Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

The accuracy of prehospital triage decisions in English trauma networks - a case-cohort study.

BACKGROUND: Care for injured patients in England is provided by inclusive regional trauma networks. Ambulance services use triage tools to identify patients with major trauma who would benefit from expedited Major Trauma Centre (MTC) care. However, there has been no investigation of triage performance, despite its role in ensuring effective and efficient MTC care. This study aimed to investigate the accuracy of prehospital major trauma triage in representative English trauma networks. METHODS: A diagnostic case-cohort study was performed between November 2019 and February 2020 in 4 English regional trauma networks as part of the Major Trauma Triage Study (MATTS). Consecutive patients with acute injury presenting to participating ambulance services were included, together with all reference standard positive cases, and matched to data from the English national major trauma database. The index test was prehospital provider triage decision making, with a positive result defined as patient transport with a pre-alert call to the MTC. The primary reference standard was a consensus definition of serious injury that would benefit from expedited major trauma centre care. Secondary analyses explored different reference standards and compared theoretical triage tool accuracy to real-life triage decisions. RESULTS: The complete-case case-cohort sample consisted of 2,757 patients, including 959 primary reference standard positive patients. The prevalence of major trauma meeting the primary reference standard definition was 3.1% (n=54/1,722, 95% CI 2.3 - 4.0). Observed prehospital provider triage decisions demonstrated overall sensitivity of 46.7% (n=446/959, 95% CI 43.5-49.9) and specificity of 94.5% (n=1,703/1,798, 95% CI 93.4-95.6) for the primary reference standard. There was a clear trend of decreasing sensitivity and increasing specificity from younger to older age groups. Prehospital provider triage decisions commonly differed from the theoretical triage tool result, with ambulance service clinician judgement resulting in higher specificity. CONCLUSIONS: Prehospital decision making for injured patients in English trauma networks demonstrated high specificity and low sensitivity, consistent with the targets for cost-effective triage defined in previous economic evaluations. Actual triage decisions differed from theoretical triage tool results, with a decreasing sensitivity and increasing specificity from younger to older ages.

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

Ratios of head circumference to ventricular size vary over time and predict eventual need for CSF diversion in intraventricular hemorrhage of prematurity.

PURPOSE: Intraventricular hemorrhage (IVH) of prematurity can lead to hydrocephalus, sometimes necessitating permanent cerebrospinal fluid (CSF) diversion. We sought to characterize the relationship between head circumference (HC) and ventricular size in IVH over time to evaluate the clinical utility of serial HC measurements as a metric in determining the need for CSF diversion. METHODS: We included preterm infants with IVH born between January 2000 and May 2020. Three measures of ventricular size were obtained: ventricular index (VI), Evan's ratio (ER), and frontal occipital head ratio (FOHR). The Pearson correlations (r) between the initial (at birth) paired measurements of HC and ventricular size were reported. Multivariable longitudinal regression models were fit to examine the HC:ventricle size ratio, adjusting for the age of the infant, IVH grade (I/II vs. III/IV), need for CSF diversion, and sex. RESULTS: A total of 639 patients with an average gestational age of 27.5 weeks were included. IVH grade I/II and grade III/IV patients had a positive correlation between initial HC and VI (r = 0.47, p < 0.001 and r = 0.48, p < 0.001, respectively). In our longitudinal models, patients with a low-grade IVH (I/II) had an HC:VI ratio 0.52 higher than those with a high-grade IVH (p-value < 0.001). Patients with low-grade IVH had an HC:ER ratio 12.94 higher than those with high-grade IVH (p-value < 0.001). Patients with low-grade IVH had a HC:FOHR ratio 12.91 higher than those with high-grade IVH (p-value < 0.001). Infants who did not require CSF diversion had an HC:VI ratio 0.47 higher than those who eventually did (p < 0.001). Infants without CSF diversion had an HC:ER ratio 16.53 higher than those who received CSF diversion (p < 0.001). Infants without CSF diversion had an HC:FOHR ratio 15.45 higher than those who received CSF diversion (95% CI (11.34, 19.56), p < 0.001). CONCLUSIONS: There is a significant difference in the ratio of HC:VI, HC:ER, and HC:FOHR size between patients with high-grade IVH and low-grade IVH. Likewise, there is a significant difference in HC:VI, HC:ER, and HC:FOHR between those who did and did not have CSF diversion. The routine assessments of both head circumference and ventricle size by ultrasound are important clinical tools in infants with IVH of prematurity.

Cognitive impairment and the associated factors among women with a history of pregnancy complications in rural southwestern Uganda.

BACKGROUND: Worldwide, there is a growing concern about the rising number of people with declining cognitive functioning. However, findings on this phenomenon are inconclusive. Our study aimed to assess the prevalence of cognitive impairment and the associated factors in women with a history of pregnancy complications in rural southwestern Uganda. METHODS: This was a cross-sectional study carried out among women above 40 years of age in the greater Kabale district of southwestern Uganda between March and April 2022. Study participants were identified using a consecutive sampling method. Predictor variables included pregnancy complications and other social demographic factors that were assessed by semi-structured interviews while cognitive functioning as an outcome variable was assessed by Montreal Cognitive Assessment (MoCA-B) tool. Data were analyzed using STATA at a 95% Confidence level. Logistic regression analyses were selected for statistical modelling while odds ratios were calculated to assess the strength of associations between the predictor and outcome variables. RESULTS: In total, 75% (212/280) of participants had some form of cognitive impairment, with 45% (123/280) falling into mild CI, 31% (86/280) moderate CI and 4% (10/280) severe CI. Twenty-three percent (68/280) of participants fell into category of normal cognitive functioning. Participants with >65 years of age had higher odds of developing cognitive impairment (OR = 2.94; 95%CI: 0.96-9.04, p = 0.06) than those with < 65 years of age. Protective factors to cognitive impairment include delivering from a health facility (OR = 0.31,95% CI:0.16-0.60, p = < .001), primary and post primary levels of education (OR = 0.05; 95% CI: 0.02-0.13, p<0.001, OR = 0.04; 95%CI: 0.02-0.23, p<0.001) respectively. CONCLUSION: Results from this study show a high prevalence of cognitive impairment among women with a history of pregnancy complications in rural southwestern Uganda. Interventions geared toward preventing cognitive impairment among females with a history of pregnancy complications should be emphasized.

Linear Free Energy Relationship for Predicting the Rate Constants of Munition Compound Reduction by the Fe(II)-Hematite and Fe(II)-Goethite Redox Couples.

Abiotic reduction by iron minerals is arguably the most important fate process for munition compounds (MCs) in subsurface environments. No model currently exists that can predict the abiotic reduction rates of structurally diverse MCs by iron (oxyhydr)oxides. We performed batch experiments to measure the rate constants for the reduction of three classes of MCs (poly-nitroaromatics, nitramines, and azoles) by hematite or goethite in the presence of aqueous Fe2+. The surface area-normalized reduction rate constant (kSA) depended on the aqueous-phase one-electron reduction potential (EH1) of the MC and the thermodynamic state (i.e., pe and pH) of the iron oxide-Feaq2+ system. A linear free energy relationship (LFER), similar to that reported previously for nitrobenzene, successfully captures all MC reduction rate constants that span 6 orders of magnitude: log(kSA)=(1.12±0.04)[0.53EH159mV-(pH+pe)]+(5.52±0.23). The finding that the rate constants of all the different classes of MCs can be described by a single LFER suggests that these structurally diverse nitro compounds are reduced by iron oxide-Feaq2+ couples through a common mechanism up to the rate-limiting step. Multiple mechanistic implications of the results are discussed. This study expands the applicability of the LFER model for predicting the reduction rates of legacy and emerging MCs and potentially other nitro compounds.

Thermodynamic Two-Site Surface Reaction Model for Predicting Munition Constituent Reduction Kinetics with Iron (Oxyhydr)oxides.

Iron (oxyhydr)oxides comprise a significant portion of the redox-active fraction of soils and are key reductants for remediation of sites contaminated with munition constituents (MCs). Previous studies of MC reduction kinetics with iron oxides have focused on the concentration of sorbed Fe(II) as a key parameter. To build a reaction kinetic model, it is necessary to predict the concentration of sorbed Fe(II) as a function of system conditions and the redox state. A thermodynamic framework is formulated that includes a generalized double-layer model that utilizes surface acidity and surface complexation reactions to predict sorbed Fe(II) concentrations that are used for fitting MC reduction kinetics. Monodentate- and bidentate Fe(II)-binding sites are used with individual oxide sorption characteristics determined through data fitting. Results with four oxides (goethite, hematite, lepidocrocite, and ferrihydrite) and four nitro compounds (NB, CN-NB, Cl-NB, and NTO) from six separate studies have shown good agreement when comparing observed and predicted surface area-normalized rate constants. While both site types are required to reproduce the experimental redox titration, only the monodentate site concentration controls the MC reaction kinetics. This model represents a significant step toward predicting the timescales of MC degradation in the subsurface.

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior.

Background: Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

Electron Transfer Energy and Hydrogen Atom Transfer Energy-Based Linear Free Energy Relationships for Predicting the Rate Constants of Munition Constituent Reduction by Hydroquinones.

No single linear free energy relationship (LFER) exists that can predict reduction rate constants of all munition constituents (MCs). To address this knowledge gap, we measured the reduction rates of MCs and their surrogates including nitroaromatics [NACs; 2,4,6-trinitrotoluene (TNT), 2,4-dinitroanisole (DNAN), 2-amino-4,6-dinitrotoluene (2-A-DNT), 4-amino-2,6-dinitrotoluene (4-A-DNT), and 2,4-dinitrotoluene (DNT)], nitramines [hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and nitroguanidine (NQ)], and azoles [3-nitro-1,2,4-triazol-5-one (NTO) and 3,4-dinitropyrazole (DNP)] by three dithionite-reduced quinones (lawsone, AQDS, and AQS). All MCs/NACs were reduced by the hydroquinones except NQ. Hydroquinone and MC speciations were varied by controlling pH, permitting the application of a speciation model to determine second-order rate constants (k) from observed pseudo-first-order rate constants. The intrinsic reactivity of MCs (oxidants) decreased upon deprotonation, while the opposite was true for hydroquinones (reductants). The rate constants spanned ∼6 orders of magnitude in the order NTO ≈ TNT > DNP > DNT ≈ DNAN ≈ 2-A-DNT > DNP- > 4-A-DNT > NTO- > RDX. LFERs developed using density functional theory-calculated electron transfer and hydrogen atom transfer energies and reported one-electron reduction potentials successfully predicted k, suggesting that these structurally diverse MCs/NACs are all reduced by hydroquinones through the same mechanism and rate-limiting step. These results increase the applicability of LFER models for predicting the fate and half-lives of MCs and related nitro compounds in reducing environments.

Excessive alcohol consumption after exposure to two types of chronic social stress: intermittent episodes vs. continuous exposure in C57BL/6J mice with a history of drinking.

RATIONALE: The attraction to alcohol can be greatly increased when it is consumed in a social context. While pro-social interactions can potentiate voluntary alcohol drinking under some conditions, aversive social experience (i.e., social stress) can similarly intensify alcohol consumption. OBJECTIVE: We sought to determine how exposure to different types of chronic social stress (i.e., intermittent episodes of social defeat or continuous social stress) influences alcohol consumption and the reinforcing effects of alcohol in mice with a history of drinking. METHODS: Separate cohorts of male C57BL/6J mice were exposed to either 10 days of continuous or intermittent social defeat stress. In experiment 1, mice were assigned to 20% w/v alcohol consumption in a two-bottle choice protocol both prior to and after exposure to social defeat stress. In a second experiment, mice engaged in an operant response sequence to gain access to alcohol wherein completion of a fixed interval (FI; 5 min) schedule was reinforced with continuous access to alcohol (fixed ratio; FR1) for up to 1.8 g/kg. Alcohol-reinforced responding and subsequent alcohol consumption were assessed daily for 4 weeks prior to the 10-day social stress exposure and for 6-week post-stress. Machine learning was implemented to standardize the analysis of defeat behaviors exhibited by the intruder mouse during confrontation with an attacking resident. RESULTS: In mice with a prior history of alcohol drinking, intermittent episodes of social defeat stress produced a significant increase in 20% EtOH consumption in preference over concurrently available water. This increased intake persisted for at least 6 weeks after the final social stress experience. Intermittently stressed mice also accelerated their anticipatory responding during the fixed interval component of the operant response chain that was reinforced by alcohol. Neither unstressed controls nor mice exposed to continuous social stress exhibited significant increases in alcohol consumption and alcohol reinforcement. DISCUSSION: Episodic social defeat stress promotes the seeking and consumption of alcohol, extending earlier work to alcohol-experienced mice. We hypothesize that intermittent access to alcohol and intermittent episodes of social stress are additive and share common sensitizing neural mechanisms that engender excessive alcohol consumption.

Gardening activity and its relationship to mental health: Understudied and untapped in low-and middle-income countries.

There is increasing awareness among researchers and health practitioners from high income countries about the potential mental health benefits of participating in gardening activities and spending substantial time in green spaces. However, this phenomenon is not well established in low- and middle-income countries. In this commentary, we discuss the evidence base surrounding the potential mental health benefits of participating in gardening activity and spending substantial time in a green space. We hope to stimulate discourse about incorporating these activities into mental health prevention in low- and middle-income countries.

To fight or not to fight: activation of the mPFC during decision to engage in aggressive behavior after ethanol consumption in a novel murine model.

RATIONALE: Alcohol consumption is a common antecedent of aggressive behavior. The effects of alcohol on the decision to engage in aggression in preference over pro-social interaction are hypothesized to arise from augmented function within the medial prefrontal cortex (mPFC). OBJECTIVE: In a newly developed procedure, we studied social decision-making in male C57BL/6 J mice based on preferentially seeking access to either sociosexual interactions with a female partner or the opportunity to attack an intruder male. While deciding to engage in aggressive vs. sociosexual behavior, corresponding neural activation was assessed via c-Fos immunoreactivity in cortical, amygdaloid and tegmental regions of interest. A further objective was to investigate how self-administered alcohol impacted social choice. METHODS: During repeated confrontations with an intruder male in their home cage, experimental mice engaged in species-specific sequence of pursuit, threat, and attack behavior within < 2 min. Mice were then conditioned to respond at one of two separate illuminated operanda in an experimental chamber (octagon) attached to their home cage; completion of 10 responses (fixed ratio 10; FR10) was reinforced by access to either a female or a male intruder which were presented in the resident's home cage. Brains were harvested following choice between the concurrently available aggressive and sociosexual options and processed for c-Fos immunoreactivity across 10 brain regions. In two separate groups, mice were trained to rapidly self-administer ethanol prior to a social choice trial in order to examine the effects of alcohol on social choice, sociosexual, aggressive acts and postures, and concurrent c-Fos activity in the mPFC and limbic regions. RESULTS AND DISCUSSION: Eight out of 65 mice consistently chose to engage in aggressive behavior in preference to sociosexual contact with a female when each outcome was concurrently available. Self-administered alcohol (experiment 1: 1.2 ± 0.02 g/kg; experiment 2: 0, 1.0, 1.5, and 1.8 g/kg) increased responding for the aggressive option in mice that previously opted predominantly for access to sociosexual interactions with the female. When choosing the aggressive, but not the sociosexual option, the prelimbic area of the mPFC revealed increased c-Fos activity, guiding future detailed inquiry into the neural mechanisms for aggressive choice.

Pharmacokinetics and Early Tumor Response to Conventional Transarterial Chemoembolization with Sorafenib and Doxorubicin in a VX2 Rabbit Tumor Model.

PURPOSE: To investigate the pharmacokinetics (PK) and early effects of conventional transarterial chemoembolization (TACE) using sorafenib and doxorubicin on tumor necrosis, hypoxia markers, and angiogenesis in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 tumor-laden New Zealand White rabbits (N = 16) were divided into 2 groups: 1 group was treated with hepatic arterial administration of ethiodized oil and doxorubicin emulsion (DOX-TACE), and the other group was treated with ethiodized oil, sorafenib, and doxorubicin emulsion (SORA-DOX-TACE). Animals were killed within 3 days of the procedure. Levels of sorafenib and doxorubicin were measured in blood, tumor, and adjacent liver using mass spectrometry. Tumor necrosis was determined by histopathological examination. Intratumoral hypoxia-inducible factor (HIF) 1α, vascular endothelial growth factor (VEGF), and microvessel density (MVD) were determined by immunohistochemistry. RESULTS: The median intratumoral concentration of sorafenib in the SORA-DOX-TACE group was 17.7 µg/mL (interquartile range [IQR], 7.42-33.5 µg/mL), and its maximal plasma concentration (Cmax) was 0.164 µg/mL (IQR, 0.0798-0.528 µg/mL). The intratumoral concentration and Cmax of doxorubicin were similar between the groups: 4.08 µg/mL (IQR, 3.18-4.79 µg/mL) and 0.677 µg/mL (IQR, 0.315-1.23 µg/mL), respectively, in the DOX-TACE group and 1.68 µg/mL (IQR, 0.795-4.08 µg/mL) and 0.298 µg/mL (IQR, 0.241-0.64 µg/mL), respectively, in the SORA-DOX-TACE group. HIF-1α expression was increased in the SORA-DOX-TACE group than in the DOX-TACE group. Tumor volume, tumor necrosis, VEGF expression, and MVD were similar between the 2 groups. CONCLUSIONS: The addition of sorafenib to DOX-TACE delivered to VX2 liver tumors resulted in high intratumoral and low systemic concentrations of sorafenib without altering the PK of doxorubicin.

Complications and outcomes of posterior fossa decompression with duraplasty versus without duraplasty for pediatric patients with Chiari malformation type I and syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: The aim of this study was to determine differences in complications and outcomes between posterior fossa decompression with duraplasty (PFDD) and without duraplasty (PFD) for the treatment of pediatric Chiari malformation type I (CM1) and syringomyelia (SM). METHODS: The authors used retrospective and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM1-SM who received PFD or PFDD and had at least 1 year of follow-up data. Preoperative, treatment, and postoperative characteristics were recorded and compared between groups. RESULTS: A total of 692 patients met the inclusion criteria for this database study. PFD was performed in 117 (16.9%) and PFDD in 575 (83.1%) patients. The mean age at surgery was 9.86 years, and the mean follow-up time was 2.73 years. There were no significant differences in presenting signs or symptoms between groups, although the preoperative syrinx size was smaller in the PFD group. The PFD group had a shorter mean operating room time (p < 0.0001), fewer patients with > 50 mL of blood loss (p = 0.04), and shorter hospital stays (p = 0.0001). There were 4 intraoperative complications, all within the PFDD group (0.7%, p > 0.99). Patients undergoing PFDD had a 6-month complication rate of 24.3%, compared with 13.7% in the PFD group (p = 0.01). There were no differences between groups for postoperative complications beyond 6 months (p = 0.33). PFD patients were more likely to require revision surgery (17.9% vs 8.3%, p = 0.002). PFDD was associated with greater improvements in headaches (89.6% vs 80.8%, p = 0.04) and back pain (86.5% vs 59.1%, p = 0.01). There were no differences between groups for improvement in neurological examination findings. PFDD was associated with greater reduction in anteroposterior syrinx size (43.7% vs 26.9%, p = 0.0001) and syrinx length (18.9% vs 5.6%, p = 0.04) compared with PFD. CONCLUSIONS: PFD was associated with reduced operative time and blood loss, shorter hospital stays, and fewer postoperative complications within 6 months. However, PFDD was associated with better symptom improvement and reduction in syrinx size and lower rates of revision decompression. The two surgeries have low intraoperative complication rates and comparable complication rates beyond 6 months.

Modeling the Reduction Kinetics of Munition Compounds by Humic Acids.

Dissolved organic matter (DOM) comprises a sizeable portion of the redox-active constituents in the environment and is an important reductant for the abiotic transformation of nitroaromatic compounds and munition constituents (NACs/MCs). Building a predictive kinetic model for these reactions would require the energies associated with both the reduction of the NACs/MCs and the oxidation of the DOM. The heterogeneous and unknown structure of DOM, however, has prohibited reliable determination of its oxidation energies. To overcome this limitation, humic acids (HAs) were used as model DOM, and their redox moieties were modeled as a collection of quinones of different redox potentials. The reduction and oxidation energies of the NACs/MCs and hydroquinones, respectively, via hydrogen atom transfer (HAT) reactions were then calculated quantum chemically. HAT energies have been used successfully in a linear free energy relationship (LFER) to predict second-order rate constants for NAC reduction by hydroquinones. Furthermore, a linear relationship between the HAT energies and the reduction potentials of quinones was established, which allows estimation of hydroquinone reactivity (i.e., rate constants) from HA redox titration data. A training set of three HAs and two NACs/MCs was used to generate a mean HA redox profile that successfully predicted reduction kinetics in multiple HA/MC systems.

Post-traumatic stress disorder, depression and the associated factors among children and adolescents with a history of maltreatment in Uganda.

Worldwide, children who grow up under adverse conditions risk the development of mental health problems. However, reliable data on the estimated magnitude of mental disorders of PTSD, depression and their associated factors among maltreated children and adolescents in low- and middle-income-countries (LMICs) is still lacking. This study estimated the magnitude of PTSD, depression and the associated factors among the children and adolescents with ahistory of maltreatment in Southwestern Uganda. Methods: In this cross-sectional study, we assessed 232 children and adolescents on the prevalence of PTSD using Child PTSD Symptoms Scale for DSM-5 - Self-Report (CPSS-VSR) and Depression using the Center for Epidemiological Studies Depression Scale for Children (CES-DC). Predictor variables were taken from the Maltreatment and Abuse Chronology of Exposure- Paediatric Version (Pedi MACE). Logistic regressions analyses were selected for statistical modelling while odds-ratios were calculated to assess the strength of associations between the predictor and outcome variables. Results: In total, 140 (60%) participants fulfiled diagnostic criteria for PTSD and 91 (39%) for depression respectively. Predictor variables of PTSD were witnessing intimate partner violence (OR = 1.48, 95% CI: 1.19-1.83, p = <0.001), having lived in more than two homes (OR = 2.69, 95%CI: 1.34-5.41, p = .005), and being cared for by non-relatives (OR = 2.25; 95%CI: 2.26-223.9, p = .008). Variables predicting depression were witnessing intimate partner violence (OR = 1.30; 95%CI: 108-1.57, p = .006); being cared for by non-relatives (OR = 5.62, 95%CI: 1.36-23.1, p = .001) and being female (OR = .054, 95% CI: 0.30-1.00, p = .005). Conclusion: Children living under adverse conditions are at a higher risk of developing PTSD and depression. We recommend interventions that aim at reducing adverse psychosocial stressors so as to improve or restore the children's mental health.Abbreviations: PTSD: Post traumatic stress disorder; LMICs: Low- and middle-income countries; IPV: Intimate partner violence; OVC: Orphans and vulnerable children.

En todo el mundo, los niños que crecen en condiciones adversas corren el riesgo de desarrollar problemas de salud mental. Sin embargo, todavía faltan datos fiables sobre la estimación de la magnitud de los trastornos mentales de estrés postraumático (TEPT), la depresión y sus factores asociados entre los niños y adolescentes víctimas de maltrato en países de ingresos bajos y medios (PIBM). Este estudio estimó la magnitud del trastorno de estrés postraumático, la depresión y los factores asociados con estos trastornos entre los niños y adolescentes con antecedentes de maltrato en el suroeste de Uganda.Método: En este estudio transversal, evaluamos a 232 niños y adolescentes en edad escolar respecto a la prevalencia de TEPT utilizando la Escala de síntomas de TEPT infantil para el DSM-5 - Autoinforme (CPSS-VSR) y la depresión utilizando la Escala de depresión del Centro de Estudios Epidemiológicos para Niños (CESDC). Las variables predictoras se tomaron de la Cronología de la Exposición al Maltrato y Abuso, versión pediátrica (Pedi MACE). Se seleccionaron análisis de regresión logística para el modelo estadístico, mientras que se calcularon las razones de probabilidad para evaluar la fuerza de las asociaciones entre las variables predictoras y resultantes.Resultados: En total, 140 (60%) participantes cumplieron los criterios de diagnóstico de TEPT y 91 (39%) de depresión, respectivamente. Las variables predictoras de TEPT fueron presenciar violencia de pareja (OR = 1,48, IC del 95%: 1,19 - 1,83, p = <0,001), haber vivido en más de dos hogares (OR = 2,69, IC del 95%: 1,34 ­ 5,41, p = 0,005), y ser atendido por no familiares (OR = 2,25; IC 95%: 2,26 - 223,9, p = 0,008). Las variables que predicen depresión fueron presenciar violencia de pareja (OR = 1,30; IC del 95%: 108­1,57, p = 0,006); estar al cuidado de no-familiares (OR = 5,62, IC 95%: 1,36-23,1, p = 0,001) y ser mujer (OR = 0,054, IC 95%: 0,30-1,00, p = 0,005).Conclusión: Los niños que viven en condiciones adversas, como la exposición a la violencia de la pareja y permanecer en varios hogares, tienen un mayor riesgo de desarrollar trastorno de estrés postraumático y depresión. Recomendamos intervenciones que tengan como objetivo reducir los estresores psicosociales adversos para mejorar o recuperar la salud mental de los niños.

Neurobiological Bases of Alcohol Consumption After Social Stress.

The urge to seek and consume excessive alcohol is intensified by prior experiences with social stress, and this cascade can be modeled under systematically controlled laboratory conditions in rodents and non-human primates. Adaptive coping with intermittent episodes of social defeat stress often transitions to maladaptive responses to traumatic continuous stress, and alcohol consumption may become part of coping responses. At the circuit level, the neural pathways subserving stress coping intersect with those for alcohol consumption. Increasingly discrete regions and connections within the prefrontal cortex, the ventral and dorsal striatum, thalamic and hypothalamic nuclei, tegmental areas as well as brain stem structures begin to be identified as critical for reacting to and coping with social stress while seeking and consuming alcohol. Several candidate molecules that modulate signals within these neural connections have been targeted in order to reduce excessive drinking and relapse. In spite of some early clinical failures, neuropeptides such as CRF, opioids, or oxytocin continue to be examined for their role in attenuating stress-escalated drinking. Recent work has focused on neural sites of action for peptides and steroids, most likely in neuroinflammatory processes as a result of interactive effects of episodic social stress and excessive alcohol seeking and drinking.

Socioeconomic and demographic factors in the diagnosis and treatment of Chiari malformation type I and syringomyelia.

OBJECTIVE: The goal of this study was to assess the social determinants that influence access and outcomes for pediatric neurosurgical care for patients with Chiari malformation type I (CM-I) and syringomyelia (SM). METHODS: The authors used retro- and prospective components of the Park-Reeves Syringomyelia Research Consortium database to identify pediatric patients with CM-I and SM who received surgical treatment and had at least 1 year of follow-up data. Race, ethnicity, and insurance status were used as comparators for preoperative, treatment, and postoperative characteristics and outcomes. RESULTS: A total of 637 patients met inclusion criteria, and race or ethnicity data were available for 603 (94.7%) patients. A total of 463 (76.8%) were non-Hispanic White (NHW) and 140 (23.2%) were non-White. The non-White patients were older at diagnosis (p = 0.002) and were more likely to have an individualized education plan (p < 0.01). More non-White than NHW patients presented with cerebellar and cranial nerve deficits (i.e., gait ataxia [p = 0.028], nystagmus [p = 0.002], dysconjugate gaze [p = 0.03], hearing loss [p = 0.003], gait instability [p = 0.003], tremor [p = 0.021], or dysmetria [p < 0.001]). Non-White patients had higher rates of skull malformation (p = 0.004), platybasia (p = 0.002), and basilar invagination (p = 0.036). Non-White patients were more likely to be treated at low-volume centers than at high-volume centers (38.7% vs 15.2%; p < 0.01). Non-White patients were older at the time of surgery (p = 0.001) and had longer operative times (p < 0.001), higher estimated blood loss (p < 0.001), and a longer hospital stay (p = 0.04). There were no major group differences in terms of treatments performed or complications. The majority of subjects used private insurance (440, 71.5%), whereas 175 (28.5%) were using Medicaid or self-pay. Private insurance was used in 42.2% of non-White patients compared to 79.8% of NHW patients (p < 0.01). There were no major differences in presentation, treatment, or outcome between insurance groups. In multivariate modeling, non-White patients were more likely to present at an older age after controlling for sex and insurance status (p < 0.01). Non-White and male patients had a longer duration of symptoms before reaching diagnosis (p = 0.033 and 0.004, respectively). CONCLUSIONS: Socioeconomic and demographic factors appear to influence the presentation and management of patients with CM-I and SM. Race is associated with age and timing of diagnosis as well as operating room time, estimated blood loss, and length of hospital stay. This exploration of socioeconomic and demographic barriers to care will be useful in understanding how to improve access to pediatric neurosurgical care for patients with CM-I and SM.

Conventional versus drug-eluting embolic transarterial chemoembolization with doxorubicin: comparative drug delivery, pharmacokinetics, and treatment response in a rabbit VX2 tumor model.

The purpose of this study was to compare intra-tumoral drug delivery, pharmacokinetics, and treatment response after doxorubicin (DOX) conventional (c-) versus drug-eluting embolic (DEE-) transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor model. Twenty-four rabbits with solitary liver tumors underwent c-TACE (n = 12) (1:2 water-in-oil emulsion, 0.6 mL volume, 2 mg DOX) or DEE-TACE (n = 12) (130,000 70-150 µm 2 mg DOX-loaded microspheres). Systemic, intra-tumoral, and liver DOX levels were measured using mass spectrometry up to 7-day post-procedure. Intra-tumoral DOX distribution was quantified using fluorescence imaging. Percent tumor necrosis was quantified by a pathologist blinded to treatment group. Lobar TACE was successfully performed in all cases. Peak concentration (CMAX, µg/mL) for plasma, tumor tissue, and liver were 0.666, 4.232, and 0.270 for c-TACE versus 0.103, 8.988, and 0.610 for DEE-TACE. Area under the concentration versus time curve (AUC, µg/mL ∗ min) for plasma, tumor tissue, and liver were 18.3, 27,078.8, and 1339.1 for c-TACE versus 16.4, 26,204.8, and 1969.6 for DEE-TACE. A single dose of intra-tumoral DOX maintained cytotoxic levels through 7-day post-procedure for both TACE varieties, with a half-life of 1.8 (c-TACE) and 0.8 (DEE-TACE) days. Tumor-to-normal liver DOX ratio was high (c-TACE, 20.2; DEE-TACE, 13.3). c-TACE achieved significantly higher DOX coverage of tumor vs. DEE-TACE (10.8% vs. 2.3%; P = 0.003). Percent tumor necrosis was similar (39% vs. 37%; P = 0.806). In conclusion, in a rabbit VX2 liver tumor model, both c-TACE and DEE-TACE achieved tumoricidal intra-tumoral DOX levels and high tumor-to-normal liver drug ratios, though c-TACE resulted in significantly greater tumor coverage.