ARF1-related disorder: phenotypic and molecular spectrum.

PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.

Optimal vaccination: various (counter) intuitive examples.

In previous articles, we formalized the problem of optimal allocation strategies for a (perfect) vaccine in an infinite-dimensional metapopulation model. The aim of the current paper is to illustrate this theoretical framework with multiple examples where one can derive the analytic expression of the optimal strategies. We discuss in particular the following points: whether or not it is possible to vaccinate optimally when the vaccine doses are given one at a time (greedy vaccination strategies); the effect of assortativity (that is, the tendency to have more contacts with similar individuals) on the shape of optimal vaccination strategies; the particular case where everybody has the same number of neighbors.

A practical guide to optimize arterial spin labeling in neonates at 1.5 Tesla: what the radiologist needs to know.

Arterial spin labeling magnetic resonance imaging is highly suited to the exploration of brain perfusion in neonates and has the potential to provide relevant complementary information to neuroimaging studies, with insights into neurodevelopmental outcomes. Applying this technique within the first days of life is challenging and requires specific technical adaptations. The literature on this topic is scarce and heterogeneous, especially on 1.5-T scanners, limiting widespread clinical adoption. This paper aims to describe a simple approach for arterial spin labeling in neonates, with key considerations for radiologists.

Brain fetal magnetic resonance imaging to evaluate maturation of normal white matter during the third trimester of pregnancy.

BACKGROUND: Quantitative magnetic resonance imaging (MRI) could improve the estimation of fetal brain maturation and the interpretation of white matter signal intensity in pathological conditions. OBJECTIVE: To investigate T2-based and diffusion-weighted imaging (DWI) measurements for the evaluation of fetal brain maturation during the last trimester of pregnancy. MATERIALS AND METHODS: One hundred sixty-eight fetal brain MRIs were retrospectively analyzed (age range: 28-37 weeks of gestation) after ensuring that none of the children developed psychomotor or cognitive impairment (median follow-up: 4.7 years). Bilateral regions of interest were drawn on the frontal, occipital, parietal and temporal lobes from T2-W imaging and DWI, when available, to evaluate signal intensity and apparent diffusion coefficient (ADC) values. Ratios were calculated with two references (pons or thalamus and cerebrospinal fluid) to standardize signal intensities. Reproducibility was evaluated with intraclass correlation coefficients (ICCs) and Bland-Altman plots. Correlations with gestational age were evaluated with univariate and multivariate linear regressions. RESULTS: T2 measurements were achieved in all cases, and DWI was available in 37 cases. Measurements and ratios were reproducible in eight localizations (i.e. intra- and interobserver ICCs >0.5): frontal T2/thalamus, parietal T2/thalamus, occipital T2/pons, parietal ADC/thalamus, occipital ADC/pons, temporal ADC/pons, occipital ADC and temporal ADC. The frontal T2/thalamus and parietal T2/thalamus correlated with gestational age (P<0.0001 and P=0.014, respectively). In the multivariate modeling, frontal T2/thalamus remained an independent predictor of the gestational age (P<0.0001). CONCLUSION: The frontal T2/thalamus ratio emerged as a potential additional biomarker of fetal brain maturation during the last trimester of pregnancy.

Acute neurosurgical management of traumatic brain injury and spinal cord injury in French armed forces during deployment.

This article aims to describe the French concept regarding combat casualty neurosurgical care from the theater of operations to a homeland hospital. French military neurosurgeons are not routinely deployed to all combat zones. As a consequence, general surgeons initially treat neurosurgical wounds. The principle of this medical support is based on damage control. It is aimed at controlling intracranial hypertension spikes when neuromonitoring is lacking in resource-limited settings. Neurosurgical damage control permits a medevac that is as safe as can be expected from a conflict zone to a homeland medical treatment facility. French military neurosurgeons can occasionally be deployed within an airborne team to treat a military casualty or to complete a neurosurgical procedure performed by a general surgeon in theaters of operation. All surgeons regardless of their specialty must know neurosurgical damage control. General surgeons must undergo the required training in order for them to perform this neurosurgical technique.

Military neurosurgery in operation: experience in the French role-3 medical treatment facility of Kabul.

BACKGROUND: In 2009, during the war in Afghanistan, the increasing number of head injuries led to the deployment of a military neurosurgeon at the Kabul International Airport (KaIA) medical treatment facility, in March 2010. The main goal of this study was to depict the neurosurgical activity in this centre and to analyse its different aspects. METHOD: A retrospective study of all the neurosurgical patients treated in KaIA from March 2010 to June 2013. RESULTS: Three hundred and seventy-three interventions performed by the neurosurgeon deployed were reported for 373 surgeries, in 335 patients, representing 10.6 % of the overall surgical activity of the centre. Among the 69 interventions performed on soldiers, 57 surgeries were undertaken in emergency (82.6 %), while 12 were elective procedures (17.4 %). On the other hand, 289 surgeries were performed in civilian Afghans, with 126 emergency procedures in (43.6 %), against 163 elective interventions (56.4 %). Among the 44.5 % (n = 149) of the traumatic casualties, cerebral lesions represented 28.7 % (n = 96) and spinal lesions 12.4 % (n = 42). Ninety patients had multiple injuries. Additionally, patients without trauma accounted for 55.5 % (n = 186) of the overall population. Thus, 49 % (n = 164) were operated on for non-traumatic lesion of the spine. These were mostly civilian Afghans treated under medical aid to the population (90.2 %, n = 148/164). CONCLUSIONS: The military neurosurgeon had two roles in KaIA: both to support the armed forces and to manage medical aid to the civilian population. This study gives food for thought on the neurosurgical needs in modern warfare, and on the skills required for the military neurosurgeon.

Predicting clinically significant events in children with ureteropelvic junction obstruction.

Introduction: Ureteropelvic junction obstruction (UPJO) syndrome is one of the most common causes of neonatal hydronephrosis. Management varies from simple monitoring to surgical intervention, with indications differing between institutions. A consensus of 8 societies recently described a new Urinary Tract Dilation (UTD) classification which aims to standardize ultrasound description of hydronephrosis, but which is also supposed to have predictive value in children with hydronephrosis. Our aim was to compare, in a monocentric prospective cohort of children with UPJO, the ability of UTD to predict the occurrence of a clinically significant event within the first year of life, as compared to anteroposterior diameter of the renal pelvis (APD). Study design: We used a preexisting cohort of children followed in a prospective study on UPJO. A pediatric radiologist, blinded to the children's outcome, classified the last antenatal ultrasound and postnatal ultrasound according to the UTD-A and UTD-P classification. He also confirmed the APD-A and APD-P measures. We defined a clinically significant event as being: increased pelvic dilation (>5 mm) and/or the presence of a febrile urinary tract infection (fUTI) and/or impaired renal function on initial nuclear scan (<40%). We performed a ROC-AUC curve and Random Forest (RF) analysis to compare the ability of the APD-A, APD-P, UTD-A and UTD-P scores to predict a clinically significant event. Results: The cohort included 28 children. Clinically significant events were noted in 20 out of 28 patients: 13 children presented an increase >5 mm in dilation, 6 presented an episode of fUTI and 9 had impaired function of the affected kidney. APD-A was the most effective individual criterion for predicting the occurrence of a significant clinical event (AUC = 0.867). Conclusion: In our series, for children with UPJO, the most significant marker was prenatal APD >15 mm to predict an increase in dilation >5 mm.

French Military Neurosurgery: At Home and Abroad.

The origins of military neurosurgery are closely linked to those of neurosurgery in France and more particularly in Paris. The history of the field starts with its origins by 2 men, Thierry de Martel and Clovis Vincent. The first note about the creation of military neurosurgery was in 1942, when Marcel David was reassigned from the Sainte Anne Hospital to practice at the Val-de-Grâce Military Hospital. David trained the first military neurosurgeon. The field of military neurosurgery was subsequently developed at the Val-de-Grâce Military Hospital, at Sainte Anne Military Teaching Hospital in Toulon in 1990 and then at Percy Military Teaching Hospital in 1996. Over 29 military neurosurgeons were trained in these institutions. Since 2000, French military neurosurgeons have been deployed from France in the Mobile Neurosurgical Unit. This Mobile Neurosurgical Unit represents 12% of all medical evacuation of casualties categorized as the high dependency level. Neurosurgeons were able to adapt to asymmetrical wars, such as in the Afghanistan campaign where they were deployed in the Role 3 medical treatment facility, and more recently in sub-Saharan conflicts where they were deployed in forward surgical roles. To manage the increasing craniocerebral war casualties in the forward surgical team, the French Military Health Service Academy established a training course referred to as the "Advanced Course for Deployment Surgery" providing neurosurgical damage control skills to general surgeons. Finally, military neurosurgery is reinventing itself to adapt to future conflicts through the enhancement of surgical practices via the addition of head, face, and neck surgeons.

Ethical Issues Regarding Neurosurgical Management of Penetrating Brain Injury in the French Armed Forces.

Combat penetrating brain injury (PBI) differs significantly from PBI in civilian environments. Differences include technical factors such as the weapons involved, strained resource environments, and limited medical materials and human resources available. Ethical issues regarding the management of PBI in military settings may occur. This case study examines the case of a 20-year-old member of the French Armed Forces that suffered a penetrating brain injury in a combat situation. The four-quadrant method along with the four principles of medical ethics (respect for autonomy, beneficence, nonmaleficence, and justice) was used to analyze this case and to apply ethics to the practice of military medicine. Nowadays, we possess the medical and surgical resources as well as the aeromedical evacuation capability to save the life of a soldier with a penetrating craniocerebral wound. Nonetheless, the functional outcome of this type of wound places military doctors in an ethical dilemma. The line of conduct and clinical protocol established by the French Medical Health Service is to manage all PBIs when the patient's life can be saved and to provide all available financial and social support for the rehabilitation of patients and their family.

Case report: Unveiling genetic and phenotypic variability in Nonketotic hyperglycinemia: an atypical early onset case associated with a novel GLRX5 variant.

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT, GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3. We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM_016417.3:c.367G>C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH's genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH.

The Origin of Surrealism: Rethinking Apollinaire's Penetrating Brain Injury with Current Knowledge Regarding White Matter Tracts.

The French poet Apollinaire enrolled in the French army during World War I. In 1916, he sustained a penetrating brain injury when a fragment of shrapnel pierced his helmet in the right temporal region. Neurosurgical techniques were at that time standardized to manage the significant number of war-related neurosurgical casualties. Apollinaire, who experienced transient fainting followed by left-sided hemiparesis 2 months after his trauma, underwent trepanation. The poet's personality and behavior changed dramatically after his trauma. These neurobehavioral changes, associated with preserved cognition and no other neurologic dysfunction, were later described as Apollinaire syndrome. These personality changes were accompanied by flourishing writing changes. Hence, 15 months after his penetrating brain injury, the poet introduced the term "surrealism" to the world in his play The Breasts of Tiresias, giving birth to a major movement that paved the way for the 20th century. Linguistic shifts such as phonologic and semantic word games were at the forefront of the narrative process of the play. Traumatic brain injury often leads to cognitive impairment. In the case of Apollinaire, if the ballistic trauma were also responsible for diffuse axonal injury, it could have also led to semantic and social cognition impairment, in addition to the neuropsychological disorders that had already been widely documented by his friends and family. The world will always remember Apollinaire's writing genius as deeply associated with the birth of surrealism. But what if the poet's new writing style was caused, at least in part, by the unexpected help of a lost shrapnel fragment?

Application of a Near-infrared Spectroscope by an Extreme Forward Medical Team for the Triage of Casualties With Traumatic Brain Injury.

BACKGROUND: During deployment of military medical teams similarly to prehospital practice, without immediate computed tomography scan access, identifying patients requiring neuro-specific care to manage pragmatic triage proves crucial. We assessed the contribution of this portable near-infrared spectroscope (NIRS) handheld device, Infrascanner Model 2000 (InfraScan Inc.; Philadelphia, PA), to screen patients suspected to require specific neurosurgical care. MATERIALS AND METHODS: This single-center retrospective analysis was based on the data from the medical records of the traumatic brain injured patients. We analyzed all the patients strictly over 18 years old presenting a clinical history of traumatic brain injury (TBI) with a Glasgow Coma Scale (GCS) < 15. RESULTS: Thirty-seven medical records of patients admitted for TBI met the inclusion criteria for our analysis. The median GCS was 9 [3-14]. Eight patients (21.6%) underwent neurosurgery and 25 (67.6%) required intensive care unit (ICU) admission, after initial assessment and resuscitation. The NIRS was the most sensible to detect intracranial hematoma (n = 21), intracranial hematoma leading to surgery (n = 8), and intracranial hematoma leading to admission in ICU (n = 25). Its negative predictive value was 100% regarding hematomas leading to surgery. False-positive results were encountered in 10 cases (27.0%). Excluding cases harboring confounding extracranial hematomas, parietal area was still the most represented (n = 3). CONCLUSION: The NIRS was relevant to detect hematoma leading to prompt surgery in our study. The lack of specificity in a nonselected cohort of patients underlines the need to associate simple clinical feature such as neurological deficit and NIRS results to perform rational triage.

Neurosurgical management of penetrating brain injury during World War I: A historical cohort.

During World War I, 25% of penetrating injuries were in the cephalic region. Major Henri Brodier described his surgical techniques in a book in which he reported every consecutive penetrating brain injury (PBI) that he operated on from August 1914 to July 1916. The aim was to collate his data and discuss significant differences in management between soldiers who survived and those who died. We conducted a retrospective survey that included every consecutive PBI patient operated on by Henri Brodier from August 1914 to April 1916 and recorded in his book. We reported medical and surgical management. Seventy-seven patients underwent trepanation by Henri Brodier for PBI. Regarding injury mechanism, 66 procedures (86%) were for shrapnel injury. Regarding location, 21 (30%) involved the whole convexity. Intracranial venous sinus wound was diagnosed intraoperatively in 11 patients (14%). Postoperatively, 7 patients (9%) had seizures, 5 (6%) had cerebral herniation, 3 (4%) had cerebral abscess, and 5 (6%) had meningitis. No patients with abscess or meningitis survived. No significant intergroup differences were found for injury mechanism or wound location, including the venous sinus. Extensive initial surgery with debridement must be prioritized. Infectious complications must not be neglected. We should not forget the lessons of the past when managing casualties in present-day and future conflicts.

Early Evaluation of a New French Surgery Course in the Best Practice of Dealing With Major Incidents and Mass Casualty Events.

OBJECTIVE: The main objective of this study is to evaluate the impact of a nationwide 5-month course aimed to prepare surgeons for Major Incidents through the acquisition of key knowledge and competencies. Learners' satisfaction was also measured as a secondary objective. DESIGN: This course was evaluated thanks to various teaching efficacy metrics, mainly based on Kirkpatrick's hierarchy in medical education. Gain in knowledge of participants was evaluated by multiple-choice tests. Self-reported confidence was measured with 2 detailed pre and post training questionnaires. SETTING: Creation in 2020 of a nationwide, optional and comprehensive Surgical Training in War and Disaster Situation as part of the French surgery residency program. In 2021, data was gathered regarding the impact of the course on participants' knowledge and competencies. PARTICIPANTS: The study included 26 students in the 2021 cohort (13 residents and 13 practitioners). RESULTS: Mean scores were significantly higher in the post-test compared to the pre-test, showing significant increase in participants' knowledge during the course: 73,3% vs. 47,3% respectively (p ≤ 0.001). Average learners' confidence scores to perform technical procedures showed at least a +1-point increase on the Likert scale for 65% of items tested (p ≤ 0.001). 89% of items showed at least a +1-point increase on the Likert scale when it came to average learners' confidence score on dealing with complicated situations (p ≤ 0.001). Our post-training satisfaction survey showed that 92% of all participants have noticed the impact of the course on their daily practice. CONCLUSION: Our study shows that the third level of Kirkpatrick's hierarchy in medical education was reached. This course therefore appears to be meeting the objectives set by the Ministry of Health. Being only 2 years old, it is on the road to gathering momentum and further development.

Intracranial empyema complicating sinusitis in childhood: Epidemiology, imaging findings and outcome.

BACKGROUND: To describe clinical presentations of intracranial sinusitis complications in childhood, their pitfalls and imaging findings. MATERIEL AND METHODS: This retrospective IRB-approved single-center study included infants diagnosed with sinusitis and empyema and/or other intracranial complications who underwent imaging between September 2008 and September 2019. Three radiologists individually reviewed clinical charts and imaging findings, including sinusitis complications and at-risk anatomical variations. RESULTS: 21 children (76% males and 24% females, mean age 13±3.1 years) with imaging pansinusitis were included. Headache (95%) and fever (90%) were the main clinical nonspecific signs. Ten (48%) children presented an extradural empyema, nine (43%) children had a subdural empyema and two (10%) children had both. Frontal location sinusitis was the most common (76%). In MRI, all empyema presented as a hypo intensity on pre-contrast T1-WI, a hyperintensity on T2-WI, a reduced apparent diffusion coefficient (ADC) on diffusion weighted imaging (DWI) and a peripheral contrast enhancement on post-contrast T1-WI. CT or MRI revealed intracranial complications such as a collection size increase (52%), a midline shift (62%), intraparenchymal abscesses (24%), a cerebral venous thrombosis (29%), an intracranial pressure increase (29%), cerebral ischemia (43%) and Pott's Puffy Tumor (10%). Imaging highlighted sinus anatomical abnormalities in 52% of cases. All children were treated with sinus drainage and/or neurosurgery. Long-term follow-up was favorable in 14 cases (67%). CONCLUSION: Complications of sinusitis are life threatening in the studied population. Empyema and cerebral complications may be misleading. Brain contrast-enhanced CT covering sinuses and orbits, is mainly the first examination done but MRI is mandatory.

Permeability of the Cyanotoxin Microcystin-RR across a Caco-2 Cells Monolayer.

Microcystins (MCs) are toxins produced by several cyanobacterial species found worldwide. While MCs have a common structure, the variation of two amino acids in their structure affects their toxicity. As toxicodynamics are very similar between the MC variants, their differential toxicity could rather be explained by toxicokinetic parameters. Microcystin-RR (MC-RR) is the second most abundant congener and induces toxicity through oral exposure. As intestinal permeability is a key parameter of oral toxicokinetics, the apparent permeability of MC-RR across a differentiated intestinal Caco-2 cell monolayer was investigated. We observed a rapid and large decrease of MC-RR levels in the donor compartment. However, irrespective of the loaded concentration and exposure time, the permeabilities were very low from apical to basolateral compartments (from 4 to 15 × 10-8 cm·s-1) and from basolateral to apical compartments (from 2 to 37 × 10-8 cm·s-1). Our results suggested that MC-RR would be poorly absorbed orally. As similar low permeability was reported for the most abundant congener microcystin-LR, and this variant presented a greater acute oral toxicity than MC-RR, we concluded that the intestinal permeability was probably not involved in the differential toxicity between them, in contrast to the hepatic uptake and metabolism.

Brain MRI after therapeutic hypothermia in asphyxiated newborns: Predictive value at one year of imaging features.

PURPOSE: To compare early brain MRI using a composite imaging score and outcome at one year in asphyxiated newborns treated by hypothermia. METHODS: This retrospective study included for two years consecutive asphyxiated term newborns treated by hypothermia for hypoxic-ischemic encephalopathy, and who had brain MRI before day 8. Therapeutic hypothermia was initiated within the first 6 h of life and continued for 72 h. Imaging protocol included T1 and T2 sequences, diffusion-weighted imaging (DWI), evaluated with a specific composite score, and spectroscopy. Clinical evaluation was performed at one year of age, outcome was classified as favorable/unfavorable. The primary endpoint was the correlation between our MRI score and outcome with the definition of a threshold. The secondary endpoints were to find the most relevant criteria within the score and to evaluate objective signal measurements to support subjective criteria. RESULTS: Among the 33 included patients, 9 died during the first days of life, 20 had a favorable outcome, 4 an unfavorable one. MRI score was correlated to a poor clinical outcome (p < 0.001). Most of the criteria within the score and spectroscopy results were relevant (p < 0.05). Cerebral edema was objectively assessed by the signal intensity ratio of white matter compared to cerebrospinal fluid (CSF) on T2-weighted images (p < 0.001). CONCLUSION: MRI score was predictive of neurodevelopmental outcome at one year. The most relevant criteria within the score were DWI abnormalities in basal ganglia and thalami and loss of white-cortical grey matter differentiation. Signal intensity ratio between white matter and CSF higher than 0.75 supports the presence of edema.

Tissue distribution, metabolism, and elimination of Victoria Pure Blue BO in rainbow trout: Main metabolite as an appropriate residue marker.

Victoria Pure Blue BO is a dye that bears some therapeutic activity and that can be retrieved in effluent or may be used in aquaculture as a prohibited drug. In this study, the metabolism and tissue distribution during uptake and depuration of VPBO were investigated in order to propose a residue marker of illegal treatment in fish. The dye was administered to rainbow trout (oncorhynchus mykiss) for one day by water bath at a dose of 0.1 mg.L-1. The concentrations of VPBO in all tissues increased rapidly during the treatment period, reaching a Cmax of 567 ± 301 µg.L-1 in plasma and 1846 µg kg-1 ±517 for liver after 2 h. After placing the rainbow trout in a clean water bath for a 64 day-period of depuration, the concentrations in the tissues and plasma decreased to reach comparable levels for muscle and for skin after 33 days. The concentrations measured were still above the LOQ at 2.26 ± 0.48 µg kg-1 for muscle and 2.85 ± 1.99 µg kg-1 for skin at the end of the depuration period. The results indicated the existence of 14 phase I metabolites and one glucuronide conjugated metabolite. Non-compartmental analysis was applied to assess the pharmacokinetic parameters. The half-life in edible muscle of the main metabolite detected, deethyl-leuco-VPBO, was found to be 22.5 days compared to a half-life of 19.7 days for the parent VPBO. This study provides new information to predict a VPBO drug treatment of aquacultured species via a proposed new residue marker.