Functional Neurological Disorder Presenting After Concussion: A Retrospective Case Series.

OBJECTIVE: Although a majority of individuals recover from a concussion within weeks of the index injury, a substantial minority of patients report persistent postconcussion symptoms. Some of these symptoms may reflect a diagnosis of functional neurological disorder (FND). The authors evaluated the relationship between persistent postconcussion symptoms and FND symptoms. METHODS: In this retrospective chart review, the authors characterized demographic and clinical information from 50 patients with a confirmed diagnosis of FND whose functional neurological symptoms started after a concussion. RESULTS: Patients who developed FND after a concussion had high rates of baseline risk factors for both persistent postconcussion symptoms and FND. After the concussive event, functional neurological symptoms presented abruptly or developed insidiously over time. Functional neurological symptoms ranged widely and included gait symptoms, seizures, speech and language symptoms, weakness, sensory symptoms, tremors, and vision and oculomotor symptoms. CONCLUSIONS: Functional neurological symptoms can arise after a concussion. FND should be considered in the differential diagnosis of individuals presenting with neurological symptoms beginning after a concussion. By failing to recognize functional symptoms, clinicians may inadvertently reinforce negative health-related beliefs regarding a patient's injured brain.

Endoxifen Approval for Bipolar Disorder in India: A Premature or a Pragmatic Decision?

ABSTRACT: In this commentary, we critique the Indian government's decision to approve endoxifen for the treatment of acute mania among adults.

Predicting disease onset from electronic health records for population health management: a scalable and explainable Deep Learning approach.

Introduction: The move from a reactive model of care which treats conditions when they arise to a proactive model which intervenes early to prevent adverse healthcare events will benefit from advances in the predictive capabilities of Artificial Intelligence and Machine Learning. This paper investigates the ability of a Deep Learning (DL) approach to predict future disease diagnosis from Electronic Health Records (EHR) for the purposes of Population Health Management. Methods: In this study, embeddings were created using a Word2Vec algorithm from structured vocabulary commonly used in EHRs e.g., Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) codes. This study is based on longitudinal medical data from ~50 m patients in the USA. We introduced a novel method of including binned observation values into an embeddings model. We also included novel features associated with wider determinants of health. Patient records comprising these embeddings were then fed to a Bidirectional Gated Recurrent Unit (GRU) model to predict the likelihood of patients developing Type 2 Diabetes Mellitus, Chronic Obstructive Pulmonary Disorder (COPD), Hypertension or experiencing an Acute Myocardial Infarction (MI) in the next 3 years. SHapley Additive exPlanations (SHAP) values were calculated to achieve model explainability. Results: Increasing the data scope to include binned observations and wider determinants of health was found to improve predictive performance. We achieved an area under the Receiver Operating Characteristic curve value of 0.92 for Diabetes prediction, 0.94 for COPD, 0.92 for Hypertension and 0.94 for MI. The SHAP values showed that the models had learned features known to be associated with these outcomes. Discussion: The DL approach outlined in this study can identify clinically-relevant features from large-scale EHR data and use these to predict future disease outcomes. This study highlights the promise of DL solutions for identifying patients at future risk of disease and providing clinicians with the means to understand and evaluate the drivers of those predictions.

Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.

Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, Setting, and Participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main Outcomes and Measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and Relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Meditation-induced psychosis: a narrative review and individual patient data analysis.

BACKGROUND: Meditation is associated with health benefits; however, there are reports that it may trigger or exacerbate psychotic states. In this review, we aim to collate case reports of psychotic disorders occurring in association with meditative practice and to discuss the relationship between psychosis and meditation. METHODOLOGY: We performed case-based analysis of all the existing studies published in English language using PubMed, PsycINFO, Cochrane, Scopus, EMBASE, CINAHL and Google Scholar with the search terms; 'Psychosis' OR 'Psychotic Symptoms' OR 'Schizophrenia' AND 'Meditation.' RESULTS: A total of 19 studies and 28 cases were included in the review. The patients described had an age range of 18-57 years; there was equal distribution of males and females. The diagnoses included acute psychosis in 14 cases, schizophrenia in 7 cases, mania with psychotic symptoms in 3 cases, and schizoaffective disorder in 1 case. The types of meditation described were Transcendent, Mindfulness, Buddhist Meditation like Qigong, Zen, and Theraveda, and others like Bikram yoga, Pranic Healing, and Hindustan Type meditation. Of the 28 cases reported, 14 patients had certain precipitating factors like insomnia, lack of food intake, history of mental illness, stress, and psychoactive substance use. CONCLUSION: There are case reports of psychotic disorder arising in association with meditative practice; however, it is difficult to attribute a causal relationship between the two. At the same time, there is a body of research describing the beneficial effect of meditative practice in clinical settings for patients with psychotic disorders. Appropriately designed studies are needed to further investigate the relationship between meditative practice and psychosis.

Clinical outcomes in high-hypoglycaemia-risk patients with type 2 diabetes switching to insulin glargine 300 U/mL versus a first-generation basal insulin analogue in the United States : Results from the DELIVER High Risk real-world study.

AIMS: To compare 12-month clinical effectiveness of insulin glargine 300 units/mL (Gla-300) versus first-generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla-100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla-300 or Gla-100/IDet) in a real-world setting. METHODS: DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla-300 (Gla-300 switchers) and were propensity score-matched (1:1) to patients who switched to Gla-100 or IDet (Gla-100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (<7% and <8%), and incidence and event rates of hypoglycaemia (all-hypoglycaemia and hypoglycaemia associated with an inpatient/emergency department [ED] contact). RESULTS: HbA1c reductions were similar following switching to Gla-300 or Gla-100/IDet (-0.51% vs. -0.53%; p = .67), and patients showed similar attainment of HbA1c goals. Patients in both cohorts had comparable all-hypoglycaemia incidence and event rates. However, the Gla-300 switcher cohort had a significantly lower risk of inpatient/ED-associated hypoglycaemia (adjusted odds ratio: 0.73, 95% confidence interval: 0.60-0.89; p = .002) and experienced significantly fewer inpatient/ED-associated hypoglycaemic events (0.21 vs. 0.33 events per patient per year; p < .001). CONCLUSION: In patients with T2D at high risk of hypoglycaemia, switching to Gla-300 or Gla-100/IDet achieved similar HbA1c reductions and glycaemic goal attainment, but Gla-300 switchers had a significantly lower risk of hypoglycaemia associated with an inpatient/ED contact during 12 months after switching.

Sleep duration, baseline cardiovascular risk, inflammation and incident cardiovascular mortality in ambulatory U.S. Adults: National health and nutrition examination survey.

INTRODUCTION: The interplay between sleep duration and inflammation on the baseline and incident cardiovascular (CV) risk is unknown. We sought to evaluate the association between sleep duration, C-reactive protein (CRP), baseline CV risk, and incident CV mortality. METHODS: We used data from the National Health and Nutrition Examination Survey 2005-2010 linked with the cause of death data from the National Center for Health Statistics for adults aged ≥18 years. The associations between self-reported sleep duration and CRP, 10-year atherosclerotic CV disease risk score (ASCVD) and CV mortality were assessed using Linear, Poisson and Cox proportional hazard modeling as appropriate. RESULTS: There were 17,635 eligible participants with a median age of 46 years (interquartile range [IQR] 31, 63). Among them, 51.3% were women and 46.9% were non-Hispanic Whites. Over a median follow-up of 7.5 years (IQR 6.0, 9.1), 350 CV deaths occurred at an incident rate of 2.7 per 1000-person years (IQR 2.4, 3.0). We observed a U-shaped associations between sleep duration and incident CV mortality rate (P-trend=0.011), sleep duration and 10-year ASCVD risk (P-trend <0.001), as well as sleep duration and CRP (P-trend <0.001). A self-reported sleep duration of 6-7 hours appeared most optimal. We observed that those participants who reported <6 or >7 hours of sleep had higher risk of CV death attributable to inflammation after accounting for confounders. CONCLUSIONS: There was a U-shaped relationship of incident CV mortality, 10-year ASCVD risk, and CRP with sleep duration. These findings suggest an interplay between sleep duration, inflammation, and CV risk.

Proteomic Portraits Reveal Evolutionarily Conserved and Divergent Responses to Spinal Cord Injury.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.

Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model.

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO2), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO2 values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.

How many people with type 2 diabetes fulfil the eligibility criteria for randomized, controlled trials of insulin glargine 300 U/mL in a real-world setting?

Randomized controlled trial (RCT) populations often do not reflect those typically seen in clinical practice. This retrospective, observational cohort study analysed the real-world data of people with type 2 diabetes (T2DM) prescribed basal insulin analogues from electronic medical records (EMRs) in the Explorys database, which includes data from 39 integrated healthcare systems in the United States, to determine how representative selected RCTs investigating insulin glargine 300 U/mL (Gla-300) are of T2DM populations in a real-world setting. Applying eligibility criteria derived from the EDITION 1, 2 and 3 (Gla-300 vs. insulin glargine 100 U/mL [Gla-100]) and BRIGHT (Gla-300 vs. insulin degludec) RCTs, we observed that only 17% (33 345/191 218) of people captured in the real-world database would have been eligible for such trials. Those who were ineligible tended to be older, had more comorbidities and a higher baseline hypoglycaemia rate than the eligible group. Using another large US EMR database (Optum Humedica) as corroboration, we found that 15% (36 285/235 697) would have been eligible to participate in the EDITION/BRIGHT RCTs. Furthermore, only 7% (1734/24 547) would have been eligible for the CONCLUDE (insulin degludec vs. Gla-300) RCT. Our findings remind us of the value of real-world data studies, complementing the results of RCTs, and providing additional insights into groups who would typically be excluded from RCTs.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

A study of pathways to care among opioid dependent individuals seeking treatment at a community de-addiction clinic in India.

Drug use, including opioid use disorder, is one of the rapidly rising and serious problems affecting populations globally. There is a treatment gap and delay in presentation of drug users to treatment centers. The present study aimed at assessing the pathways to care among opioid-dependent individuals seeking treatment from a community-based treatment center in India. In a cross-sectional observational study conducted at a community clinic of the National Drug Dependence Treatment Centre (NDDTC), New Delhi, India, a total of 100 treatment-seeking drug users (age 18-60 years) fulfilling DSM IV TR criteria for opioid dependence were recruited. The data were collected using a semistructured pro forma based on patient self-report and the encounter form used in the World Health Organization (WHO) Pathway Study. All participants were male, were mostly married, were employed, and belonged to nuclear families. Ninety-eight percent of participants has ever used heroin in a dependent fashion and 20% were using it currently. Mean age of the participants was 40.83 years (SD 12.7). Median age of onset of heroin use was 22 years (IQR 12). Median duration of heroin use was 138 months (IQR 132). Only 21% of participants visited the community deaddiction clinic at the first contact with care. The median time for first treatment-seeking attempt was 9.5 years (IQR 7). The study findings suggest significant delay between onset of drug-related problems and first treatment contact. There is a need to increase the availability and accessibility of treatment services to reduce the delay in treatment seeking.

Cerebrospinal Fluid Proteomics For Identification Of α2-Macroglobulin As A Potential Biomarker To Monitor Pharmacological Therapeutic Efficacy In Dopamine Dictated Disease States Of Parkinson's Disease And Schizophrenia.

AIM: Parkinson's disease and schizophrenia are clinical end points of dopaminergic deficit and excess, respectively, in the mid-brain. In accordance, current pharmacological interventions aim to restore normal dopamine levels, the overshooting of which culminates in adverse effects which results in psychotic symptoms in Parkinson's disease and extra-pyramidal symptoms in schizophrenia. Currently, there are no laboratory assays to assist treatment decisions or help foresee these drug side-effect outcomes. Therefore, the aim was to discover a protein biomarker that had a varying linear expression across the clinical dopaminergic spectrum. MATERIALS AND METHODS: iTRAQ-based proteomic experiments along with mass spectrometric analysis was used for comparative proteomics using cerebrospinal fluid (CSF). CSF fluid was collected from 36 patients with Parkinson's disease, 15 patients with urological diseases that served as neurological controls, and seven schizophrenic patients with hallucinations. Validation included ELISA and pathway analysis to highlight the varying expression and provide plausible molecular pathways for differentially expressed proteins in the three clinical phenotypes. RESULTS: Protein profiles were delineated in CSF from Parkinson's disease patients, neurological control and schizophrenia, respectively. Ten of the proteins that were identified had a linear relationship across the dopaminergic spectrum. α-2-Macroglobulin showed to be having high statistical significance on inter-group comparison on validation studies using ELISA. CONCLUSIONS: Non-gel-based proteomic experiments are an ideal platform to discover potential biomarkers that can be used to monitor pharmaco-therapeutic efficacy in dopamine-dictated clinical scenarios. α-2 Macroglobulin is a potential biomarker to monitor pharmacological therapy in Parkinson's disease and schizophrenia.

Effect of a Community Health Worker-Based Approach to Integrated Cardiovascular Risk Factor Control in India: A Cluster Randomized Controlled Trial.

BACKGROUND: Eighty percent of premature mortality from cardiovascular disease occurs in low- and middle-income countries. Hypertension, diabetes, and smoking are the top risk factors causing this disease burden. OBJECTIVES: The study aimed to test the hypothesis that utilizing community health workers (CHWs) to manage hypertension, diabetes and smoking in an integrated manner would lead to improved control of these conditions. METHODS: This was a 2-year cluster (n = 12) randomized controlled trial of 3,556 adults (35 to 70 years of age) in a single town in India, who were screened at home for hypertension, diabetes, and smoking. Of these adults, 1,242 (35%) had at least 1 risk factor (hypertension = 650, diabetes = 317, smoking = 500) and were enrolled in the study. The intervention group had behavioral change communication through regular home visits from community health workers. The control group received usual care in the community. The primary outcomes were changes in systolic blood pressure, fasting blood glucose, and average number of cigarettes/bidis smoked daily among individuals with respective risk factors. RESULTS: The mean ± SD change in systolic blood pressure at 2 years was -12.2 ± 19.5 mm Hg in the intervention group as compared with -6.4 ± 26.1 mm Hg in the control group, resulting in an adjusted difference of -8.9 mm Hg (95% confidence interval [CI]: -3.5 to -14.4 mm Hg; p = 0.001). The change in fasting blood glucose was -43.0 ± 83.5 mg/dl in the intervention group and -16.3 ± 77.2 mg/dl in the control group, leading to an adjusted difference of -21.3 mg/dl (95% CI: 18.4 to -61 mg/dl; p = 0.29). The change in mean number of cigarettes/bidis smoked was nonsignificant at +0.2 cigarettes/bidis (95% CI: 5.6 to -5.2 cigarettes/bidis; p = 0.93). CONCLUSIONS: A population-based strategy of integrated risk factor management through community health workers led to improved systolic blood pressure in hypertension, an inconclusive effect on fasting blood glucose in diabetes, and no demonstrable effect on smoking. (Study of a Community-Based Approach to Control Cardiovascular Risk Factors in India [SEHAT]; NCT02115711).