Neurological Sequelae In Survivors Research Articles

West Nile virus meningoencephalitis and cytokines analysis: review and case report

West Nile virus (WNV) is transmitted via mosquito bites and causes ubiquitous zoonosis. Most infections in humans are asymptomatic, approximately 20% present as fever, and less than 1% as neuroinvasive disease. Central nervous system involvement is presented as meningitis, encephalitis, acute flaccid paralysis, or a combination of them. West Nile neuroinvasive disease (WNND) has a severe clinical course, potentially fatal outcome and frequent neurological sequelae in survivors. Risk factors for neurological impairment are advanced age and immunosuppression. Here we present a clinical case of meningoencephalitis caused by WNV and a brief literature review. Clinical and epidemiological data, laboratory, microbiological, molecular methods and imaging techniques were used. The cytokine levels of IL-6, IL-8, IL-10, IL-12(p40) and TNF-α in cerebrospinal fluid (CSF) and serum were also measured. We present a 55-year-old man with a sudden onset of headache, vomiting and fever. The symptoms appeared after a recent trip to Türkiye and involved multiple mosquito bites. Neck stiffness, disturbances in consciousness, signs of cerebral edema and subsequently focal neurological deficits were observed. The etiological diagnosis was verified by positive polymerase chain reaction for WNV and the presence of specific IgM antibodies in the CSF. After a 28-day hospital stay, the patient was discharged and referred to a Physiotherapy Unit due to residual motor deficits. WNV etiology should be suspected in patients with clinical and laboratory signs of viral neuroinfection, mosquito bites, and/or travel to endemic regions.

Burden of Neurologic Health Care and Incident Neurologic Diagnoses in the Year After COVID-19 or Influenza Hospitalization.

Following the outbreak of viral infections from the severe acute respiratory syndrome coronavirus 2 virus in 2019 (coronavirus disease 2019 [COVID-19]), reports emerged of long-term neurologic sequelae in survivors. To better understand the burden of neurologic health care and incident neurologic diagnoses in the year after COVID-19 vs influenza, we performed an analysis of patient-level data from a large collection of electronic health records (EMR). We acquired deidentified data from TriNetX, a global health research network providing access to EMR data. We included individuals aged 18 years or older during index event, defined as hospital-based care for COVID-19 (from April 1, 2020, until November 15, 2021) or influenza (from 2016 to 2019). The study outcomes were subsequent health care encounters over the following year for 6 neurologic diagnoses including migraine, epilepsy, stroke, neuropathy, movement disorders, and dementia. We also created a composite of the 6 diagnoses as an incident event, which we call "incident neurologic diagnoses." We performed a 1:1 complete case nearest-neighbor propensity score match on age, sex, race/ethnicity, marital status, US census region patient residence, preindex years of available data, and Elixhauser comorbidity score. We fit time-to-event models and reported hazard ratios for COVID-19 vs influenza infection. After propensity score matching, we had a balanced cohort of 77,272 individuals with COVID-19 and 77,272 individuals with influenza. The mean age was 51.0 ± 19.7 years, 57.7% were female, and 41.5% were White. Compared with patients with influenza, patients with COVID-19 had a lower risk of subsequent care for migraine (HR 0.645, 95% CI 0.604-0.687), epilepsy (HR 0.783, 95% CI 0.727-0.843), neuropathies (HR 0.567, 95% CI 0.532-0.604), movement disorders (HR 0.644, 95% CI 0.598-0.693), stroke (HR 0.904, 95% CI 0.845-0.967), or dementia (HR 0.931, 95% CI 0.870-0.996). Postinfection incident neurologic diagnoses were observed in 2.79% of the COVID-19 cohort vs 4.91% of the influenza cohort (HR 0.618, 95% CI 0.582-0.657). Compared with a matched cohort of adults with a hospitalization or emergency department visit for influenza infection, those with COVID-19 had significantly fewer health care encounters for 6 major neurologic diagnoses over a year of follow-up. Furthermore, we found that COVID-19 infection was associated with a lower risk of an incident neurologic diagnosis in the year after infection.

Japanese encephlu emergence in Australia: the potential population at risk.

Japanese encephalitis virus (JEV), an RNA virus transmitted by Culex mosquitoes, primarily cycles between aquatic birds and mosquitoes with pigs as amplifying hosts, posing a significant global encephalitis threat. The emergence and spread of the JEV in new epidemiological regions, such as recent cases in Australia and nonendemic areas like Pune, India, raise significant concerns. With an estimated 68000 clinical cases and 13600 to 20400 deaths annually, JEV poses a substantial global health threat. The virus primarily affects children, with a case-fatality ratio of 20-30% and long-term neurological sequelae in survivors. The changing epidemiology, influenced by factors like bird migration, climate change, and increased urbanization, contributes to the geographic expansion of JEV. The recent outbreaks underscore the potential for the virus to establish itself in nonendemic regions, posing a threat to populations previously considered at low-risk. With limited treatment options and high rates of neurological complications, continued surveillance, traveler vaccination, and research into treatments are crucial to mitigate the impact of JEV on human health. The evolving scenario necessitates proactive measures to prevent and control the spread of the virus in both endemic and newly affected areas.

Japanese Encephalitis: Risk of Emergence in the United States and the Resulting Impact.

Japanese encephalitis virus is a mosquito-borne member of the Flaviviridae family. JEV is the leading cause of viral encephalitis in Asia and is characterized by encephalitis, high lethality, and neurological sequelae in survivors. The virus also causes severe disease in swine, which are an amplifying host in the transmission cycle, and in horses. US agricultural authorities have recently recognized the threat to the swine industry and initiated preparedness activities. Other mosquito-borne viruses exotic to the Western Hemisphere have been introduced and established in recent years, including West Nile, Zika, and chikungunya viruses, and JEV has recently invaded continental Australia for the first time. These events amply illustrate the potential threat of JEV to US health security. Susceptible indigenous mosquito vectors, birds, feral and domestic pigs, and possibly bats, constitute the receptive ecological ingredients for the spread of JEV in the US. Fortunately, unlike the other virus invaders mentioned above, an inactivated whole virus JE vaccine (IXIARO®) has been approved by the US Food and Drug Administration for human use in advance of a public health emergency, but there is no veterinary vaccine. This paper describes the risks and potential consequences of the introduction of JEV into the US, the need to integrate planning for such an event in public health policy, and the requirement for additional countermeasures, including antiviral drugs and an improved single dose vaccine that elicits durable immunity in both humans and livestock.

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study

BackgroundOne of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden.MethodsWe conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI.ResultsAmong the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0–231.0). The median CSI dose was 18 Gy (15.0–24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38–99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03–29.11, p value 0.044 for overall survival).ConclusionAlthough these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

PupillOmetry for preDIction of DeliriUM in ICU (PODIUM): protocol for a prospective multicentre cohort study

IntroductionDelirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate...

Prematurity and Neurological Sequelae

Any birth that takes place three weeks or more before the baby’s due date is a premature birth. Prematurity is a public health problem worldwide. Every year, 15 million infants are born premature, accounting for a prevalence of 11% in 84 surveyed countries. Premature births alone account for a quarter of all neonatal deaths. Survivors of premature births have high rates of postnatal morbidities. With the development technologies and medical procedures, the morbidities are increasing due to improving survival of borderline viable cases. The prevalence of cerebral palsy, intellectual and cognitive dysfunction, retinopathy, hearing loss, epilepsy, ADHD and autistic disorder are more in babies born preterm. The risk of cerebral palsy is 8- 10 times higher in preterm infants and nearly 30 times higher in infants born &lt;32 weeks. Children born preterm have an average 12.9 IQ points lower than term born controls and these children face difficulty in making communication, executive functioning and cognition. ADHD and autism spectrum disorders are frequently diagnosed (OR 3.3) in children born preterm. ROP associated blindness is 10% in high income countries and 40% in middle and low income countries. As many as 10% children born preterm have hearing loss and 35% suffer from different types of epilepsy. Adequate antenatal check-up and immediate postnatal care are key issues to reduce or prevent neurological sequelae in survivors of premature birth. J Medicine 2023; Vol. 34, No. 2(1) Supplement: 212

Immunological Analysis of Cryptococcal Meningoencephalitis in a Murine Model.

Cryptococcal meningoencephalitis (CM), caused by the fungal pathogen Cryptococcus neoformans species complex, can lead to high mortality or severe neurological sequelae in survivors that are associated with excessive inflammation in the central nervous system (CNS), especially in those who develop immune reconstitution inflammatory syndrome (IRIS) or postinfectious immune response syndrome (PIIRS). While the means to establish a cause-and-effect relationship of a specific pathogenic immune pathway during CM by human studies are limited, mouse models allow dissection of the potential mechanistic links within the CNS immunological network. In particular, these models are useful for separating pathways contributing predominantly to immunopathology from those important for fungal clearance. In this protocol, we described methods to induce a robust, physiologically relevant murine model of C. neoformans CNS infection that reproduces multiple aspects of human cryptococcal disease immunopathology and subsequent detailed immunological analysis. Combined with tools including gene knockout mice, antibody blockade, cell adoptive transfer, as well as high throughput techniques such as single-cell RNA sequencing, studies using this model will provide new insights regarding the cellular and molecular processes that elucidate the pathogenesis of cryptococcal CNS diseases in order to develop more effective therapeutic strategies.

Analysis of the association between location and patient prognosis in spontaneous intracerebral hemorrhage in the basal ganglia and thalamus: A retrospective single-center study

Spontaneous intracerebral hemorrhage (ICH) causes profound neurological sequelae in survivors. The patient's prognosis is closely linked to the location and amount of hemorrhage. Therefore, we explored the relationship between the hemorrhage location within the basal ganglia, including the thalamus, and its clinical outcomes in patients with spontaneous intracerebral hemorrhage. A retrospective analysis of consecutively enrolled patients with basal ganglia and thalamic intracerebral hemorrhage treated conservatively at a single tertiary neurosurgical center was conducted between January 2014 and December 2020. Patients were divided into 2 groups according to the lateralization of the right or left hemisphere hemorrhage. Furthermore, baseline patient demographics, hematoma volume, location of the hemorrhage (i.e., caudate nucleus, globus palidus, putamen, internal capsule anterior limb, internal capsule posterior limb, thalamus), and clinical outcomes were evaluated. Clinical outcomes were assessed using the modified Rankin scale at the 1-year follow-up. An modified Rankin scale score between 3 and 6 was considered a poor outcome. In the analysis according to location, the prognosis was poor when the ICH was localized to the posterior limb of the internal capsule (P < .000) and globus palidus (P = .001) in the right hemisphere. Similarly, the prognosis was also poor when the ICH was localized to the posterior limb of the internal capsule (P < .000), globus palidus (P < .000), putamen (P = .018), and thalamus (P < .000) of the left hemisphere. In the spontaneous intracerebral hemorrhages of the basal ganglia and thalamus, hemorrhaging within the internal capsule and the left thalamus's bilateral posterior limbs is associated with a poor prognosis. Multivariable logistic analysis showed that hematoma volume (odds ratio [OR] = 70.85, 95% confidence interval [CI]: 1.95-60.53, P = .007) and the posterior limb of the internal capsule (OR = 10.98, 95% CI:1.02-118.49, P = .048) were independent predictors of poor outcomes in the right hemisphere, while hematoma volume (OR = 70.85, 95% CI: 1.95-60.53, P = .007), the posterior limb of the internal capsule (OR = 10.98, 95% CI:1.02-118.49, P = .048) and thalamus (OR = 10.98, 95% CI:1.02-118.49, P = .048) were independent predictors of poor outcomes in the left hemisphere.

Critical care management of meningitis and encephalitis: an update.

Meningitis and encephalitis represent severe neurological syndromes associated with encephalopathy, seizures, focal deficits, and neurological sequelae in survivors. We update on the critical care management of adult patients with severe meningitis and encephalitis. Large multicenter studies conducted in the adult population improved current knowledge on the epidemiology and outcomes of patients with severe meningitis and encephalitis. An early multimodal diagnostic workup (including CSF analysis, brain MRI, EEG, and serum studies) is mandatory for diagnosis and prognostication in those patients.New diagnostic methods, including multiplex PCR and next-generation sequencing techniques, allow for a faster differential diagnosis of infectious causes that may require specific antimicrobial therapy. Autoimmune causes of encephalitis, which may require urgent immunotherapy, are also increasingly recognized in the ICU setting. Although observational data suggest that early combined immunotherapy is associated with better neurological outcomes in patients with autoimmune encephalitis, randomized clinical trials have yet to be performed. Our review highlights the importance of an early multimodal approach for diagnosing severe meningitis and encephalitis. Randomized clinical trials are needed to identify pharmacological interventions that may improve patients' outcomes.

MEDB-30. Subclassification of Group 3/4 medulloblastoma as a potential prognostic biomarker to reduce the dose of craniospinal irradiation in patients with metastatic tumors: A Japanese Pediatric Molecular Neuro-Oncology Group study

BACKGROUND: In patients with medulloblastoma, one of the most significant challenges is to reduce the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients treated using lower-dose CSI rather than standard therapy is important for further reducing the treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and were treated using lower-dose CSI rather than standard-dose radiation therapy. RESULTS: Among the patients, 23 were classified as having a “standard-risk” and 15 as having a “high-risk” according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months. The median CSI dose was 18 Gy in both groups, and 10 patients in the “high-risk” group received a CSI dose of 23.4 Gy or 24 Gy. Molecular subgrouping revealed the “standard-risk” cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the “high-risk” cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 13 of the 16 “standard-risk” patients were subclassified as subtypes I, IV, VI, and VII, which were associated with a good prognosis according to the novel sub-subclassification among Group 3/4 medulloblastomas. However, only 6 of the 15 “high-risk” patients were included in the subtypes. The good prognostic subtype cases among “high-risk” cohort were all survived without recurrence, in contrast to a worse prognosis (5-year progression free survival=33.3%; p=0.01) of the other cases. CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that the novel sub-subclassification of Group 3/4 medulloblastoma may be a promising prognostic biomarker for reducing the dose of CSI in patients with metastatic medulloblastoma.

Non-corticosteroid adjuvant therapies for acute bacterial meningitis.

Non-corticosteroid adjuvant therapies for acute bacterial meningitis.

The Potential Roles of Glial Cells in the Neuropathogenesis of Cerebral Malaria.

Cerebral malaria (CM) is a severe neurological complication of malaria caused by the Plasmodium falciparum parasite. It is one of the leading causes of death in children under 5 years of age in Sub-Saharan Africa. CM is associated with blood-brain barrier disruption and long-term neurological sequelae in survivors of CM. Despite the vast amount of research on cerebral malaria, the cause of neurological sequelae observed in CM patients is poorly understood. In this article, the potential roles of glial cells, astrocytes, and microglia, in cerebral malaria pathogenesis are reviewed. The possible mechanisms by which glial cells contribute to neurological damage in CM patients are also examined.

Synergistic Effect of Combined Artesunate and Tetramethylpyrazine in Experimental Cerebral Malaria.

Intravenous artesunate is effective against cerebral malaria (CM), but high mortality and neurological sequelae in survivors are inevitable. We investigated the effect of combined artesunate and tetramethylpyrazine using mouse models of experimental cerebral malaria (ECM). Artesunate + tetramethylpyrazine reduced microvascular blockage and improved neurological function, including the rapid murine coma and behavior scale (RMCBS), leading to improved survival and reduced pathology in ECM. This combination downregulated the expression of adhesion molecules and sequestration of parasitized red blood cells (pRBCs), increased cerebral blood flow, nerve growth factor (b-NGF), vascular endothelial growth factor A (VEGF-A), and neurotrophin (brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3)) levels, and alleviated hippocampal neuronal damage and astrocyte activation. Down- (n = 128) and upregulated (n = 64) proteins were identified in the artesunate group, while up- (n = 217) and downregulated (n = 177) proteins were identified in the artesunate + tetramethylpyrazine group, presenting a significantly altered proteome profile. KEGG analysis showed that 166 differentially expressed proteins were enriched in the Art group and 234, in the artesunate + tetramethylpyrazine group. The neuroprotective effects of artesunate + tetramethylpyrazine were mainly related to proteins involved in axon development and transportation between blood and brain. These results suggested that artesunate + tetramethylpyrazine could be a potential adjuvant therapy against CM, but this will have to be confirmed in future studies and trials.

A functional observational battery for evaluation of neurological outcomes in a rat model of acute bacterial meningitis

BackgroundAcute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae.MethodsWe developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate of Streptococcus pneumoniae. Rats were evaluated for 6 days following the infection.ResultsPneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats; p = 0.0003), involuntary motor movements (75% of infected vs 0% of control rats; p = 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats; p = 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 ± 4.0 vs 4.0 ± 2.0; 48 h 17.3 ± 7.1 vs 3.4 ± 1.8; 6 days 17.8 ± 7.4 vs 1.7 ± 2.4; p < 0.0001 for all).ConclusionsThe functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.

Neurodevelopmental outcome of healthy term newborn with serum bilirubin >15 mg/dl at one year.

Neonatal hyperbilirubinemia is a common medical emergency in early neonatal period. Unconjugated bilirubin is neurotoxic and can lead to lifelong neurological sequelae in survivors. To find out the association between serum bilirubin and neurodevelopmental outcome at 1 year of age using Development Assessment Scale for Indian Infants (DASII). A prospective cohort study was conducted in the Department of Pediatrics of a tertiary care institution of Central India between January 2018 and August 2019. Total 108 term healthy neonates, with at least one serum bilirubin value of >15 mg/dl, were included. Subjects were divided into three groups based on the serum bilirubin; group 1: (15-20 mg/dl) -85(78.7%) cases, group 2: (20-25 mg/dl) -17(15.7%), and group 3: (>25 mg/dl) -6(5.5%). Developmental assessment was done using DASII at 3, 6, 9, 12 months of age. Out of 108 cases, 101(93.5%) received phototherapy, and 7(6.5%) received double volume exchange transfusion. Severe delay was observed in 5(4.6%) and mild delay in 2(1.9%) cases in the motor domain of DASII at one year. Severe delay in the motor domain was associated with mean TSB of 27.940±2.89 mg/dl and mild delay with mean TSB of 22.75±1.76 mg/dl (p = 0.001). On cluster analysis, delay was observed in locomotion 1 score in 11(13%) cases (p = 0.003) and manipulation score in 6(7.1%) cases in group 1. Increased serum bilirubin was a significant risk factor for the delayed neurodevelopment in babies with neonatal jaundice. Even a moderate level of bilirubin significantly affects the developmental outcome.

Bioenergetic dysfunction in a zebrafish model of acute hyperammonemic decompensation

Acute hyperammonemic encephalopathy is a life-threatening manifestation of individuals with urea cycle disorders, which is associated with high mortality rates and severe neurological sequelae in survivors. Cerebral bioenergetic failure has been proposed as one of the key mechanisms underlying hyperammonemia-induced brain damage, but data supporting this hypothesis remain inconclusive and partially contradictory. Using a previously established zebrafish model of acute hyperammonemic decompensation, we unraveled that acute hyperammonemia leads to a transamination-dependent withdrawal of 2-oxoglutarate (alpha-ketoglutarate) from the tricarboxylic acid (TCA) cycle with consecutive TCA cycle dysfunction, ultimately causing impaired oxidative phosphorylation with ATP shortage, decreased ATP/ADP-ratio and elevated lactate concentrations. Thus, our study supports and extends the hypothesis that cerebral bioenergetic dysfunction is an important pathophysiological hallmark of hyperammonemia-induced neurotoxicity.

Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT): Guidance to Reduce the Risk of Intracranial Bleeding

IntroductionFNAIT is associated with severe bleeding, especially intracranial hemorrhage (ICH), in the fetus and/or newborn. More than 75% of ICHs occur in utero and up to 50% before 32 weeks gestation. The consequences of ICH include death (35%) or serious neurological sequelae in survivors (83%). FNAIT requires prompt identification and treatment antepartum, postpartum and in subsequent pregnancies. An international panel was convened by the International Collaboration for Transfusion Medicine Guidelines (ICTMG) to develop evidence based recommendations for diagnosis and management of FNAIT.MethodsThe international panel consisted of specialists in adult and pediatric hematology, maternal fetal medicine (MFM), neonatology, methodology, transfusion medicine, and a patient representative. Clinical questions were developed for diagnostic testing, antenatal screening and management, and postnatal interventions. A systematic search for articles published between 1946 and June 2017 in MEDLINE, EMBASE and Cochrane was conducted. Recommendations were formulated based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method which incorporates the quality of the evidence, benefits and risks, and resource utilization. Web conferences and electronic correspondence were used to discuss the results of the systematic reviews and formulate recommendations. Considerations for clinical practice such as dosing of intravenous immunoglobulin (IVIG) and corticosteroids were detailed. Electronic surveys were sent to all members to assess agreement with recommendations. The final guidance document was sent to maternal fetal, hematology and pediatric societies for comments.ResultsThree systematic reviews (antenatal management, postnatal management and use of laboratory investigations to identify pregnancies at risk) were developed. Antenatal recommendations: Women with FNAIT in a previous pregnancy or sisters of women with FNAIT should be referred to MFM centers. Fetal HPA typing (e.g. HPA-1a/1b) should be performed in HPA-immunized pregnant women when the paternity is unknown or the partner is heterozygous or unavailable for testing. Prenatal HPA-1 typing should preferentially be performed by a non-invasive method e.g. cell-free fetal DNA (cffDNA) in maternal plasma if adequately quality assured. Antenatal IVIG administration to the mother commencing at 12-16 weeks gestation should be offered to all women in a subsequent pregnancy with maternal fetal incompatibility who have had a previous fetus or neonate with FNAIT related ICH. For all other pregnancies with a previous neonate with FNAIT (without ICH), administering antenatal IVIG to the mother should be discussed prior to a subsequent pregnancy or when pregnancy with maternal fetal incompatibility is confirmed. If corticosteroids are used with IVIG, dexamethasone should not be used because of the associated risk of oligohydramnios. Postnatal recommendations: HPA-selected platelets should be made available at delivery for potentially affected infants to increase the neonatal platelet count. If HPA-selected platelets are not immediately available, unselected platelets should be used. In the presence of life-threatening neonatal hemorrhage such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain platelet counts above 50 to 100x109/L for at least 7 days. In the absence of life-threatening bleeding in a neonate such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain a platelet count above 30x109/L.ConclusionsThe intent of this guidance document developed from systematic reviews is to promote best practices in the management of FNAIT. The guideline development group developed algorithms for treatment, podcasts for physicians and patients, pamphlets for patients and a slide set to assist with the implementation of recommendations into practice. This expert panel identified key areas for future research. One is the optimal approach to antenatal management of the next affected pregnancy. Developing biomarkers of fetal severity would be critical to this endeavor. In addition, creating comprehensive screening to identify HPA-1b1b women at risk of FNAIT would advance successful prevention of this disease. DisclosuresBakchoul:German Research Society (DFG): Research Funding; Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; Robert Bosch gGmbH: Research Funding. Kjaer:Prophylix Pharma: Equity Ownership. Kjeldsen-Kragh:Prophylix Pharma: Equity Ownership. Oepkes:Towards routine HPA screening in pregnancy: Research Funding. Bussel:Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Protalex: Consultancy; Amgen Inc.: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Momenta: Consultancy. Arnold:Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Savoia:Neonatal Alloimmune Thrombocytopenia Registry of the Transfusion Outcomes Research Collaborative (TORC) Australia: Membership on an entity's Board of Directors or advisory committees.

Repurposed FDA-Approved drug sorafenib reduces replication of Venezuelan equine encephalitis virus and other alphaviruses

The New World alphaviruses –Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, and WEEV respectively) – cause a febrile disease that is often lethal in equines and children and leads to long-term neurological sequelae in survivors. Endemic to the Americas, epizootic outbreaks of the three viruses occur sporadically in the continental United States. All three viruses aerosolize readily, replicate to high titers in cell culture, and have low infectious doses. Additionally, there are no FDA-approved vaccines or therapeutics for human use. To address the therapeutic gap, a high throughput assay utilizing a luciferase reporter virus, TC83-luc, was performed to screen a library of commercially available, FDA-approved drugs for antiviral activity. From a group of twenty compounds found to significantly decrease luminescence, the carcinoma therapeutic sorafenib inhibited replication of VEEV-TC83 and TrD in vitro. Additionally, sorafenib inhibited replication of EEEV and two Old World alphaviruses, Sindbis virus and chikungunya virus, at 8 and 16 h post-infection. Sorafenib caused no toxicity in Vero cells, and coupled with a low EC50 value, yielded a selectivity index of >19. Mechanism of actions studies suggest that sorafenib inhibited viral translation through dephosphorylation of several key proteins, including eIF4E and p70S6K, leading to a reduction in viral protein production and overall viral replication.

Acute inhalation of combustion smoke triggers neuroinflammation and persistent anxiety-like behavior in the mouse

Context: Acute inhalation of combustion smoke triggers neurologic sequelae in survivors. Due to the challenges posed by heterogeneity of smoke exposures in humans, mechanistic links between acute smoke inhalation and neuropathologic sequelae have not been systematically investigated.Methods: Here, using mouse model of acute inhalation of combustion smoke, we studied longitudinal neurobehavioral manifestations of smoke exposures and molecular/cellular changes in the mouse brain.Results: Immunohistochemical analyses at eight months post-smoke, revealed hippocampal astrogliosis and microgliosis accompanied by reduced myelination. Elevated expression of proinflammatory cytokines was also detected. Longitudinal testing in different neurobehavioral paradigms in the course of post-smoke recovery, revealed lasting anxiety-like behavior. The examined paradigms included the open field exploration/anxiety testing at two, four and six months post-smoke, which detected decreases in total distance traveled and time spent in the central arena in the smoke-exposed compared to sham-control mice, suggestive of dampened exploratory activity and increased anxiety-like behavior. In agreement with reduced open field activity, cued fear conditioning test revealed increased freezing in response to conditioned auditory stimulus in mice after acute smoke inhalation. Similarly, elevated plus maze testing demonstrated lesser presence in open arms of the maze, consistent with anxiety-like behavior, for the post-smoke exposure mice.Conclusions: Taken together, our data demonstrate for the first time persistent neurobehavioral manifestations of acute inhalation of combustion smoke and provide new insights into long-term progression of events initiated by disrupted brain oxygenation that might contribute to lasting adverse sequelae in survivors of smoke inhalation injuries.