioning among gay and bisexual men that considers trajectories of sexual identity development-including onset and duration-as potential precursors to mental health difficulties in adulthood. Given the early onset of sexual identity development and potential lifelong sequelae, early prevention programs promoting positive sexual identity development are warranted.

Comparison of risk and protective factors for preterm birth in rural, suburban, and urban Fresno County, California

Preterm birth (PTB, &lt; 37 weeks’ gestation) may impose lifelong sequelae or death. Fresno County reports the highest rate of PTB in California. A place-based approach investigating local risk factors for PTB may provide important opportunities for intervention and prevention. In this study, we examine risk and protective factors for PTB in rural, suburban, and urban Fresno County, California. The sample was drawn from Fresno County, California singleton births 2007-2012 (n = 81,021). Multivariate models of maternal risk and protective factors for PTB were stratified by rural, suburban, and urban residence. Women with diabetes, hypertension, infection, fewer than three prenatal care visits, previous PTB, interpregnancy interval less than six months, or were of Black race/ethnicity were at increased risk of PTB. The risk of PTB was highest for women residing in rural locations with preeclampsia superimposed on preexisting hypertension (adjusted relative risk (aRR) 5.7, 95% confidence interval (CI) 4.4-7.4). For women living in urban residences, maternal birth in Mexico and overweight body mass index (BMI) offered protection from PTB (aRRs 0.9), whereas participation in the Women, Infants and Children program was protective for women in either urban or rural residences (aRRs 0.8). Public insurance, &lt;12 year of education, underweight BMI, and interpregnancy interval of five years or more were risk factors only for women in urban residences. These findings may provide important opportunities for local intervention.

Childhood maltreatment, psychological resources, and depressive symptoms in women with breast cancer

Childhood maltreatment is associated with elevated risk for depression across the human lifespan. Identifying the pathways through which childhood maltreatment relates to depressive symptoms may elucidate intervention targets that have the potential to reduce the lifelong negative health sequelae of maltreatment exposure. In this cross-sectional study, 271 women with early-stage breast cancer were assessed after their diagnosis but before the start of adjuvant treatment (chemotherapy, radiation, endocrine therapy). Participants completed measures of childhood maltreatment exposure, psychological resources (optimism, mastery, self-esteem, mindfulness), and depressive symptoms. Using multiple mediation analyses, we examined which psychological resources uniquely mediated the relationship between childhood maltreatment and depressive symptoms. Exposure to maltreatment during childhood was robustly associated with lower psychological resources and elevated depressive symptoms. Further, lower optimism and mindfulness mediated the association between childhood maltreatment and elevated depressive symptoms. These results support existing theory that childhood maltreatment is associated with lower psychological resources, which partially explains elevated depressive symptoms in a sample of women facing breast cancer diagnosis and treatment. These findings warrant replication in populations facing other major life events and highlight the need for additional studies examining childhood maltreatment as a moderator of treatment outcomes.

Septal myectomy after failed septal alcohol ablation.

Despite septal myectomy remaining the gold standard septal reduction therapy for hypertrophic obstructive cardiomyopathy (HOCM), there has been a disproportionate use of alcohol septal ablation (ASA) worldwide. Absolute resolution of left ventricular outflow tract (LVOT) obstruction with ASA is not achieved in a substantial proportion of patients. The mechanisms of failure from ASA are partially understood and described. Residual obstruction in hypertrophic cardiomyopathy is associated with worse clinical outcomes and mortality. There is a growing number of patients who present with significant residual gradients after ASA and require a rescue septal myectomy operation, which then carries an increased risk of perioperative complications and life-long sequelae. This contrasts with the excellent outcomes achieved by septal myectomy without previous percutaneous intervention. Despite complete resolution of obstruction in rescue myectomy, the outcomes remain compromised by the prior ASA.

Spinal cord infarction: Not to be mistaken for acute transverse myelitis

Objective: Vascular lesions that affect the spinal cord pose a diagnostic challenge as the common symptoms are often seen in a variety of other disorders. This devastating condition has challenging lifelong sequelae. Our two cases highlight that spinal cord lesions can easily be mistaken for acute transverse myelitis and how this impacts on patient management. Methods: Cases: A 14-year-old boy presented with neck pain, headache and difficulty with breathing. He had an initial CT brain plus angiogram, which was normal, followed by an MRI scan demonstrating high signal change in the cord from C2 to C6 thought to be transverse myelitis. Following a lumbar puncture, which did not indicate infection, a diffusion restricted MR scan was carried out and the changes seen were in keeping with anterior cord syndrome. The second patient is a 13-year-old boy who presented with acute lower limb paralysis, which was initially diagnosed as transverse myelitis and treated with steroids. Despite treatment he showed little improvement and had subsequent scans revealing a spinal infarct from T4 to the conus. Both patients received rehabilitation to manage bladder and bowel dysfunction, limb weakness, contractures and the psychological impact of this devastating condition. Results: The investigative aids in diagnosing a spinal infarct are serial scans during the admission especially in circumstances of slow improvement of symptoms, alongside diffusion weighted MRI scans. Not only is the physical management of the condition imperative but also the consideration of the psychological impact on the child and their family. Conclusion: The recognition of this demanding condition is essential to allow for the correct management such as early input from a wide range of health care professionals, who all provide support for the patient and family. When children present with sudden flaccid paralysis, anterior spinal cord infarction should be considered as a differential diagnosis.

MEDU-17. SEXUALLY DIMORPHIC ROLES OF STAT3 IN MEDULLOBLASTOMA

AbstractMedulloblastoma is the most common childhood malignant brain tumour, and represents 20% of all paediatric central nervous system neoplasms. Although advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represents a major health care burden for patients, parents, and society. Recent progress in the molecular subtyping of medulloblastoma have revealed at least four distinct subsets of tumours with dramatically different biology. Additionally, medulloblastoma predominately occurs in males and maleness correlates with worse outcome. However, the drivers of this sexual dimorphism in medulloblastoma are unclear. We have identified that STAT3 is one such factor. Deletion of STAT3 from granule cell precursors in a mouse model of SHh medulloblastoma driven by the loss of one PTCH1 allele results in complete protection of males, but has no effect in females. Stratification of transcriptomics data from a cohort of SHh medulloblastoma patients on the basis of STAT3 expression shows that male patients with low STAT3 expression have improved overall survival - an outcome not observed in females. Additionally, we identified STAT3-dependent genes, specific to males which correlate with overall survival. This is one of the first observations of a gene that could, in part, explain the sex dimorphism in medulloblastoma and offer insights into altered treatment options for patients on the basis of their sex and/or STAT3 expression.