Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): Statistical analysis plan

Background: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. Methods/design: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data

Treatment Patterns and Use of Resources in Patients With Tuberous Sclerosis Complex: Insights From the TOSCA Registry

Tuberous Sclerosis Complex (TSC) is a rare autosomal-dominant disorder caused by mutations in the TSC1 or TSC2 genes. Patients with TSC may suffer from a wide range of clinical manifestations; however, the burden of TSC and its impact on healthcare resources needed for its management remain unknown. Besides, the use of resources might vary across countries depending on the country-specific clinical practice. The aim of this paper is to describe the use of TSC-related resources and treatment patterns within the TOSCA registry. A total of 2,214 patients with TSC from 31 countries were enrolled and had a follow-up of up to 5 years. A search was conducted to identify the variables containing both medical and non-medical resource use information within TOSCA. This search was performed both at the level of the core project as well as at the level of the research projects on epilepsy, subependymal giant cell astrocytoma (SEGA), lymphangioleiomyomatosis (LAM), and renal angiomyolipoma (rAML) taking into account the timepoints of the study, age groups, and countries. Data from the quality of life (QoL) research project were analyzed by type of visit and age at enrollment. Treatments varied greatly depending on the clinical manifestation, timepoint in the study, and age groups. GAB Aergics were the most prescribed drugs for epilepsy, and mTOR inhibitors are dramatically replacing surgery in patients with SEGA, despite current recommendations proposing both treatment options. mTOR inhibitors are also becoming common treatments in rAML and LAM patients. Forty-two out of the 143 patients (29.4%) who participated in the QoL research project reported inpatient stays over the last year. Data from non-medical resource use showed the critical impact of TSC on job status and capacity. Disability allowances were more common in children than adults (51.1% vs 38.2%). Psychological counseling, social services and social worker services were needed by <15% of the patients, regardless of age. The long-term nature, together with the variability in its clinical manifestations, makes TSC a complex and resource-demanding disease. The present study shows a comprehensive picture of the resource use implications of TSC

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project.

BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters

Evaluation of a system-specific function to describe the pharmacokinetics of benzylpenicillin in term neonates undergoing moderate hypothermia

The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with a priori birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The systemspecific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3, 000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability [IIV] of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75, 000 IU/kg/day every 8 h (q8h), 150, 000 IU/kg/day q8h, and 200, 000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. Thesystem-specific model may be used for other drugs cleared through the same pathway accelerating model development

Newly Diagnosed and Growing Subependymal Giant Cell Astrocytoma in Adults With Tuberous Sclerosis Complex: Results From the International TOSCA Study

The onset and growth of subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis complex (TSC) typically occurs in childhood. There is minimal information on SEGA evolution in adults with TSC. Of 2,211 patients enrolled in TOSCA, 220 of the 803 adults (27.4%) ever had a SEGA. Of 186 patients with SEGA still ongoing in adulthood, 153 (82.3%) remained asymptomatic, and 33 (17.7%) were reported to ever have developed symptoms related to SEGA growth. SEGA growth since the previous scan was reported in 39 of the 186 adults (21%) with ongoing SEGA. All but one patient with growing SEGA had mutations in TSC2. Fourteen adults (2.4%) were newly diagnosed with SEGA during follow-up, and majority had mutations in TSC2. Our findings suggest that surveillance for new or growing SEGA is warranted also in adulthood, particularly in patients with mutations in TSC2

Clinical Characteristics of Subependymal Giant Cell Astrocytoma in Tuberous Sclerosis Complex

BACKGROUND: This study evaluated the characteristics of subependymal giant cell astrocytoma (SEGA) in patients with tuberous sclerosis complex (TSC) entered into the TuberOus SClerosis registry to increase disease Awareness (TOSCA). METHODS: The study was conducted at 170 sites across 31 countries. Data from patients of any age with a documented clinical visit for TSC in the 12 months preceding enrollment or those newly diagnosed with TSC were entered. RESULTS: SEGA were reported in 554 of 2,216 patients (25%). Median age at diagnosis of SEGA was 8 years (range, 18 years. SEGA were symptomatic in 42.1% of patients. Symptoms included increased seizure frequency (15.8%), behavioural disturbance (11.9%), and regression/loss of cognitive skills (9.9%), in addition to those typically associated with increased intracranial pressure. SEGA were significantly more frequent in patients with TSC2 compared to TSC1 variants (33.7 vs. 13.2 %, p < 0.0001). Main treatment modalities included surgery (59.6%) and mammalian target of rapamycin (mTOR) inhibitors (49%). CONCLUSIONS: Although SEGA diagnosis and growth typically occurs during childhood, SEGA can occur and grow in both infants and adults

Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis

INTRODUCTION:This study describes cerebral ultrasound abnormalities caused by late-onset sepsis (LOS) in very preterm infants with a gestational age of < 32 weeks and/or birthweight < 1500 grams. METHODS:The prospective study ("INFANT study") included 117 preterm infants with suspected LOS. Proven LOS was defined as a positive blood culture after 72 hours of life. In case of coagulase-negative staphylococci an elevated C-reactive protein was additionally required to establish proven LOS. Patients were identified as proven LOS and patients with only clinical symptoms of LOS. Cerebral ultrasound images were obtained in the first week after birth, during/after LOS and before discharge. Cerebral findings were divided in no/minor and major abnormalities. RESULTS:Eighty-six preterm infants had proven LOS and 31 preterm infants had only clinical signs of LOS. Four infants were excluded because pre-existing major brain abnormalities. No significant differences (p = 0.624) for incidence of major brain abnormalities on cerebral ultrasound were found. CONCLUSION:No differences were revealed in prevalence of major brain abnormalities between the groups with proven LOS and with clinical signs of LOS. Both infants with a gram negative sepsis developed major brain abnormalities, whereas only two of 66 preterm infants coagulase-negative staphylococci sepsis developed major brain abnormalities

Neurodevelopmental outcome at 2 years of age in preterm infants with late-onset sepsis

Late-onset sepsis is associated with impaired neurodevelopmental outcome in preterm infants. This prospective cohort study aims to establish the effect of sepsis after 72 h of life on cognitive, psychomotor, and language development of preterm infants (below 32 weeks gestational age and/or below 1500 g). At 2 years corrected age, neurodevelopmental outcome was tested using Bayley’s Scales of Infant Development-II, Lexilijst (lexical development questionnaire), and behavior checklists. Of 117 patients included, 85 experienced blood culture–proven infection. Coagulase-negative staphylococci were responsible for 55% of the episodes. No significant differences were found in cognitive, motor, and behavioral scores or lexiquotient comparing patients with versus no proven infection. When comparing three groups (coagulase-negative staphylococci, other, and negative blood culture), a significant difference was found in composite cognitive scores (p = 0.016), in favor of the coagulase-negative staphylococci group versus other causal agent group (p = 0.007). No significant differences were found in other subscales. Conclusion: In this cohort, no differences were found in neurodevelopmental outcome at 2 years corrected age between proven and no proven infection groups; confirmation in larger cohorts with a control group is needed. Patients encountering coagulase-negative staphylococci sepsis showed a significant better cognitive outcome compared to other causal agents.What is Known:• Late-onset sepsis is associated with impaired neurodevelopmental outcome in preterm infants.What is New:• Preterm infants encountering late-onset sepsis by coagulase-negative staphylococci show a better cognitive outcome in comparison to other causal infectious agents in this cohort.• No differences were found in neurodevelopment at 2 years of age in preterm infants with suspected lateonset sepsis, between proven and no proven infection groups. Confirmation is needed in larger cohorts with a substantial control group

Trauma in pregnancy, obstetrical outcome in a tertiary centre in the Netherlands

Purpose: To determine obstetrical outcome and predictive value of obstetrical symptoms and diagnostic examinations on adverse outcome after maternal trauma in pregnancy. Materials and methods: Retrospective study in a Dutch tertiary medical center, including women admitted for trauma in pregnancy between 1995 and 2005 and infants born from these pregnancies. Characteristics at trauma (type of trauma, severity) and obstetrical outcome were recorded, as well as prevalence and severity of trauma; prevalence of obstetrical symptoms and abnormal diagnostic examinations. Composite adverse obstetrical outcome was defined as fetal death, placental abruption, birth <37 weeks and/or birth weight <10th percentile. The predictive value of obstetrical symptoms or abnormal diagnostic tests on an adverse pregnancy outcome was analyzed (logistic regression analysis). Results: Trauma admissions occurred in 10 per 1000 deliveries. Injuries were non-severe in 147/159 (92%). Obstetrical symptoms and/or abnormal diagnostic tests were present in 64/159 (40%) and 12/159 (8%) respectively. Adverse pregnancy outcome was encountered in 17/80 cases, mainly preterm births (13/80 (16%)). Severe injuries were predictive for an adverse pregnancy outcome. Conclusions: We found a considerable rate of trauma during pregnancy. There was an increased risk for preterm birth and severity of injuries was predictive for adverse outcome

Comparison of psychomotor outcome in patients with perinatal asphyxia with versus without therapeutic hypothermia at 4 years using the Ages and Stages Questionnaire screening tool

INTRODUCTION: Therapeutic hypothermia improves outcome after perinatal asphyxia. The Ages and Stages Questionnaire is a screening tool to detect neurodevelopmental delay. In this study we examined the outcome of patients with perinatal asphyxia (defined as Apgar score <5 at 10 min, or continued need for resuscitation, or pH < 7.00 in umbilical cord or within one hour after birth) with and without therapeutic hypothermia treatment at the age of four years. METHODS: Cohort study of patients with perinatal asphyxia admitted to the Neonatal Intensive Care Units of the VU University Medical Center, Amsterdam and the Wilhelmina Children's Hospital, Utrecht in the year 2008. Parents were asked to fill out the 48 months Ages and Stages Questionnaire (ASQ). In Wilhelmina Children's Hospital treatment with therapeutic hypothermia was implemented in 2008, in the VU University Medical Center in 2009, providing a historical cohort. RESULTS/DISCUSSION: Twenty-three questionnaires were evaluated. Response rate of questionnaires for the VU Medical Center was 63% (n = 10) and Wilhelmina's Childrens Hospital 93% (n = 13). No significant differences were found in the mean scores between both groups. However, the untreated group scored more frequently under the -2 SD threshold. In the fine motor skills domain the difference was statistically significant (p = 0.031). In the treated group no patients developed cerebral palsy and in the untreated group two patients developed cerebral palsy. CONCLUSION: In this study patients treated with hypothermia tend to have a better neurodevelopmental outcome. No significant differences were found between the two groups, apart from the fine motor skills