Behavioral Comorbidities Research Articles

Formative qualitative research to guide implementation of the Collaborative Care Model in a low-barrier HIV clinic

ABSTRACT Integrated behavioral healthcare interventions have increased access to care for people with behavioral health conditions in primary care settings. However, they have not been widely implemented in low-barrier HIV care settings where undertreated behavioral health needs remain high. We conducted a formative qualitative evaluation, using in-depth interviews with purposively selected stakeholders (n = 13) and patients (n = 16), to identify anticipated barriers and facilitators to integrating care for depression and opioid use disorder for people with HIV via the Collaborative Care Model at a low-barrier HIV clinic. Patients and stakeholders expressed their enthusiasm for the Collaborative Care Model based on its perceived relative advantage over the standard of care referral system. Availability of resources, practical concerns about perceived fit with low-barrier HIV care, and anticipated suitability given other behavioral health comorbidities and patients’ complex socioeconomic needs partially tempered stakeholder perceptions of appropriateness for the Collaborative Care Model. Patients and service delivery stakeholders were receptive to the Collaborative Care Model, but felt it was moderately appropriate in the context of low-barrier HIV care, which necessitated key adaptations to core model components to improve its contextual fit.

TBICoE approach to concussion rehabilitation in service members and veterans.

Concussion, also known as mild traumatic brain injury (mTBI), is a condition with unique ties to military service. Service members (SMs) are inherently at a higher risk for concussive injuries due to the intense physical training environment and combat operational tempo required to serve. The Traumatic Brain Injury Center of Excellence (TBICoE) is the US Department of Defense authority on this condition and provides a thorough approach to management of concussion and associated symptom sequela. This article seeks to review the TBICoE approach to the management and rehabilitation of military SMs with mTBI, and highlight resources available to military medical providers. The authors reviewed evidence and TBICoE resources to provide this comprehensive overview of the TBICoE approach to management and rehabilitation of concussion in military SMs. A progressive return to activity protocol in conjunction with symptom-guided management of common post-concussive sequelae, including headache, vestibular and oculomotor issues, sleep dysfunction, cognitive rehabilitation, and behavioral health comorbidities are essential for concussion management in the acute, post-acute and chronic phases of injury. The TBICoE approach to the rehabilitation of military SMs is comprehensive, and includes initial management with a stepwise return to duty protocol and an objective return to duty screening. The mainstays of treatment for SMs with post-acute and chronic post-concussion symptoms are headache management, vestibular and oculomotor rehabilitation, sleep interventions, cognitive rehabilitation, and early intervention for behavioral health comorbidities. These evidence-based strategies may be applied in the treatment of SMs in the US and internationally.

Long-Term High-Fat Diet Aggravates Absence Seizures and Neurobehavioral Disorders Without Inducing Metabolic Disorders in WAG/Rij Rats: Involvement of Systemic and Central Inflammation.

The consumption of a high-fat diet (HFD) represents a risk factor for diseases such as obesity, diabetes, insulin resistance (IR), and different brain disorders. HFD-induced obesity is linked with systemic and neuroinflammation implicated in the pathogenesis of metabolic impairment and epilepsy. In this study, we studied the negative effects of HFD consumption (16weeks) on absence epilepsy and behavior comorbidities in WAG/Rij rats, a well-validated idiopathic model of absence epilepsy and comorbidities. Moreover, we investigated how, by restoring a normocaloric diet (NCD; 12weeks), epileptic seizures and neuropsychiatric comorbidities could improve. We found that the HFD group showed a worsening of absence seizures, aggravation of depressive-like behavior, and performance in learning and memory than the NCD group even in the absence of hyperglycemia and/or obesity. In addition, intestinal villus rupture, inflammatory infiltrate, and intestinal permeability alteration increased after prolonged HFD intake, which could prevent weight gain. Inflammatory protein levels were found higher in the colon of the HFD group than in the NCD group, and also in the cortex and hippocampus, regions involved in absence seizures and behavioral alterations. After replacing HFD with NCD, a reduction in absence seizures and behavioral alterations was observed, and this decrease was well correlated with an improvement in inflammatory pathways. In conclusion, HFD consumption is sufficient to disrupt gut integrity resulting in systemic and brain inflammation contributing to the worsening of absence epilepsy and its comorbidities also without obesity development. These alterations can be improved by switching back the diet to NCD.

Caregiver burden and therapeutic needs in Dravet syndrome - A national UK cross-sectional questionnaire study

Background and objectivesDravet Syndrome is a severe developmental and epileptic encephalopathy with significant care needs for affected individuals and families. Our objective was to characterise the caregiver burden and therapeutic needs of families caring for an individual with Dravet Syndrome from child to adulthood, to examine age related differences in co-morbidities, and identify current gaps in health and social care. MethodsCross-sectional national survey conducted by the patient advocacy group Dravet Syndrome UK (DSUK) emailed to registered families caring for an individual with a confirmed diagnosis of Dravet syndrome. To characterise the sample, quantitative data on demographics, diagnostic journey, co-morbidities, therapies, healthcare utilisation, social care and funding, and impact on family life were collected. Qualitative data were analysed using grounded theory to develop a model of impact and service need. Results165 out of 381 families (43 %) responded. 90 % of adult Dravet syndrome patients waited >12 months to receive a diagnosis, compared to 25 % families with a young child (p < 0.001). 96 % reported intellectual disability as co-morbidity, more frequently observed in older Dravet syndrome individuals (p < 0.001), alongside autism/autistic-like symptoms (χ2 = 15.3, df = 3 p = 0.001) and scoliosis (χ2 = 28.4, df = 3, p < 0.001). Sleep problems are associated with greater impact on caregiver's mental well-being (χ2 = 13.2, df = 2, p < 0.001). 77 % of families wished more discussions about sudden unexpected death in epilepsy (SUDEP) and 50 % rated the paediatric to adult transition experience as ‘poor’. 90 % of caregivers were unable to continue working as normal with negative impact on their quality of life (p = 0.024) and mental well-being (p = 0.007). DiscussionFamilies are profoundly impacted by Dravet syndrome. Their experience changes over time as people with Dravet syndrome become older and present with increasing levels of health, cognitive and behavioural comorbidities. Families will benefit from improved communication with health care professionals, psychosocial interventions and better access to social care.

Conference proceedings: Inaugural meeting of the consortium for autism, genetic neurodevelopmental disorders, and digestive diseases.

Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi-stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians' and researchers' perspectives, and (c) determine actionable steps for future research. The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified. The pre-conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non-Hispanic (87%). Constipation (80%), GI reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans. Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders.

Early life stress influences epilepsy outcomes in mice.

Stress is a common seizure trigger that has been implicated in worsening epilepsy outcomes. The neuroendocrine response to stress is mediated by the hypothalamic-pituitary-adrenal (HPA) axis and HPA axis dysfunction worsens epilepsy outcomes, increasing seizure burden, behavioral comorbidities, and risk for sudden unexpected death in epilepsy (SUDEP) in mice. Early life stress (ELS) reprograms the HPA axis into adulthood, impacting both the basal and stress-induced activity. Thus, we propose that ELS may influence epilepsy outcomes by influencing the function of the HPA axis. To test this hypothesis, we utilized the maternal separation paradigm and examined the impact on seizure susceptibility. We show that ELS exerts a sex dependent effect on seizure susceptibility in response to acute administration of the chemoconvulsant, kainic acid, which is associated with an altered relationship between seizure activity and HPA axis function. To further examine the impact of ELS on epilepsy outcomes, we utilized the intrahippocampal kainic acid model of chronic epilepsy in mice previously exposed to maternal separation. We find that the relationship between corticosterone levels and the extent of epileptiform activity is altered in mice subjected to ELS. We demonstrate that ELS impacts behavioral outcomes associated with chronic epilepsy in a sex-dependent manner, with females being more affected. We also observe reduced mortality (presumed SUDEP) in female mice subjected to ELS, consistent with previous findings suggesting a role for HPA axis dysfunction in SUDEP risk. These data demonstrate for the first time that ELS influences epilepsy outcomes and suggest that previous life experiences may impact the trajectory of epilepsy.

Transmethylation and Oxidative Biomarkers in Children with Autism Spectrum Disorder: A Cross Sectional Study.

We aimed to investigate the potential role of biomarkers of transmethylation, oxidative stress, and mitochondrial dysfunction in children with Autism Spectrum Disorder (ASD) by comparing them with that of typically developing children (TDC) controls. We also tried to correlate them with severity of autism, sensory issues, behavioural comorbidities and developmental quotients 119 with ASD and 52 age and sex matched typically developing children (TDC) controls were enrolled excluding those with chronic-illness or on any antioxidant therapy/multivitamins/anti-epileptic drugs. Median levels of biomarkers- serum homocysteine, cysteine, methionine, urine uric acid-to-creatinine ratio, arterial lactate, serum vitamin E, vitamin B12, folate, Nε-carboxymethyllysine, Nω- carboxymethylarginine (CMA), dityrosine and MTHFR C677T polymorphism were calculated. Children with ASD were further characterised using Childhood Autism Rating Scale-2, Childhood behavioural checklist, child sensory profile 2 caregiver questionnaire, Developmental Profile 3 for any correlation with the various biomarker levels. The median level of serum homocysteine in ASD group was 9 μmol/L(Range, 7- 16μmol/L), which was significantly higher than controls 7 μmol/L(Range, 4- 11μmol/L)(p=0.01). The prevalence of hyper-homocystinemia(>15μmol/L) was 13.4% in ASD as compared to 3.8% in controls with a significant difference(p=0.04). Dityrosine level was higher among ASD children when compared to TDC (9.8 vs 2.2 counts per second(cps), p<0.001). No significant correlation was found between prevalence of hyperhomocysteinemia and severity of autism/DQ/behavioural issues. No significant difference was found between the median levels of other biomarkers. Results support possible role of transmethylation defects and oxidative stress in ASD pathogenesis. Further studies are warranted for a better understanding of ASD pathogenesis.

Agomelatine Is Unable to Attenuate Kainic Acid-Induced Deficits in Early Life Communicative Behavior.

Early life seizures are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults; however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-h post-status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine's efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine's ability to correct neonatal communicative deficits is limited.

Social and emotional alterations in mice lacking the short dystrophin-gene product, Dp71

BackgroundThe Duchenne and Becker muscular dystrophies (DMD, BMD) are neuromuscular disorders commonly associated with diverse cognitive and behavioral comorbidities. Genotype–phenotype studies suggest that severity and risk of central defects in DMD patients increase with cumulative loss of different dystrophins produced in CNS from independent promoters of the DMD gene. Mutations affecting all dystrophins are nevertheless rare and therefore the clinical evidence on the contribution of the shortest Dp71 isoform to cognitive and behavioral dysfunctions is limited. In this study, we evaluated social, emotional and locomotor functions, and fear-related learning in the Dp71-null mouse model specifically lacking this short dystrophin. ResultsWe demonstrate the presence of abnormal social behavior and ultrasonic vocalization in Dp71-null mice, accompanied by slight changes in exploratory activity and anxiety-related behaviors, in the absence of myopathy and alterations of learning and memory of aversive cue-outcome associations.ConclusionsThese results support the hypothesis that distal DMD gene mutations affecting Dp71 may contribute to the emergence of social and emotional problems that may relate to the autistic traits and executive dysfunctions reported in DMD. The present alterations in Dp71-null mice may possibly add to the subtle social behavior problems previously associated with the loss of the Dp427 dystrophin, in line with the current hypothesis that risk and severity of behavioral problems in patients increase with cumulative loss of several brain dystrophin isoforms.

Specific Activation of Dopamine Receptor D1 Expressing Neurons in the PrL Alleviates CSDS-Induced Anxiety-Like Behavior Comorbidity with Postoperative Hyperalgesia in Male Mice.

Postoperative pain is a type of pain that occurs in clinical patients after surgery. Among the factors influencing the transition from acute postoperative pain to chronic postoperative pain, chronic stress has received much attention in recent years. Here, we investigated the role of dopamine receptor D1/D2 expressing pyramidal neurons in the prelimbic cortex (PrL) in modulating chronic social defeat stress (CSDS)-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice. Our results showed that preoperative CSDS induced anxiety-like behavior and significantly prolonged postoperative pain caused by plantar incision, but did not affect plantar wound recovery and inflammation. Reduced activation of dopamine receptor D1 or D2 expressing neurons in the PrL is a remarkable feature of male mice after CSDS, and chronic inhibition of dopamine receptor D1 or D2 expressing neurons in the PrL induced anxiety-like behavior and persistent postoperative pain. Further studies found that activation of D1 expressing but not D2 expressing neurons in the PrL ameliorated CSDS-induced anxiety-like behavior and postoperative hyperalgesia. Our results suggest that dopamine receptor D1 expressing neurons in the PrL play a crucial role in CSDS-induced anxiety-like behavior comorbidity with postoperative hyperalgesia in male mice.

Deep brain stimulation for Tourette's syndrome.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and harm of deep brain stimulation for motor symptoms, with psychiatric and behavioural comorbidities, either individually or in combination, in adults and adolescents with Tourette's syndrome compared to placebo, sham intervention, or the best available behavioural and pharmacological treatment.

Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner.

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from loss-of-function mutations in the neurofibromin gene and subsequent reduction in the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increases spontaneous grooming in a nonlinear spatial and temporal pattern, differentially increasing grooming of certain body parts, including the abdomen, head, and wings. This increase in grooming could be overridden by hunger in food-deprived foraging animals, demonstrating that the Nf1 effect is plastic and internal state-dependent. Stimulus-evoked grooming patterns were altered as well, with nf1 mutants exhibiting reductions in wing grooming when coated with dust, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. Thus, loss of Nf1 alters motor function without affecting overall motor coordination, in contrast to other genetic disorders that impair coordination. Overall, these results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting motor coordination.

Clinical and financial significance of insomnia within a large payor-provider health system.

Insomnia has profound negative effects on behavioral health, physical health, and functional domains. Leveraging claims data from one of the nation's largest payor-provider systems, the current study examined the real-world prevalence of insomnia, comorbidity of insomnia with behavioral health and other sleep disorders, and the impact of insomnia on total health care costs. Prevalence and costs associated with insomnia were assessed by examining claims data on approximately 3 million insured members during the year 2022. Using propensity score matching, total health care expenditures were calculated and compared for members with insomnia relative to matched cohorts without insomnia. Generalized linear modeling tested for differences between the cohorts. Nine percent of members were identified as having insomnia; 64% of those also had depression, anxiety, and/or substance use disorder. Median total health care costs among individuals with insomnia were 4-6 times greater than among those without insomnia. A disproportionate amount (21.1%) of total claims spend came from members with insomnia. Findings demonstrate a high degree of clinical need and behavioral health comorbidity associated with insomnia within a large insured cohort. Beyond the clinical significance, the current results demonstrate substantial financial need and opportunity for adequately treating insomnia. This is especially the case for the high proportion of members with insomnia and cooccurring depression, anxiety, and/or substance use disorders. Overall, the findings point to the important role payors and providers may have in promoting greater attention to sleep and insomnia.

(Auto)immunity in focal epilepsy: mechanisms of (auto‑)immune-inflammatory epileptogenic neurodegeneration

While the neuronal mechanisms of epileptic hyperexcitability (HE) have been studied in detail, recent findings suggest that extraneuronal, mainly immune-mediated inflammatory and vascular mechanisms play an important role in the development and progression of HE in epilepsy and the cognitive and behavioral comorbidities. Narrative review. As in autoimmune (limbic) encephalitis (ALE/AIE) or Rasmussen's encephalitis (RE), the primary adaptive and innate immune responses and associated changes in the blood-brain barrier (BBB) and neurovascular unit (NVU) can cause acute cortical hyperexcitability (HE) and the development of hippocampal sclerosis (HS) and other structural cortical lesions with chronic HE. Cortical HE, which is associated with malformation of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT), for example, can be accompanied by secondary adaptive and innate immune responses and alterations in the BBB and NVU, potentially modulating the ictogenicity and epileptogenicity. These associations illustrate the influence of adaptive and innate immune mechanisms and associated changes in the BBB and NVU on cortical excitability and vice versa, suggesting adynamic and complex interplay of these factors in the development and progression of epilepsy in general. The described concept of a neuro-immune-vascular interaction in focal epilepsy opens up new possibilities for the pathogenetic understanding and thus also for the selective therapeutic intervention.

Biochemical risk factors associated with refractory epilepsy: alpha synuclein and adenosine deaminase

Abstract Background Epilepsy is a common chronic neurological disorder affecting all age groups. A significant portion of children with epilepsy develop drug-resistant seizures. These children are at risk of cognitive and behavioral comorbidities and death. Some clinical features provide important information about the prognosis of epilepsy. However, currently, there is no objective biochemical indicator associated with refractory epilepsy. This study aimed to determine whether serum alpha-synuclein (αS), pglycoprotein (P-gp), and adenosine deaminase activity (ADA) were biochemical risk factors for refractory epilepsy. Methods The cross-sectional study included patients diagnosed with refractory epilepsy (n=32), non-refractory epilepsy (n=35) and 20 healthy children under the age of 18 who applied to the Pediatric Neurology outpatient clinic. In the serum samples, αS and P-gp were analyzed by ELISA and ADA activity was analyzed by spectrophotometric method. ROC analysis was applied and the area under the curve (AUC) was calculated to define cut-off values in distinguishing refractory epilepsy patients from non-refractory epilepsy patients. Binary logistic regression analysis was performed to define risk factors associated with resistance in patients with epilepsy. Results Children with epilepsy whose ADA activity and αS values were higher than the determined cut-off values had 10-fold and 5.3-fold increased risk of refractory epilepsy, respectively. Conclusions αS and ADA activity can be used as biochemical risk factors for refractory epilepsy. However, these results need to be confirmed by prospective studies with many patients.

Prevalence and clinical phenotypes of adult patients with attention deficit hyperactivity disorder and comorbid behavioral addictions.

Although the correlation between substance use disorder and attention deficit hyperactivity disorder (ADHD) has been largely studied, less is known about the correlation between behavioral addictions and ADHD. Thus, the aim of the present study was to investigate the prevalence of behavioral addictions in a large sample of adult patients with a primary diagnosis of ADHD and to compare the clinical profile of ADHD patients with and without behavioral addictions comorbidity. 248 consecutive adults newly diagnosed as ADHD patients were assessed through a series of validated scales for gambling disorder, internet, sex, shopping and food addictions. ADHD patients with at least one comorbid behavioral addiction were compared to non-comorbid patients on ADHD symptoms, impulsivity, mood and anxiety symptoms and functional impairment. 58.9% of patients had at least one behavioral addiction comorbidity. Of the whole sample, 31.9% of the patients had a comorbidity with one behavioral addiction while the 27% showed a comorbidity with two or more behavioral addictions. Internet addiction was the most common comorbidity (33.9%) followed by food addiction (28.6%), shopping addiction (19%), sex addiction (12.9%) and gambling disorder (3.6%). ADHD patients with comorbid behavioral addictions showed higher ADHD current and childhood symptoms, higher cognitive and motor impulsivity, higher mood and anxiety symptoms and higher functional impairment. Behavioral addictions are highly frequent in adult ADHD patients. Comorbid patients seem to have a more complex phenotype characterized by more severe ADHD, mood and anxiety symptoms, higher impulsivity levels and greater functional impairment.

Behavioral comorbidities treatment by fecal microbiota transplantation in canine epilepsy: a pilot study of a novel therapeutic approach.

Anxiety and cognitive dysfunction are frequent, difficult to treat and burdensome comorbidities in human and canine epilepsy. Fecal microbiota transplantation (FMT) has been shown to modulate behavior in rodent models by altering the gastrointestinal microbiota (GIM). This study aims to investigate the beneficial effects of FMT on behavioral comorbidities in a canine translational model of epilepsy. Nine dogs with drug-resistant epilepsy (DRE) and behavioral comorbidities were recruited. The fecal donor had epilepsy with unremarkable behavior, which exhibited a complete response to phenobarbital, resulting in it being seizure-free long term. FMTs were performed three times, two weeks apart, and the dogs had follow-up visits at three and six months after FMTs. Comprehensive behavioral analysis, including formerly validated questionnaires and behavioral tests for attention deficit hyperactivity disorder (ADHD)- and fear- and anxiety-like behavior, as well as cognitive dysfunction, were conducted, followed by objective computational analysis. Blood samples were taken for the analysis of antiseizure drug (ASD) concentrations, hematology, and biochemistry. Urine neurotransmitter concentrations were measured. Fecal samples were subjected to analysis using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based Dysbiosis Index (DI) assessment, and short-chain fatty acid (SCFA) quantification. Following FMT, the patients showed improvement in ADHD-like behavior, fear- and anxiety-like behavior, and quality of life. The excitatory neurotransmitters aspartate and glutamate were decreased, while the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABA/glutamate ratio were increased compared to baseline. Only minor taxonomic changes were observed, with a decrease in Firmicutes and a Blautia_A species, while a Ruminococcus species increased. Functional gene analysis, SCFA concentration, blood parameters, and ASD concentrations remained unchanged. Behavioral comorbidities in canine IE could be alleviated by FMT. This study highlights FMT's potential as a novel approach to improving behavioral comorbidities and enhancing the quality of life in canine patients with epilepsy.

Unraveling GRIA1 neurodevelopmental disorders: Lessons learned from the p.(Ala636Thr) variant.

Ionotropic glutamate receptors (iGluRs), specifically α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), play a crucial role in orchestrating excitatory neurotransmission in the brain. AMPARs are intricate assemblies of subunits encoded by four paralogous genes: GRIA1-4. Functional studies have established that rare GRIA variants can alter AMPAR currents leading to a loss- or gain-of-function. Patients affected by rare heterozygous GRIA variants tend to have family specific variants and only few recurrent variants have been reported. We deep-phenotyped a cohort comprising eight unrelated children and adults, harboring a recurrent and well-established disease-causing GRIA1 variant (NM_001114183.1: c.1906G>A, p.(Ala636Thr)). Recurrent symptoms included motor and/or language delay, mild-severe intellectual disability, behavioral and psychiatric comorbidities, hypotonia and epilepsy. We also report challenges in social skills, autonomy, living and work situation, and occupational levels. Furthermore, we compared their clinical manifestations in relation to those documented in patients presenting with rare heterozygous variants at analogous positions within paralogous genes. This study provides unprecedented details on the neurodevelopmental outcomes, cognitive abilities, seizure profiles, and behavioral abnormalities associated with p.(Ala636Thr) refining and broadening the clinical phenotype.

Natural history of adults with KBG syndrome: A physician-reported experience

PurposeKBG syndrome (KBGS) is a rare neurodevelopmental syndrome caused by haploinsufficiency of ANKRD11. The childhood phenotype is extensively reported but limited for adults. Thus, we aimed to delineate the clinical features of KBGS. MethodsWe collected physician-reported data of adults with molecularly confirmed KBGS through an international collaboration. Moreover, we undertook a systematic literature review to determine the scope of previously reported data. ResultsThe international collaboration identified 36 adults from 31 unrelated families with KBGS. Symptoms included mild/borderline intellectual disability (n = 22); gross and/or fine motor difficulties (n = 15); psychiatric and behavioral comorbidities including aggression, anxiety, reduced attention span, and autistic features (n = 26); nonverbal (n = 3), seizures with various seizure types and treatment responses (n = 10); ophthalmological comorbidities (n = 20). Cognitive regression during adulthood was reported once. Infrequent features included dilatation of the ascending aorta (n = 2) and autoimmune conditions (n = 4). Education, work, and residence varied, and the diversity of professional and personal roles highlighted the range of abilities seen. The literature review identified 154 adults reported across the literature, and we have summarized the features across both data sets. ConclusionOur study sheds light on the long-term neurodevelopmental outcomes, seizures, behavioral and psychiatric features, and education, work, and living arrangements for adults with KBGS.

Long-Term Mortality Predictors Using a Machine-Learning Approach in Patients With Chronic Limb-Threatening Ischemia After Peripheral Vascular Intervention.

Patients with chronic limb-threatening ischemia (CLTI) face a high long-term mortality risk. Identifying novel mortality predictors and risk profiles would enable individual health care plan design and improved survival. We aimed to leverage a random survival forest machine-learning algorithm to identify long-term all-cause mortality predictors in patients with CLTI undergoing peripheral vascular intervention. Patients with CLTI undergoing peripheral vascular intervention from 2017 to 2018 were derived from the Medicare-linked VQI (Vascular Quality Initiative) registry. We constructed a random survival forest to rank 66 preprocedural variables according to their relative importance and mean minimal depth for 3-year all-cause mortality. A random survival forest of 2000 trees was built using a training sample (80% of the cohort). Accuracy was assessed in a testing sample (20%) using continuous ranked probability score, Harrell C-index, and out-of-bag error rate. A total of 10 114 patients were included (mean±SD age, 72.0±11.0 years; 59% men). The 3-year mortality rate was 39.1%, with a median survival of 1.4 years (interquartile range, 0.7-2.0 years). The most predictive variables were chronic kidney disease, age, congestive heart failure, dementia, arrhythmias, requiring assisted care, living at home, and body mass index. A total of 41 variables spanning all domains of the biopsychosocial model were ranked as mortality predictors. The accuracy of the model was excellent (continuous ranked probability score, 0.172; Harrell C-index, 0.70; out-of-bag error rate, 29.7%). Our random survival forest accurately predicts long-term CLTI mortality, which is driven by demographic, functional, behavioral, and medical comorbidities. Broadening frameworks of risk and refining health care plans to include multidimensional risk factors could improve individualized care for CLTI.