Shock-formed carbon materials with intergrown sp3- and sp2-bonded nanostructured units.

Studies of dense carbon materials formed by bolide impacts or produced by laboratory compression provide key information on the high-pressure behavior of carbon and for identifying and designing unique structures for technological applications. However, a major obstacle to studying and designing these materials is an incomplete understanding of their fundamental structures. Here, we report the remarkable structural diversity of cubic/hexagonally (c/h) stacked diamond and their association with diamond-graphite nanocomposites containing sp3-/sp2-bonding patterns, i.e., diaphites, from hard carbon materials formed by shock impact of graphite in the Canyon Diablo iron meteorite. We show evidence for a range of intergrowth types and nanostructures containing unusually short (0.31 nm) graphene spacings and demonstrate that previously neglected or misinterpreted Raman bands can be associated with diaphite structures. Our study provides a structural understanding of the material known as lonsdaleite, previously described as hexagonal diamond, and extends this understanding to other natural and synthetic ultrahard carbon phases. The unique three-dimensional carbon architectures encountered in shock-formed samples can place constraints on the pressure-temperature conditions experienced during an impact and provide exceptional opportunities to engineer the properties of carbon nanocomposite materials and phase assemblages.

Translation initiation in cancer at a glance.

Cell division, differentiation and function are largely dependent on accurate proteome composition and regulated gene expression. To control this, protein synthesis is an intricate process governed by upstream signalling pathways. Eukaryotic translation is a multistep process and can be separated into four distinct phases: initiation, elongation, termination and recycling of ribosomal subunits. Translation initiation, the focus of this article, is highly regulated to control the activity and/or function of eukaryotic initiation factors (eIFs) and permit recruitment of mRNAs to the ribosomes. In this Cell Science at a Glance and accompanying poster, we outline the mechanisms by which tumour cells alter the process of translation initiation and discuss how this benefits tumour formation, proliferation and metastasis.

Hyperspectral Visualization-Based Mass Spectrometry Imaging by LMJ-SSP: A Novel Strategy for Rapid Natural Product Profiling in Bacteria.

Mass spectrometry imaging (MSI) has been widely used to discover natural products (NPs) from underexplored microbiological sources. However, the technique is limited by incompatibility with complicated/uneven surface topography and labor-intensive sample preparation, as well as lengthy compound profiling procedures. Here, liquid micro-junction surface sampling probe (LMJ-SSP)-based MSI is used for rapid profiling of natural products from Gram-negative marine bacteria Pseudoalteromonas on nutrient agar media without any sample preparation. A conductance-based autosampling platform with 1 mm spatial resolution and an innovative multivariant analysis-driven method was used to create one hyperspectral image for the sampling area. NP discovery requires general spatial correlation between m/z and colony location but not highly precise spatial resolution. The hyperspectral image was used to annotate different m/z by straightforward color differences without the need to directly interrogate the spectra. To demonstrate the utility of our approach, the rapid analysis of Pseudoalteromonas rubra DSM6842, Pseudoalteromonas tunicata DSM14096, Pseudoalteromonas piscicida JCM20779, and Pseudoalteromonas elyakovii ATCC700519 cultures was directly performed on Agar. Various natural products, including prodiginine and tambjamine analogues, were quickly identified from the hyperspectral image, and the dynamic extracellular environment was shown with compound heatmaps. Hyperspectral visualization-based MSI is an efficient and sensitive strategy for direct and rapid natural product profiling from different Pseudoalteromonas strains.

3D printer platform and conductance feedback loop for automated imaging of uneven surfaces by liquid microjunction-surface sampling probe mass spectrometry.

RATIONALE: Molecular imaging of samples using mass spectrometric techniques, such as matrix-assisted laser desorption ionization or desorption electrospray ionization, requires the sample surface to be even/flat and sliced into thin sections (c. 10 µm). Furthermore, sample preparation steps can alter the analyte composition of the sample. The liquid microjunction-surface sampling probe (LMJ-SSP) is a robust sampling interface that enables surface profiling with minimal sample preparation. In conjunction with a conductance feedback system, the LMJ-SSP can be used to automatically sample uneven specimens. METHODS: A sampling stage was built with a modified 3D printer where the LMJ-SSP is attached to the printing head. This setup can scan across flat and even surfaces in a predefined pattern ("static sampling mode"). Uneven samples are automatically probed in "conductance sampling mode" where an electric potential is applied and measured at the probe. When the probe contacts the electrically grounded sample, the potential at the probe drops, which is used as a feedback signal to determine the optimal position of the probe for sampling each location. RESULTS: The applicability of the probe/sensing system was demonstrated by first examining the strawberry tissue using the "static sampling mode." Second, porcine tissue samples were profiled using the "conductance sampling mode." With minimal sample preparation, an area of 11 × 15 mm was profiled in less than 2 h. From the obtained results, adipose areas could be distinguished from non-adipose parts. The versatility of the approach was further demonstrated by directly sampling the bacteria colonies on agar and resected human kidney (intratumoral hemorrhage) specimens with thicknesses ranging from 1 to 4 mm. CONCLUSION: The LMJ-SSP in conjunction with a conductive feedback system is a powerful tool that allows for fast, reproducible, and automated assessment of uneven surfaces with minimal sample preparation. This setup could be used for perioperative assessment of tissue samples, food screening, and natural product discovery, among others.

The Effect of Patient Positioning on Ureteral Efflux During Intraoperative Cystoscopy: A Randomized Controlled Trial.

STUDY OBJECTIVE: To identify the relationship between patient position during surgery and time to confirmation of ureteral patency on cystoscopy. DESIGN: Randomized controlled trial. SETTING: Academic tertiary care medical center. PATIENTS OR PARTICIPANTS: A total of 91 adult women undergoing laparoscopic (either conventional or robotic) hysterectomy between February 2021 and February 2022 were randomized to intervention (n = 45) or control (n = 46). Exclusion criteria included known kidney disease or urinary tract anomaly, current ureteral stent, pregnancy, malignancy, and recognized intraoperative urinary tract injury. INTERVENTIONS: Subjects in the control group were placed in a 0° supine position during cystoscopy. Subjects in the intervention group were placed in a 20° angle in reverse Trendelenburg (RT) position during cystoscopy. MEASUREMENTS AND MAIN RESULTS: The primary outcome, time to confirmation of bilateral ureteral patency, was measured at the time the second ureteral jet was viewed during intraoperative cystoscopy. There was no significant difference in mean time to confirmation (66.5 seconds in supine vs 67 seconds in RT, p = .2) nor in total cystoscopy time (111 seconds in supine vs 104.5 seconds in RT, p = .39). There were no significant differences in need for alternative modalities to aid in ureteral efflux visualization, delayed diagnosis of ureteric injury, and operative time. RT position seemed to have reduced the time to confirmation for the small group of patients with longer confirmation time (>120 seconds). CONCLUSION: RT position does not change time to confirmation of bilateral ureteral patency compared with supine position. However, there may be a benefit in position change if time to confirmation is >120 seconds.

Interactions among multiple stressors vary with exposure duration and biological response.

Coastal ecosystems are exposed to multiple anthropogenic stressors. Effective management actions would be better informed from generalized predictions of the individual, combined and interactive effects of multiple stressors; however, few generalities are shared across different meta-analyses. Using an experimental study, we present an approach for analysing regression-based designs with generalized additive models that allowed us to capture nonlinear effects of exposure duration and stressor intensity and access interactions among stressors. We tested the approach on a globally distributed marine diatom, using 72 h photosynthesis and growth assays to quantify the individual and combined effects of three common water quality stressors; photosystem II-inhibiting herbicide exposure, dissolved inorganic nitrogen (DIN) enrichment and reduced light (due to excess suspended sediment). Exposure to DIN and reduced light generally resulted in additivity, while exposure to diuron and reduced light resulted in additive, antagonistic or synergistic interactions, depending on the stressor intensity, exposure period and biological response. We thus find the context of experimental studies to be a primary driver of interactions. The experimental and modelling approaches used here bridge the gap between two-way designs and regression-based studies, which provides a way forward to identify generalities in multiple stressor interactions.

The surgical gender gap: the impact of surgeon gender in medicine and gynecologic surgery.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current literature evaluating the effect of surgeon gender on patient outcomes and satisfaction, and the impact of gender bias on female surgeons. RECENT FINDINGS: The proportion of female physicians has increased in recent years, especially in Obstetrics and Gynecology. Recent literature assessing this impact supports equivalent or superior medical and surgical outcomes for women surgeons and physicians. It also reveals superior counseling and communication styles as perceived by patients. However, women in medicine receive lower patient ratings in competence, medical knowledge, and technical skills despite the existing evidence. Additionally, female physicians experience pay inequality, limited advancement opportunities, higher prevalence of microaggressions, and higher rates of burnout. SUMMARY: Recognition of gender bias is essential to correcting this issue and improving the negative impact it has on female physicians, our patients, and the field of women's health.

Individual and combined effects of diuron and light reduction on marine microalgae.

Coastal ecosystems such as those in the Great Barrier Reef (GBR) lagoon, are exposed to stressors in flood plumes including low light (caused by increased turbidity) and agricultural pesticides. Photosystem II (PSII)-inhibiting herbicides are the most frequently detected pesticides in the GBR lagoon, but it is not clear how their toxicity to phototrophic species depends on light availability. This study investigated the individual and combined effects of PSII-inhibiting herbicide, diuron, and reduced light intensity (as a proxy for increased turbidity) on the marine diatom, Phaeodactylum tricornutum. Effective quantum yield (EQY) and cell density were measured to calculate responses relative to the controls over 72-h, in tests with varying stressor intensities. Individually, diuron concentrations (0.1-3 µg l-1) were not high enough to significantly reduce growth (cell density), but led to decreased EQY; while, low light generally led to increased EQY, but only reduced growth at the lowest tested light intensity (5 µmol photons m-2 s-1) after 48-hours. P. tricornutum was less affected by diuron when combined with low light scenarios, with increased EQY (up to 163% of the controls) that was likely due to increased electron transport per photon, despite lesser available photons at this low light intensity. In contrast, growth was completely inhibited relative to the controls when algae were simultaneously exposed to the highest stressor levels (3 µg l-1 diuron and 5 µmol photons m-2 s-1). This study highlights the importance of measuring more than one biological response variable to capture the combined effects of multiple stressors. Management of water quality stressors should consider combined impacts rather than just the impacts of individual stressors alone. Reducing suspended sediment and diuron concentrations in marine waters can decrease harmful effects and bring synergistic benefits to water quality.

Modulation of locomotor behaviors by location-specific epileptic spiking and seizures.

INTRODUCTION: Epilepsy is a debilitating neurological condition characterized by spontaneous seizures as well as significant comorbid behavioral abnormalities. In addition to seizures, epileptic patients exhibit interictal spikes far more frequently than seizures, often, but not always observed in the same brain areas. The exact relationship between spiking and seizures as well as their respective effects on behavior are not well understood. In fact, spiking without overt seizures is seen in various psychiatric conditions including attention-deficit hyperactivity disorder. METHODS: In order to study the effects of spiking and seizures on behavior in an epileptic animal model, we used long-term video-electroencephalography recordings at six cortical recording sites together with behavioral activity monitoring. Animals received unilateral injections of tetanus toxin into either the somatosensory or motor cortex. RESULTS: Somatosensory cortex-injected animals developed progressive spiking ipsilateral to the injection site, while those receiving the injection into the motor cortex developed mostly contralateral spiking and spontaneous seizures. Animals with spiking but no seizures displayed a hyperactive phenotype, while animals with both spiking and seizures displayed a hypoactive phenotype. Not all spikes were equivalent as spike location strongly correlated with distinct locomotor behaviors including ambulatory distance, vertical movements, and rotatory movement. CONCLUSIONS: Together, our results demonstrate relationships between brain region-specific spiking, seizures, and behaviors in rodents that could translate into a better understanding for patients with epileptic behavioral comorbidities and other neuropsychiatric disorders.

Impact of Retained Cystoscopy Fluid after Laparoscopic Hysterectomy: A Randomized Controlled Trial.

STUDY OBJECTIVE: To investigate the impact of retained cystoscopy fluid after laparoscopic hysterectomy on time to spontaneous void, time to discharge, urinary retention, bladder discomfort, and patient satisfaction. DESIGN: Single-blind randomized controlled trial. SETTING: An academic medical center. PATIENTS: One hundred and twenty patients who underwent laparoscopic hysterectomy with universal cystoscopy for benign indications, excluding pelvic organ prolapse and urinary incontinence indications. INTERVENTIONS: From October 10, 2018, to October 17, 2019, we compared 200 mL retained cystoscopy fluid and complete bladder emptying after laparoscopic hysterectomy with universal cystoscopy. MEASUREMENTS AND MAIN RESULTS: A total of 120 patients were enrolled and randomized (59 in the retained cystoscopy fluid group and 61 in the emptied fluid group). The primary outcome was time to first spontaneous void. The secondary outcomes were time to discharge, urinary retention rates, bladder discomfort, and patient satisfaction. A sample size of 120 was calculated to detect a 57-minute difference in time to spontaneous void. There were minimal differences in baseline demographics and surgical characteristics between the groups. There was an apparent, although not significant, difference in time to void of 25 minutes (143 minutes vs 168 minutes, p = .20). Time to discharge and urinary retention rates did not differ (199 minutes vs 214 minutes, p = .40, and 13.6% vs 8.2%, p = .51, respectively). There was no difference in postoperative bladder discomfort and patient satisfaction. CONCLUSION: Retained cystoscopy fluid after laparoscopic hysterectomy did not significantly affect time to first spontaneous void, time to discharge, urinary retention, bladder discomfort, or patient satisfaction.

Diamond-Graphene Composite Nanostructures.

The search for new nanostructural topologies composed of elemental carbon is driven by technological opportunities as well as the need to understand the structure and evolution of carbon materials formed by planetary shock impact events and in laboratory syntheses. We describe two new families of diamond-graphene (diaphite) phases constructed from layered and bonded sp3 and sp2 nanostructural units and provide a framework for classifying the members of this new class of materials. The nanocomposite structures are identified within both natural impact diamonds and laboratory-shocked samples and possess diffraction features that have previously been assigned to lonsdaleite and postgraphite phases. The diaphite nanocomposites represent a new class of high-performance carbon materials that are predicted to combine the superhard qualities of diamond with high fracture toughness and ductility enabled by the graphitic units and the atomically defined interfaces between the sp3- and sp2-bonded nanodomains.

Adjusting Tropical Marine Water Quality Guideline Values for Elevated Ocean Temperatures.

Increased frequency of summer heatwaves and poor water quality are two of the most prevalent and severe pressures faced by coral reefs. While these pressures often co-occur, their potential risks to tropical marine species are usually considered independently. Here, we extended the application of multisubstance-Potentially Affected Fraction (ms-PAF) to a nonchemical stressor, elevated sea surface temperature. We then applied this method to calculate climate-adjusted water quality guideline values (GVs) for two reference toxicants, copper and the herbicide diuron, for tropical marine species. First, we developed a species sensitivity distribution (SSD) for thermal stress based on published experimental data for 41 tropical benthic marine species using methods adapted from water quality GV derivation. This enabled quantitative predictions of community effects as temperatures exceeded acclimation values. The resulting protective temperature values (PTx) were similar to temperatures known to initiate coral bleaching and are therefore relevant for application in multistressor risk assessments. The extended ms-PAF method enabled the adjustment of current water quality GVs to account for thermal stress events. This approach could be applied to other ecosystems and other non-contaminant stressors (e.g., sediment, low salinity, anoxia, and ocean acidification), offering an alternative approach for deriving environmental GVs, reporting and assessing the risk posed by multiple stressors.

Perioperative pain management in minimally invasive gynecologic surgery.

PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent evidence-based interventions for perioperative pain management in minimally invasive gynecologic surgery. RECENT FINDINGS: With particular emphasis on preemptive interventions in recent studies, we found preoperative counseling, nutrition, exercise, psychological interventions, and a combination of acetaminophen, celecoxib, and gabapentin are highly important and effective measures to reduce postoperative pain and opioid demand. Intraoperative local anesthetics may help at incision sites, as a paracervical block, and a transversus abdominus plane block. Postoperatively, an effort should be made to utilize non-narcotic interventions such as abdominal binders, ice packs, simethicone, bowel regimens, gabapentin, and scheduled NSAIDs and acetaminophen. When prescribing narcotics, providers should be aware of recommended amounts of opioids required per procedure so as to avoid overprescribing. SUMMARY: Our findings emphasize the evolving importance of preemptive interventions, including prehabilitation and pharmacologic agents, to improve postoperative pain after minimally invasive gynecologic surgery. Additionally, a multimodal approach to nonnarcotic intraoperative and postoperative interventions decreases narcotic requirement and improves opioid stewardship.

Robotic Transabdominal Cerclage vs Laparotomy: A Comparison of Obstetric and Surgical Outcomes.

STUDY OBJECTIVE: To compare obstetric and surgical outcomes of transabdominal cerclage (TAC) via laparotomy (TAC-LAP) versus robotic-assisted (TAC-RA) approaches. DESIGN: Retrospective cohort study. SETTING: An academic medical center. PATIENTS: Sixty-nine women with acquired or congenital cervical insufficiency. INTERVENTIONS: All women underwent TAC either by laparotomy or robotic-assisted approaches by 2 primary surgeons between January 2003 and July 2018. Women with a preconceptional TAC without a subsequent pregnancy were excluded. MEASUREMENTS AND MAIN RESULTS: A total of 69 women met inclusion criteria in the 15-year study period with 40 in the historical TAC-LAP group and 29 in the TAC-RA group. Gestational age at delivery was similar in the 2 groups (36 weeks 3 days vs 37 weeks; median difference -1 day, 95% confidence interval [CI] -6 to 2, p = .36). There were no differences in birth weight, Apgar scores, neonatal intensive care unit admission, or neonatal survival. Estimated blood loss and length of stay were significantly greater in the TAC-LAP group (50 mL vs 20 mL; median difference 25, 95% CI 5-40, p = .007 and 76 hours vs 3 hours; median difference 71, 95% CI 65-75, p <.001, respectively). Operative time was significantly shorter in the TAC-LAP group (65 minutes vs 132 minutes; median difference -64.7, 95% CI -79 to -49, p <.001). There was one intra-operative complication and 4 minor postoperative complications in the TAC-LAP group and none observed in the TAC-RA group. All outcomes were similar when comparing postconceptional TAC alone, except there was no longer a difference in blood loss. When comparing pre- versus postconceptional robotic TAC, there were no differences in surgical outcomes. CONCLUSION: Robotic TAC has similar favorable obstetric outcomes to traditional laparotomy and is associated with reduced blood loss and shorter hospital stays. Despite longer operative times, the robotic group did not experience any intra-operative or postoperative complications, which speaks to the benefits of this minimally invasive approach to TAC.

Social information changes stress hormone receptor expression in the songbird brain.

Social information is used by many vertebrate taxa to inform decision-making, including resource-mediated movements, yet the mechanisms whereby social information is integrated physiologically to affect such decisions remain unknown. Social information is known to influence the physiological response to food reduction in captive songbirds. Red crossbills (Loxia curvirostra) that were food reduced for several days showed significant elevations in circulating corticosterone (a "stress" hormone often responsive to food limitation) only if their neighbors were similarly food restricted. Physiological responses to glucocorticoid hormones are enacted through two receptors that may be expressed differentially in target tissues. Therefore, we investigated the influence of social information on the expression of the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA in captive red crossbill brains. Although the role of MR and GR in the response to social information may be highly complex, we specifically predicted social information from food-restricted individuals would reduce MR and GR expression in two brain regions known to regulate hypothalamic-pituitary-adrenal (HPA) activity - given that reduced receptor expression may lessen the efficacy of negative feedback and release inhibitory tone on the HPA. Our results support these predictions - offering one potential mechanism whereby social cues could increase or sustain HPA-activity during stress. The data further suggest different mechanisms by which metabolic stress versus social information influence HPA activity and behavioral outcomes.

Duration of action of mepivacaine and lidocaine in equine palmar digital perineural blocks in an experimental lameness model.

OBJECTIVE: To establish and compare the onset and duration of action of 2 local anesthetics based on objective lameness and skin sensitivity assessment. STUDY DESIGN: Interventional crossover experimental trial with balanced randomization. ANIMALS: Eight horses. METHODS: Reversible forelimb lameness was induced in 8 horses. A palmar digital nerve block (PDNB) was applied with mepivacaine or lidocaine (both 2%). Quantitative lameness and skin sensitivity data were collected with an inertial sensor system and a force gauge, respectively. The times to lameness resolution/skin desensitization (T1), consistent lameness detection/partial return of skin sensitivity (T2), and complete return of lameness/skin sensitivity (T3) were determined and compared between treatments and assessment methods. RESULTS: Mepivacaine blocks resolved lameness in 8/8 horses, compared to 3/8 horses with lidocaine blocks. Both agents led to skin desensitization in 8/8 horses. Skin desensitization occurred sooner than lameness resolution after mepivacaine (P = .047). Duration of action was longer with mepivacaine than lidocaine (mean T3_lameness mepivacaine 366 minutes, lidocaine 113 minutes (P = .038); T3_skin mepivacaine 195 minutes, lidocaine 63 minutes [P ≤ .001]). Skin sensitivity returned sooner than lameness after lidocaine block at T3 (P = .015). CONCLUSION: The use of lidocaine in PDNBs for the purpose of lameness diagnosis should be reassessed, as it may not resolve lameness despite loss of skin sensation. Mepivacaine is superior, with a reliable onset and longer duration of action. Skin desensitization as an indicator for the onset of action or effectiveness of PDNBs for mepivacaine and lidocaine, or as a measure of the duration of action of lidocaine PDNBs should be interpreted with caution.

Elevated stress is associated with prefrontal cortex dysfunction during a verbal memory task in women with HIV.

HIV-infected women may be particularly vulnerable to verbal learning and memory deficits. One factor contributing to these deficits is high perceived stress, which is associated with prefrontal cortical (PFC) atrophy and memory outcomes sensitive to PFC function, including retrieval and semantic clustering. We examined the association between stress and PFC activation during a verbal memory task in 36 HIV-infected women from the Chicago Consortium of the Women's Interagency HIV Study (WIHS) to better understand the role of the PFC in this stress-related impairment. Participants completed standardized measures of verbal learning and memory and stress (perceived stress scale-10). We used functional magnetic resonance imaging to assess brain function while participants completed encoding and recognition phases of a verbal memory task. HIV-infected women with higher stress (scores in top tertile) performed worse on all verbal memory outcomes including strategic encoding (p < 0.05) compared to HIV-infected women with lower stress (scores in lower two tertiles). Patterns of brain activation during recognition (but not encoding) differed between women with higher vs. lower stress. During recognition, women with higher stress demonstrated greater deactivation in medial PFC and posterior cingulate cortex compared to women with lower stress (p < 0.05). Greater deactivation in medial PFC marginally related to less efficient strategic retrieval (p = 0.06). Similar results were found in analyses focusing on PTSD symptoms. Results suggest that stress might alter the function of the medial PFC in HIV-infected women resulting in less efficient strategic retrieval and deficits in verbal memory.

Raman spectroscopy: an evolving technique for live cell studies.

One of the most exciting developments in Raman spectroscopy in the last decade has been its application to cells and tissues for diagnostic and pharmaceutical applications, and in particular its use in the analysis of cellular dynamics. Raman spectroscopy is rapidly advancing as a cell imaging method that overcomes many of the limitations of current techniques and is earning its place as a routine tool in cell biology. In this review we focus on important developments in Raman spectroscopy that have evolved into the exciting technique of live-cell Raman microscopy and highlight some of the most recent and significant applications to cell biology.

Challenges of Integrating an Evidence-based Intervention in Health Departments to Prevent Excessive Gestational Weight Gain among Low-income Women.

OBJECTIVE: To examine health departments' (HD) capacity to adapt and implement an intervention to prevent excessive gestational weight gain. DESIGN AND SAMPLE: Seventy-seven stakeholders (nurses, nutritionists, social workers, health educators, health directors, and multilingual service providers) in nine HDs participated. A descriptive mixed methods approach was used to collect data at workshops held onsite to introduce the evidence-based intervention (EBI) and discuss its adaptation. MEASURES: A survey was administered to assess the intervention's fit with the HDs context. Generalized logit mixed models were used to analyze the survey data. The discussions of adaptation were audiotaped and thematically analyzed to identify factors influencing implementation. RESULTS: The majority of stakeholders desired to participate in the training portion of the EBI, but they were reluctant to adopt it, and noted a lack of adequate resources. From the audiotaped narratives, three themes emerged: (1) Patient needs and resources, (2) Perception about adaptability of the EBI, and (3) The complexity of the EBI for pregnant populations. CONCLUSION: Although the EBI was effective for low-income nonpregnant populations in southeastern regions, pregnancy and complex antenatal services make this intervention unrealistic to be adapted as a part of prenatal care at HDs.

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition.

Interictal spikes are electroencephalographic discharges that occur at or near brain regions that produce epileptic seizures. While their role in generating seizures is not well understood, spikes have profound effects on cognition and behaviour, depending on where and when they occur. We previously demonstrated that spiking areas of human neocortex show sustained MAPK activation in superficial cortical Layers I-III and are associated with microlesions in deeper cortical areas characterized by reduced neuronal nuclear protein staining and increased microglial infiltration. Based on these findings, we chose to investigate additional neuronal populations within microlesions, specifically inhibitory interneurons. Additionally, we hypothesized that spiking would be sufficient to induce similar cytoarchitectonic changes within the rat cortex and that inhibition of MAPK signalling, using a MAP2K inhibitor, would not only inhibit spike formation but also reduce these cytoarchitectonic changes and improve behavioural outcomes. To test these hypotheses, we analysed tissue samples from 16 patients with intractable epilepsy who required cortical resections. We also utilized a tetanus toxin-induced animal model of interictal spiking, designed to produce spikes without seizures in male Sprague-Dawley rats. Rats were fitted with epidural electrodes, to permit EEG recording for the duration of the study, and automated algorithms were implemented to quantify spikes. After 6 months, animals were sacrificed to assess the effects of chronic spiking on cortical cytoarchitecture. Here, we show that microlesions may promote excitability due to a significant reduction of inhibitory neurons that could be responsible for promoting interictal spikes in superficial layers. Similarly, we found that the induction of epileptic spikes in the rat model produced analogous changes, including reduced neuronal nuclear protein, calbindin and parvalbumin-positive neurons and increased microglia, suggesting that spikes are sufficient for inducing these cytoarchitectonic changes in humans. Finally, we implicated MAPK signalling as a driving force producing these pathological changes. Using CI-1040 to inhibit MAP2K, both acutely and after spikes developed, resulting in fewer interictal spikes, reduced microglial activation and less inhibitory neuron loss. Treated animals had significantly fewer high-amplitude, short-duration spikes, which correlated with improved spatial memory performance on the Barnes maze. Together, our results provide evidence for a cytoarchitectonic pathogenesis underlying epileptic cortex, which can be ameliorated through both early and delayed MAP2K inhibition. These findings highlight the potential role for CI-1040 as a pharmacological treatment that could prevent the development of epileptic activity and reduce cognitive impairment in both patients with epilepsy and those with non-epileptic spike-associated neurobehavioural disorders.