Surgery is associated with better long-term outcomes than pharmacological treatment for obesity: a systematic review and meta-analysis.

Obesity is a highly prevalent disease with numerous complications. Both intensive medical treatment with the use of pharmacological drugs and bariatric surgery are current options. The objective of this meta-analysis was to compare, in the long-term, intensive medical treatment and surgery based on twelve parameters related to weight loss, cardiovascular and endocrine changes. A review of the literature was conducted in accordance with the PRISMA guidelines (PROSPERO: CRD42021265637). The literature screening was done from inception to October 2023 through PubMed, EMBASE and Web of Science databases. We included randomized clinical trials that had separate groups for medical treatment and bariatric surgery as an intervention for obesity. The risk of bias was assessed through RoB2. A meta-analysis was performed with measures of heterogeneity and publication bias. Subgroup analysis for each surgery type was performed. Data is presented as forest-plots. Reviewers independently identified 6719 articles and 6 papers with a total 427 patients were included. All studies were randomized controlled trials, three had a follow up of 5 years and two had a follow up of 10 years. Both groups demonstrated statistical significance for most parameters studied. Surgery was superior for weight loss (- 22.05 kg [- 28.86; - 15.23), total cholesterol (- 0.88 [- 1.59; - 0.17]), triglycerides (- 0.70 [- 0.82; - 0.59]), HDL (0.12 [0.02; 0.23]), systolic pressure (- 4.49 [- 7.65; - 1.33]), diastolic pressure (- 2.28 [- 4.25; - 0.31]), Hb glycated (- 0.97 [- 1.31; - 0.62]), HOMA IR (- 2.94; [- 3.52; - 2.35]) and cardiovascular risk (- 0.08; [- 0.10; - 0.05]). Patient in the surgical treatment group had better long term outcomes when compared to the non-surgical group for most clinical parameters.

The Relationship between Injury Characteristics and Post-Traumatic Recovery after Diffuse Axonal Injury.

BACKGROUND: The diagnosis and prognosis of diffuse axonal injury (DAI) remain challenging. This research aimed to analyze the impact on activities of daily living (ADL), functional outcomes, quality of life (QoL), and the association between lesion severity and DAI location identified through imaging exams. METHODS: This prospective cohort study included 95 patients diagnosed with DAI. Data were collected at admission, three, six, and twelve months post-injury. The associations between variables were evaluated using a mixed-effects model. RESULTS: Functional recovery and QoL improved between three and twelve months after DAI. An interaction was observed between independence in performing ADL and subarachnoid hemorrhage (p = 0.043) and intraventricular hemorrhage (p = 0.012). Additionally, an interaction over time was observed between the Glasgow Outcome Scale (GOS) and DAI severity (p < 0.001), brain lesions (p = 0.014), and the Disability Rating Scale (DRS) with injury in brain hemispheres (p = 0.026) and Adams classification (p = 0.013). Interaction effects over time were observed with the general health perceptions and energy/vitality domains with intraventricular hemorrhage, and the social functioning domain with the obliteration of basal cisterns and Gentry's classification. CONCLUSION: The use of CT in the acute phase of DAI is important for predicting outcomes. The severity and location of DAI are associated with functional outcomes, ADL, and QoL.

New perspectives on assessment and understanding of the patient with cranial bone defect: a morphometric and cerebral radiodensity assessment.

Background: Skull defects after decompressive craniectomy (DC) cause physiological changes in brain function and patients can have neurologic symptoms after the surgery. The objective of this study is to evaluate whether there are morphometric changes in the cortical surface and radiodensity of brain tissue in patients undergoing cranioplasty and whether those variables are correlated with neurological prognosis. Methods: This is a prospective cohort with 30 patients who were submitted to cranioplasty and followed for 6 months. Patients underwent simple head CT before and after cranioplasty for morphometric and cerebral radiodensity assessment. A complete neurological exam with Mini-Mental State Examination (MMSE), modified Rankin Scale, and the Barthel Index was performed to assess neurological prognosis. Results: There was an improvement in all symptoms of the syndrome of the trephined, specifically for headache (p = 0.004) and intolerance changing head position (p = 0.016). Muscle strength contralateral to bone defect side also improved (p = 0.02). Midline shift of intracranial structures decreased after surgery (p = 0.004). The Anterior Distance Difference (ADif) and Posterior Distance Difference (PDif) were used to assess morphometric changes and varied significantly after surgery. PDif was weakly correlated with MMSE (p = 0.03; r = -0.4) and Barthel index (p = 0.035; r = -0.39). The ratio between the radiodensities of gray matter and white matter (GWR) was used to assess cerebral radiodensity and was also correlated with MMSE (p = 0.041; r = -0.37). Conclusion: Morphological anatomy and radiodensity of the cerebral cortex can be used as a tool to assess neurological prognosis after DC.

Left-sided epileptiform activity influences language lateralization in right mesial temporal sclerosis.

OBJECTIVE: To investigate the association between left epileptiform activity and language laterality indices (LI) in patients with right mesial temporal sclerosis (MTS). METHODS: Twenty-two patients with right MTS and 22 healthy subjects underwent fMRI scanning while performing a language task. LI was calculated in multiple regions of interest (ROI). Data on the presence of left epileptiform abnormalities were obtained during prolonged video-EEG monitoring. RESULTS: After correction for multiple comparisons, LI was reduced in the middle temporal gyrus in the left interictal epileptiform discharges (IED+) group, compared with the left IED- group (p < 0.05). SIGNIFICANCE: Using a responsive reading naming fMRI paradigm, right MTS patients who presented left temporal interictal epileptiform abnormalities on video-EEG showed decreased LI in the middle temporal gyrus, indicating decreased left middle temporal gyrus activation, increased right middle temporal gyrus activation or a combination of both, demonstrative of language network reorganization, specially in the MTG, in this patient population. PLAIN LANGUAGE SUMMARY: This research studied 22 patients with right mesial temporal sclerosis (a specific type of epilepsy) comparing them to 22 healthy individuals. Participants were asked to perform a language task while undergoing a special brain imaging technique (fMRI). The findings showed that patients with epilepsy displayed a change in the area of the brain typically responsible for language processing. This suggests that their brains may have adapted due to their condition, altering the way language is processed.

Role of temporary arterial occlusion in subarachnoid hemorrhage outcomes: a prospective cohort study.

PURPOSE: Temporary arterial occlusion (TAO) is a widespread practice in the surgical treatment of intracranial aneurysms. This study aimed to investigate TAO's role during ruptured aneurysm clipping as an independent prognostic factor on short- and long-term outcomes. METHODS: This prospective cohort included 180 patients with ruptured intracranial aneurysms and an indication of microsurgical treatment. Patients who died in the first 12 hours after admission were excluded. RESULTS: TAO was associated with intraoperative rupture (IOR) (odds ratio - OR = 10.54; 95% confidence interval - 95%CI 4.72-23.55; p < 0.001) and surgical complications (OR = 2.14; 95%CI 1.11-4.07; p = 0.01). The group with TAO and IOR had no significant difference in clinical (p = 0.06) and surgical (p = 0.94) complications compared to the group that had TAO, but no IOR. Among the 111 patients followed six months after treatment, IOR, number of occlusions, and total time of occlusion were not associated with Glasgow Outcome Scale (GOS) in the follow-up (respectively, p = 0.18, p = 0.30, and p = 0.73). Among patients who underwent TAO, IOR was also not associated with GOS in the follow-up (p = 0.29). CONCLUSIONS: TAO was associated with IOR and surgical complications, being the latter independent of IOR occurrence. In long-term analysis, neither TAO nor IOR were associated with poor clinical outcomes.

Bilateral ictal EEG is associated with better memory outcome after hippocampal sclerosis surgery.

OBJECTIVE: To compare memory outcomes after surgery for unilateral hippocampal sclerosis (HS)-associated epilepsy in patients with unilateral and bilateral ictal electrographic involvement. METHODS: We prospectively evaluated HS patients, aged 18-55 years and IQ ≥70. Left (L) and right (R) surgical groups underwent noninvasive video-EEG monitoring and Wada test. We classified patients as Ipsilateral if ictal EEG was restricted to the HS side, or Bilateral, if at least one seizure onset occurred contralaterally to the HS, or if ictal discharge evolved to the opposite temporal region. Patients who declined surgery served as controls. Memory was evaluated on two occasions with Rey Auditory-Verbal Learning Test and Rey Visual-Design Learning Test. Baseline neuropsychological test scores were compared between groups. Pre- and postoperative scores were compared within each group. Reliable change index Z-scores (RCI) were obtained using controls as references, and compared between surgical groups. RESULTS: We evaluated 64 patients. Patients were classified as: L-Ipsilateral (9), L-Bilateral (15), L-Control (9), R-Ipsilateral (10), R-Bilateral (9), and R-Control (12). On preoperative evaluation, memory performance did not differ among surgical groups. Right HS patients did not present postoperative memory decline. L-Ipsilateral group presented postoperative decline on immediate (P = 0.036) and delayed verbal recall (P = 0.011), while L-Bilateral did not decline. L-Ipsilateral had lower RCI Z-scores, indicating delayed verbal memory decline compared to L-Bilateral (P = 0.012). SIGNIFICANCE: Dominant HS patients with bilateral ictal involvement presented less pronounced postoperative verbal memory decline compared to patients with exclusive ipsilateral ictal activity. Surgery was indicated in these patients regardless of memory impairment on neuropsychological testing, since resection of the left sclerotic hippocampus could result in cessation of contralateral epileptiform activity, and, therefore, improved memory function.

Prospective Analysis of Cerebral Edema Admission and Clinical Outcome in Ruptured Intracranial Aneurysm.

AIM: To evaluate the association between global cerebral edema (GCE) after subarachnoid hemorrhage (SAH) and its impact on functional outcome evaluated by the modified Rankin scale (mRS). MATERIAL AND METHODS: This is a prospective cohort study with patients who were admitted to the hospital due to SAH. During the period from January 2018 to November 2019, 107 patients with intracranial aneurysms were enrolled. Using univariate and multivariate analysis, we sought to identify predictors and evaluated the impact of GCE on outcome after 6 months using the mRS. RESULTS: GCE was present in 54 (50.5%) patients, of which 27 (25.2%) were mild, 20 (18.7%) moderate and 7 (6.5%) were severe. Univariate analysis identified high Hunt-Hess and Glasgow coma scale on clinical admission as predictors factors of GCE (p < 0.05), and higher modified Fisher scale as a radiological predictor of Glasgow coma scale (p < 0.05). Thirty-three (30.8%) patients were deceased at 6 months. Death or severe disability were predicted by higher age, poor clinical scale on admission and severe GCE (p < 0.05). CONCLUSION: GCE on admission is independently associated with poor clinical outcomes at discharge, and six months after SAH. Given its strong association with poor clinical grade on admission, GCE should be considered a straightforward and radiological important marker of early brain injury, with ominous implications.

Cost, efficacy, and safety comparison between early intensive and escalating strategies for multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: The optimal treatment strategy of multiple sclerosis (MS) is a matter of debate. The classical approach is the escalating (ESC) strategy, which consists of starting with low- to moderate-efficacy disease-modifying drugs (DMDs) and upscale to high-efficacy DMDs when noting some evidence of active disease. Another approach, the early intensive (EIT) strategy, is starting with high-efficiency DMDs as first-line therapy. Our goal was to compare effectiveness, safety, and cost of ESC and EIT strategies. METHODS: We searched MEDLINE, EMBASE and SCOPUS until September 2022, for studies comparing EIT and ESC strategies in adult participants with relapsing-remitting MS and a minimum follow-up of 5 years. We examined the Expanded Disability Severity Scale (EDSS), the proportion of severe adverse events, and cost in a 5-year period. Random-effects meta-analysis summarized the efficacy and safety and an EDSS-based Markov model estimated the cost. RESULTS: Seven studies with 3,467 participants showed a 30% reduction in EDSS worsening in 5 years (RR 0.7; [0.59-0.83]; p < 0.001) in the EIT group vs in the ESC group. Two studies with 1,118 participants suggested a similar safety profile for these strategies (RR 1.92; [0.38-9.72]; p = 0.4324). EIT with natalizumab in extended interval dosing, rituximab, alemtuzumab, and cladribine demonstrated cost-effectiveness in our model. DISCUSSION: EIT presents higher efficacy in preventing disability progression, a similar safety profile, and can be cost-effective within a 5-year timeline.

Is percutaneous balloon compression better than microvascular decompression to treat trigeminal neuralgia? A systematic review and meta-analysis.

BACKGROUND: Trigeminal neuralgia (TN) is a neuropathic pain that affects one or more branches of the trigeminal nerve. Surgical options after pharmacological failure are Microvascular Decompression (MVD) or percutaneous procedures, which include Balloon Compression (PBC). This study aims to describe pain outcomes and complications after PBC and MVD procedures for patients with trigeminal neuralgia. METHODS: We performed a systematic review and meta-analysis on PubMed, EMBASE, LILACS, and Web of Science databases up to April 2022, following PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and meta-Analysis). Articles that separately describe pain outcome for MVD and PBC were included. MINORS tool was used for bias assessment. Meta-analysis results are presented in forest plot and funnel plot. RESULTS: 853 studies were assessed for screening, and 11 studies met the inclusion criteria for this review. A total of 1046 patients underwent PBC and 1324 underwent MVD. The subgroup analysis for patients without multiple sclerosis shows that MVD was associated with lower number of patients with pain than PBC, with an OR value of 0.54 (95 % CI 0.34-0.84). All other analyses evidenced a tendency for better outcomes after the MVD procedure, but with no statistically significant difference. CONCLUSION: Considering short and long pain relief, recurrence of pain and total complications for MVD and PBC, our study found that MVD is the best surgical option available for trigeminal neuralgia.

Role of temporary arterial occlusion in subarachnoid hemorrhage outcomes: a prospective cohort study

Purpose: Temporary arterial occlusion (TAO) is a widespread practice in the surgical treatment of intracranial aneurysms. This study aimed to investigate TAO's role during ruptured aneurysm clipping as an independent prognostic factor on short- and long-term outcomes. Methods: This prospective cohort included 180 patients with ruptured intracranial aneurysms and an indication of microsurgical treatment. Patients who died in the first 12 hours after admission were excluded. Results: TAO was associated with intraoperative rupture (IOR) (odds ratio ­ OR = 10.54; 95% confidence interval ­ 95%CI 4.72­23.55; p < 0.001) and surgical complications (OR = 2.14; 95%CI 1.11­4.07; p = 0.01). The group with TAO and IOR had no significant difference in clinical (p = 0.06) and surgical (p = 0.94) complications compared to the group that had TAO, but no IOR. Among the 111 patients followed six months after treatment, IOR, number of occlusions, and total time of occlusion were not associated with Glasgow Outcome Scale (GOS) in the follow-up (respectively, p = 0.18, p = 0.30, and p = 0.73). Among patients who underwent TAO, IOR was also not associated with GOS in the follow-up (p = 0.29). Conclusions: TAO was associated with IOR and surgical complications, being the latter independent of IOR occurrence. In long-term analysis, neither TAO nor IOR were associated with poor clinical outcomes.

External validation of the Glasgow coma scale-pupils in low- to middle-income country patients with traumatic brain injury: Could "motor score-pupil" have higher prognostic value?

Background: The objective of this study is to validate the admission Glasgow coma scale (GCS) associated with pupil response (GCS-P) to predict traumatic brain injury (TBI) patient's outcomes in a low- to middle-income country and to compare its performance with that of a simplified model combining the better motor response of the GCS and the pupilar response (MS-P). Methods: This is a prospective cohort of patients with TBI in a tertiary trauma reference center in Brazil. Predictive values of the GCS, GCS-P, and MS-P were evaluated and compared for 14 day and in-hospital mortality outcomes and length of hospital stay (LHS). Results: The study enrolled 447 patients. MS-P demonstrated better discriminative ability than GCS to predict mortality (AUC 0.736 × 0.658; P < 0.001) and higher AUC than GCS-P (0.736 × 0.704, respectively; P = 0.073). For hospital mortality, MS-P demonstrated better discrimination than GCS (AUC, 0.750 × 0.682; P < 0.001) and higher AUC than GCS-P (0.750 × 0.714; P = 0.027). Both scores were good predictors of LHS (r2 = 0.084 [GCS-P] × 0.079 [GCS] × 0.072 [MS-P]). Conclusion: The predictive value of the GCS, GCS-P, and MS-P scales was demonstrated, thus contributing to its external validation in low- to middle-income country.

Cirrhosis and hernia repair in a cohort of 6352 patients in a tertiary hospital: Risk assessment and survival analysis.

The prevalence of hernias in patient with cirrhosis can reach up to 40%. The pathophysiology of cirrhosis is closely linked to that of the umbilical hernia, but other types are also common in this population. The aim of this study is to evaluate factors that influence in the prognosis after hernia repair in patients with cirrhosis. A historical cohort of 6419 patients submitted to hernia repair was gathered. Clinical, epidemiological data and hernia characteristics were obtained. For patient with cirrhosis, data from exams, surgery and follow-up outcomes were also analyzed. Survival curves were constructed to assess the impact of clinical and surgical variables on survival. 342 of the 6352 herniated patients were cirrhotic. Patient with cirrhosis had a higher prevalence of umbilical hernia (67.5% × 24.2%, P < .001) and a lower prevalence of epigastric (1.8% × 9.0%, P < .001) and lumbar (0% × 0.18%, P = .022). There were no significant differences in relation to inguinal hernia (P = .609). Ascites was present in 70.1% of patient with cirrhosis and its prevalence was different in relation to the type of hernia (P < .001). The survival curve showed higher mortality for emergency surgery, MELD > 14 and ascites (HR 12.6 [3.79-41.65], 4.5 [2.00-10.34], and 6.1 [1.15-20.70], respectively, P < .05). Hernia correction surgery in patient with cirrhosis has a high mortality, especially when performed under urgent conditions associated with more severe clinical conditions of patients, such as the presence of ascites and elevated MELD.

Long-Term Outcomes in Severe Traumatic Brain Injury and Associated Factors: A Prospective Cohort Study.

OBJECTIVE: The presence of focal lesion (FL) after a severe traumatic brain injury is an important factor in determining morbidity and mortality. Despite this relevance, few studies show the pattern of recovery of patients with severe traumatic brain injury (TBI) with FL within one year. The objective of this study was to identify the pattern of recovery, independence to perform activities of daily living (ADL), and factors associated with mortality and unfavorable outcome at six and twelve months after severe TBI with FL. METHODOLOGY: This is a prospective cohort, with data collected at admission, hospital discharge, three, six, and twelve months after TBI. RESULTS: The study included 131 adults with a mean age of 34.08 years. At twelve months, 39% of the participants died, 80% were functionally independent by the Glasgow Outcome Scale Extended, 79% by the Disability Rating Scale, 79% were independent for performing ADLs by the Katz Index, and 53.9% by the Lawton Scale. Report of alcohol intake, sedation time, length of stay in intensive care (ICU LOS), Glasgow Coma Scale, trauma severity indices, hyperglycemia, blood glucose, and infection were associated with death. At six and twelve months, tachypnea, age, ICU LOS, trauma severity indices, respiratory rate, multiple radiographic injuries, and cardiac rate were associated with dependence. CONCLUSIONS: Patients have satisfactory functional recovery up to twelve months after trauma, with an accentuated improvement in the first three months. Clinical and sociodemographic variables were associated with post-trauma outcomes. Almost all victims of severe TBI with focal lesions evolved to death or independence.

Microsurgery versus embolization: different risk factors for short- and longterm outcomes of patients with ruptured aneurysms.

PURPOSE: To evaluate the risk factors for poor outcomes after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Patients with ≥ 18-years of age and aSAH were included, while patients who died within 12 h of admission or lost follow-up were excluded. All participants underwent standardized clinical and radiological assessment on admission and were reassessed at discharge and at 6-months follow-up using the Glasgow Outcome Scale (GOS). RESULTS: Death at discharge was associated with female gender, anterior communication artery (ACoA) aneurysm location and presence of atherosclerotic plaque in the surgical group, and with age in the endovascular group. Both groups had clinical condition on follow-up associated with mFisher score on admission and hypertension. GOS on follow-up was also associated with presence of atherosclerotic plaque and multiple aneurysms in surgical group, and with age in endovascular group. CONCLUSIONS: Subjects treated surgically are prone to unfavorable outcomes if atherosclerotic plaques and multiple aneurysms are present. In patients with endovascular treatment, age was the main predictor of clinical outcome.

Homocysteine is associated with higher risks of ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: High levels of homocysteine (Hct) have been associated with great risks of ischemic stroke. However, some controversy still exists. We performed a systematic review and meta-analysis to compare the levels of Hct between patients with ischemic stroke and controls. METHODS: We performed a systematic literature search for articles reporting Hct levels of patients with occurrence of ischemic stroke. We employed a random-effects inverse-variance weighted meta-analytical approach in order to pool standardized mean differences, with estimation of τ2 through the DerSimonian-Laird method. RESULTS: The initial search yielded 1361 studies. After careful analysis of abstracts and full texts, the meta-analysis included data from 38 studies, which involved almost 16 000 stroke events. However, only 13 studies reported means and standard deviations for cases and controls, and therefore were used in the meta-analysis. Those studies presented data from 5002 patients with stroke and 4945 controls. Standardized mean difference was 1.67 (95% CI 1.00-2.25, P < 0.01), indicating that Hct levels were significantly larger in patients with ischemic stroke compared to controls. Between-study heterogeneity was very large (I2 = 99%), particularly because three studies showed significantly large mean differences. CONCLUSION: This meta-analysis shows that patients with ischemic stroke have higher levels of Hct compared to controls. Whether this is a modifiable risk factor remains to be assessed through larger prospective cohorts.

MICRObiota on BILIOpancreatic malignant diseases [MICROBILIO]: A systematic review.

INTRODUCTION: The increase in the incidence of pancreatic and biliary cancers has attracted the search for methods of early detection of diseases and biomarkers. The authors propose to analyze new findings on the association between microbiota and Pancreatic Ductal Adenocarcinoma (PDAC) or Cholangiocarcinoma (CCA). METHODS: This systematic review was carried out according to the items of Preferred Reports for Systematic Reviews and Protocol Meta-Analysis (PRISMA-P). This study was registered by the Prospective Register of Systematic Reviews (PROSPERO), identification code CRD42020192748 before the review was carried out. Articles were selected from the PUBMED, EMBASE, and Cochrane databases. RESULTS: Most studies (86.67%) used 16s rRNA as a sequencing method. The main comorbidities found were diabetes mellitus, systemic arterial hypertension, and dyslipidemia. Many studies were limited by the small number of participants, but the biases were mostly low. There was very little concordance about the composition of the microbiome of different sites, for both case and control groups when compared to other studies' results. Bile sample analysis was the one with a greater agreement between studies, as three out of four studies found Escherichia in cases of CCA. CONCLUSION: There was great disagreement in the characterization of both the microbiota of cases and control groups. Studies are still scarce, making it difficult to adequately assess the data in this regard. It was not possible to specify any marker or to associate any genus of microbiota bacteria with PDAC or CCA.

Seizure control in mono- and combination therapy in a cohort of patients with Idiopathic Generalized Epilepsy.

Idiopathic Generalized Epilepsy (IGE) patients may not achieve optimal seizure control with monotherapy. Our goal was to evaluate the efficacy of combination therapy in a retrospective series of IGE patients receiving different antiseizure medication (ASM) regimens. We retrospectively identified all patients with adolescence onset IGE with typical clinical and EEG features from a single epilepsy specialist clinic from 2009 to 2020. We evaluated long-term seizure control, for VPA, LEV, LTG mono and combination therapy. We studied 59 patients. VPA was more commonly used in men (84%) than in women (44%) (p < 0.05). VPA was the initial drug of choice in 39% of patients, followed by LEV (22%) and LTG (14.9%). Thirty-nine patients (66.1%) achieved complete seizure control for at least one year. Fifty patients (84.7)% had partial control, without GTC occurrence, for at least one year. VPA was superior to LTG for complete seizure control (p = 0.03), but not for minor seizure control or pseudoresistance (p > 0.05). Combination therapy was superior to LEV and LTG monotherapy for complete control (p = 0.03), without differences for minor seizures and pseudoresistance outcomes (p > 0.05). Combination therapy not including VPA was also non-inferior to VPA monotherapy in all settings. Combination therapy was superior to LTG and LEV monotherapy in IGE, and may be equally effective including or not VPA. Combination therapy including LTG, LEV, and/or VPA is an effective treatment option after monotherapy failure with one of these ASM in IGE. Dual therapy with LEV-LTG should be considered in monotheraphy failure, to avoid fetal effects of in utero VPA exposure.