Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Preliminary results on validity and reliability from two prospective cohort studies on a new Neonatal Coma Score.

OBJECTIVE: To collect data on content/face validity and interobserver agreement for a Neonatal Coma Score (NCS) in well full-term neonates and on construct validity in unwell and preterm babies, specifically how the NCS changed with gestational age and illness. DESIGN: Prospective cohort studies. SETTING: Two UK tertiary neonatal units (Sheffield and Leeds). PATIENTS: 151 well full-term (≥37 weeks gestational age) newborn babies recruited between January and February 2020 in Sheffield and April and May 2021 in Leeds; 101 sick preterm and full-term babies admitted to Sheffield neonatal unit between January 2021 and May 2022. INTERVENTION: A new NCS. MAIN OUTCOME MEASURES: Determination of normal values in well babies born ≥37 weeks gestational age; data on how the NCS changes with gestational age and illness. RESULTS: Face validity was demonstrated during development of the NCS. The median NCS of well, full-term newborn babies was 15 and the intraclass correlation coefficient was 0.78 (95% CI 0.70 to 0.84). In the 'well' preterm population, 95% <28 weeks had a score ≥11; 28-31 weeks ≥11; 32-36 weeks ≥13 and 37-44 weeks 14-15. The NCS dropped during periods of deterioration, demonstrating evidence of construct validity. Criterion validity was not assessed. CONCLUSIONS: The NCS has good intraobserver agreement in well full-term babies, with a normal NCS 14-15. The NCS in preterm neonates depended on gestational age, and deterioration from baseline was associated with illness. Further work is needed to determine normal scores each gestational age, reliability at lower levels, how early the NCS identifies deterioration and comparison with other assessment tools to demonstrate criterion validity.

Site Variability in Cerebral Embolic Protection for Transcatheter Aortic Valve Implantation and Association With Outcomes.

Background: The effectiveness of cerebral embolic protection devices (CEPD) in mitigating stroke after transcatheter aortic valve implantation (TAVI) remains uncertain, and therefore CEPD may be utilized differently across US hospitals. This study aims to characterize the hospital-level pattern of CEPD use during TAVI in the US and its association with outcomes. Methods: Patients treated with nontransapical TAVI in the 2019 Nationwide Readmissions Database were included. Hospitals were categorized as CEPD non-users and CEPD users. The following outcomes were compared: the composite of in-hospital stroke or transient ischemic attack (TIA), in-hospital ischemic stroke, death, and cost of hospitalization. Logistic regression models were used for risk adjustment of clinical outcomes. Results: Of 41,822 TAVI encounters, CEPD was used in 10.6% (n = 4422). Out of 392 hospitals, 65.8% were CEPD non-user hospitals and 34.2% were CEPD users. No difference was observed between CEPD non-users and CEPD users in the risk of in-hospital stroke or TIA (adjusted odds ratio (OR) = 0.99 [0.86-1.15]), ischemic stroke (adjusted OR = 1.00 [0.85-1.18]), or in-hospital death (adjusted OR = 0.86 [0.71-1.03]). The cost of hospitalization was lower in CEPD non-users. Conclusions: Two-thirds of hospitals in the US do not use CEPD for TAVI, and no significant difference was observed in neurologic outcomes among patients treated at CEPD non-user and CEPD user hospitals.

Family experiences of antenatal counselling of spina bifida: a systematic review.

OBJECTIVE: To describe families' experiences of antenatal counselling of spina bifida. DESIGN: Systematic review. METHODS: MEDLINE, CINAHL, PsycINFO and Embase databases were searched using a combination of Medical Subject Headings and text/abstract terms. Case reports, survey results and qualitative interview data were included. The quality of research was evaluated using the Critical Appraisal Skills Programme checklist. RESULTS: 8 papers were included. Families described shock and grief at diagnosis, with some immediately offered termination of pregnancy (TOP) even though they knew little about the condition. Positive and negative aspects of care were found. Teams that were gentle, kind and empathetic, who did not use jargon, and highlighted positive and negative aspects of the baby's life were seen favourably. Callous language, and overly negative or incorrect counselling was not, particularly if there was pressure to agree to TOP. Families based their decisions on how they would cope, the effect on siblings and the baby's likely quality of life. Prenatal surgery was viewed positively. The views of families who chose TOP, were happy with their care, partners, families, and the LGBTQ+ community were under-represented in the literature. CONCLUSIONS: Unlike other conditions where limited data on outcome exist or the spectrum is genuinely broad, the outcomes of children with spina bifida is well described. Poor aspects of antenatal counselling were described frequently by families, and further work is needed to capture the full spectrum of views on antenatal counselling, how it can be improved, and what training and resources healthcare professionals need to perform it better.

Meta-Dynamic Network Modelling for Biochemical Networks.

ODE modelling requires accurate knowledge of parameter and state variable values to deliver accurate and robust predictions. Parameters and state variables, however, are rarely static and immutable entities, especially in a biological context. This observation undermines the predictions made by ODE models that rely on specific parameter and state variable values and limits the contexts in which their predictions remain accurate and useful. Meta-dynamic network (MDN) modelling is a technique that can be synergistically integrated into an ODE modelling pipeline to assist in overcoming these limitations. The core mechanic of MDN modelling is the generation of a large number of model instances, each with a unique set of parameters and/or state variable values, followed by the simulation of each to determine how parameter and state variable variation affects protein dynamics. This process reveals the range of possible protein dynamics for a given network topology. Since MDN modelling is integrated with traditional ODE modelling, it can also be used to investigate the underlying causal mechanics. This technique is particularly suited to the investigation of network behaviors in systems that are highly heterogenous or systems wherein the network properties can change over time. MDN is a collection of principles rather than a strict protocol, so in this chapter, we have introduced the core principles using an example, the Hippo-ERK crosstalk signalling network.

Attitudes towards the neurological examination in an unwell neonate: a mixed methods approach.

BACKGROUND: The neurological examination of an unwell neonate can aid management, such as deciding if hypothermia treatment is warranted in hypoxic ischaemic encephalopathy or directing investigations in hypotonic neonates. Current standardised examinations are not designed for unwell or ventilated neonates, and it is unclear how confident paediatricians feel about the examination or what aspects they perform.  AIM: This study aimed to review the confidence of UK paediatricians on the neurological examination in unwell neonates, describe their attitudes towards it, and determine what could improve practice. METHODS: An explanatory sequential mixed methods approach (QUAN → QUAL) with equal weighting between stages. A survey on attitudes to the neonatal neurological examination was sent to all UK neonatal units and members of the British Paediatric Neurology Association. Volunteers were sought for semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data. RESULTS: One hundred ninety-three surveys were returned, 31.0% from neonatologists, 9.3% paediatric neurologist. The median range for confidence was 4 (IQR3-5). Twenty-three interviews occurred. Thematic analysis revealed three themes: "Current culture on neonatal units", " Practicalities of the neurological examination in unwell neonates", and "Changing the culture". Most interviewees did not feel confident performing or interpreting the neurological examination in unwell neonates. Many units had a culture of seeing it as low priority, did not see its relevance in the acute management of unwell neonates. A few interviewees worked in units with a positive culture towards the neurological examination who used adapted standardised examinations and provided training. 72% of questionnaire responders wanted a new standardised neurological examination designed for the unwell neonate, which should be short, utilise pictures like the Hammersmith Neonatal Neurological Examination, contain an assessment of consciousness, be developmentally appropriate and achievable in unwell, ventilated neonates, be accompanied by a schematic to aid interpretation, and for greater training and assessments of competence. CONCLUSIONS: There are barriers preventing paediatricians being able to perform a neurological examination in unwell neonates, and a culture of neurophobia is common. A new standardised examination is needed, alongside aids to interpretation, training, and assessment.

How paediatricians investigate early developmental impairment in the UK: a qualitative descriptive study.

BACKGROUND: Early developmental impairment (EDI) is common and has many aetiologies and, therefore, potential investigations. There are several published guidelines recommending aetiological investigations, and paediatricians' views of them varies. Little is known on the thought processes underlying clinical decisions in investigating EDI. This study aimed to describe the thought processes affecting clinical decisions on the investigation of EDI within a nationalised health care system. METHODS: A qualitative descriptive study using semi-structured qualitative interviews performed in person or via video link with paediatricians who see children with EDI in England. As part of the interview, a case study of a fictional disease, Cavorite deficiency, modelled on biotinidase deficiency, was given to participants with the cost of testing, incidence and likelihood it would respond to treatment. This allowed exploration of cost without encumbrance from predisposing views and training on the condition. Thematic analysis was performed by iterative approach. Where participants stated they wanted to redirect money from investigations to treatment, were that even possible, we asked which services they would like to be better funded in their area. RESULTS: Interviews were conducted with 14 consultant paediatricians: 9 Community / Neurodisability, 2 General paediatricians, and 3 Paediatric Neurologists. Two themes were identified: the value of an aetiological diagnosis to families and managing risk and probability when investigating EDI. The latter contained 4 subthemes: 'circumspection' involved blanket investigations chosen irrespective of phenotype and high regard for guidelines; 'accepting appropriate risk' involved participants choosing investigations based on clinical phenotype, recognising some aetiologies would be missed; consultants found they 'transitioned between practices' during their career; and 'improved practice' was thought possible with better evidence on how to stratify investigations based on phenotype. Services that were most frequently reported to need additional funding were therapy services, early community developmental services, management of behaviour, sleep and mental health, and educational support. CONCLUSIONS: There are many factors that influence paediatricians' choice of aetiological investigation in EDI, but clinical factors are the most important. Paediatricians want better evidence to allow them to select the right investigations for each child without a significant risk of missing an important diagnosis.

A risk-adjustment model for patients presenting to hospitals with out-of-hospital cardiac arrest and ST-elevation myocardial infarction.

BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) complicated by an out-of-hospital-cardiac-arrest (OHCA) may vary widely in their probability of dying. Large variation in mortality may have implications for current national efforts to benchmark operator and hospital mortality rates for coronary angiography. We aimed to build a risk-adjustment model of in-hospital mortality among OHCA survivors with concurrent STEMI. METHODS: Within the Cardiac Arrest Registry to Enhance Survival (CARES), we included adults with OHCA and STEMI who underwent emergent angiography within 2 hours of hospital arrival between January 2013 and December 2019. Using multivariable logistic regression to adjust for patient and cardiac arrest factors, we developed a risk-adjustment model for in-hospital mortality and examined variation in patients' predicted mortality. RESULTS: Of 2,999 patients (mean age 61.2 ± 12.0, 23.1% female, 64.6% white), 996 (33.2%) died during their hospitalization. The final risk-adjustment model included higher age (OR per 10-year increase, 1.50 [95% CI: 1.39-1.63]), unwitnessed OHCA (OR, 2.51 [1.99-3.16]), initial non-shockable rhythm [OR, 5.66 [4.52-7.13]), lack of sustained pulse for > 20 minutes (OR, 2.52 [1.88-3.36]), and longer resuscitation time (increased with each 10-minute interval) (c-statistic = 0.804 with excellent calibration). There was large variability in predicted mortality: median, 25.2%, inter-quartile-range: 14.0% to 47.8%, 10th-90th percentile: 8.2 % to 74.1%. CONCLUSIONS: In a large national registry, we identified 5 key predictors for mortality in patients with STEMI and OHCA and found wide variability in mortality risk. Our findings suggest that current national benchmarking efforts for coronary angiography, which simply adjusts for the presence of OHCA, may not adequately capture patient case-mix severity.

Predicting neurodevelopmental outcomes in fetuses with isolated mild ventriculomegaly.

BACKGROUND: Fetal ventriculomegaly is the the most common intracranial abnormality detected antenatally. When ventriculomegaly is mild and the only, isolated, abnormality detected (isolated mild ventriculomegaly (IMVM)) the prognosis is generally considered to be good. We aim to determine if there are features on in utero MRI (iuMRI) that can identify fetuses with IMVM who have lower risks of abnormal neurodevelopment outcome. METHODS: We studied cases recruited into the MRI to enhance the diagnosis of fetal developmental brain abnormalities in utero (MERIDIAN) study, specifically those with: confirmed IMVM, 3D volume imaging of the fetal brain and neurodevelopmental outcomes at 3 years. We explored the influence of sex of the fetus, laterality of the ventriculomegaly and intracranial compartmental volumes in relation to neurodevelopmental outcome. FINDINGS: Forty-two fetuses met the criteria (33 male and 9 female). There was no obvious correlation between fetal sex and the risk of poor neurodevelopmental outcome. Unilateral IMVM was present in 23 fetuses and bilateral IMVM in 19 fetuses. All fetuses with unilateral IMVM had normal neurodevelopmental outcomes, while only 12/19 with bilateral IMVM had normal neurodevelopmental outcomes. There was no obvious correlation between measure of intracranial volumes and risk of abnormal developmental outcomes. INTERPRETATION: The most important finding is the very high chance of a good neurodevelopmental outcome observed in fetuses with unilateral IMVM, which is a potentially important finding for antenatal counselling. There does not appear to be a link between the volume of the ventricular system or brain volume and the risk of poor neurodevelopmental outcome.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 1, experiences and recommendations for service design.

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 2, risks of adverse outcome in common anomalies.

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.

Octopus djinda (Cephalopoda: Octopodidae): a new member of the Octopus vulgaris group from southwest Australia.

A new Octopus Cuvier, 1797 species, Octopus djinda Amor, 2021 (previously treated as O. cf. tetricus and O. aff. tetricus), is described from the shallow waters off southwest Australia. This species was classified as conspecific with O. tetricus Gould, 1852 from Australias east coast and New Zealand but is shown here to be morphologically and genetically distinct. This description is based on 25 individuals across three localities in southwest Australia, encompassing most of its distribution. Greater and non-overlapping sucker counts on the males hectocotylised arm delimit east and west coast forms. DNA barcoding using cytochrome c oxidase subunit I also successfully differentiates between these taxa; 13 polymorphisms along a 349 bp partial fragment (3.7% sequence divergence). A close relative of the O. vulgaris Cuvier, 1797 species-group, O. djinda, sp. nov. supports a highly productive fishery and is currently one of two octopod fisheries worldwide to have received sustainable certification from the Marine Stewardship Council. The taxonomic description presented here provides formal recognition of the taxonomic status of southwest Australias common octopus, O. djinda, sp. nov. and facilitates appropriate fisheries catch reporting and management.

Feedback, Crosstalk and Competition: Ingredients for Emergent Non-Linear Behaviour in the PI3K/mTOR Signalling Network.

The PI3K/mTOR signalling pathway plays a central role in the governing of cell growth, survival and metabolism. As such, it must integrate and decode information from both external and internal sources to guide efficient decision-making by the cell. To facilitate this, the pathway has evolved an intricate web of complex regulatory mechanisms and elaborate crosstalk with neighbouring signalling pathways, making it a highly non-linear system. Here, we describe the mechanistic biological details that underpin these regulatory mechanisms, covering a multitude of negative and positive feedback loops, feed-forward loops, competing protein interactions, and crosstalk with major signalling pathways. Further, we highlight the non-linear and dynamic network behaviours that arise from these regulations, uncovered through computational and experimental studies. Given the pivotal role of the PI3K/mTOR network in cellular homeostasis and its frequent dysregulation in pathologies including cancer and diabetes, a coherent and systems-level understanding of the complex regulation and consequential dynamic signalling behaviours within this network is imperative for advancing biology and development of new therapeutic approaches.

Knowledge and attitudes of critical care providers towards neurophysiological monitoring, seizure diagnosis, and treatment.

AIM: To explore the attitudes of paediatric intensive care unit (PICU) health care professionals towards diagnosis and neurophysiological monitoring of seizures. METHOD: This study used an explanatory sequential mixed-methods approach, interconnecting quantitative and qualitative features, comprising questionnaires and interviews, with equal weighting between stages, of health care professionals working in UK PICUs. Interview data were analysed using thematic analysis and triangulated with questionnaire data. RESULTS: Seventy-two questionnaires were returned: 49 out of 60 (71.0%) of respondents reported that seizures were extremely hard or somewhat hard to diagnose in a critically ill child, and 81.2% had seen misdiagnosis occur. Thematic analysis revealed two main themes: (1) feeling out of control when faced with 'grey areas'; and (2) regaining control, which compromised three subthemes: aggressive intervention, accurate diagnosis, and eschewing diagnosis. INTERPRETATION: Health care professionals find accurate diagnosis of seizures difficult, particularly in sedated/paralysed children and those with chronic neurological disorders. They report they would like better educational opportunities on discriminating between epileptic and non-epileptic events to improve their confidence. Professionals want routine neurophysiological monitoring that can be applied and interpreted at the bedside throughout the day to regain a sense of control over their patient, direct treatment appropriately, and, potentially, improve outcomes, but report appropriate training and peer review are essential if it is to be introduced into routine care. What this study adds Paediatric intensive care unit (PICU) staff feel out of control when faced with diagnosing seizures. Neurophysiological monitoring is wanted to help diagnosis and treatment. Amplitude-integrated electroencephalography is the preferred, pragmatic tool by PICU staff.

Anticoagulation Management for Impella Percutaneous Ventricular Assist Devices: An Analysis of a Single-Center Experience.

BACKGROUND: Impella devices offer temporary mechanical circulatory support for cardiogenic shock. The manufacturer recommends systemic anticoagulation with a target activated clotting time of 160 to 180 s but provides no guidance on how to manage both the heparinized purge solution and the additional intravenous heparin needed to reach this therapeutic range. Previous publications demonstrated a lack of standardization in heparin management for Impella devices. OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of 2 different heparin protocols for long-term Impella support. METHODS: This single-center, retrospective study included adult patients on Impella support for greater than 24 hours. The primary end point was time to therapeutic range measured in hours, from time of implantation to the first of 2 consecutive measurements within the therapeutic range. Secondary end points included percentage of time in therapeutic range, rates of major bleeding, pump thrombosis, hemolysis, and nursing satisfaction. RESULTS: There were 19 patients identified, with 7 using the original protocol and 12 using the revised protocol. Time to therapeutic range was similar between protocols (15.5 vs 12 hours, P = NS). Another 14 patients were managed with patient-specific protocols as a result of bleeding or physician preference. In total, 42% of all patients in this study experienced major bleeding. There were no confirmed thrombosis events. This study was limited by a small sample size. CONCLUSION AND RELEVANCE: Despite using different heparin protocols, outcomes and bleeding events were similar between groups. Future studies are needed to determine the optimal degree of anticoagulation necessary to reduce bleeding risk.

Investigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach.

BACKGROUND: Neonatal seizures are difficult to diagnose and, when they are, tradition dictates first line treatment is phenobarbital. There is little data on how consultants diagnose neonatal seizures, choose when to treat or how they choose aetiological investigations or drug treatments. The purpose of this study was to assess the variation across the UK in the management of neonatal seizures and explore paediatricians' views on their diagnosis and treatment. METHODS: An explanatory sequential mixed methods approach was used (QUAN→QUAL) with equal waiting between stages. We collected quantitative data from neonatology staff and paediatric neurologists using a questionnaire sent to neonatal units and via emails from the British Paediatric Neurology Association. We asked for copies of neonatal unit guidelines on the management of seizures. The data from questionnaires was used to identify16 consultants using semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data. RESULTS: One hundred questionnaires were returned: 47.7% thought levetiracetam was as, or equally, effective as phenobarbital; 9.2% thought it was less effective. 79.6% of clinicians had seen no side effects in neonates with levetiracetam. 97.8% of unit guidelines recommended phenobarbital first line, with wide variation in subsequent drug choice, aetiological investigations, and advice on when to start treatment. Thematic analysis revealed three themes: 'Managing uncertainty with neonatal seizures', 'Moving practice forward' and 'Multidisciplinary team working'. Consultants noted collecting evidence on anti-convulsant drugs in neonates is problematic, and recommended a number of solutions, including collaboration to reach consensus guidelines, to reduce diagnostic and management uncertainty. CONCLUSIONS: There is wide variation in the management of neonatal seizures and clinicians face many uncertainties. Our data has helped reveal some of the reasons for current practice and decision making. Suggestions to improve certainty include: educational initiatives to improve the ability of neonatal staff to describe suspicious events, greater use of video, closer working between neonatologists and neurologists, further research, and a national discussion to reach a consensus on a standardised approach to managing neonatal epileptic seizures.