Factors involved in parental decision-making when providing consent on behalf of extremely preterm infants in the PENUT Trial

BACKGROUND: Neurodevelopment and growth are primary concerns when neonates are born extremely premature (between 23 and 28 weeks gestation). The focus of the PENUT Trial is to administer erythropoietin (Epo) to extremely preterm infants and to study the potential neuroprotective effects of Epo. The PENUT ethics survey was designed to provide study investigators with parental feedback regarding the consent process for the PENUT Trial and to improve the consent process for future research trials. OBJECTIVES: The objectives of this research thesis are to learn (1) what factors are important to parents who are approached for informed consent to include their infants in a research study and (2) how parents may be influenced by demographic and social factors. The hypothesis is that parents approached prenatally may be more likely to consider enrolling their infants into the PENUT Trial. METHODS: All parents approached to enroll their eligible infants into the PENUT Trial (both consenting and non-consenting parents) were eligible to complete the ethics survey. While completing the survey, parents (1) responded to statements about factors involved in their decision-making process, (2) rated their overall experiences in being asked to join the PENUT Trial, (3) described what ultimately led them to enroll or not to enroll their infants in the PENUT Trial, and (4) responded to demographic questions. RESULTS: Thirty mothers of infants eligible for the PENUT Trial (22 consenting, 8 non-consenting) were approached by a research study coordinator to complete the survey. Of the 22 consenting mothers, 10 were approached prenatally, and 12 were approached postnatally for the PENUT Trial. However, of the 8 non-consenting mothers, only 1 was approached prenatally, whereas 7 were approached postnatally for the PENUT Trial. The ethics survey was completed by 20 of 22 consenting mothers and 6 of 8 non-consenting mothers. The average rating among mothers of their overall experiences with the consenting process for the PENUT Trial was 3.77 (2.75 among non-consenters, 4.00 among consenters) on a scale of 1 (= poor) to 5 (= excellent). Thirteen mothers preferred to be approached for the PENUT Trial by their baby’s neonatologist (6 preferred their OB/GYN, 5 preferred another doctor, 1 preferred a study coordinator, and 10 had no preference). In addition, 14 mothers preferred that the person approaching them was involved in the research trial (5 preferred person not involved, 2 preferred to be approached by those involved and not involved, and 9 had no preference). Lastly, 18 mothers preferred to be approached prenatally (5 postnatally, and 7 had no preference). CONCLUSIONS: Preliminary findings from the PENUT Trial ethics survey support the hypothesis that mothers prefer to be approached prenatally when considering enrollment of their newborn infants into the PENUT Trial. Survey responses also suggest that during the consent process mothers prefer to be approached by either (1) two neonatologists, with one responsible for the baby’s care and the other responsible for the research trial, or (2) one neonatologist who is involved in both the baby’s care and the research trial

Magnetic resonance imaging in patients with meningitis induced hearing loss

The aim of this multicentre study was to compare T1 with T2 weighted MRI scans of the labyrinth after meningitis and to investigate whether waiting with scanning improved the reliability of diagnosing an ongoing process such as cochlear osteogenesis. Forty-five patients were included who suffered from meningitis induced hearing loss (radiological imaging <1 year after meningitis). Twenty-one gadolinium enhanced T1 and 45 T2 weighted MRI scans were scored by two radiologists regarding the condition of the labyrinth. These radiological observations were compared with the condition of the cochlea as described during cochlear implantation. A higher percentage of agreement with surgery was found for T2 (both radiologists 73%) than for T1 weighted MRI scans (radiologist 1: 62%, radiologist 2: 67%), but this difference is not significant. There was no significant difference between early (0–3 months) and late (>3 months) scanning, showing that radiological imaging soon after meningitis allows early diagnosis without suffering from a lower agreement with surgical findings

Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials

A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability

AIM To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. METHODS The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP = 362, MSA = 398), 627 had per protocol images (PSP = 297, MSA = 330). Intra-rater (n = 60) and inter-rater (n = 555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n = 441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. RESULTS Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥ 0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75-0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1-F2; MSA: F2-F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity. CONCLUSIONS The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA. Clinical Trial Registration Number The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224