Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Catheterization for Congenital Heart Disease Adjustment for Risk Method II.

BACKGROUND: Current metrics used to adjust for case mix complexity in congenital cardiac catheterization are becoming outdated due to the introduction of novel procedures, innovative technologies, and expanding patient subgroups. This study aims to develop a risk adjustment methodology introducing a novel, clinically meaningful adverse event outcome and incorporating a modern understanding of risk. METHODS: Data from diagnostic only and interventional cases with defined case types were collected for patients ≤18 years of age and ≥2.5 kg at all Congenital Cardiac Catheterization Project on Outcomes participating centers. The derivation data set consisted of cases performed from 2014 to 2017, and the validation data set consisted of cases performed from 2019 to 2020. Severity level 3 adverse events were stratified into 3 tiers by clinical impact (3a/b/c); the study outcome was clinically meaningful adverse events, severity level ≥3b (3bc/4/5). RESULTS: The derivation data set contained 15 224 cases, and the validation data set included 9462 cases. Clinically meaningful adverse event rates were 4.5% and 4.2% in the derivation and validation cohorts, respectively. The final risk adjustment model included age <30 days, Procedural Risk in Congenital Cardiac Catheterization risk category, and hemodynamic vulnerability score (C statistic, 0.70; Hosmer-Lemeshow P value, 0.83; Brier score, 0.042). CONCLUSIONS: CHARM II (Congenital Heart Disease Adjustment for Risk Method II) risk adjustment methodology allows for equitable comparison of clinically meaningful adverse events among institutions and operators with varying patient populations and case mix complexity performing pediatric cardiac catheterization.

Strongyloides stercoralis Infection in Humans: A Narrative Review of the Most Neglected Parasitic Disease.

Strongyloidiasis is a helminth infection affecting 613.9 million people annually, mainly in the tropics and subtropics. The reported seroprevalence in the United States is 4% with most of the cases reported in immigrants. Human T-lympho-tropic virus 1 (HTLV-1) infections, hypogammaglobulinemia, immunosuppressant use - particularly steroid use, alcoholism, and malnutrition have been associated with an increased risk of strongyloidiasis. Recently, cases of strongyloidiasis hyperinfection syndrome have been described in coronavirus disease 2019 (COVID-19) patients treated with steroids as well. This brief review discusses the epidemiology, clinical features, management, and prevention of strongyloidiasis including some facts about the infection in pregnancy, transplant recipients, and COVID-19 patients. We conducted an online search using the PubMed, Scopus, and Google Scholar databases. Strongyloidiasis can be asymptomatic or present with mild symptoms. Strongyloides stercoralis is known to cause autoinfection. In immunocompromised individuals, it can present with severe symptoms, hyperinfection, or disseminated disease. Reported mortality in cases of disseminated Strongyloidiasis is 87.1%. Serology and detection of larvae in stool by direct microscopy are the most commonly used methods to diagnose strongyloidiasis. The drug of choice for the treatment is ivermectin. However, the use of ivermectin in human pregnancy is not well studied, and its teratogenic risks are unknown. Proactive screening of strongyloidiasis is necessary in immunocompromised individuals to prevent severe disease.

Sleep characteristics and inflammatory markers in women with post-traumatic stress disorder.

INTRODUCTION: Sexual violence is one of the most severe traumatic events. It is associated with a higher risk for post-traumatic stress disorder (PTSD) development. Sleep disturbances such as insomnia are frequently reported by PTSD patients and play a key role in the development and course of the disorder. Sleep disturbances are associated with higher levels of pro-inflammatory cytokines emphasizing the importance of sleep studies in individuals with PTSD. OBJECTIVES: To investigate the association between subjective and objective sleep measurements and PTSD symptoms with inflammatory markers in women with PTSD following sexual assault. METHODS: In this longitudinal study fifty-seven women with PTSD were evaluated for sleep measurements and inflammatory markers. Participants completed the Clinician-Administered PTSD Scale, the Beck Depression Inventory, the Pittsburgh Sleep Quality Index (PSQI), and the Insomnia Severity Index. In addition, patients underwent full in-lab polysomnography and serum levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) measurement. All assessments were performed at baseline and after one year. Patients received pharmacological and/or psychological interventions between baseline and one-year follow-up. RESULTS: Despite improving PTSD symptoms severity and sleep quality (expressed in PSQI), we found an increase in the inflammatory markers IL-1ß, TNF-α, IL-6 and CRP after one year of follow-up. These findings suggest that neurobiological processes may advance independently of PTSD symptoms. We found a significant increase in the levels of IL-1ß and TNF-α associated with decreased slow-wave sleep (p = 0.019 and p = 0.018 respectively), IL-6 associated with arousal index (p = 0.024), and CRP associated with insomnia severity (p = 0.012), and sleep duration longer than 6 h per night (p < 0.001). CONCLUSIONS: Sleep impairments in PTSD may be associated with a gradual and persistent alteration in the immune system, resulting in a progressive inflammatory process. Our results suggest that sleep mechanisms are involved in this incident inflammatory process in young women with PTSD.

Exploring procedure duration and risk for serious adverse events during congenital cardiac catheterization.

Objectives: While procedure length is considered an important metric for cardiothoracic surgical procedures, the relationship between procedure length and adverse events (AEs) in congenital cardiac catheterizations has little published data available. Furthermore, most existing congenital cardiac catheterization risk prediction models are built on logistic regression models. This study aimed to characterize the relationship between case length and AE occurrence in congenital cardiac catheterization while adjusting for known risk factors and to investigate the potential role of non-linear analysis in risk modeling. Design: Age, case type, and procedure duration were evaluated for relationships with the primary outcome using logistic regression. Non-linearity of the associations with continuous risk factors was assessed using restricted cubic spline transformations. Setting and participants: All diagnostic and interventional congenital cardiac catheterization cases performed at Boston Children's Hospital between January 1, 2014 and October 31, 2019 were analyzed. Main outcome measure: The primary outcome was defined as the occurrence of any clinically significant (level 3/4/5) AE. Results: A total of 7011 catheterization cases met inclusion criteria, with interventional procedures accounting for 68% of cases. Median case duration was 97 min. A multivariable model including age, procedure type, and case duration showed a significant relationship between case duration and AE occurrence (OR 1.07 per 10 min increase, 95% CI 1.06 to 1.09, p<0.001). Conclusions: This study demonstrated the importance of procedure duration as a potential frontier for procedure risk management. Better understanding of the role of procedure duration in cardiac catheterizations may provide opportunities for quality improvement in patient safety and resource planning.

COVID-19 international experience in paediatric patients with congenital heart disease.

OBJECTIVE: As COVID-19 continues to affect the global population, it is crucial to study the impact of the disease in vulnerable populations. This study of a diverse, international cohort aims to provide timely, experiential data on the course of disease in paediatric patients with congenital heart disease (CHD). METHODS: Data were collected by capitalising on two pre-existing CHD registries, the International Quality Improvement Collaborative for Congenital Heart Disease: Improving Care in Low- and Middle-Income Countries and the Congenital Cardiac Catheterization Project on Outcomes. 35 participating sites reported data for all patients under 18 years of age with diagnosed CHD and known COVID-19 illness during 2020 identified at their institution. Patients were classified as low, moderate or high risk for moderate or severe COVID-19 illness based on patient anatomy, physiology and genetic syndrome using current published guidelines. Association of risk factors with hospitalisation and intensive care unit (ICU) level care were assessed. RESULTS: The study included 339 COVID-19 cases in paediatric patients with CHD from 35 sites worldwide. Of these cases, 84 patients (25%) required hospitalisation, and 40 (12%) required ICU care. Age <1 year, recent cardiac intervention, anatomical complexity, clinical cardiac status and overall risk were all significantly associated with need for hospitalisation and ICU admission. A multivariable model for ICU admission including clinical cardiac status and recent cardiac intervention produced a c-statistic of 0.86. CONCLUSIONS: These observational data suggest risk factors for hospitalisation related to COVID-19 in paediatric CHD include age, lower functional cardiac status and recent cardiac interventions. There is a need for further data to identify factors relevant to the care of patients with CHD who contract COVID-19 illness.

Early Postoperative Congenital Cardiac Catheterization Outcomes: A Multicenter Study.

BACKGROUND: Early postoperative catheterizations (EPOCs) within 6 weeks after a congenital heart surgical procedure can treat residual lesions and provide important clinical information. However, EPOCs are often assumed to impose additional risk on a vulnerable patient population. This study aimed to describe the EPOC population, evaluate procedural safety, compare EPOC patients with procedure-matched non-EPOC patients, and determine risk factors for poor outcomes using data from the Congenital Cardiac Catheterization Project on Outcomes registry. METHODS: In a retrospective cohort, demographic, clinical, and procedural characteristics were analyzed for diagnostic and interventional catheterizations performed in 13 participating institutions from January 2014 to December 2017, excluding patients after heart transplant. The primary outcome was a high-severity adverse event (AE). Three distinct analyses included (1) describing the full cohort and EPOC patients, (2) comparing EPOC patients with and without a high-severity AE, and (3) comparing EPOC patients with controls matched on case type. RESULTS: This study included 17,776 catheterizations, with 1399 EPOCs. The high-severity AE rate was 6.4% overall, 8.9% in the EPOC cohort, and 8.4% in matched controls (P = .74). The association between EPOC status and high-severity AE was not significant in a multivariable model (P = .17). In EPOCs with a high-severity AE, median procedure duration was 30 minutes longer (P < .001), and median time from surgical procedure to catheterization was 3 days longer (P = .05). CONCLUSIONS: EPOC was not associated with additional risk. Individual patient characteristics of size and hemodynamic vulnerability may serve as informative predictors. Timely catheterization may preempt further clinical deterioration, and intraprocedure duration optimization may correlate with improved outcomes.

Peri-Traumatic Dissociation and Tonic Immobility as Severity Predictors of Posttraumatic Stress Disorder After Rape.

Some individuals show abnormal reactions to extreme fear and life-threatening situations, including tonic immobility (TI) and peri-traumatic dissociation (PTD). We aimed to investigate the association of TI and PTD with posttraumatic stress disorder (PTSD) in women who experienced sexual violence and the risk factors for PTD occurrence. We compared PTSD severity in 86 young adult women with PTSD after a sexual violence exposure grouped according to the presence of PTD and TI. In addition, we investigated whether PTD is associated with depression and anxiety symptoms and assessed potential risk factors for PTD reaction. We found a significant positive correlation between PTSD severity and PTD occurrence (R2 = .132; p = .001). PTD was also positively correlated with all clusters of PTSD symptoms except the Clinician-Administered PTSD Scale avoidance cluster (p = .058). PTD was strongly correlated with anxiety (R2 = .619; p < .001) and depressive symptoms (R2 = .547; p < .001). Multiple logistic regression showed that history of physical abuse (odds ratio [OR]: 1.386; p = .011) and sexual abuse (OR: 1.947; p = .004) during childhood were associated with PTD occurrence. Other risk factors for PTD were having less years of study (OR: 0.216; p = .016) and lower income (OR: 7.403; p = .028). TI measures were available for a subsample of 29 women. We found no association between TI and PTSD severity. PTD, but not TI, is significantly associated with more severe PTSD, depressive, and anxiety symptoms. Less-educated women with a history of childhood abuse and a lower income are at risk of PTD occurrence during a sexual violence episode.

Changes in Practice/Outcomes of Pediatric/Congenital Catheterization in Response to the First Wave of COVID.

Background: The COVID-19 pandemic has posed tremendous stress on the health care system. Its effects on pediatric/congenital catheterization program practice and performance have not been described. Objectives: The purpose of this study was to evaluate how case volumes, risk-profile, and outcomes of pediatric/congenital catheterization procedures changed in response to the first wave of COVID-19 and after that wave. Methods: A multicenter retrospective observational study was performed using Congenital Cardiac Catheterization Project on Outcomes Registry (C3PO) data to study changes in volume, case mix, and outcomes (high-severity adverse events [HSAEs]) during the first wave of COVID (March 1, 2020, to May 31, 2020) in comparison to the period prior to (January 1, 2019, to February 28, 2020) and after (June 1, 2020, to December 31, 2020) the first wave. Multivariable analyses adjusting for case type, hemodynamic vulnerability, and age group were performed. Hospital responses to the first wave were captured with an electronic study instrument. Results: During the study period, 12,557 cases were performed at 14 C3PO hospitals (with 8% performed during the first wave of COVID and 32% in the postperiod). Center case volumes decreased from a median 32.1 cases/month (IQR: 20.7-49.0 cases/month) before COVID to 22 cases/month (IQR: 13-31 cases/month) during the first wave (P = 0.001). The proportion of cases with risk factors for HSAE increased during the first wave, specifically proportions of infants and neonates (P < 0.001) and subjects with renal insufficiency (P = 0.02), recent cardiac surgery (P < 0.001), and a higher hemodynamic vulnerability score (P = 0.02). The observed HSAE risk did not change significantly (P = 0.13). In multivariable analyses, odds of HSAE during the first wave of COVID (odds ratio: 0.75) appeared to be lower than that before COVID, but the difference was not significant (P = 0.09). Conclusions: Despite increased case-mix complexity, C3PO programs maintained, if not improved, their performance in terms of HSAE. Exploratory analyses of practice changes may inform future harm-reduction efforts.

ICU Admission Tool for Congenital Heart Catheterization (iCATCH): A Predictive Model for High Level Post-Catheterization Care and Patient Management.

OBJECTIVES: Currently, there are no prediction tools available to identify patients at risk of needing high-complexity care following cardiac catheterization for congenital heart disease. We sought to develop a method to predict the likelihood a patient will require intensive care level resources following elective cardiac catheterization. DESIGN: Prospective single-center study capturing important patient and procedural characteristics for predicting discharge to the ICU. Characteristics significant at the 0.10 level in the derivation dataset (July 1, 2017 to December 31, 2019) were considered for inclusion in the final multivariable logistic regression model. The model was validated in the testing dataset (January 1, 2020 to December 31, 2020). The novel pre-procedure cardiac status (PCS) feature, collection started in January 2019, was assessed separately in the final model using the 2019 through 2020 dataset. SETTING: Tertiary pediatric heart center. PATIENTS: All elective cases coming from home or non-ICU who underwent a cardiac catheterization from July 2017 to December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 2,192 cases were recorded in the derivation dataset, of which 11% of patients ( n = 245) were admitted to the ICU, while 64% ( n = 1,413) were admitted to a medical unit and 24% ( n = 534) were discharged home. In multivariable analysis, the following predictors were identified: 1) weight less than 5 kg and 5-9.9 kg, 2) presence of systemic illness, 3) recent cardiac intervention less than 90 days, and 4) ICU Admission Tool for Congenital Heart Catheterization case type risk categories (1-5), with C -statistics of 0.79 and 0.76 in the derivation and testing cohorts, respectively. The addition of the PCS feature fit into the final model resulted in a C -statistic of 0.79. CONCLUSIONS: The creation of a validated pre-procedural risk prediction model for ICU admission following congenital cardiac catheterization using a large volume, single-center, academic institution will improve resource allocation and prediction of capacity needs for this complex patient population.

Interpreting Quality Improvement When Introducing New Technology: A Collaborative Experience in ASD Device Closures.

The objective of this study was to evaluate the impact of the regular introduction of new technologies into interventional cardiac catheterization procedures, in this case new atrial septal defect (ASD) closure devices, while conducting a multi-center collaborative initiative to reduce radiation usage during all procedures. Data were collected prospectively by 8 C3PO institutions between January 1, 2014 and December 31, 2017 for ASD device closure procedures in the cardiac catheterization lab during a quality improvement (QI) initiative aimed at reducing patient radiation exposure. Radiation exposure was measured in dose area product per body weight (µGy*m2/kg). Use of proposed practice change strategies at the beginning and end of the QI intervention period was assessed. Radiation exposure was summarized by institution and by initial type of device used for closure. This study included 602 ASD device closures. Without changes in patient characteristics, total fluoroscopy duration, or number of digital acquisitions, median radiation exposure decreased from 37 DAP/kg to 14 DAP/kg from 2014 to 2017. While all individual centers decreased overall median DAP/kg, the use of novel devices for ASD closure correlated with a temporary period of worsening institutional radiation exposure and increased fluoroscopy time. The introduction of new ASD closure devices resulted in increased radiation exposure during a QI project designed to reduce radiation exposure. Therefore, outcome assessment must be contextualized in QI projects, hospital evaluation, and public reporting, to acknowledge the expected variation during innovation and introduction of novel therapies.

Procedural Risk in Congenital Cardiac Catheterization (PREDIC3T).

Background Advancements in the field, including novel procedures and multiple interventions, require an updated approach to accurately assess patient risk. This study aims to modernize patient hemodynamic and procedural risk classification through the creation of risk assessment tools to be used in congenital cardiac catheterization. Methods and Results Data were collected for all cases performed at sites participating in the C3PO (Congenital Cardiac Catheterization Project on Outcomes) multicenter registry. Between January 2014 and December 2017, 23 119 cases were recorded in 13 participating institutions, of which 88% of patients were <18 years of age and 25% <1 year of age; a high-severity adverse event occurred in 1193 (5.2%). Case types were defined by procedure(s) performed and grouped on the basis of association with the outcome, high-severity adverse event. Thirty-four unique case types were determined and stratified into 6 risk categories. Six hemodynamic indicator variables were empirically assessed, and a novel hemodynamic vulnerability score was determined by the frequency of high-severity adverse events. In a multivariable model, case-type risk category (odds ratios for category: 0=0.46, 1=1.00, 2=1.40, 3=2.68, 4=3.64, and 5=5.25; all P≤0.005) and hemodynamic vulnerability score (odds ratio for score: 0=1.00, 1=1.27, 2=1.89, and ≥3=2.03; all P≤0.006) remained independent predictors of patient risk. Conclusions These case-type risk categories and the weighted hemodynamic vulnerability score both serve as independent predictors of patient risk for high-severity adverse events. This contemporary procedure-type risk metric and weighted hemodynamic vulnerability score will improve our understanding of patient and procedural outcomes.

Subjective and objective sleep quality in young women with posttraumatic stress disorder following sexual assault: a prospective study.

Background: Most posttraumatic stress disorder (PTSD) sleep disturbances reports have been conducted in male combat veteran populations, usually decades after the disorder's onset. Given the increase in the prevalence of violence against women and the fact that women are at greater risk for developing PTSD, it is critical to examine sleep abnormalities in this population. Objectives: To examine subjective and objective sleep quality in young women with PTSD following sexual assault compared with a control group at baseline and after one year of treatment. Methods: Seventy-four women with PTSD following sexual assault and 64 healthy controls with no history of sexual assault were assessed using the Clinician-Administered PTSD Scale (CAPS-5), the Beck Depression Inventory, the Beck Anxiety Inventory, the Pittsburgh Sleep Quality Index (PSQI), the Modified Fatigue Impact Scale, and the Insomnia Severity Index. Subjects also underwent full in-lab polysomnography. PTSD participants received pharmacological and/or psychological therapy between baseline and one-year follow-up. Results: The PTSD group had significantly higher scores in the clinical and sleep measurements than the control group. Although the PTSD group reported poorer subjective sleep quality than healthy controls, there were few between-group differences in objective sleep. Analysis of the PTSD group at baseline and one-year follow-up showed that the PSQI global score was a significant predictor of PTSD improvement. Conclusions: Sleep quality is impaired in young women with PTSD and may impact long-term treatment responses. Better sleep quality is significantly associated with PTSD improvement, independent of depression and anxiety.

Antecedentes: la mayoría de los reportes de trastornos del sueño en el trastorno por estrés postraumático (TEPT) se han realizado en poblaciones de hombres veteranos de guerra, generalmente décadas después del inicio del trastorno. Dado el aumento en la prevalencia de la violencia contra las mujeres y el hecho de que las mujeres tienen un mayor riesgo de desarrollar TEPT, es fundamental examinar las anomalías del sueño en esta población.Objetivos: Examinar la calidad del sueño subjetiva y objetiva en mujeres jóvenes con trastorno de estrés postraumático después de una agresión sexual en comparación con un grupo control al inicio y después de un año de tratamiento.Métodos: Se evaluaron 74 mujeres con TEPT después de agresión sexual y 64 controles sanos sin antecedentes de agresión sexual utilizando la Escala de TEPT administrada por un médico (CAPS-5, en su sigla en inglés), el Inventario de Depresión de Beck, el Inventario de Ansiedad de Beck, la Calidad del Sueño de Pittsburgh. (PSQI, en su sigla en inglés), la escala de impacto de fatiga modificada y el índice de gravedad del insomnio. Los sujetos también se sometieron a una polisomnografía completa en el laboratorio. Los participantes con TEPT recibieron terapia farmacológica y/o psicológica entre el inicio y el seguimiento al año.Resultados: El grupo de TEPT tuvo puntuaciones significativamente más altas en las mediciones clínicas y del sueño que el grupo de control. Aunque el grupo de TEPT reportó una peor calidad del sueño subjetivo que los controles sanos, hubo pocas diferencias entre grupos en el sueño objetivo. El análisis del grupo de TEPT al inicio y al año de seguimiento mostró que la puntuación global del PSQI fue un predictor significativo de la mejoría del TEPT.Conclusiones: La calidad del sueño se ve afectada en mujeres jóvenes con TEPT y puede afectar las respuestas al tratamiento a largo plazo. Una mejor calidad del sueño se asocia significativamente con la mejora del TEPT, independientemente de la depresión y la ansiedad.

Carbamazepine Reduces Sharp Wave-Ripple Complexes and Exerts Synapse-Specific Inhibition of Neurotransmission in Ex Vivo Hippocampal Slices.

Higher therapeutic concentrations of the antiseizure medication carbamazepine (CBZ) are associated with cognitive side effects. Hippocampal sharp wave-ripple complexes (SPW-Rs) are proposed to participate in memory consolidation during periods of quiet and slow-wave sleep. SPW-Rs are generated in the CA3 region and are regulated by multiple synaptic inputs. Here, we used a multi-electrode array to determine the effects of CBZ on SPW-Rs and synaptic transmission at multiple hippocampal synapses. Our results demonstrate that CBZ reduced SPW-Rs at therapeutically relevant concentrations (IC50 = 37 µM) and altered the core characteristics of ripples, important for information processing and consolidation. Moreover, CBZ inhibited neurotransmission in a synapse-specific manner. CBZ inhibition was most potent at the medial-perforant-path-to-CA3 and mossy-fiber-to-CA3 synapses (IC50s ~ 30 and 60 µM, respectively) and least potent at medial-perforant-path-to-dentate granule cell synapses (IC50 ~ 120 µM). These results suggest that the synapse-specific CBZ inhibition of neurotransmission reduces SPW-Rs and that the CBZ inhibition of SPW-Rs may underlie the cognitive impairments observed with therapeutic doses of CBZ.

Posttraumatic Stress Disorder and Neuroprogression in Women Following Sexual Assault: Protocol for a Randomized Clinical Trial Evaluating Allostatic Load and Aging Process Acceleration.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and severe disorder related to traumatic events. Women are disproportionately affected by PTSD than men and are more at risk in the occurrence of sexual assault victimization. Estimates suggest that 50% of women develop PTSD following sexual assault and successful clinical management can be challenging. Growing evidence has implicated neural, immune, and endocrine alterations underpinning PTSD, but only few studies have assessed the evolution of acute PTSD in women. OBJECTIVE: This study aims to measure whether the onset of PTSD is associated with accelerated aging in women following sexual assault. We hypothesize that the increase of allostatic load caused by PTSD leads to neuroprogression. We will implement a randomized clinical trial to compare responses to treatment with either interpersonal psychotherapy adapted for PTSD (IPT-PTSD) or the selective serotonin reuptake inhibitor sertraline. METHODS: We will include women between 18 and 45 years of age, who experienced sexual assault from 1 to 6 months before the initial evaluation, and present with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnosis of PTSD. Baseline evaluation will comprise clinical and psychometric assessments, structural and functional magnetic resonance imaging, neuropsychological testing, polysomnography, evaluation of immune and endocrine parameters, and genetic analyses. Age-matched female healthy controls will be included and subjected to the same evaluation. Patients will be randomized for treatment in 1 of the 2 arms of the study for 14 weeks; follow-up will continue until 1 year after inclusion via treatment as usual. The researchers will collect clinical and laboratory data during periodic clinical assessments up to 1-year follow-up. RESULTS: Data collection started in early 2016 and will be completed by the end of the first semester of 2020. Analyses will be performed soon afterward, followed by the elaboration of several articles. Articles will be submitted in early 2021. This research project has obtained a grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2014/12559-5). CONCLUSIONS: We expect to provide insight into the consequences of recent sexual assault exposure in women by investigating the degree of neuroprogression developing from an early stage of PTSD. We also expect to provide important evidence on the efficacy of a non-exposure psychotherapy (IPT-PTSD) to mitigate PTSD symptoms in recently sexually assaulted women. Further, we aim to obtain evidence on how treatment outcomes are associated with neuroprogression measures. TRIAL REGISTRATION: Brazilian Clinical Trials Registry RBR-3z474z; http://www.ensaiosclinicos.gov.br/rg/RBR-3z474z/. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/19162.

Prospective assessment of deep inspiration breath-hold using 3-dimensional surface tracking for irradiation of left-sided breast cancer.

PURPOSE: Deep inspiration breath hold (DIBH) is used to decrease cardiac irradiation during radiation therapy (RT) for breast cancer. The patients most likely to benefit and the impact on treatment time remain largely unknown. We sought to identify predictors for the use of DIBH and to quantify differences in dosimetry and treatment time using a prospective registry. METHODS AND MATERIALS: A total of 150 patients with left breast cancer were enrolled. All patients were simulated with both free breathing (FB) and DIBH. RT was delivered by either modality. Alternate scans were planned with use of deformable registration to include identical RT volumes. DIBH patients were monitored by a real-time surface tracking system, AlignRT (Vision RT, Ltd, London, United Kingdom). Baseline characteristics and treatment times were compared by Fisher exact test and Wilcoxon rank sum test. Dosimetric endpoints were analyzed by Wilcoxon signed rank test, and linear regression identified predictors for change in mean heart dose (∆MHD). RESULTS: We treated 38 patients with FB and 110 with DIBH. FB patients were older, more likely to have heart and lung disease, and less likely to receive chemotherapy or immediate reconstruction (all P < .05). Treatment times were not significantly different, but DIBH patients had greater variability in times (P = .0002). Of 146 evaluable patients, DIBH resulted in >20 cGy improvement in MHD in 107 patients but a >20 cGy increase in MHD in 14. Both MHD and lung V20 were significantly lower in DIBH than in paired FB plans. On multivariate analysis, younger age (4.18 cGy per year; P < .0001), higher body mass index (6.06 cGy/kg/m(2); P = .0018), and greater change in lung volumes (130 cGy/L; P = .003) were associated with greater ∆MHD. CONCLUSIONS: DIBH improves cardiac dosimetry without significantly impacting treatment time in most patients. Greater inspiratory lung volumes augment this benefit. Because the improvement with DIBH was not uniform, patients should be scanned with both FB and DIBH.

DMT1 (IRE) expression in intestinal and erythroid cells is regulated by peripheral benzodiazepine receptor-associated protein 7.

The divalent metal transporter 1 (DMT1) is essential for cellular uptake of iron, mediating iron absorption across the duodenal brush border membrane. We have previously shown that with iron feeding DMT1 in the brush border membrane undergoes endocytosis into the subapical compartment of enterocytes. To understand the mechanisms of iron-induced endocytosis of DMT1, we used the yeast two-hybrid system to find proteins that interact with DMT1 and isolated from a rat duodenal cDNA library a protein that interacts specifically with the IRE containing isoform of DMT1 {DMT1 [iron-responsive element (IRE)]}. The protein (Genbank AY336075) is 97.5% identical with peripheral benzodiazepine receptor-associated protein 7 (PAP7), a protein that interacts with the peripheral benzodiazepine receptor. PAP7 is ubiquitously expressed in the rat and in multiple cell lines with consensus sequences including a nuclear localization signal and a Golgi dynamic domain. PAP7, expressed on the brush border of rat duodenum, copurified with DMT1 in brush border membrane vesicles, and following iron feeding, was internalized in parallel with the internalization of DMT1. To determine if PAP7 plays a role in cellular iron metabolism, we downregulated PAP7 expression in K562 cells with small interfering RNA. Following the decrease in PAP7 protein, DMT1 (IRE) protein but not mRNA was significantly downregulated but without effect on DMT1 (non-IRE), transferin (Tf)R1, or ferritin expression. Lowered levels of PAP7 resulted also in decreased cell proliferation and G(1) cell cycle arrest. These data are consistent with PAP7 interacting with DMT1 (IRE) and regulating DMT1 (IRE) expression in K562 cells by modulating expression of DMT1 (IRE) protein.

A double-blind randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD.

OBJECTIVE: To evaluate the efficacy and tolerability of topiramate in patients with posttraumatic stress disorder (PTSD). METHOD: We conducted a 12-week double-blind, randomized, placebo-controlled study comparing topiramate to placebo. Men and women aged 18-62 years with diagnosis of PTSD according to DSM-IV were recruited from the outpatient clinic of the violence program of Federal University of São Paulo Hospital (Prove-UNIFESP), São Paulo City, between April 2006 and December 2009. Subjects were assessed for the Clinician-Administered Posttraumatic Stress Scale (CAPS), Clinical Global Impression, and Beck Depression Inventory (BDI). After 1-week period of washout, 35 patients were randomized to either group. The primary outcome measure was the CAPS total score changes from baseline to the endpoint. RESULTS: 82.35% of patients in the topiramate group exhibited improvements in PTSD symptoms. The efficacy analysis demonstrated that patients in the topiramate group exhibited significant improvements in reexperiencing symptoms: flashbacks, intrusive memories, and nightmares of the trauma (CAPS-B; P= 0.04) and in avoidance/numbing symptoms associated with the trauma, social isolation, and emotional numbing (CAPS-C; P= 0.0001). Furthermore, the experimental group demonstrated a significant difference in decrease in CAPS total score (topiramate -57.78; placebo -32.41; P= 0.0076). Mean topiramate dose was 102.94 mg/d. Topiramate was generally well tolerated. CONCLUSION: Topiramate was effective in improving reexperiencing and avoidance/numbing symptom clusters in patients with PTSD. This study supports the use of anticonvulsants for the improvement of symptoms of PTSD.

Interactions between ferroportin and hephaestin in rat enterocytes are reduced after iron ingestion.

BACKGROUND & AIMS: Ferroportin (Fpn) is a multiple transmembrane protein required for iron export into the systemic circulation, in cooperation with hephaestin (Heph). Despite the importance of Fpn in iron transport, there is controversy about its topology and functional state upon interaction with Heph. METHODS: The topology of Fpn was determined using monospecific antisera against its different epitopes, in sheets of cells from duodenum that were or were not permeabilized with detergent. Immunoprecipitation and blue native polyacrylamide gel electrophoresis, followed by immunoblot analysis, were used to determine the extent of interactions between Fpn and Heph. Antisera against the intracellular, C-termini of divalent metal transporter (Dmt1) and Heph served as controls. RESULTS: Immunofluorescence analysis with antisera against amino acids 172-193 of Fpn (anti-Fpn 172) detected Fpn only in permeabilized cells, whereas anti-Fpn 232 (amino acids 232-249), anti-Fpn 370 (amino acids 370-420), and anti-Fpn C (the C-terminus) detected Fpn in nonpermeabilized and permeabilized cells. Immunoprecipitation studies showed that Fpn and Heph coprecipitated with either anti-Fpn or anti-Heph. Blue native polyacrylamide gel electrophoresis studies revealed that a fraction of Fpn comigrates with Heph; the apparent interaction decreases after iron ingestion. CONCLUSIONS: Studies with antisera to different epitopes of Fpn indicate that the topology of Fpn is consistent with an 11-transmembrane model, with the C-terminus exposed on the cell surface. Reduced interactions between Fpn and Heph after iron ingestion indicate that this is a regulatory mechanism for limiting further iron absorption.