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"Recognizing a surprising fact is the first step towards discovery." This famous quote from Louis Pasteur is particularly appropriate to describe what led us to study mycolactone, a lipid toxin produced by the human pathogen Mycobacterium ulcerans. M. ulcerans is the causative agent of Buruli ulcer, a neglected tropical disease manifesting as chronic, necrotic skin lesions with a "surprising" lack of inflammation and pain. Decades after its first description, mycolactone has become much more than a mycobacterial toxin. This uniquely potent inhibitor of the mammalian translocon (Sec61) helped reveal the central importance of Sec61 activity for immune cell functions, the spread of viral particles and, unexpectedly, the viability of certain cancer cells. We report in this review the main discoveries that marked our research into mycolactone, and the medical perspectives they opened up. The story of mycolactone is not over and the applications of Sec61 inhibition may go well beyond immunomodulation, viral infections, and oncology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid‐β peptide (Aβ) in the form of senile plaques. Aβ can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with Aβ peptides, suggesting that it may be a carrier protein which prevents aggregation of Aβ. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work, we gain insights into the interaction of Aβ with ERp57, with a special focus on the contribution of ERp57 to the defense system of the cell. Here, we show that recombinant ERp57 directly interacts with the Aβ25−35 fragment in vitro with high affinity via two in silico‐predicted main sites of interaction. Furthermore, we used human neuroblastoma cells to show that short‐term Aβ25−35 treatment induces ERp57 decrease in intracellular protein levels, different intracellular localization, and ERp57 secretion in the cultured medium. Finally, we demonstrate that recombinant ERp57 counteracts the toxic effects of Aβ25−35 and restores cellular viability, by preventing Aβ25−35 aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from Aβ toxicity and highlights it as a possible therapeutic tool in the treatment of AD. [ABSTRACT FROM AUTHOR]

The high rate of antibody production places considerable metabolic and folding stress on plasma cells (PC). Not surprisingly, they rely on the unfolded protein response (UPR), a universal signaling, and transcriptional network that monitors the health of the secretory pathway and mounts cellular responses to stress. Typically, the UPR utilizes three distinct stress sensors in the ER membrane, each regulating a subset of targets to re‐establish homeostasis. PC use a specialized UPR scheme—they preemptively trigger the UPR via developmental signals and suppress two of the sensors, PERK and ATF6, relying on IRE1 alone. The specialized PC UPR program is tuned to the specific needs at every stage of development—from early biogenesis of secretory apparatus, to massive immunoglobulin expression later. Furthermore, the UPR in PC integrates with other pathways essential in a highly secretory cell—mTOR pathway that ensures efficient synthesis, autophagosomes that recycle components of the synthetic machinery, and apoptotic signaling that controls cell fate in the face of excessive folding stress. This specialized PC program is not shared with other secretory cells, for reasons yet to be defined. In this review, we give a perspective into how and why PC need such a unique UPR program. [ABSTRACT FROM AUTHOR]

The unfolded protein response plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1a is a major transducer that conveys endoplasmic reticulum stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its endoplasmic reticulum luminal domain, IRE1a dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1a, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix aK, located between the kinase and RNase domains of IRE1a, in conveying this critical conformational change. Using constructs containing mutations within this interdomain helix, we show that distinct substitutions affect oligomerization, kinase activity, and the RNase activity of IRE1a differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Of importance, an RNase-inactive mutant, L827P, can still dimerize with wildtype monomers, but this mutation inactivates the wildtype molecule and renders leukemic cells more susceptible to stress. We surmise that helix aK is a conduit for the activation of IRE1a in response to stress. [ABSTRACT FROM AUTHOR]

This article offers an analysis of the documentary Land Rush by Osvalde Lewat and Hugo Berkeley. The study shows how the film is an example of the multiple points of view, particularly sensitive to people's living conditions. This is the result of a dual gaze of the filmmakers and also of the specific positioning of Osvalde Lewat, a Cameroonian who navigates between various countries and lives in the space of the diaspora. From her 'situated gaze', she offers a particular perspective on the fragility of villagers confronting environmental issues, international market and economic rules. Far removed from stereotypes, she shows how rural communities are faced with choices that can change their lives. At the same time, she attests to the fact that no matter the condition, one can resist and define one's own destiny. It is a contemporary practice of documentary that Osvalde Lewat uses her experiences as a journalist and then as a filmmaker, to fight against injustices of all kinds. [ABSTRACT FROM AUTHOR]

The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress-induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase-inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase-inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress-independent cluster, with distinct physical properties and half-lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor. [ABSTRACT FROM AUTHOR]

Activation of the endoplasmic reticulum (ER) stress sensor inositol‐requiring enzyme‐1α (IRE1α) contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the contrary, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1α, we used a mouse model expressing a C148S variant of IRE1α with increased and sustained activation. Surprisingly, the mutation did not affect the differentiation of highly secretory antibody‐producing cells but exhibited a beneficial effect in a mouse model of experimental autoimmune encephalomyelitis (EAE). Although mechanical allodynia was unaffected, significant improvement in motor function was found in IRE1C148S mice with EAE relative to wild type (WT) mice. Coincident with this improvement, there was reduced microgliosis in the spinal cord of IRE1C148S mice, with reduced expression of proinflammatory cytokine genes. This was accompanied by reduced axonal degeneration and enhanced 2',3'‐cyclic nucleotide 3'‐phosphodiesterase (CNPase) levels, suggesting improved myelin integrity. Interestingly, while the IRE1C148S mutation is expressed in all cells, the reduction in proinflammatory cytokines and in the microglial activation marker ionized calcium‐binding adapter molecule (IBA1), along with preservation of phagocytic gene expression, all point to microglia as the cell type contributing to the clinical improvement in IRE1C148S animals. Our data suggest that sustained increase in IRE1α activity can be beneficial in vivo, and that this protection is cell type and context dependent. Considering the overwhelming but conflicting evidence for the role of ER stress in neurological diseases, a better understanding of the function of ER stress sensors in physiological contexts is clearly needed.Enhancing the physiological activation of IRE1α reduces the symptoms of experimental autoimmune encephalomyelitis (EAE) in mice. The IRE1α (C148S) mutant is characterized by increased and prolonged activation of IRE1α relative to the wild‐type IRE1α. Animals carrying this mutation exhibit improved clinical scores when challenged with EAE, presenting with decrease in inflammatory markers, higher myelin integrity, and decreased axonal degeneration. Thus, specific activators of IRE1α may be useful in treating MS. The clinical protection may be explained by the action of the activated IRE1α(C148S) mutant in microglial cells, via decrease in inflammation, or directly in neurons or oligodendrocytes. Surprisingly, the mutation does not enhance antibody production in B cells stimulated with LPS, where IRE1α is known to be activated, suggesting that the outcomes of enhanced IRE1α activity depend either on the type of stress or are cell‐specific. [ABSTRACT FROM AUTHOR]

[Display omitted] • SARS-CoV-2 promotes an inflammatory phenotype in human monocytes. • In SARS-CoV-2 stimulated PBMC Tα1 mitigates monocyte and myeloid DC activation. • Tα1 dampens SARS-CoV-2 mediated induction of pro-inflammatory cytokines. • Tα1 promotes release of the anti-inflammatory factors IL-10 from SARS-CoV- 2-stimulated PBMC. The peculiar property of Thymosin alpha 1 (Tα1) to act as master regulator of immune homeostasis has been successfully defined in different physiological and pathological contexts ranging from cancer to infection. Interestingly, recent papers also demonstrated its mitigating effect on the "cytokine storm" as well as on the T-cell exhaustion/activation in SARS-CoV-2 infected individuals. Nevertheless, in spite of the increasing knowledge on Tα1-induced effects on T cell response confirming the distinctive features of this multifaceted peptide, little is known on its effects on innate immunity during SARS-CoV-2 infection. Here, we interrogated peripheral blood mononuclear cell (PBMC) cultures stimulated with SARS-CoV-2 to disclose Tα1 properties on the main cell players of early response to infection, namely monocytes and myeloid dendritic cells (mDC). Moving from ex vivo data showing an enhancement in the frequency of inflammatory monocytes and activated mDC in COVID-19 patients, a PBMC-based experimental setting reproduced in vitro a similar profile with an increased percentage of CD16+ inflammatory monocytes and mDC expressing CD86 and HLA-DR activation markers in response to SARS-CoV-2 stimulation. Interestingly, the treatment of SARS-CoV-2-stimulated PBMC with Tα1 dampened the inflammatory/activation status of both monocytes and mDC by reducing the release of pro-inflammatory mediators, including TNF-α, IL-6 and IL-8, while promoting the production of the anti-inflammatory cytokine IL-10. This study further clarifies the working hypothesis on Tα1 mitigating action on COVID-19 inflammatory condition. Moreover, these evidence shed light on inflammatory pathways and cell types involved in acute SARS-CoV-2 infection and likely targetable by newly immune-regulating therapeutic approaches. [ABSTRACT FROM AUTHOR]

The Hammersmith Infant Neurological Examination (HINE) has been proposed as one of the early neurological examination tools for the diagnosis of cerebral palsy (CP). The aim of the present study was to critically review the existing literature and our experience with the use of the HINE in infants at risk of CP. The published papers confirm that the HINE can play an important role in the diagnosis and prognosis of infants at risk of developing CP, and provide information on aspects of neurological findings impaired in different forms of CP and brain lesions. [ABSTRACT FROM AUTHOR]

An up-to-date review on neuropsychological phenotypes in Dravet syndrome is reported. After recalling the results of various though not numerous studies in the literature, primarily retrospectively, the hypothesis of an original neuropsychological phenotype in Dravet syndrome is presented, consisting of a defect in sensorimotor integration, especially of visuoconstructive abilities. That is particularly evident in the less impaired patients and in the first several years of life. This core phenotype is eventually considered inside the analysis of the etiological multifactorial origin of the cognitive decline, which is especially expressed by the encephalopathy/channelopathy controversy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Green tea is a rich source of polyphenols, mainly catechins (flavanols), which significantly contribute to the beneficial health effects of green tea in the prevention and treatment of various diseases. In this study the effects of four green tea catechins on protein ERp57, also known as protein disulfide isomerase isoform A3 (PDIA3), have been investigated in an in vitro model. Methods: The interaction of catechins with ERp57 was explored by fluorescence quenching and surface plasmon resonance techniques and their effect on ERp57 activities was investigated. Results: A higher affinity was observed for galloylated cathechins, which bind close to the thioredoxin-like redox-sensitive active sites of the protein, with a preference for the oxidized form. The effects of these catechins on ERp57 properties were also investigated and a moderate inhibition of the reductase activity of ERp57 was observed as well as a strong inhibition of ERp57 DNA binding activity. Conclusions: Considering the high affinity of galloylated catechins for ERp57 and their capability to inhibit ERp57 binding to other macromolecular ligands, some effects of catechins interaction with this protein on eukaryotic cells may be expected. General significance: This study provides information to better understand the molecular mechanisms underlying the biological activities of catechins and to design new polyphenol-based ERp57-specific inhibitors. [Copyright &y& Elsevier]

Abstract: Aim: To describe the development of visual functions in a population of low-risk late preterm infants. Subjects and methods: Eighty low-risk late preterm with a gestational age between 34.0 and 36.9weeks were assessed at birth and at term equivalent age (TEA) using a structured visual assessment battery. The results were compared to those previously obtained in term born infants using the same battery. Results: For 5 items (spontaneous ocular motility, ocular motility with target, fixation, horizontal tracking and color tracking) the results were similar both at birth and TEA; for the other 4 (vertical and arc tracking, ability to discriminate striped black/white targets and attention at distance) visual findings at TEA were more mature than at birth. Comparing the responses in late preterm at TEA and term-born infants at 48h of life, only 2 items (attention at distance, ability to discriminate black/white stripes) were different, with more mature findings in late preterm infants. Conclusions: Our results show that in late preterm some aspects of visual functions have a progressive maturation infants between birth and TEA, confirming that the time between birth and term age appears to be crucial for the development of these abilities. [Copyright &y& Elsevier]

The aim of this study was to assess the onset of forward parachute reaction (FPR) in infants with brain lesions and its correlation with age of walking. FPR was assessed at 6, 9, and 12 months in 140 infants with brain lesions (78 males, 62 females; mean gestational age 31wks; SD 3.6wks; mean birthweight 1450g, SD 252g). On cranial ultrasound 62 infants had mild and 78 had major abnormalities; 86 developed cerebral palsy. All were followed for 5 years, and the age at which each child achieved independent walking was recorded. Infants who had been born small for gestational age (weight <10th centile) were excluded, as were those who had major congenital malformations, severe postnatal infectious diseases, or metabolic or haematological complications. A complete FPR was present in eight infants at 6 months, in 42 at 9 months, and in 71 at 12 months. At 12 months, 29 infants presented incomplete FPR and 40 presented absent FPR. Seventy-three infants were able to walk independently between the ages of 11 months and 60 months (67 with complete FPR and six with incomplete FPR at 12mo). A complete FPR at 12 months was a good predictor of independent walking. The age at onset of complete FPR was also a good predictor of age of walking. The late acquisition of a complete FPR appears to be an early sign of a more general delayed maturation of functional abilities. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several studies have reported the development of various aspects of visual function in infancy and early childhood in both preterm and term-born infants, but only a few studies have focused on the predictive power of neonatal visual findings in infants with brain lesions. Aims: To explore visual findings at term age, and at 3 and 12months corrected age in preterm infants (gestational age <33weeks) with and without brain lesions; to compare the assessment at term age and at 12months; and to assess the relationship between visual findings and neurodevelopmental outcome at 12months. Study design: Cranial ultrasound scans (US) were classified in normal, mild or major abnormalities. One-hundred and forty-five infants were assessed with age specific tests for visual function at term age, and at 3 and 12months. Neurodevelopmental assessment (Griffiths'' Scales) was performed at 12months. Results: A good correlation was found between early and late visual assessment and neurodevelopment outcome. Of the 121 infants with normal neonatal visual assessment, 119 were also normal at 12months and 116 had normal developmental quotient. Of the 24 infants with abnormal neonatal visual assessment, 12 were also abnormal at 12months. All the false positives had normalised by 3months. Of the 35 infants with major US abnormalities, 20 had normal and 15 abnormal scores on the neonatal assessment. At 1year 17 had normal and 18 abnormal scores. Conclusion: A normal visual assessment at term age is a good predictor of normal visual and neurodevelopmental outcome at 12months. An abnormal visual examination in the neonatal period was a less reliable prognostic indicator, infant should be reassessed at 3months. [Copyright &y& Elsevier]

Summary: Aim of the study was to describe prospectively the early neuropsychological evolution including the first pre-cognitive stages of the Severe Myoclonic Epilepsy in Infancy (SMEI) or Dravet syndrome. Five cases, four of whom since before a diagnostic evidence of the Dravet syndrome, were followed up. Full clinical assessment including developmental, visual function and behaviour assessments were serially performed. In four cases, a variable onset age of cognitive decline assessed with developmental scales was preceded some months before by an impairment of visual function; the remaining patient during all the course of follow-up till 51 months of age showed a normal development without visual impairment. A cognitive decline with variable onset was generally confirmed in Dravet syndrome. The previous early impairment of visual function seems to herald the cognitive decline and provides useful prognostic information; furthermore, it possibly suggests some clues for a better understanding of the mechanisms of cognitive deterioration in this syndrome. [Copyright &y& Elsevier]

Abstract: Background: Several studies reported on various aspects of visual function at term age and in the first months after birth but less has been reported in preterm infants before they reach termequivalent age. Aims: To assess the suitability of a battery of tests of visual function for use in infants born at <33weeks gestation (GA) and assessed before 34weeks post-menstrual age (PMA); to evaluate the distribution of the findings according to GA, and to compare the data with those previously published on preterm infants assessed at 35weeks PMA. Study design: Cross-sectional study. Subjects: Sixty-four preterm infants with a GA <33weeks were studied. Outcome measures: We used a battery of visual function tests previously validated at 35 and 40weeks PMA in low-risk preterm infants. All the infants in this current study underwent the same assessment before 34weeks PMA. Results: Before 31weeks PMA most infants could not be reliably assessed because of clinical instability, whilst after 31weeks PMA most infants could be assessed and they showed progressive maturation in their responses with PMA. Some items (spontaneous ocular motility, horizontal tracking, tracking a coloured stimulus, and ocular fixation) showed similar results at 32–33weeks PMA to those found in low-risk preterm at 35weeks PMA. Ocular movements to a target and arc tracking were the items with the most immature responses. Conclusions: Our results provide further evidence that a structured assessment of visual function can be used in clinical routine and for research purposes in infants as young as 31weeks PMA. [Copyright &y& Elsevier]

Abstract: Backgrounds: We previously reported the neurological findings of the Dubowitz neonatal examination in a cohort of 157 low-risk preterms born between 25 and 33 weeks gestational age (GA) and examined at term equivalent age (TEA). Median and range of scores were wider than those found in term-born infants and preterms showed a different neurological behaviour in specific items. However, the cohort number was too small to draw any definitive conclusion about the distribution of findings. Aims: We provide normative data from a low-risk cohort of 380 preterm infants; we also assess the findings and their relationship to motor outcome in preterms with major cranial ultrasound (US) abnormality. Study design: We assessed, at TEA, 380 low-risk preterms born <35 weeks gestation (range 25–34.9, median 29) with normal 2 year motor outcome and 85 preterm infants with major US abnormality. Results: At TEA low-risk preterms had less flexor limb tone, poorer head control but better visual following than term-born infants. For 28/34 of the neurological items the range and median scores were similar across gestational ages. In infants with major US lesions the range and median scores differed from low-risk preterms in 20/34 items; 40% of infants developing a diplegia and 80% developing a tetraplegia had >7 items outside the 90th centile; all infants with >12 items outside the 90th centile developed a tetraplegia. Conclusions: We provide reference values for the neurological examination of low-risk preterms at TEA. In infants with major US abnormality the number of items outside the 90th centile was an indicator of outcome severity. [Copyright &y& Elsevier]

Abstract: Background: We have previously developed and described a battery of 9 items suitable for assessing different clinical aspects of visual function in newborn infants. Aim of the study: Application of the test battery to a cohort of low risk term-born infants at 48 and 72 h after birth 1) to define the normative distribution of results for each item and 2) to document any effect of postnatal age. Study design and subjects: 124 term-born low risk infants were assessed at 48 h; fifty of them were re-assessed 24 h later at 72 h. Results: The visual test battery was successfully completed in 110 of the 124 infants assessed at 48 h and in all the 50 infants assessed at 72 h after birth. For 3 of the 9 items (fixation on a black/white target of concentric circles, on a coloured (red/yellow) face and horizontal tracking), the findings were very similar at both ages. For the remaining 6 items the range of findings was wider. There was a statistical difference in the responses obtained at 48 and 72 h for vertical and arc tracking (p <0.05) and the ability to discriminate stripes and attention at distance (p <0.001). Conclusion: Our results provide information on the visual abilities in a low risk population of term-born infants and the distribution of frequency of their visual responses to our battery of visual tests. These findings may be used as reference data when using our visual test battery in both clinical and research settings. [Copyright &y& Elsevier]

Abstract: Background:: The assessment of visual function is part of all the neonatal neurological examination but it is often limited to the evaluation of ocular movements and the ability to fix and follow a target. Aim of the study:: To develop a simple battery of test items assessing different aspects of visual function that could be used as early as 48 h after birth. Study design and subjects:: The final battery, which has been used in 50 full term low risk neonates, includes 9 items assessing ocular motility, both spontaneous and with focus on a visual target, fixation and tracking (horizontal, vertical and in an arc), the ability to discriminate stripes of different spatial frequency, and attention at distance. Results:: The battery proved easy to perform and did not require long training. The testing did not require a specific setting and was easy to use even for infants in incubators. The equipment is small and cleanable. Conclusion:: Our paper suggests that a simple battery, which can be performed in 5/10 min, can be easily applied and provides useful information on various aspects of early neonatal visual function. [Copyright &y& Elsevier]

Objective: The aim of this study was to assess visual function in 13 infants with evidence of prenatal post haemorrhagic ventricular dilatation. Design: Infants were assessed at 5, 12 and 24 months using a battery of tests specifically designed to assess various aspects of visual function in infancy. Visual findings were correlated with several variables, including extent of the lesion and presence of epilepsy. Results and conclusions: Abnormalities of visual function were frequent (over 60%) in our cohort at age 2 years, ranging from isolated abnormal ocular movements to severe abnormalities of all the aspects of visual function assessed. The most severe and persistent abnormalities of visual function were found in infants with grade IV intraventricular haemorrhage and shunted hydrocephalus who also had epilepsy in the first year. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this retrospective study was to establish the presence and severity of cerebral visual impairment in preterm infants with PVL. We also wished to establish whether abnormalities of visual function are related to brain MRI findings and more specifically not only to the involvement of optic radiations and occipital cortex but also to changes in the thalami, that are often affected in infants with PVL. Twelve infants with cystic PVL were assessed at 1 year (+2) corrected age with a battery of tests specifically designed to assess various aspects of visual function in infancy, such as ocular movements, visual acuity, visual fields and fixation shift. All infants also had a brain MRI. Eleven of the 12 had involvement of the optic radiations: all had some abnormalities of visual function and visual impairment was more severe in infants with more extensive involvement of the optic radiations. The child with normal optic radiations had normal visual function. Six of the 12 infants also had obvious signs of atrophy of the thalami and all had severe and wide-ranging abnormalities of visual function in all testing domains. Two children had equivocal atrophy of the thalami, both had some abnormalities of visual function. Four children had normal thalami and had normal visual function or only minor abnormalities on one of the visual tests. Our results suggest that the atrophy of the thalami may play an additional role in the abnormal development of visual function in infants with PVL and abnormal optic radiations. [Copyright &y& Elsevier]

Abstract: This paper provides an overview of the value of a structured neonatal neurological examination that may be performed in different settings, from routine examination to research settings. We will report how a structured neurological examination can help to identify infants with central and peripheral nervous system involvement. We also describe a short but structured proforma to be used for the routine examination of full-term infants. We will finally describe a quantitative assessment to be used in research settings. [Copyright &y& Elsevier]

ABSTRACT. Objectives. The aims of the study were to establish the relationship between head growth in the first year of life with the pattern on injury on neonatal magnetic resonance imaging (MRI) in infants with hypoxic-ischemic encephalopathy (HIE) and to relate these to the neurodevelopmental outcome. Methods. Fifty-two term infants who presented at birth with a neonatal encephalopathy consistent with HIE and who had neonatal brain MRI were entered into the study. Head circumference charts were evaluated retrospectively and the head growth over the first year of life compared with the pattern of brain lesions on MRI and with the neurodevelopmental outcome at 1 year of age. Suboptimal head growth was classified as a drop of >2 standard deviations across the percentiles with or without the development of microcephaly, which was classified as a head circumference below the third percentile. Results. There was no statistical difference between the neonatal head circumferences of the infants presenting with HIE and control infants. At 12 months, microcephaly was present in 48% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was documented in 53% of the infants with HIE, compared with 3% of the controls. Suboptimal head growth was significantly associated with the pattern of brain lesions, in particular to involvement of severe white matter and to severe basal ganglia and thalamic lesions. Suboptimal head growth predicted abnormal neurodevelopmental outcome with a sensitivity of 79% and a specificity of 78%, compared with the presence of microcephaly at 1 year of age, which had a sensitivity of only 65% and a specificity of 73%. The exceptions were explained by infants with only moderate white matter abnormalities who had suboptimal head growth but normal outcome at 1 year of age and by infants with moderate basal ganglia and thalamic lesions only who had normal head growth but significant motor abnormality. Pediatrics 2000;106:235... [ABSTRACT FROM AUTHOR]

Aim: To develop a short version of the original Hammersmith Infant Neurological Examination (HINE) to be used as a screening tool (Brief‐HINE) and to establish if the short examination maintains good accuracy and predictive power for detecting infants with cerebral palsy (CP). Method: Eleven items were selected from the original HINE ('visual response'; 'trunk posture'; 'movement quantity'; 'movement quality'; 'scarf sign'; 'hip adductor angles'; 'popliteal angle'; 'pull to sit'; 'lateral tilting'; 'forward parachute reaction'; 'tendon reflexes') identifying those items previously found to be more predictive of CP in both low‐ and high‐risk infants. In order to establish the sensitivity of the new module, the selected items were applied to existing data, previously obtained using the full HINE at 3, 6, 9, and 12 months, in 228 infants with typical development at 2 years and in 82 infants who developed CP. Results: Brief‐HINE scores showed good sensitivity and specificity, at each age of assessment, for detecting infants with CP. At 3 months, a score of less than 22 was associated with CP with a sensitivity of 0.88 and a specificity of 0.92; at 6, 9, and 12 months, the cut‐off scores were less than 25 (sensitivity 0.93; specificity 0.87), less than 27 (sensitivity 0.95; specificity 0.81), and less than 27 (sensitivity 1; specificity 0.86) respectively. The presence of more than one warning sign, or items that are not optimal for the age of assessment, imply the need for a full examination reassessment. Interpretation: These findings support the validity of the Brief‐HINE as a routine screening method and the possibility of its use in clinical practice. This original article is commented by Hewawitharana and Phillips on pages 1117–1118 of this issue. This original article is linked to letter to the editor by Fehlings et al. on pages 1255–1257 of this issue. [ABSTRACT FROM AUTHOR]

The vulnerability of humankind to SARS-CoV-2 in the absence of a pre-existing immunity, the unpredictability of the infection outcome, and the high transmissibility, broad tissue tropism, and ability to exploit and subvert the immune response pose a major challenge and are likely perpetuating the COVID-19 pandemic. Nevertheless, this peculiar infectious scenario provides researchers with a unique opportunity for studying, with the latest immunological techniques and understandings, the immune response in SARS-CoV-2 naïve versus recovered subjects as well as in SARS-CoV-2 vaccinees. Interestingly, the current understanding of COVID-19 indicates that the combined action of innate immune cells, cytokines, and chemokines fine-tunes the outcome of SARS-CoV-2 infection and the related immunopathogenesis. Indeed, the emerging picture clearly shows that the excessive inflammatory response against this virus is among the main causes of disease severity in COVID-19 patients. In this review, the innate immune response to SARS-CoV-2 infection is described not only in light of its capacity to influence the adaptive immune response towards a protective phenotype but also with the intent to point out the multiple strategies exploited by SARS-CoV-2 to antagonize host antiviral response and, finally, to outline inborn errors predisposing individuals to COVID-19 disease severity. [ABSTRACT FROM AUTHOR]

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype–ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype–phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do. [ABSTRACT FROM AUTHOR]

R2360 --> Endoplasmic reticulum (ER) stress results in accumulation of misfolded proteins and profoundly regulates cellular protein synthesis. The regulation includes both inhibition of translation of most proteins and upregulation of synthesis of a select group of stress‐related polypeptides. This differential regulation has long been attributed to the kinase PERK, but recently the related stress sensor, inositol requiring enzyme 1 (IRE1), was suggested to be linked to translation by virtue of its physical association with both ribosomes1 and the Sec61 translocon2,3. ER stress causes the quiescent IRE1 to dissociate from the inhibitor BiP, self‐phosphorylate, oligomerize (an event also called clustering) and activate its RNase activity. Consequently, active IRE1 activates the critical transcription factor XBP1, and also reduces the expression of select other transcripts, to cope with increased ER stress. We previously showed that IRE1 clustering is a response to stress4, but is not related to its RNase activity, raising the question – what is the function of IRE1 clustering? In examining the requirements for IRE clustering we discovered that ongoing protein synthesis and translocation are necessary for both the formation of IRE1 clusters upon ER stress and their maintenance. IRE1 clusters do not develop when cells are treated with either cycloheximide or lactimidomycin, which inhibit nascent chain elongation and 'freeze' membrane‐bound ribosomes on the ER membrane. If added after clusters were allowed to form under ER stress, both inhibitors caused rapid disappearance of the pre‐formed clusters. IRE1 clustering is similarly sensitive to Eeyarestatin I (EEY), an inhibitor of the Sec61 translocon. When translocation is inhibited, IRE1 is dissociated from Sec61 and its interaction with BiP is increased. Concomitantly, more IRE1 is found in high molecular weight species, which perhaps represent ubiquitinylated species. Paradoxically, EEY also induces IRE1 activation (XBP1 splicing). To explain the paradox, we hypothesize the following model: in unstressed conditions, IRE1 binds the translocon and is kept inactive by the interaction with the chaperone BiP. Upon ER stress, different scenarios with distinct IRE1 populations can appear at the same time: 1) IRE1 is released from BiP and clusters on a subset of translocons that are engaged in synthesis of stress‐related polypeptides; 2) translocons not engaged in active translocation release IRE1 which is then kept inactive by increased interaction with BiP; 3) some activated IRE1 dimerizes (appearing as non‐clustered) and binds the ribosomes that recruit XBP1 mRNA, facilitating its splicing. Acosta‐Alvear D et al. eLife 2018 Dec 24;7:e43036.Plumb R et al. eLife 2015 2015 May 20;4:e07426.Sundaram A et al. eLife 2017 May 15;6:e27187.Ricci, D. et al. The FASEB Journal 2019; Sep;33(9):9811‐9827. [ABSTRACT FROM AUTHOR]

Abstract: The presence of abnormal visual function has been related to overt lesions in the thalami, peritrigonal white matter (such as cavitational-necrotic periventricular leucomalacia) and optic radiations, and also to the extent of occipital cortex involvement. The normal development of visual function seems to depend on the integrity of a network that includes not only optic radiations and the primary visual cortex but also other cortical and subcortical areas, such as the frontal or temporal lobes or basal ganglia, which have been found to play a topical role in the development of vision. Therefore, the complex functions and functional connectivity of the developing brain of premature infants can be studied only with highly sophisticated techniques such as diffusion tensor tractography. The combined use of visual tests and neonatal structural and functional neuroimaging, which have become available for newborn infants, provides a better understanding of the correlation between structure and function from early life. This appears to be particularly relevant considering the essential role of early visual function in cognitive development. The identification of early visual impairment is also important, as it allows for early enrolment in intervention programmes. The association of clinical and functional studies to newer imaging techniques, which are being increasingly used also in neonates, are likely to provide further information on early aspects of vision and the mechanisms underlying brain plasticity, which are still not fully understood. Early exposure to a difficult postnatal environment together with early and unexpected removal from a protective milieu are exclusive and peculiar factors of prematurity that interfere with the normal development of the visual system in pre-term babies. The problem is further compounded by the influence of different perinatal brain lesions affecting the developing brain of premature babies. Nevertheless, in the last few decades, there have been considerable advances in our understanding of the development of vision in pre-term infants during early infancy. This has mainly been due to the development of age-specific tests assessing various aspects of visual function, from ophthalmological examination to more cortical aspects of vision, such as the ability to process orientation or different aspects of visual attention . Improvements in understanding very early and specific neurological impairments in neurological functions have been reported in pre-term infants, known to be at risk of developing visual and visual-perceptual impairment. These impairments are due not only to retinopathy, a common finding in premature infants, but also to cerebral (central) visual impairment, secondary to brain lesions affecting the central visual pathway. [Copyright &y& Elsevier]

Background: Retinopathy of prematurity (ROP) is often associated with visual impairment and multiple developmental disabilities.Aims: As most of the previous studies include infants with brain lesions, that can determine visual impairment per se, a cohort of low neurological risk preterm infants without ROP and with various degree of severity of ROP was assessed in order to establish visual and neurodevelopmental outcome.Study Design: Preterm infants born at <31 weeks gestation, without major brain lesions, underwent visual function assessment at 1 year corrected age and neurodevelopmental assessment at 2 years corrected age.Subjects: One hundred and five infants were included in the study: 42 infants did not develop ROP, 7 reached stage 1 in zone 2 ROP, 37 reached prethreshold (untreated) type 2 ROP. The remaining 19 infants were classified as type 1 ROP.Outcome Measures: Visual function (including fixing, tracking, visual acuity, visual field, attention at distance and nystagmus) were assessed at 12 months corrected age and Griffiths Scales at 2 years corrected age.Results: The severity of ROP was strongly correlated (p < 0.001) with both visual function at 1 year and neurodevelopment at 2 years. Similarly, the presence of nystagmus was also strongly correlated with visual and neurodevelopmental sequelae.Conclusions: Infants with no or milder retinopathy showed normal visual function at 1 year and neurodevelopment at 2 years. Infants who underwent treatment more frequently showed abnormal results on several aspects of visual function. Presence of nystagmus appeared to increase the risk for abnormal visual function and neurodevelopmental outcome. [ABSTRACT FROM AUTHOR]

Premature birth is associated with a high risk of damage in the parietal cortex, a key area for numerical and non-numerical magnitude perception and mathematical reasoning. Children born preterm have higher rates of learning difficulties for school mathematics. In this study, we investigated how preterm newborns (born at 28–34 weeks of gestation age) and full-term newborns respond to visual numerosity after habituation to auditory stimuli of different numerosities. The results show that the two groups have a similar preferential looking response to visual numerosity, both preferring the incongruent set after crossmodal habituation. These results suggest that the numerosity system is resistant to prematurity. [ABSTRACT FROM AUTHOR]

The Tick-borne encephalitis virus (TBEV) causes different disease symptoms varying from asymptomatic infection to severe encephalitis and meningitis suggesting a crucial role of the human host immune system in determining the fate of the infection. There is a need to understand the mechanisms underpinning TBEV-host interactions leading to protective immunity. To this aim, we studied the response of human peripheral blood mononuclear cells (PBMC) to the whole formaldehyde inactivated TBEV (I-TBEV), the drug substance of Encepur, one of the five commercially available vaccine. Immunophenotyping, transcriptome and cytokine profiling of PBMC revealed that I-TBEV generates differentiation of a sub-population of plasmacytoid dendritic cells (pDC) that is specialized in type I interferon (IFN) production. In contrast, likely due to the presence of aluminum hydroxide, Encepur vaccine was a poor pDC stimulus. We demonstrated I-TBEV-induced type I IFN together with Interleukin 6 and BAFF to be critical for B cell differentiation to plasmablasts as measured by immunophenotyping and immunoglobulin production. Robust type I IFN secretion was induced by pDC with the concerted action of both viral E glycoprotein and RNA mirroring previous data on dual stimulation of pDC by both S. aureus and influenza virus protein and nucleic acid that leads to a type I IFN-mediated sustained immune response. E glycoprotein neutralization or high temperature denaturation and inhibition of Toll-like receptor 7 signalling confirmed the importance of preserving the functional integrity of these key viral molecules during the inactivation procedure and manufacturing process to produce a vaccine able to stimulate strong immune responses. Author summary: Though vaccination is generally considered effective in reducing tick-borne encephalitis (TBE) incidence, several studies have shown that the antibody response to TBEV vaccination declines with age resulting in more frequent TBE cases among 50+ year-old vaccinees. These observations together with the lack of a specific antiviral drug impose to pinpoint novel host- and pathogen-directed therapies and to improve the control of vaccine efficacy. Thus, we interrogated in vitro human PBMC, whose response to TBEV may provide a picture closer to what occurs in vivo in humans after vaccination or natural infection compared to animal models. The role of E glycoprotein and viral RNA in promoting antiviral and B cell-mediated responses was investigated. Thus, these key viral molecules should be considered, in future, for novel subunit vaccine formulations than the current whole inactivated TBEV-based vaccines, which require laborious manipulation in biosafety level-3 laboratory and animal testing for manufacturing and batch release. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Hellgren et al. on pages 1109–1114 of this issue. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by van Buuren et al. on pages 934–940 of this issue. [ABSTRACT FROM AUTHOR]

Background: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit α of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. Objective: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. Methods: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. Results: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object–face exploration, recognition and environmental control, appeared to be preserved and improved with age. Significance: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less. [ABSTRACT FROM AUTHOR]

Objectives: The very rapidly approved mRNA‐based vaccines against SARS‐CoV‐2 spike glycoprotein, including Pfizer‐BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID‐19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine‐induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine‐induced protective humoral responses. Methods: Healthy subjects (n = 20) and matched pwMS (n = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)‐associated type I and II interferon (IFN)‐inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti‐SARS‐COV‐2 antibodies (Abs) were measured. Results: We identified an early immune module composed of the IFN‐inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL‐15, IL‐6, TNF‐α and IFN‐γ and the chemokines IP‐10, MCP‐1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID‐19 vaccine. Conclusion: Overall, this study suggests that the vaccine‐induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine‐induced humoral protection. [ABSTRACT FROM AUTHOR]

Abstract: In this review, we report our experience on early neurological and visual developments in preterm infants assessed during the neonatal period using the Dubowitz neonatal neurological assessment and a new battery for visual assessment. The assessments were performed in both very and late low-risk preterm infants and in healthy term-born infants. We report the findings in the three cohorts, evaluating the influence of gestational age and extrauterine exposure on both neurological and visual developments. [Copyright &y& Elsevier]

An abstract of the article "Visual Function at 35 and 40 Weeks' Postmenstrual Age in Low-Risk Preterm Infants," by Daniela Ricci, Laura Cesarini, Domenico M. M. Romeo, Francesca Gallini, Francesca Serrao, Michaela Groppo, Agnese De Carli, Francesco Cota, Domenico Lepore, Fernando Molle, Roberto Ratiglia, Maria Pia De Carolis, Fabio Mosca, Costantino Romagnoli, Francesco Guzzetta, Frances Cowan, Luca A. Ramenghi, and Eugenio Mercuri is presented.

This review has the purpose of retracing the work of Professor Bernard Sabel and his group over the last 2-3 decades, in order to understand how they achieved formulation of the 'Residual Vision Activation Theory'. The methodology proposed is described, from the first studies in 1995 with High Resolution Perimetry requiring a six-months training period, to the new technologies, such as repetitive transorbital Alternating Current Stimulation, that require ten days of training. Vision restoration therapy has shown improvement in visual responses irrespective of age at the training, lesion aetiology and site of lesion. The hypothesis that visual training may induce network plasticity, improving neuronal networks in cortical and subcortical areas of both hemispheres, appears to be confirmed by recent studies including observation of the cerebral activity by fMRI and EEG. However, the results are quite variable and the mechanisms that influence cerebral activity are still unclear. The residual vision activation theory has been much criticized, both for its methodology and analysis of the results, but it gave a new impulse to the research in this area, stimulating more studies on induced cerebral plasticity. [ABSTRACT FROM AUTHOR]

These data are consistent with that we reported in a population of infants born preterm,8 in which there was a clear gradient, as infants performing normally at 2 years had higher HINE scores than those with delayed cognitive performance but without CP, followed by those with CP but an MDI greater than 70, and last those with CP and an MDI less than 70 having the lowest HINE scores in the first year. The low incidence of infants with CP is probably due to the characteristics of the population, that included infants with sepsis, small for gestational age, heart disease, and mild asphyxia that are not often associated with the development of CP. Abbreviations HINE Hammersmith Infant Neurological Examination MDI Mental Developmental Index ROC receiver operating characteristic What this paper adds The Hammersmith Infant Neurological Examination (HINE) can be used in the first year to detect risk of delayed cognitive performance at age 2 years. At each time-point (Figure 1), infants with a normal/mildly delayed cognitive performance but no CP at 2 years had significantly higher ( I p i < 0.001) HINE global scores than infants with significantly delayed cognitive performance and no CP and those with CP. [Extracted from the article]

Introduction: The objective of the current study was to design and pilot-test a nonverbal intelligence test for children and adolescents with visual impairment (i.e., blindness and low vision) aged 10 to 16 years. Method: A three-dimensional haptic matrix test of nonverbal cognitive abilities (3-DHMT-CA), initially developed for adults with visual impairment, was adapted and administered to 25 juveniles with severe low vision or blindness and 25 sighted peers. The test consisted of 22 tactual matrices with a missing element, and juveniles were asked to understand the logical scheme underlying each matrix and to complete it. Convergent validity was assessed in the sighted group with the Standard Progressive Matrices. Divergent validity was measured with the Verbal Comprehension Index (VCI) and the Working Memory Index (WMI) of the Italian version of the Wechsler Intelligence Scale for Children–Fourth Edition. Between-group differences were analyzed with Student's t-test and ANOVA. Results: Results show a high correlation with the convergent measure (with the Standard Progressive Matrices), and the moderate correlations with divergent measures (VCI and WMI). Between-group differences showed significantly higher scores for sighted peers than juveniles with visual impairment at 3-DHMT-CA, and non-significant differences at VCI and WMI. Discussion: This haptic nonverbal cognitive test showed good psychometric properties, but it needs to be validated in a larger sample with a qualitative analysis of solution strategies because juveniles with visual impairment seem to use different verbal and working memory strategies. Implications for Practitioners: The 3-DHMT-CA and the haptic two-hands modality seem to be suitable to test nonverbal cognitive abilities in juveniles with visual impairment. Practitioners should focus on empowering verbal and working memory abilities, since they may affect nonverbal cognitive abilities as well. [ABSTRACT FROM AUTHOR]

The long-term outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are still unknown. We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery. Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48–72 h of life, auxological growth and neurological development, serologic testing, and audiological and ophthalmological assessments. One-hundred ninety-eight mothers and 199 newborns were enrolled. Of the 199 newborns, 171 underwent nasopharyngeal swab, four (2.3%) and two (1.15%) children tested positive at birth and 48–72 h of life, respectively. None had SARS-CoV-2 related symptoms. Auxologic and neurologic development were normal in all children during follow-up. Nine out of 59 infants had SARS-CoV-2 IgG at 3 months of life, which was associated with a positive nasopharyngeal swab at birth (P = 0.04). Twenty seven out of 143 (18.8%) newborns had pathologic transitory evoked otoacoustic emissions at birth, although 14/27 repeated after 1 month were normal. Audiological evaluation was completed with Auditory Brainstem Response between the third and sixth month of life in 34 children, showing in all normal hearing threshold. The ophthalmological evaluation found retinal vascular anomalies in 3/20 (15%) children, immature visual acuity in 5/20 (25%) children, and reduced distance attention in 6/20 cases (30%). Conclusions: Our study showed that the neonatal and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life are mostly positive, with the exception of ophthalmologic findings which, in a preliminary cohort, were abnormal in about 15% of cases. Further prospective, longitudinal studies are needed to better understand the clinical outcomes of children exposed to SARS-CoV-2 in utero and in the early postnatal life. What is Known: • In utero mother-to-child transmission of SARS-CoV-2 has been documented by several independent studies. • Neonatal COVID-19 is a systemic disease that can be severe, although rarely. What is New: • Newborns exposed in utero to SARS-CoV-2 have mostly a normal auxological, audiological, and neurological development during the first months of life. • Fundus fluorescein angiography revealed that up to 5% of newborns exposed in utero to SARS-CoV2 can show retinal and choroidal abnormalities, including peripheral hypofluorescence of the choroid and increased vascular tortuosity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several studies have reported on neonatal tremors or “jitteriness” or, as described by Precthl “hyperexcitability syndrome” including tremors and increased resistance to passive movement. Aim: To describe the evolution of signs and the outcome at one year in low risk term born infants with neonatal tremors persisting beyond 10days. Subjects: 84 low risk term born neonates with tremors at birth and persisting after 10days, underwent a longitudinal neurological assessment paying attention to the evolution of tremors and increased resistance to passive movement. Results: At 1month 74 of the 84 infants had persistent tremors, isolated in 27 or associated with increased resistance to passive movement in the other 47. The remaining 10 had isolated increased resistance to passive movement and none had a normal assessment. The percentage of infants with a normal assessment progressively increased at 6, 9 and 12months (34.5%, 77%, 93% respectively). Conclusion: Our data suggest that neonatal tremors can have a variable evolution and rate of resolution, with 70% of recovery by 9months with a normal outcome at 24months in all. The risk of persistence of signs (at 12months) in infants with either isolated tremors or increased resistance to passive movements is lower than in the subgroup with both signs at one month. [Copyright &y& Elsevier]

Summary: Purpose: To study prospectively the evolution of visual attention in children with West syndrome to evaluate its development before the onset of spasms, its possible deterioration as a consequence of epileptic disorders, and its outcome at the age of 2 years, and the possible relation between the impairment of visual attention and cognitive development. Methods: Infants with symptomatic West syndrome were examined before the onset of spasms and until age 24 ± 2 months. Visual attention study (through a clinical observation and the fixation-shift test), cognitive assessment, and complete clinical examination including brain magnetic resonance imaging were performed. Results: A maturation defect of fixation shift skills was generally observed in infants with West syndrome. In some cases, the impaired visual-attention abilities paralleled a cognitive deterioration, even months before the onset of spasms. During the acute stage of West syndrome, infants lost the previously acquired visual and cognitive abilities, with a typical fluctuation of arousal. Usually at 2 years, there was a persistent defective visual attention detected with the fixation-shift test. Conclusions: The parallel defect of visual attention and of cognitive competencies is a constant finding in infants with West syndrome; these can precede the clinical onset of epileptic spasms. The severity and persistence of visual inattention might be explained by the age of visual maturation, corresponding to the usual onset of West syndrome. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients. Author summary: SARS-CoV-2 pandemic has resulted in millions of infections and deaths worldwide, yet the role of host innate immune responses in COVID-19 pathogenesis remains only partially characterized. Innate immunity represents the first line of host defense against viruses. Upon viral recognition, the secretion of type I and III interferons (IFN) establishes the cellular state of viral resistance, and contributes to induce the specific adaptive immune responses. Moving from in vitro evidences on the protective role played by plasmacytoid dendritic cells (pDC)-released type I IFN in the early phase of SARS-CoV-2 infection, here we characterized ex vivo the pDC phenotype and the balance between anti-viral and pro-inflammatory cytokines of COVID-19 patients stratified according to disease severity. Our study confirms in COVID-19 the crucial and protective role of pDC/type I IFN axis, whose deeper understanding may contribute to the development of novel pharmacological strategies and/or host-directed therapies aimed at boosting pDC response since the early phases of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Aim: We explored the ability of the Hammersmith Infant Neurological Examination (HINE) to identify typical and delayed cognitive performance in a large population of infants born preterm, both with and without cerebral palsy (CP). Method: We conducted a retrospective study of infants born preterm who had repeated HINEs between 3 and 12 months corrected age. At 2 years, cognition was assessed using the Mental Development Index (MDI; from the Bayley Scales of Infant Development, Second Edition) and the presence and severity of CP was determined. All children were classified as cognitively typical/mildly delayed or significantly delayed (MDI <70) and CP. The predictive validity of HINE scores for significantly delayed cognitive performance, in children with and without CP, was calculated using specific cut‐off scores according to age at assessment. Results: Of 1229 eligible infants (gestational age 25–36wks, mean [SD] 34.9 [2.3]; 646 males, 583 females), 1108 did not develop CP, 891 had an MDI that was typical/mildly delayed, and 217 had an MDI less than 70. Of the 121 infants who developed CP, the MDI was typical in 28, mildly delayed in 27, and less than 70 in 66. HINE scores showed a good sensitivity and specificity, especially after 3 months, for detecting significantly delayed cognitive performance in infants without CP. In those who developed CP, the score was associated with their cognitive level. Interpretation: The HINE provides information about the risk of delayed cognitive performance in infants born preterm with and without CP. What this paper addsThe Hammersmith Infant Neurological Examination (HINE) can be used in the first year to identify infants born preterm at risk for delayed cognitive performance.Age‐dependent HINE cut‐off scores are proposed for detecting increased risk of delayed cognitive performance. What this paper adds: The Hammersmith Infant Neurological Examination (HINE) can be used in the first year to identify infants born preterm at risk for delayed cognitive performance.Age‐dependent HINE cut‐off scores are proposed for detecting increased risk of delayed cognitive performance. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations. This article is commented on by Bos on page 891 of this issue. [ABSTRACT FROM AUTHOR]

Aim: To develop and validate the Visual Function Classification System (VFCS), which was created to classify how children with cerebral palsy (CP) use visual abilities in daily life.Method: The process of development and validation of the VFCS involved four phases: (1) drafting of the five levels from the analysis of literature and clinical experience; (2) validation of constructs and revision of the levels for concept meaningfulness, using nominal group process; (3) refinement by international Delphi survey; and(4) assessment of interrater reliability among professionals and with caregivers, and of test-retest reliability.Results: Five nominal groups involved 29 participants; 65 people completed the first round and 51 the second round of the Delphi survey. Construct validity was demonstrated within an expert group and external validation through several stakeholders, with the involvement of patients and families to ensure meaningfulness of the concept. Discussions continued until consensus was reached about the construct and content of the five levels. Participants in the reliability study included 29 professionals, 39 parents, and a total sample of 160 children with CP (mean age [SD] 6y 6mo [3y 4mo]; median 5y 7mo, range 1-19y). Absolute interrater agreement among professionals was 86% (weighted κ=0.88; 95% confidence interval [CI] 0.83-0.93). Test-retest reliability was high (weighted κ=0.97; 95% CI 0.95-0.99). Parent-professional interrater reliability on 39 children was moderate (weighted κ=0.51; 95% CI 0.39-0.63).Interpretation: The VFCS has been appropriately constructed and provides a reliable system to classify visual abilities of children with CP both in clinical and in research settings.What This Paper Adds: The Visual Function Classification System is a valid and reliable system. It classifies visual abilities of children with cerebral palsy in clinical and research settings. At a clinical level, it can be used to harmonize communication among professionals and identify patients' strengths and weaknesses. In research settings, it can be used to stratify patients, define natural history evolution, and interpret intervention studies. [ABSTRACT FROM AUTHOR]

Purpose To compare structural outcome at age 4 years of eyes treated with intravitreal injection of bevacizumab with fellow eyes treated with conventional laser photoablation in type 1 retinopathy of prematurity (ROP). Design Single, randomized, controlled trial. Participants All inborn babies with type 1 zone 1 ROP at the Neonatal Intensive Care Unit of the Catholic University, Rome, from September 1, 2009, to March 31, 2012. Methods In 21 infants (42 eyes), 1 eye was randomized to receive an intravitreal injection of 0.5 mg bevacizumab; the fellow eye underwent conventional laser photoablation. Digital retinal imaging and fluorescein angiography (FA) were performed at an average of 4 years after treatment in follow-up after these studies performed at treatment and 9 months. Main Outcome Measures Fluorescein angiograms were examined by 2 experts to document retinal and choroidal findings. Results Among the 20 bevacizumab-treated eyes available at 4 years of age, all showed abnormalities at the periphery (avascular area, vessel leakage, shunts, abnormal vessel branching, and tangles) or the posterior pole (hyperfluorescent lesions, absence of foveal avascular zone). These lesions were not observed in the majority of the lasered eyes. Among the 19 laser-treated eyes, leakage was noted in 1 eye, shunts and tangles were noted in 3 eyes, and macular abnormalities were noted in 3 eyes. Conclusions Fluorescein angiography has shown potentially serious and long-term ocular effects that are present more commonly after treatment with bevacizumab for acute-phase ROP than after laser. [ABSTRACT FROM AUTHOR]

Background: Few neurological assessments are easily performed during the first 6h after birth.Aims: To assess a cohort of low risk term born newborns within the first 6h and at 48h after birth using the Hammersmith Neonatal Neurological Examination.Study Design and Subjects: A population of low risk term born newborns was examined within 3h from birth or between 3 and 6h. Each infant was re-assessed at 48h, establishing the range and frequency distribution of neonatal neurological scores at each time point.Results: Of the 124 full-term born newborns, 62 were assessed at 0-3h and 62 at 3-6h. All infants were re-assessed at 48h. For 23/34 of the neurological items, the range and median scores were similar across the 3 time points. In the remaining 11 items the three groups had a similar range of scores but the median scores were different with different rates of changes. In 6 of the 11 the median scores at 3-6h were similar to those observed at 48h but they appeared to be 'less mature' at 0-3h. Only in one item the median scores were consistently different at the 3 time points.Conclusions: Our results suggest that a neurological examination can already be reliably performed soon after birth. These findings will help in the interpretation of the few items that show changes with increasing postnatal age. [ABSTRACT FROM AUTHOR]

A correction to the article "Short- and mid-term multidisciplinary outcomes of newborns exposed to SARS-CoV-2 in utero or during the perinatal period: Preliminary findings" in an issue is presented.