Rapid-Onset Obsessive-Compulsive Disorder With Hallucinations in a Post-seizure Four-Year-Old Male.

Rapid-onset obsessive-compulsive disorder (OCD) has been classically described in the context of infectious and autoimmune stressors, most famously PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) and then PANS (pediatric autoimmune neuropsychiatric syndrome). PANS itself, however, specifically excludes neurological and medical disorders, including seizures, from the diagnostic criteria. Changes in affect, such as depression/anxiety and new-onset psychosis, have been previously described in the post-seizure period but often self-resolve. To the best of our knowledge, neither rapid onset nor exacerbation of OCD have been previously reported in a post-seizure patient. We present the case of a four-year five-month-old male with a history of poor weight gain who presented to the emergency department for a seizure in the context of hypoglycemia. During the hospital course and within one month following discharge, he became significant for a myriad of new behaviors, rituals, and even visual hallucinations. We propose that the seizure itself is a highly unique and likely neurophysiological stressor. We consider neurologically exacerbated OCD to be an area ripe for further investigation.

Elevated antibody binding to striatal cholinergic interneurons in patients with pediatric acute-onset neuropsychiatric syndrome.

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is characterized by the abrupt onset of significant obsessive-compulsive symptoms (OCS) and/or severe food restriction, together with other neuropsychiatric manifestations. An autoimmune pathogenesis triggered by infection has been proposed for at least a subset of PANS. The older diagnosis of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS) describes rapid onset of OCD and/or tics associated with infection with Group A Streptococcus. The pathophysiology of PANS and PANDAS remains incompletely understood. We recently found serum antibodies from children with rigorously defined PANDAS to selectively bind to cholinergic interneurons (CINs) in the striatum. Here we examine this binding in children with relapsing and remitting PANS, a more heterogeneous condition, collected in a distinct clinical context from those examined in our previous work, from children with a clinical history of Streptococcus infection. IgG from PANS cases showed elevated binding to striatal CINs in both mouse and human brain. Patient plasma collected during symptom flare decreased a molecular marker of CIN activity, phospho-riboprotein S6, in ex vivo brain slices; control plasma did not. Neither elevated antibody binding to CINs nor diminished CIN activity was seen with plasma collected from the same children during remission. These findings replicate what we have seen previously in PANDAS and support the hypothesis that at least a subset of PANS cases have a neuroimmune pathogenesis. Given the critical role of CINs in modulating basal ganglia function, these findings confirm striatal CINs as a locus of interest in the pathophysiology of both PANS and PANDAS.

Narcolepsy and pediatric acute-onset neuropsychiatric syndrome: A case report that suggests a putative link between the two disorders.

Narcolepsy with cataplexy (NT1) is a rare hypothalamic disorder that presents with a dysregulation of the sleep-wake cycle (i.e., excessive daytime sleepiness and sleep and cataplectic attacks) and other motor, cognitive, psychiatric, metabolic, and autonomic disturbances, with putative autoimmune pathogenesis. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder that presents with acute-onset obsessive-compulsive symptoms and/or a severe eating restriction, with concomitant cognitive, behavioral, or affective symptoms caused by infections and other environmental triggers provoking an inflammatory brain response, which evolves into a chronic or progressive neuroimmune disorder. In this study, we present the case of a 13-year-old boy with vocal tics and syncopal-like episodes, eventually diagnosed as NT1 and PANS, and from this we discuss the hypothesis that both NT1 and PANS might belong to the same immunological spectrum, resulting in comparable imbalances in key neurotransmitter axes (i.e., orexinergic and dopaminergic), with conceptual and operational implications, especially with regards to the pharmacological tretament.

Bioremediation of Aflatoxin B1 by Meyerozyma guilliermondii AF01 in Peanut Meal via Solid-State Fermentation.

The use of microorganisms to manage aflatoxin contamination is a gentle and effective approach. The aim of this study was to test the removal of AFB1 from AFB1-contaminated peanut meal by a strain of Meyerozyma guilliermondii AF01 screened by the authors and to optimize the conditions of the biocontrol. A regression model with the removal ratio of AFB1 as the response value was established by means of single-factor and response surface experiments. It was determined that the optimal conditions for the removal of AFB1 from peanut meal by AF01 were 75 h at 29 °C under the natural pH, with an inoculum of 5.5%; the removal ratio of AFB1 reached 69.31%. The results of simulating solid-state fermentation in production using shallow pans and fermentation bags showed that the removal ratio of AFB1 was 68.85% and 70.31% in the scaled-up experiments, respectively. This indicated that AF01 had strong adaptability to the environment with facultative anaerobic fermentation detoxification ability. The removal ratio of AFB1 showed a positive correlation with the growth of AF01, and there were no significant changes in the appearance and quality of the peanut meal after fermentation. This indicated that AF01 had the potential to be used in practical production.

Developmental Impacts of PANS/PANDAS and Inadequate Support for Children and Families.

This article examines the degree to which major domains of child development are affected by Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS)/Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). Using cross-sectional survey data collected with an international sample of parents who identify as having children with PANS/PANDAS (N = 402), this study analyzed parent-reported developmental impacts and access to treatment and adequate supports. Parents reported that PANS/PANDAS negatively impacted their children's development across all domains: Emotional Development (92% of children), Social Development (90%), Cognitive Development (86%), Academic Growth (86%), Identity Development (83%), Talent Development (73%) and Language Development (50%). In addition, developmental impacts were likely to be more severe for children whose parents reported a greater number of inadequate supports with parenting, school, extracurricular activities, and crisis situations. These results indicate that children and families affected by PANS/PANDAS need better support to maximize children's opportunities, at home, in school, and in their communities, to continue developing despite challenging neuropsychiatric symptoms.

Neurological consequences after portosystemic shunt attenuation in cats: A meta-analysis study.

Neurological symptoms that occur after treatment of portosystemic shunts, in cats, known as post-attenuation neurological signs (PANS) can be quite severe. This study seeks to analyze a better understanding of the neurological outcomes that result from reducing portosystemic shunts in felines and provide insights that could guide future clinical approaches and treatment strategies for congenital portosystemic shunts (CPSS).The research utilized the MOOSE Checklist as a guide. PubMed/MEDLINE, Web of Science ScienceDirect, Embase, Scopus, ProQuest, and Google Scholar were used. The study investigated diversity using variance, Cochran Q tests with Applied fixed effects, and random effects models. A meta-regression model identified contributors. Eggers test funnel plot and Beggs test for asymmetry addressed publication bias. 12 high-quality studies were discovered from 664 research papers. This research covered years, shunt morphology, and surgery. PANS occurred 38.9 % of the time in cats, while PAS occurred 20.2 %. The overall PANS mortality rate was 17 %, while PAS was 37.2 %. The complete ligation technique was most common in subgroup analysis. PANS occurrence ranged from 26.8 % to 56.5 % in cats with congenital extrahepatic portosystemic shunts The cause of PANS in cats is still unknown, and there is only limited evidence to justify the use of preventive antiepileptic medications such as levetiracetam. The treatment primarily aims to control neurologic symptoms, and the long-term outlook varies, with the potential for the reappearance of symptoms.

Psychometric Properties of the PANS 31-Item Symptom Rating Scale.

Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by sudden onset of obsessive-compulsive disorder and/or eating restriction with associated neuropsychiatric symptoms from at least two of seven categories. The PANS 31-Item Symptom Rating Scale (PANS Rating Scale) was developed to identify and measure the severity of PANS symptoms. The objective of this study was to define the psychometric properties of the PANS Rating Scale. Methods: Children with PANS (N = 135) and their parents participated. Parents completed the PANS Rating Scale and other scales on Research Electronic Data Capture. The PANS Rating Scale includes 31 items that are rated on a Likert scale from 0 = none to 4 = extreme. Pearson's correlations were run between the PANS Total score and scores on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), Yale Global Tic Severity Scale (YGTSS), Modified Overt Aggression Scale (MOAS), Columbia Impairment Scale (CIS), PANS Global Impairment Score (GIS), and Children's Global Assessment Scale (CGAS). Results: Convergent validity was supported by significant correlations between the PANS Total and scores on the CY-BOCS, YGTSS, MOAS, CIS, GIS, and CGAS. The largest correlations were with measures of functional impairment: PANS Total and CIS (r = 0.81) and PANS Total and GIS (r = 0.74). Cronbach's alpha was 0.89 which demonstrates strong internal consistency of the 31 items. PANS Total score was significantly higher in children in a flare of their neuropsychiatric symptoms compared to children who were not in a flare. Conclusions: This study provides preliminary support for the PANS Rating Scale as a valid research instrument with good internal consistency. The PANS Rating Scale appears to be a useful measure for assessing children with PANS.

Folate Receptor Alpha Autoantibodies in the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Population.

The folate receptor alpha autoantibodies (FRAAs) are associated with cerebral folate deficiency (CFD) and autism spectrum disorder (ASD). Both of these syndromes have overlapping characteristics with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Thus, we propose that the FRAAs may contribute to the symptomatology of PANS/PANDAS. To test this hypothesis, 1 mL of serum from 47 patients (age range = 6-18 years old) clinically diagnosed with PANS/PANDAS was sent to Vascular Strategies (Plymouth Meeting, PA, USA) for analysis of FRAAs. Moreover, 63.8% of PANS/PANDAS patients (male = 15; female = 15) were found to have either the blocking and/or blinding FRAAs, with 25 (83.3%; male = 14; female = 11) having binding FRAAs, two (6.7%; all female = 2) having blocking FRAAs, and 3 (10%; male = 1; female = 2) having both binding and blocking. Furthermore, surprisingly, ASD was associated with a 0.76 lower binding titer (p = 0.02), and severe tics were associated with a 0.90 higher binding titer (p = 0.01). A case of a FRAA-positive patient is provided to illustrate that a treatment plan including leucovorin can result in symptom improvement in patients with PANS/PANDAS who are FRAA-positive. These data, for the first time, demonstrate that PANS/PANDAS is associated with FRAAs and suggest folate metabolism abnormalities may contribute to PANS/PANDAS symptomatology. Further studies investigating the therapeutic nature of leucovorin in the treatment of PANS/PANDAS are needed. Such studies may open up an alternative, safe, and well-tolerated treatment for those with the PANS/PANDAS diagnosis.

Sensory processing in children with Paediatric Acute-onset Neuropsychiatric Syndrome.

INTRODUCTION: Previous research indicates that children with Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) experience sensory reactivity differences that impact occupational performance. The purpose of this study was to determine whether there are differences in sensory reactivity in these children across two different time points; during exacerbation and during remission, using the Sensory Processing Measure (SPM) Home-Form. The study also sought to investigate whether children with PANS experience sensory differences during remission periods, when compared with SPM Home-Form norms. METHODS: A two-period bidirectional case-crossover design was used, and an online assessment was conducted to measure sensory reactivity. Parents of children aged 4.6 to 13.1 years with a diagnosis of PANS were recruited from various sites across Australia, USA, England, Ireland, Scotland, Canada, and New Zealand. The SPM Home-Form was used to measure sensory reactivity at two time points, when PANS was in remission (T-R) and in exacerbation (T-E). Study entry was permitted at either T-E or T-R. Participant exacerbation status was monitored over a maximum 12-month period, and a follow-up SPM Home-Form was sent when a change in exacerbation status was indicated. A linear mixed model was used to assess the difference between SPM Home-Form norm-referenced scores during exacerbation and remission. RESULTS: The study included 82 participants, with 80 providing data at study entry, and 27 providing data at follow-up. Results showed a statistically significant decline in performance across the SPM Home-Form domains of Hearing, Social Participation, Planning and Ideas, and Total Sensory Systems T-scores during exacerbation when compared with remission data. Results also demonstrated atypical sensory reactivity across Vision, Hearing, Touch, Balance and Motion, and Total Sensory Systems domains during periods of remission compared with SPM Home-Form norms. CONCLUSION: This study found that children with PANS experience significant sensory reactivity differences during exacerbation and remission across multiple sensory domains, with a decline in performance during exacerbation. Where there are occupational performance challenges, occupational therapists should consider administering sensory assessments so that effective intervention plans addressing the unique sensory reactivity needs of children with PANS can be developed.

Diversity of Microbial Mats in the Makgadikgadi Salt Pans, Botswana.

The Makgadikgadi Salt Pans are the remnants of a mega paleo-lake system in the central Kalahari, Botswana. Today, the Makgadikgadi Basin is an arid to semi-arid area receiving water of meteoric origin during the short, wet season. Large microbial mats, which support primary production, are formed due to desiccation during the dry season. This study aimed to characterise the microbial diversity of the microbial mats and the underlying sediment. The focus was the Ntwetwe Pan, located west of the Makgadikgadi Basin. Metagenomic analyses demonstrated that the mats consisted of a high relative abundance of Cyanobacteriota (synonym Cyanobacteria) (20.50-41.47%), Pseudomonadota (synonym Proteobacteria) (15.71 to 32.18%), and Actinomycetota (synonym Actinobacteria) (8.53-32.56%). In the underlying sediments, Pseudomonadota, Actinomycetota, and Euryarchaeota represented over 70% of the community. Localised fluctuations in water content and pH did not significantly affect the microbial diversity of the sediment or the mats.

Intravenous immunoglobulin treatment improves multiple neuropsychiatric outcomes in patients with pediatric acute-onset neuropsychiatric syndrome.

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is defined by acute onset of diverse neuropsychiatric manifestations, presumably in the setting of underlying immune dysfunction. We used standardized neuropsychological testing to assess how intravenous immunoglobulins (IVIG) impact neurological and cognitive functions in PANS patients by comparing pretreatment with post-treatment scores. A 5-year retrospective study was undertaken in Children's Postinfectious Autoimmune Encephalopathy Center at University of Arizona. We identified 12 children diagnosed with PANS and treated with immunomodulatory IVIG doses, who also completed neuropsychological testing before and after treatment. We tracked multiple patient characteristics, type/timeline of testing, and number of IVIG courses. Score change of 1 standard deviation in any tested domain/subdomain was considered improvement. We further reviewed records for laboratory signs of triggering infection and immune dysfunction. Improvement occurred in 11/12 patients, in one or multiple domains/subdomains, independently of time between disease onset and IVIG initiation (0-7 years). Participants received 1-7 IVIG courses. Improvement was primarily seen in memory (58%), sensory-motor (37%) and visual-motor integration (30%). In 5/12 patients we detected hypogammaglobulinemia requiring ongoing IVIG replacement, one patient had isolated low IgA. Only one patient had to discontinue IVIG therapy due to severe adverse effects. Standardized neuropsychological testing represents an important tool to objectively measure improvement in PANS patients. IVIG was tolerated well and showed efficacy in the vast majority of participants, independently from timelapse since disease onset, emphasizing impact of immunomodulation in PANS. Significant presence of baseline hypogammaglobulinemia in children with PANS emphasizes the presumed role of immune dysfunction in disease pathogenesis.

Estimate of the incidence of PANDAS and PANS in 3 primary care populations.

Objective: Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute-Onset Neuropsychiatric syndrome (PANS) are presumed autoimmune complications of infection or other instigating events. To determine the incidence of these disorders, we performed a retrospective review for the years 2017-2019 at three academic medical centers. Methods: We identified the population of children receiving well-child care at each institution. Potential cases of PANS and PANDAS were identified by including children age 3-12 years at the time they received one of five new diagnoses: avoidant/restrictive food intake disorder, other specified eating disorder, separation anxiety disorder of childhood, obsessive-compulsive disorder, or other specified disorders involving an immune mechanism, not elsewhere classified. Tic disorders was not used as a diagnostic code to identify cases. Data were abstracted; cases were classified as PANDAS or PANS if standard definitions were met. Results: The combined study population consisted of 95,498 individuals. The majority were non-Hispanic Caucasian (85%), 48% were female and the mean age was 7.1 (SD 3.1) years. Of 357 potential cases, there were 13 actual cases [mean age was 6.0 (SD 1.8) years, 46% female and 100% non-Hispanic Caucasian]. The estimated annual incidence of PANDAS/PANS was 1/11,765 for children between 3 and 12 years with some variation between different geographic areas. Conclusion: Our results indicate that PANDAS/PANS is a rare disorder with substantial heterogeneity across geography and time. A prospective investigation of the same question is warranted.

Factors Associated with Symptom Persistence in PANS: Part II-Presenting Features, Medical Comorbidities, and IVIG Treatment History.

Objective: Individuals with Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) experience neuropsychiatric symptoms following an infection or other trigger. Although PANS is typically described as relapsing-remitting, a large community-based 2017 study revealed a range of courses. The present study examined clinical predictors of symptom persistence, measured as % days symptom-free, in this same sample. Methods: A 146-question online survey gathered histories (infections and other triggers, medical and developmental comorbidities), symptomatology, interventions, and outcomes (including school functioning) of PANS patients. Multivariate analyses were applied to examine associations between these variables and % days symptom-free across the disease course. Results: Among the 646 subjects included, significant relationships were found between greater symptom persistence and higher rates of medical comorbidities (especially rashes, headaches, chronic sinusitis, frequent diarrhea, and immune deficiencies), developmental diagnoses, and respondent-perceived developmental lags. Subjects with greater symptom persistence were significantly more likely to report PANS exacerbations associated with infections in close contacts, vaccinations, environmental triggers, and exacerbations of comorbidities and were more likely to report PANS recurrences triggered by Epstein Barr Virus, mycoplasma, and sinus infections. More persistent PANS was also associated with significantly higher frequencies of certain symptoms (sleep disturbance, urinary incontinence, muscle pain, brain fog, sensory defensiveness, irritability, and aggression-related symptoms), less effectiveness of intravenous immunoglobulin in combating symptoms, and more difficulty attending school. Conclusions: Our results suggest high symptom persistence in PANS to be associated with more pervasive medical and neuropsychiatric symptoms. Differences in symptom persistence are associated with both intrinsic (e.g., immune competence) and extrinsic (e.g., infections, treatment) factors. Because extrinsic factors are potentially modifiable, it is critical that providers be aware of current guidelines on PANS evaluation and treatment.

Young adults' experiences of living with paediatric acute-onset neuropsychiatric syndrome. An interview study.

AIM: This article explores experiential knowledge of living with paediatric acute-onset neuropsychiatric syndrome (PANS), and the factors that are associated with perceived good care. METHODS: Ten people with lived experience of PANS participated, five women and five men aged 19-34. Semi-structured interviews were used to explore their experience of living with PANS and their encounters with healthcare. Thematic analysis was carried out to identify central themes in the transcribed interviews. RESULTS: The study revealed a group of young adults living fairly isolated lives, dependent on care from relatives. To them, the illness was a tangible presence. They perceived a lack of knowledge among healthcare staff on PANS in healthcare, and negative consequences linked to this. In addition, their experience-based knowledge of their own illness is devalued in healthcare encounters. A feeling of being pushed around in healthcare, without anyone taking responsibility for the treatment, emerged in the interviews. The participants emphasized the need for increased knowledge among staff to identify PANS and be able to offer effective treatment. CONCLUSION: There is a need to increase the knowledge about PANS in healthcare and to coordinating care between neurology, immunology and psychiatry. To be able to offer evidence-based care to children with PANS, in-depth knowledge is needed about aetiology, treatment effects, and user experiences and preferences.

Factors Associated with Symptom Persistence in PANS: Part I-Access to Care.

Objective: Pediatric acute-onset neuropsychiatric syndrome (PANS) presents with abrupt neuropsychiatric symptoms, often after an immunologic trigger. A 2017 survey of 698 subjects found diagnostic delays to be associated with recurrences, suggesting that timely care impacts course. This secondary analysis explores the impact of barriers to care on symptom persistence. Methods: A 146-question online survey gathered history, symptomatology, intervention, and outcome data from subjects with PANS. Multivariate analyses examined associations between symptom persistence over the entire reported disease course, measured as % days symptom-free over reporting periods averaging approximately 4 years, and access-to-care history, reflected in availability of medical expertise and affordability of care. The impacts of time from symptom onset to treatment and effectiveness of initial antibiotics were also examined. Results: Among the 646 subjects analyzed, greater symptom persistence was associated with longer intervals between symptom onset and treatment (F = 4.43, p = 0.002). Thirty-four percent of subjects with the least symptom persistence (>75% symptom-free days), versus 13% of those with the most (symptoms every day), had been diagnosed by the first practitioner seen (likelihood ratio [L-R] χ2 = 36.55, p < 0.0001, for comparison across all groups). Diagnosis and treatment had not been impeded by lack of access to expertise for 52% of subjects with the least persistent symptoms, versus 22% of those with the most (L-R χ2 = 22.47, p < 0.0001). Affordability had not impacted diagnosis and treatment for 76% of subjects with the least persistent symptoms, versus 42% of those with the most (L-R χ2 = 27.83, p < 0.0001). The subjects whose PANS symptoms resolved with antibiotic treatment of the inciting infection experienced less symptom persistence than others (χ2 = 23.27, p = 0.0001). More persistently symptomatic subjects were more likely to have discontinued intravenous immunoglobulin (IVIG) treatment for access-to-care reasons. Conclusions: Unimpeded access to care for PANS is associated with more symptom-free days over reporting periods averaging approximately 4 years. Difficulty reaching expert providers, missed opportunities for diagnoses, and financial limitations may worsen outcomes. Practitioners, particularly primary providers, should adhere to published diagnostic and treatment guidelines promptly upon presentation.

Case report: Substantial improvement of autism spectrum disorder in a child with learning disabilities in conjunction with treatment for poly-microbial vector borne infections.

Poly-microbial vector-borne infections may have contributed to neuropsychiatric symptoms in a boy diagnosed with autism spectrum disorder. Targeted antimicrobial treatment resulted in substantial improvement in cognitive (such as learning disabilities, focus, concentration) and neurobehavioral (such as oppositional, defiant, anti-social, disordered mood, immaturity, tics) symptoms.

Pediatric neuropsychiatric disorders with motor and nonmotor phenomena.

The concept of pediatric autoimmune neuropsychiatric disorders associated with group A beta-hemolytic streptococcus (PANDAS) has become seminal since first introduced more than two decades ago. At the time of this writing, most neurologists, pediatricians, psychiatrists, and general pediatricians will probably have heard of this association or treated an affected child with PANDAS. The concept of an acute-onset, and typically self-limited, postinfectious autoimmune neuropsychiatric disorder resembling PANDAS manifesting vocal and motor tics and obsessive-compulsive disorder has broadened to other putative microbes and related endogenous and exogenous disease triggers. These disorders with common features of hypometabolism in the medial temporal lobe and hippocampus in brain 18fluorodeoxyglucose positron emission tomography fused to magnetic resonance imaging (FDG PET-MRI), form a spectrum: with the neuropsychiatric disorder Tourette syndrome and PANDAS with its well-defined etiopathogenesis at one end, and pediatric abrupt-onset neuropsychiatric syndrome (PANS), alone or associated with specific bacterial and viral pathogens, at the other end. The designation of PANS in the absence of a specific trigger, as an exclusionary diagnosis, reflects the current problem in nosology.

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome.

Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs.

Pediatric Acute-Onset Neuropsychiatric Syndrome: Current Perspectives.

Pediatric acute-onset neuropsychiatric syndrome (PANS) features a heterogeneous constellation of acute obsessive-compulsive disorder (OCD), eating restriction, cognitive, behavioral and/or affective symptoms, often followed by a chronic course with cognitive deterioration. An immune-mediated etiology is advocated in which the CNS is hit by different pathogen-driven (auto)immune responses. This narrative review focused on recent clinical (ie, diagnostic criteria, pre-existing neurodevelopmental disorders, neuroimaging) and pathophysiological (ie, CSF, serum, genetic and autoimmune findings) aspects of PANS. We also summarized recent points to facilitate practitioners with the disease management. Relevant literature was obtained from PubMed database which included only English-written, full-text clinical studies, case reports, and reviews. Among a total of 1005 articles, 205 were pertinent to study inclusion. Expert opinions are converging on PANS as the effect of post-infectious events or stressors leading to "brain inflammation", as it is well-established for anti-neuronal psychosis. Interestingly, differentiating PANS from either autoimmune encephalitides and Sydenham's chorea or from alleged "pure" psychiatric disorders (OCD, tics, Tourette's syndrome), reveals several overlaps and more analogies than differences. Our review highlights the need for a comprehensive algorithm to help both patients during their acute distressing phase and physicians during their treatment decision. A full agreement on the hierarchy of each therapeutical intervention is missing owing to the limited number of randomized controlled trials. The current approach to PANS treatment emphasizes immunomodulation/anti-inflammatory treatments in association with both psychotropic and cognitive-behavioral therapies, while antibiotics are suggested when an active bacterial infection is established. A dimensional view, taking into account the multifactorial origin of psychiatric disorders, should suggest neuro-inflammation as a possible shared substrate of different psychiatric phenotypes. Hence, PANS and PANS-related disorders should be considered as a conceptual framework describing the etiological and phenotypical complexity of many psychiatric disorders.

Deriving a high-quality daily dataset of large-pan evaporation over China using a hybrid model.

Global warming is expected to increase the atmospheric evaporative demand and make more surface water for evapotranspiration, aggerating water sources' social and ecological shortage. Pan evaporation, as a routine observation worldwide, is an excellent metric to indicate the response of terrestrial evaporation to global warming. However, several non-climatic effects, such as instrument upgrades, have destroyed the homogenization of pan evaporation and limited its applications. In China, 2400s meteorological stations have observed daily pan evaporation since 1951. The observed records became discontinuous and inconsistent due to the instrument upgrade from micro-pan D20 to large-pan E601. Here, combining the Penpan model (PM) and random forest model (RFM), we developed a hybrid model to assimilate different types of pan evaporation into a consistent dataset. Based on the cross-validation test, on a daily scale, the hybrid model has a lower bias (RMSE=0.41 mm day-1) and better stability (NSE=0.94) than the two sub-models and the conversion coefficient method. Finally, we produced a homogenized daily dataset of E601 across China from 1961 to 2018. Based on this dataset, we analyzed the long-term trend of pan evaporation. Pan evaporation showed a -1.23±0.57 mm a-2 downward trend from 1961-1993, primarily caused by decreased pan evaporation in warm seasons over North China. After 1993, the pan evaporation in South China increased significantly, resulting in a 1.83±0.87 mm a-2 upward trend across China. With better homogeneity and higher temporal resolution, the new dataset is expected to promote drought monitoring, hydrological modeling, and water resources management. Free access to the dataset can be found at https://figshare.com/s/0cdbd6b1dbf1e22d757e.