Implanted Pulse Generators in Lower Extremity Neuroprostheses: A 25-Year Review.

OBJECTIVES: Neuroprosthetic devices can improve quality of life by providing an alternative option for motor function lost after spinal cord injury, stroke, and other central nervous system disorders. The objective of this study is to analyze the outcomes of implanted pulse generators that our research group installed in volunteers with paralysis to assist with lower extremity function over a 25-year period, specifically, to determine survival rates and common modes of malfunction, reasons for removal or revision, and precipitating factors or external events that may have adversely influenced device performance. MATERIALS AND METHODS: Our implantable receiver-stimulator (IRS-8) and implantable stimulator-telemeter (IST-12 and IST-16) device histories were retrospectively reviewed through surgical notes, regulatory documentation, and manufacturing records from 1996 to 2021. RESULTS: Most of the 65 devices (64.6%) implanted in 43 volunteers remain implanted and operational. Seven underwent explantation owing to infection; seven had internal failures, and six were physically broken by external events. Of the 22 devices explanted, 15 were successfully replaced to restore recipients' enhanced functionality. There were no instances of sepsis or major health complications. The five infections that followed all 93 IRS and IST lower extremity research surgeries during this period indicate a pooled infection rate of 5.4%. The Kaplan-Meier analysis of technical malfunctions between the implant date and most recent follow-up shows five-, ten-, and 20-year device survival rates of 92%, 84%, and 71%, respectively. CONCLUSIONS: Incidence of malfunction is similar to, whereas infection rates are slightly higher than, other commonly implanted medical devices. Future investigations will focus on infection prevention, modifying techniques on the basis of recipient demographics, lifestyle factors, and education, and integrating similar experience of motor neuroprostheses used in other applications.

Incidence and Outcomes of Eye Trauma Associated With Recreative Use of Nonpowder Toy Guns: A 12-Year Retrospective Study.

PURPOSE: Nonpowder toy guns (NPTGs) are responsible for many ocular traumas. This study aims to detail the outcomes of these injuries depending on the causative NPTG. DESIGN: Retrospective, observational case series. METHODS: Cases of NPTG-associated ocular trauma managed in a Parisian eye emergency department between August 1, 2010, and January 1, 2023, were reviewed. The date of trauma, causative NPTG, patient demographics, initial and follow-up eye examinations, any surgical procedure, and visual outcomes for each ocular trauma were analyzed. RESULTS: Over 12 years, NPTGs were responsible for 324 eye injuries and 980 visits. Patients were mostly male (77.5%), and mean age at trauma was 16.2 years. Foam bullets or foam dart blasters accounted for 54.9% of traumas and were mainly responsible for corneal injuries and hyphema (30.9% and 27%, respectively). BB guns and airsoft guns were frequently responsible for anterior segment lesions, as well as intravitreal hemorrhages (14.7%) and commotio retinae (21.1%). Paintball guns accounted for the largest proportion of posterior segment lesions (eg, intraretinal or subretinal hemorrhages leading to macular atrophy/contusion maculopathy), and one-third of casualties had undergone ocular surgery. Among all traumas, final visual acuity was lower than 20/200 in 6.5% of cases. Phthisis occurred in 8 cases: Two were related to foam bullets or foam dart blaster injuries (1 contusion and 1 rupture), 2 other cases followed a rupture due to BB guns/airsoft guns, 1 case occurred after a rupture related to a paintball gunshot, and 3 others were due to other types of compressed air guns (1 rupture, 1 intraocular foreign body, and 1 total retinal detachment). CONCLUSIONS: NPTG-related ocular trauma outcomes differ according to the causative toy. Paintball guns and BB guns/airsoft gun-related traumas were more likely to be associated with severe lesions, but an increasing number of ocular injuries related to the use of foam bullets or foam dart blasters are reported in younger and younger children. Public health policies should promote the use of protective eyewear.

Specificities of pediatric ocular emergencies before and during the COVID-19 era: A retrospective comparative study in an eye-related emergency department in Paris.

INTRODUCTION: Epidemiological data on the use of eye-related emergency services by children are limited. The objective of this study was to determine how COVID-19 affected the epidemiological trends of pediatric ocular emergencies. METHODS: We performed a retrospective chart review of children under the age of 18 years who visited our eye-related emergency department between March 17 and June 7, 2020 and between March 18 and June 9, 2019. This was a descriptive and comparative analysis of the two study periods based on the demographic characteristics of patients and the diagnosis reported by the ophthalmologist in the digital medical charts. One of the investigators performed a second reading of the files to homogenize the diagnosis classification based on the most frequently found items. RESULTS: In total, 754 children were seen in our eye-related emergency department during the 2020 study period versus 1399 in 2019, representing a 46% decrease. In 2019, the four main diagnoses were traumatic injury (30%), allergic conjunctivitis (15%), infectious conjunctivitis (12%), and chalazion/blepharitis (12%). In the 2020 study period there was a significant decrease in the proportion of patients presenting with traumatic injuries (p < 0.001), infectious conjunctivitis (p = 0.03), and chalazion/blepharitis (p < 0.001). Consultations for chalazion/blepharitis were the most affected by the pandemic, followed by traumatic injuries (-72% and -64%, respectively). The proportion of patients who required surgery after trauma was higher in 2020 than in 2019 (p < 0.01), but the absolute number of severe trauma cases remained stable. CONCLUSIONS: The COVID-19 pandemic was accompanied by a decrease in the overall use of a pediatric eye-related emergency services in Paris. Visits due to benign causes and ocular trauma also decreased, but visits for more severe pathologies were not affected. Longer-term epidemiological studies may confirm or refute a change in eye emergency department use habits.

Incidence of Eye Trauma in Children Associated With Foam Bullets or Foam Darts From Nonpowder Guns.

This case series estimates the annual incidence of pediatric eye injuries associated with recreational use of nonpowder guns at an ophthalmologic emergency department in France.

Optopharmacological tools for precise spatiotemporal control of oxytocin signaling in the central nervous system and periphery.

Oxytocin is a neuropeptide critical for maternal physiology and social behavior, and is thought to be dysregulated in several neuropsychiatric disorders. Despite the biological and neurocognitive importance of oxytocin signaling, methods are lacking to activate oxytocin receptors with high spatiotemporal precision in the brain and peripheral mammalian tissues. Here we developed and validated caged analogs of oxytocin which are functionally inert until cage release is triggered by ultraviolet light. We examined how focal versus global oxytocin application affected oxytocin-driven Ca2+ wave propagation in mouse mammary tissue. We also validated the application of caged oxytocin in the hippocampus and auditory cortex with electrophysiological recordings in vitro, and demonstrated that oxytocin uncaging can accelerate the onset of mouse maternal behavior in vivo. Together, these results demonstrate that optopharmacological control of caged peptides is a robust tool with spatiotemporal precision for modulating neuropeptide signaling throughout the brain and body.

Predictive factors of graft detachment and rebubbling after descemet membrane endothelial keratoplasty.

PURPOSE: To identify risk and predictive factors associated with the need of rebubbling in the eye of patients who underwent a descemet membrane endothelial keratoplasty (DMEK). METHODS: The records of patients who underwent DMEK were retrospectively analyzed. Data regarding comorbidities, intraoperative characteristics, and postoperative treatments or complications were collected. The central corneal thickness (CCT) was measured by optical coherence tomography before and the day after DMEK. Univariate and multivariate analyses were performed. RESULTS: Of the 333 DMEK, rebubbling was performed in 119 cases (36%). Preoperative subepithelial fibrosis and a history of penetrating keratoplasty (PK) were associated with significantly more graft detachment [OR of 3.55 (2.02-6.32; P < 0.001) and 5.89 (2.00-21.86; P = 0.003), respectively]. A decreased CCT the day after surgery reduced by 5.7-fold the risk of rebubbling (sensitivity/specificity of 0.42/0.93). Conversely, a 20% increase in the CCT the day after surgery increased by 4.5-fold the risk of rebubbling (sensitivity/specificity of 0.42/0.91). CONCLUSION: Variation of the CCT could be used as a predictive factor of rebubbling after DMEK. Patients with a 20% increase of CCT the day after surgery are at higher risk of graft detachment. Conversely, a reduced CCT the day after the surgery is associated with a reduced risk of rebubbling. Subepithelial fibrosis and history of PK were also identified as risk factors for rebubbling. Those predictive factors may help develop a customized approach for patients undergoing DMEK surgery.

Cystoid macular oedema after descemet membrane endothelial keratoplasty.

AIMS: To determine the incidence and risk factors of cystoid macular oedema (CMO) following descemet membrane endothelial keratoplasty (DMEK) with or without combined cataract surgery (triple-DMEK). METHODS: We reviewed the records of patients who underwent DMEK surgery alone or triple-DMEK performed at the Rothschild Foundation Hospital (Paris, France) between January 2019 and March 2020. Patients with pre-existing CMO observed on the preoperative macular optical coherence tomography (OCT) were excluded. Spectral-domain OCT was performed in patients with postoperative visual impairment. Data regarding comorbidities, intraoperative characteristics and postoperative treatments or complications were collected and analysed. Univariate and multivariate analyses were performed. RESULTS: Twenty three of 246 eyes (9.36%) developed clinically significant (cs)-CMO after DMEK. Triple-DMEK was not associated with a higher risk to develop CMO (12.2% in DMEK alone and 6.1% in triple-DMEK). Pseudophakic bullous keratopathy (PBK ; 39.1% vs 9%; OR=3.5 (1.0 to 11.8), p=0.045) and epiretinal membrane (ERM; 39.1% vs 7.7%; OR=10.5 (3.4 to 32.3), p<0.001) were more frequently observed in patients who developed CMO. The occurrence of hyphaema during surgery was statistically associated with postoperative CMO (13% vs 1.3%; OR=7.1 (1.0 to 48.8) p=0.045). Peroperative epithelial debridement was statistically associated with postoperative CMO (65.2% vs 33.2%, p=0.005), but only in univariate analysis. CONCLUSIONS: We identified a clinically significant CMO incidence of 9.35% after DMEK. Patients with a history of ERM, PBK and intraoperative hyphaema may be at risk of developing CMO after DMEK surgery and should be monitored.

Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one of the most common findings in the disease, frequently occurring before the onset of neurological manifestations. While early treatment with chenodeoxycholic acid can prevent the onset of neurological impairment, poor awareness of CTX accounts for a markedly delayed diagnosis. The objective of this study was to evaluate the utility of plasma cholestanol analysis at the moment of cataract diagnosis and before the onset of neurological impairment in CTX. METHODS: Multicenter prospective cohort study of patients with juvenile-onset unexplained bilateral cataracts recruited from seven French ophthalmology departments. Plasma cholestanol analysis was performed at diagnosis from January 2018 to January 2020. CYP27A1 genetic testing was performed at the ophthalmologist's discretion. Cholestanol levels were compared with those of a similar population of patients without cataracts (control cohort). RESULTS: 30 patients were finally recruited, with a mean age at cataract diagnosis of 7.1 years (± 4.8 SD, range 1-19 years). One patient had a very high cholestanol level (68 µmol/L, reference < 10) and carried two pathogenic heterozygous mutations in CYP27A1 confirming CTX. This patient was a 19-year-old female, reporting chronic diarrhea only in childhood, and diagnosed with bilateral posterior cataracts with cortical fleck-like opacities. Therefore, the incidence of CTX in our cohort of patients was 3.3%. Five further patients (5/29; 17.2%) had moderate elevations of cholestanol level (between 10.3 and 16.5 µmol/L), compared to 12/286 (4.2%) in the control cohort (p = 0.014) after adjustment for age. CONCLUSION: Our study argue for the relevance of plasma cholestanol CTX screening in all patients with juvenile-onset unexplained cataracts, even without other CTX identified manifestations. Whether moderate elevations of plasma cholestanol unrelated to CTX may be a risk factor for bilateral cataracts occurrence needs further examination.

Clinical course and treatment of archipelago keratitis: a Herpesviridae keratitis subtype.

PURPOSE: Archipelago keratitis (ApK) is a subtype of Herpesviridae stromal keratitis that consists of subepithelial nummular inflammatory infiltrates arranged in a radial centripetal pattern. This rare and poorly described form is not often recognised early. We report the first large series of ApK, with an analysis of clinical settings at presentation, evolution of the disease with time and a description of factors associated with recurrence. METHODS: The clinical records of 82 patients (83 eyes) with a diagnosis of ApK between 2011 and 2021 in two centres were reviewed. RESULTS: The median age of the 82 patients at referral was 37±28 years. ApK was unilateral in all but one case. A total of 76% of patients had at least one second diagnostic criteria suggesting a herpetic aetiology. Overall, 44 (53%) eyes exhibited least one recurrence after a median of 12 months. Recurrence was frequently associated with neovascularisation (HR 2.1, 95% CI 1.1 to 3.9; p=0.02) and tapering corticosteroids (HR 3.5, 95% CI 1.8 to 7.1; p<0.01) or valaciclovir use (HR=2.3, 95% CI 1.2 to 4.6; p=0.01). Antiviral treatment was used in all patients, whereas local anti-inflammatory drugs such as corticosteroids and/or ciclosporin were used in 73 (88%) cases. CONCLUSION: ApK is a Herpesviridae stromal keratitis that is typically unilateral in presentation and features a high risk of recurrence. Combined treatment with antiviral and anti-inflammatory drugs are usually required over the long term. Topical ciclosporin can be useful as a corticosteroid-sparing treatment.

Retinal atrophy and markers of systemic and cerebrovascular severity in homozygous sickle cell disease.

INTRODUCTION: While paramacular retinal atrophy (PRA) is known to be found in 48% of eyes of adults and 42% of eyes of children with homozygous SCD (SS-SCD), the aim of this study is to assess the association between PRA and red blood cell (RBC) deformability, hematological markers and brain imaging abnormalities in SS-SCD. METHODS: This study is a subset of DREAM2, a prospective observational study performed between August 2015 and August 2016. Children (5-17 years) with SS-SCD and no history of large vessel vasculopathy, were included. Ophthalmological characteristics including visual acuity, fundus examination, OCT of central and temporal retina (with several retinal thickness measurements) were explored in relation with RBC deformability (ektacytometry), hematological and biochemical (hemolysis parameters), and neurological (cerebral oxygenation estimated by Near Infrared Spectroscopy, brain magnetic resonance imaging) investigations. RESULTS: 17 children (5 boys; mean age: 13 years) with complete ophthalmological investigations were included in the analysis; 8 exhibited PRA. RBC deformability was found to be significantly lower in children with PRA for measurements made at 1.69 Pa (0.16 a.u ± 0.02 vs 0.21 a.u ± 0.03, p = 0.02) and above, as well as cerebral oxygenation (59.25% ± 9.9 vs 71.53% ± 4.9, p = 0.02). A significant positive correlation was found between temporal retinal thickness and hemoglobin level (ρ = 0.65, p = 0.007), hematocrit (ρ = 0.53, p = 0.04) and RBC deformability at 3 Pa (ρ = 0.75, p = 0.005) and above. CONCLUSIONS: These results suggest that PRA could be an early marker of systemic severity and cerebral oxygenation in SCD. Whether it could help predicting cerebral vasculopathy requires further investigations.

Brain-wide visual habituation networks in wild type and fmr1 zebrafish.

Habituation is a form of learning during which animals stop responding to repetitive stimuli, and deficits in habituation are characteristic of several psychiatric disorders. Due to technical challenges, the brain-wide networks mediating habituation are poorly understood. Here we report brain-wide calcium imaging during larval zebrafish habituation to repeated visual looming stimuli. We show that different functional categories of loom-sensitive neurons are located in characteristic locations throughout the brain, and that both the functional properties of their networks and the resulting behavior can be modulated by stimulus saliency and timing. Using graph theory, we identify a visual circuit that habituates minimally, a moderately habituating midbrain population proposed to mediate the sensorimotor transformation, and downstream circuit elements responsible for higher order representations and the delivery of behavior. Zebrafish larvae carrying a mutation in the fmr1 gene have a systematic shift toward sustained premotor activity in this network, and show slower behavioral habituation.

From calcium imaging to graph topology.

Systems neuroscience is facing an ever-growing mountain of data. Recent advances in protein engineering and microscopy have together led to a paradigm shift in neuroscience; using fluorescence, we can now image the activity of every neuron through the whole brain of behaving animals. Even in larger organisms, the number of neurons that we can record simultaneously is increasing exponentially with time. This increase in the dimensionality of the data is being met with an explosion of computational and mathematical methods, each using disparate terminology, distinct approaches, and diverse mathematical concepts. Here we collect, organize, and explain multiple data analysis techniques that have been, or could be, applied to whole-brain imaging, using larval zebrafish as an example model. We begin with methods such as linear regression that are designed to detect relations between two variables. Next, we progress through network science and applied topological methods, which focus on the patterns of relations among many variables. Finally, we highlight the potential of generative models that could provide testable hypotheses on wiring rules and network progression through time, or disease progression. While we use examples of imaging from larval zebrafish, these approaches are suitable for any population-scale neural network modeling, and indeed, to applications beyond systems neuroscience. Computational approaches from network science and applied topology are not limited to larval zebrafish, or even to systems neuroscience, and we therefore conclude with a discussion of how such methods can be applied to diverse problems across the biological sciences.

RNA-induced inflammation and migration of precursor neurons initiates neuronal circuit regeneration in zebrafish.

Tissue regeneration and functional restoration after injury are considered as stem- and progenitor-cell-driven processes. In the central nervous system, stem cell-driven repair is slow and problematic because function needs to be restored rapidly for vital tasks. In highly regenerative vertebrates, such as zebrafish, functional recovery is rapid, suggesting a capability for fast cell production and functional integration. Surprisingly, we found that migration of dormant "precursor neurons" to the injury site pioneers functional circuit regeneration after spinal cord injury and controls the subsequent stem-cell-driven repair response. Thus, the precursor neurons make do before the stem cells make new. Furthermore, RNA released from the dying or damaged cells at the site of injury acts as a signal to attract precursor neurons for repair. Taken together, our data demonstrate an unanticipated role of neuronal migration and RNA as drivers of neural repair.

[Contribution of « GIGA-Cancer ¼ at ULiege to the research on tumour microenvironment]. / Apport du «GIGA-Cancer¼ de l'ULiège à la recherche sur le microenvironnement tumoral.

The evolution of cancers is dictated by the intrinsic characteristics of malignant cells, but also by the multiple dynamic and reciprocal interactions that they establish with their tissue and cellular environment. This tumour microenvironment is therefore the subject of an ever-increasing part of cancer researches. These notably shed light on the plasticity of function of these non-malignant cells and on the diversity of their impact on the progression of the disease, both in primary tumours and during the formation of metastases. The improvement of the current therapy and the development of innovative treatments therefore require the identification of these cell subpopulations, either «allies¼ or «enemies¼ of aggressive cancer cells, as well as a more extensive understanding of the mechanisms modulating their phenotypes. This article summarizes some research projects carried out in two GIGA-Cancer laboratories supported by «Télévie¼ and the «Fondation Léon Frédéricq¼.

L'évolution de la pathologie cancéreuse est dictée par les caractéristiques intrinsèques des cellules malignes, mais également par les multiples interactions dynamiques et réciproques qu'elles établissent avec leur environnement tissulaire et cellulaire. Ce microenvironnement tumoral est donc l'objet d'une part sans cesse croissante des recherches en cancérologie. Celles-ci ont, notamment, mis en lumière la plasticité de fonction de ces cellules non malignes et la diversité de leurs impacts sur l'évolution de la maladie, tant dans les tumeurs primaires que lors de la formation des métastases. L'amélioration des traitements actuels et la mise au point de traitements novateurs nécessiteront donc l'identification fine de ces sous-populations cellulaires «alliées¼ ou «ennemies¼ des cellules cancéreuses agressives, ainsi qu'une compréhension accrue des mécanismes modulant leurs phénotypes. Cet article résume quelques projets de recherche menés dans deux laboratoires du GIGA-Cancer, soutenus notamment par Télévie et la Fondation Léon Fredericq.

Antifungal Properties, Abiotic Stress Resistance, and Biocontrol Ability of Bacillus mojavensis PS17.

Plant-protecting Bacillus sp. strains used as biocontrol agents frequently produce metabolites inhibiting phytopathogenic fungi. Recently, the search for a novel biocontrol agent with a wide spectrum of disease control drew attention to Bacillus subtilis and their related species, including Bacillus mojavensis. In this study, we determined the antifungal properties of the endophytic B. mojavensis PS17 isolated from wheat seeds. Metabolites produced by B. mojavensis PS-17 inhibit the growth of Fusarium graminearum, Fusarium oxysporum, Fusarium chlamydosporum, Ascochyta pisi, Alternaria alternate, Sclerotinia sclerotiorum, Verticillium dahliaee, and Epicoccum nigrum strains. B. mojavensis strain PS17 produces several hydrolytic enzymes, such as chitinase, ß-glucanase, cellulase, lipase, and protease. Additionally, strain B. mojavensis PS17 demonstrates drought tolerance under osmotic pressure of -2.2 MPa and a moderate halotolerance in 5% (w/v) of NaCl. B. mojavensis PS17 on tomato seedlings was able to reduce lesions of Forl ZUM2407 by 48.11% ± 1.07, showing the potentials of B. mojavensis PS17 to be adapted as a biocontrol agent for agricultural use.