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Background: While many transgender and gender diverse individuals rapidly achieve amenorrhea on testosterone, emerging data have identified that breakthrough bleeding can occur in up to one-third of individuals with long-term use. Breakthrough bleeding can worsen dysphoria and patients may seek management to reattain amenorrhea. Because of this, there is a need to assess efficacy of management approaches., Objective: The primary aim of the study was to evaluate methods used by patients and their providers to manage breakthrough bleeding which arises after 1 year of testosterone use. Secondary aims included describing the diagnostic approaches to breakthrough bleeding, and proposing an algorithm for classification and management of breakthrough bleeding in this patient population., Study Design: This was an institutional review board-approved single tertiary center, retrospective chart review of transgender and gender diverse individuals on testosterone gender affirming hormone therapy who experienced breakthrough bleeding after 1 year of use. Charts were reviewed to determine patient characteristics, testosterone use, and breakthrough bleeding management approaches., Results: Of the 96 individuals who had been on testosterone for 1 year and experienced breakthrough bleeding, 97% (n=93) engaged in at least 1 approach to management. The mean age at initiation of testosterone was 21.9 (standard deviation 5.4) and the median duration of time on testosterone was 54.5 months (interquartile range 33.5, 82). Only 16% (n=15) were using menstrual suppression at the time of their breakthrough bleeding episode. Breakthrough bleeding was successfully managed in 77 (79%), following between 1 and 4 attempted approaches. More than half of management attempts (63%) were successful on the first try. When management approaches were analyzed independently, the range of success associated with any particular approach was between 33% and 100%. Other than hysterectomy, which was fully successful at managing breakthrough bleeding, no approach was significantly better than no intervention. This was true both for individuals who did and did not bleed with missed testosterone doses. Regardless of what approach was used, after a failed attempt, the next attempt was successful in more than half of individuals. Of the 16 who underwent hysterectomy, 1 did so in part as a first line approach to manage breakthrough bleeding., Conclusion: In this study, use of medical management methods was not found to be superior to observation alone in the management of breakthrough bleeding. In the absence of data supporting superiority of any method, we recommend tailoring method attempts to patients' goals., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Little is known about the maintenance of amenorrhea among transgender and gender-diverse individuals with uteri who are using long-term testosterone gender-affirming hormone therapy. Emerging data describe breakthrough bleeding among adolescents on long-term testosterone therapy and among adults who are seeking a gender-affirming hysterectomy. More studies are needed to better understand breakthrough bleeding patterns among transgender and gender-diverse individuals with uteri who are using testosterone, including the frequency, timing, and etiology of bleeding and how these patterns may differ between adults and younger populations., Objective: The primary aim of this study was to characterize the incidence and patterns of breakthrough bleeding in a cohort of transgender and gender-diverse individuals who had been on testosterone for longer than 12 months and who had uteri in situ. Secondary aims included identifying the time to first bleed for those who experienced breakthrough bleeding and the risk factors associated with breakthrough bleeding while on testosterone therapy., Study Design: This was an institutional review board-approved, single tertiary center, retrospective chart review of transgender and gender diverse individuals who had been on testosterone for at least 1 year. A primary survival analysis that evaluated the incidence of bleeding was combined with descriptive analyses and an evaluation of the factors associated with bleeding., Results: Of the 279 patients included in the analysis, the median age of testosterone initiation was 22 years (interquartile range, 19-41), and the median follow-up time was 34 months (range, 12-278). The absolute proportion of individuals who ever experienced breakthrough bleeding on testosterone was 34% (n=96; 95% confidence interval, 29-40). Patients who experienced breakthrough bleeding initiated testosterone at a younger age (20.5 vs 22.0 years; P=.04), had lower mean serum testosterone levels (389.14 vs 512.7 ng/dL; P=.001), were more likely to have a mean testosterone level <320 ng/dL (52% vs 48%; P=.001), and had higher mean estradiol levels (62% vs 49%; P=.003). Survival analyses estimated a breakthrough bleeding incidence rate of 0.09 per year (95% confidence interval, 0.07-1.0). Although 58 people underwent a hysterectomy during the follow-up period, 64% of the cohort who maintained a uterus eventually experienced breakthrough bleeding. The median time to the initial bleeding episode was 22 months (interquartile range, 12-201) after testosterone initiation., Conclusion: These results suggest that a substantial fraction of transgender and gender-diverse individuals who are using testosterone will experience at least 1 episode of breakthrough bleeding even after their initial year of testosterone use. We recommend that clinicians inform all patients that breakthrough bleeding is a common occurrence even after the first year on testosterone therapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pelvic pain has been reported in transmasculine individuals taking testosterone. There is a need for further investigation to increase understanding of the prevalence and risk factors of this pain., Aim: We sought to determine the prevalence of pelvic pain reported by transmasculine individuals who had both a uterus and ovaries and were taking testosterone., Methods: We conducted an institutional review board-approved retrospective study of all transmasculine individuals who had been taking testosterone for at least 1 year and had a uterus and ovaries at the time of testosterone initiation. Charts of participating patients were reviewed to determine patient characteristics, testosterone use, and pelvic pain symptoms both before and after initiation of testosterone., Outcomes: Patients reported experiences of pelvic pain while on testosterone., Results: Of 280 individuals who had been on testosterone for at least 1 year, 100 (36%) experienced pelvic pain while on testosterone. Of those patients, 71% (n = 71) had not experienced pelvic pain prior to starting testosterone. There were 42 patients (15%) who had pelvic pain prior to starting testosterone, 13 (31%) of whom no longer experienced pain once starting testosterone. The median (IQR) age at initiation of testosterone was 22 (19-41) years and duration of testosterone treatment was 48 (27-251) months.Those patients who experienced pelvic pain while on testosterone were significantly more likely to have also reported pelvic pain prior to starting testosterone (29% vs 7%, P < .001). These patients were also more likely to have a pre-existing diagnosis of dysmenorrhea (27% vs 7%, P < .001), endometriosis (6% vs 2%, P = .049), or ovarian cysts and/or masses (12% vs 2% P < .001). Patients with pelvic pain were also more likely to have been on a menstrual suppression agent prior to and overlapping testosterone initiation (22% vs 12%, P = .03) and to have used menstrual suppression for longer durations (median [IQR] 18 [6-44] vs 8 [4-15] months, P = .04)., Clinical Implications: Pelvic pain is common in transmasculine individuals who are initiating testosterone treatment, although testosterone has both positive and negative effects on pelvic pain in different individuals., Strengths and Limitations: The major strengths of this study included large numbers of patients, ability to assess for documentation of pelvic pain prior to testosterone, and ability to determine an actual prevalence of pelvic pain. Major limitations included the study being a retrospective analysis in a single tertiary care center, the limitations of clinical documentation, and the lack of a standard pelvic pain evaluation process., Conclusion: More than one-third of transmasculine patients with a uterus and ovaries had pelvic pain while on testosterone, with the majority reporting onset of pain after initiating testosterone., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Community-Research Advisory Councils (C-RAC) provide a unique mechanism for building sustainable community-academic partnership, fostering bidirectional understanding of complex research issues, disseminating timely research findings, and thereby improving public trust in science. Created in 2009, the Johns Hopkins C-RAC has a mission to achieve diversity, equity, and inclusion (DEI) of stakeholders across the entire research continuum. It has nurtured over a decade of partnership among community and academic stakeholders toward addressing health disparity, health equity, structural racism, and discrimination. Evidence of successful strategies to ensure DEI in partnership and lessons learned are illustrated in this special communication., Competing Interests: The authors have no conflict of interest to declare., (© The Author(s) 2023.)

Background: Addiction to opioids, a well-known public health crisis, is now more prevalent in pregnant women as evidenced by the parallel rise with pregnant women in the epidemic with the general population. Evidence is now available that substantiates the need for global awareness to increase efforts in the treatment of pregnant women with opioid use disorder (OUD) as this vulnerable population lacks equal access to opioid abuse treatment across the United States., Aim: The overarching aim and purpose of this quality improvement project was to increase access to treatment for pregnant women with OUD who are currently underserved in a community located in Florida., Methods: Between January and April 2022, the 4Ps (parents, partners, past, and pregnancy), a validated screening tool, was implemented in an organization that accepts individuals with substance abuse. Each positive screen was referred for assessment for buprenorphine induction and medication-assisted treatment follow-up. Descriptive statistics were collected counting the number of screens completed, the number of positive screens, the number of referrals, and the number of patients remaining in treatment for 30 and 60 days., Results: Twenty-two screens were completed. The results yielded an increase in referrals, a 75% increase in treatment of pregnant women, and an average of 83% of participants remained in treatment., Conclusion: The implementation of a validated screening tool assisted in increasing access to treatment for pregnant women with OUD. Once implemented, the screening tool forges a pathway for referrals and evidence-based treatment for pregnant women with OUD., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2023 International Nurses Society on Addictions.)

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO 2 ), behavioral outcomes, and neuropathology in 16-18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1-3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30-60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

Background: Self-care is a multicomponent set of capacities that influence beliefs about health and well-being., Objectives: We examined the relationship between self-care capacity, age, and disability status with two perceptions of well-being in a cohort of Medicare beneficiaries., Methods: The current study is part of a multisite research project to determine factors associated with cross-sectional and longitudinal morbidity and mortality trajectories observed in Medicare beneficiaries. Variable selection was informed by the health disparities and outcomes model. Using data from the 2013 Medicare Current Beneficiary Survey and logistic regression models, we determined associations between self-care capacity, including indicators of self-care ability and self-care agency and two perceptions of well-being. Participants were divided into four groups based on how they qualified for Medicare: (a) over 65 years of age, and below 65 years of age and disabled because of (b) physical or (c) mental disorder, or (d) disabled and could not be classified as physically or mentally disabled as the primary cause of eligibility., Results: Self-care ability limitations in activities of daily living (ADL), instrumental activities of living (IADL), and social activity participation were associated with both health perceptions. Those with physical disabilities reported more ADL and IADL limitations when compared with the other eligibility groups and were significantly more likely to have negative health perceptions. Those with serious mental illness were most likely to report the most severe IADL limitations. The over 65 years of age group reported less self-care incapacity than the other three eligibility types. Other components of self-care, including health literacy, agency, and health behaviors, significantly influenced perceptions of health. Women and people identifying as non-Whites were more likely to have negative health perceptions., Discussion: Self-care capacity is a complex construct, and its varied elements have differential relationships with perceptions of well-being. Those with physical disabilities reported more self-care limitations, poorer perceived health, and more health worries than the other groups. Still, there were different patterns of self-care capacities in the serious mental illness type-especially in IADL limitations. The study adds empirical evidence to previous research documenting inequities in health outcomes for women and non-Whites. Findings provide empirical support for the health disparities and outcomes model., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this emergent mixed methods study was to measure hope in individuals living in poverty and to explore potential contextual influences on hope. We used a sequential mixed methods study in which the quantitative phase was administered first followed by a qualitative phase. Participants in impoverished areas scored higher in hope than a comparison group of university students. In a follow-up qualitative phase, participants named contributors to and detractors from hope that included experiences driven by environmental factors. Findings were organized according to Ecological Systems Theory (EST). Participants named factors from all levels of EST, and interactions between levels were evident. These results and findings support the inclusion of relevant contextual factors in psychological inquiry, and we suggest deliberate inclusion of individuals from all socioeconomic groups in future positive psychological research., (© 2021 Wiley Periodicals LLC.)

Decreased cerebral blood flow (CBF) after cardiac arrest (CA) contributes to secondary ischemic injury in infants and children. We previously reported cortical hypoperfusion with tissue hypoxia early in a pediatric rat model of asphyxial CA. In order to identify specific alterations as potential therapeutic targets to improve cortical hypoperfusion post-CA, we characterize the CBF alterations at the cortical microvascular level in vivo using multiphoton microscopy. We hypothesize that microvascular constriction and disturbances of capillary red blood cell (RBC) flow contribute to cortical hypoperfusion post-CA. After resuscitation from 9 min asphyxial CA, transient dilation of capillaries and venules at 5 min was followed by pial arteriolar constriction at 30 and 60 min (19.6 ± 1.3, 19.3 ± 1.2 µm at 30, 60 min vs. 22.0 ± 1.2 µm at baseline, p < 0.05). At the capillary level, microcirculatory disturbances were highly heterogeneous, with RBC stasis observed in 25.4% of capillaries at 30 min post-CA. Overall, the capillary plasma mean transit time was increased post-CA by 139.7 ± 51.5%, p < 0.05. In conclusion, pial arteriolar constriction, the no-reflow phenomenon and increased plasma transit time were observed post-CA. Our results detail the microvascular disturbances in a pediatric asphyxial CA model and provide a powerful platform for assessing specific vascular-targeted therapies.

The Health Disparities and Outcomes (HDO) model originally created to explain the complexity of obtaining healthcare in rural settings has been revised and updated using emerging theoretical models of adversity and inequity and two decades of empirical work by the authors. With a strong orientation to explaining population-based health inequities, the HDO is applied to individuals with Serious Mental Illness (SMI), to explain their high rates of morbidity and mortality compared to the general population. Individual-, community-, and system-level factors that reflect an understanding of life-long risk, accrued hazards associated with multiple and intersecting disadvantages, and difficulty obtaining healthcare that meets accepted standards are described. The revised HDO can be applied to populations with disproportionate health challenges to identify multi-level factors that affect illness trajectory and overall health outcomes.

Objective: This study examines temporal trends in treatment-related outcomes surrounding a diabetic ketoacidosis (DKA) performance improvement intervention consisting of mandated intensive care unit admission and implementation of a standardized management pathway, and identifies physical and biochemical characteristics associated with outcomes in this population., Methods: A retrospective cohort of 1225 children with DKA were identified in the electronic health record by international classification of diseases codes and a minimum pH less than 7.3 during hospitalization at a quaternary children's hospital between April, 2009 and May, 2016. Multivariable regression examined predictors and trends of hypoglycemia, central venous line placement, severe hyperchloremia, head computed tomography (CT) utilization, treated cerebral edema and hospital length of stay (LOS)., Results: The incidence of severe hyperchloremia and head CT utilization decreased during the study period. Among patients with severe DKA (presenting pH < 7.1), the intervention was associated with decreasing LOS and less variability in LOS. Lower pH at presentation was independently associated with increased risk for all outcomes except hypoglycemia, which was associated with higher pH. Patients treated for cerebral edema had a lower presenting mean systolic blood pressure z score (0.58 [95% confidence interval (CI) -0.02-1.17] vs 1.23 [1.13-1.33]) and a higher maximum mean systolic blood pressure (SBP) z score during hospitalization (3.75 [3.19-4.31] vs 2.48 [2.38-2.58]) compared to patients not receiving cerebral edema treatment. Blood pressure and cerebral edema remained significantly associated after covariate adjustment., Conclusion: Treatment-related outcomes improved over the entire study period and following a performance improvement intervention. The association of SBP with cerebral edema warrants further study., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The recent clinical availability of the PARP inhibitor olaparib (Lynparza) opens the door for potential therapeutic repurposing for non-oncological indications. Considering (a) the preclinical efficacy data with PARP inhibitors in non-oncological diseases and (b) the risk-benefit ratio of treating patients with a compound that inhibits an enzyme that has physiological roles in the regulation of DNA repair, we have selected indications, where (a) the severity of the disease is high, (b) the available therapeutic options are limited, and (c) the duration of PARP inhibitor administration could be short, to provide first-line options for therapeutic repurposing. These indications are as follows: acute ischaemic stroke; traumatic brain injury; septic shock; acute pancreatitis; and severe asthma and severe acute lung injury. In addition, chronic, devastating diseases, where alternative therapeutic options cannot halt disease development (e.g. Parkinson's disease, progressive multiple sclerosis or severe fibrotic diseases), should also be considered. We present a preclinical and clinical action plan for the repurposing of PARP inhibitors., Linked Articles: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc., (© 2017 The British Pharmacological Society.)

Pharmacotherapy for traumatic brain injury (TBI) is focused on resuscitation, prevention of secondary injury, rehabilitation and recovery. Pharmacogenomics may play a role in TBI for predicting therapies for sedation, analgesia, seizure prevention, intracranial pressure-directed therapy and neurobehavioral/psychiatric symptoms. Research into genetic predictors of outcomes and susceptibility to complications may also help clinicians to tailor therapeutics for high-risk individuals. Additionally, the expanding use of genomics in the drug development pipeline has provided insight to novel investigational and repurposed medications that may be useful in the treatment of TBI and its complications. Genomics in the context of treatment and prognostication for patients with TBI is a promising area for clinical progress of pharmacogenomics.

Introduction: Tobacco use among young people is a complex and serious global dilemma that demands innovative and diverse research approaches. The purpose of this methodological review was to examine the current use of mixed methods research in tobacco control with youth and young adult populations and to develop practical recommendations for tobacco control researchers interested in this methodology., Methods: Using PubMed, we searched five peer-reviewed journals that publish tobacco control empirical literature for the use of mixed methods research to study young populations, age 12-25 years. Our team analyzed the features of each article in terms of tobacco control topic, population, youth engagement strategies, and several essential elements of mixed methods research., Results: We identified 23 mixed methods studies published by authors from five different countries reported between 2004 and 2015. These 23 articles examined various topics that included tobacco use behavior, tobacco marketing and branding, and cessation among youth and young adults. The most common mixed methods approach was variations of the concurrent design in which the qualitative and quantitative strands were administered at the same time and given equal priority. This review documented several innovative applications of mixed methods research as well as challenges in the reporting of the complex research designs., Conclusions: The use of mixed methods research in tobacco control has great potential for advancing the understanding of complex behavioral and sociocultural issues for all groups, especially youth and young adults.

Oral and maxillofacial surgeons have been providing safe anesthesia to their patients using the anesthesia team model; this has allowed access to care for patients that have significant anxiety. The AAOMS strives to maintain the excellent safety record of the anesthesia team model by creating simulation programs in anesthesia, regularly updating the office anesthesia evaluation program, convening anesthesia safety conferences and strengthening the standards in our training programs. Through these efforts, our delivery of anesthesia to our patients will remain safe and effective., (Copyright © 2017. Published by Elsevier Inc.)

Resuscitation with polynitroxylated pegylated hemoglobin (PNPH), a pegylated bovine hemoglobin decorated with nitroxides, eliminated the need for fluid administration, reduced intracranial pressure (ICP) and brain edema, and produced neuroprotection in vitro and in vivo versus Lactated Ringer's solution (LR) in experimental traumatic brain injury (TBI) plus hemorrhagic shock (HS). We hypothesized that resuscitation with PNPH would improve acute physiology versus whole blood after TBI+HS and would be safe and effective across a wide dosage range. Anesthetized mice underwent controlled cortical impact and severe HS to mean arterial pressure (MAP) of 25-27 mm Hg for 35 min, then were resuscitated with PNPH, autologous whole blood, or LR. Markers of acute physiology, including mean arterial blood pressure (MAP), heart rate (HR), blood gases/chemistries, and brain oxygenation (PbtO 2 ), were monitored for 90 min on room air followed by 15 min on 100% oxygen. In a second experiment, the protocol was repeated, except mice were resuscitated with PNPH with doses between 2 and 100 mL/kg. ICP and 24 h %-brain water were evaluated. PNPH-resuscitated mice had higher MAP and lower HR post-resuscitation versus blood or LR (p < 0.01). PNPH-resuscitated mice, versus those resuscitated with blood or LR, also had higher pH and lower serum potassium (p < 0.05). Blood-resuscitated mice, however, had higher PbtO 2 versus those resuscitated with LR and PNPH, although PNPH had higher PbtO 2 versus LR (p < 0.05). PNPH was well tolerated across the dosing range and dramatically reduced fluid requirements in all doses-even 2 or 5 mL/kg (p < 0.001). ICP was significantly lower in PNPH-treated mice for most doses tested versus in LR-treated mice, although %-brain water did not differ between groups. Resuscitation with PNPH, versus resuscitation with LR or blood, improved MAP, HR, and ICP, reduced acidosis and hyperkalemia, and was well tolerated and effective across a wide dosing range, supporting ongoing pre-clinical development of PNPH for TBI resuscitation.

Objective: The international scope of critical neurologic insults in children is unknown. Our objective was to assess the prevalence and outcomes of children admitted to PICUs with acute neurologic insults., Design: Prospective study., Setting: Multicenter (n = 107 PICUs) and multinational (23 countries, 79% in North America and Europe)., Patients: Children 7 days to 17 years old admitted to the ICU with new traumatic brain injury, stroke, cardiac arrest, CNS infection or inflammation, status epilepticus, spinal cord injury, hydrocephalus, or brain mass., Interventions: None., Measurements and Main Results: We evaluated the prevalence and outcomes of children with predetermined acute neurologic insults. Child and center characteristics were recorded. Unfavorable outcome was defined as change in pre-post insult Pediatric Cerebral Performance Category score greater than or equal to 2 or death at hospital discharge or 3 months, whichever came first. Screening data yielded overall prevalence of 16.2%. Of 924 children with acute neurologic insults, cardiac arrest (23%) and traumatic brain injury (19%) were the most common. All-cause mortality at hospital discharge was 12%. Cardiac arrest subjects had highest mortality (24%), and traumatic brain injury subjects had the most unfavorable outcomes (49%). The most common neurologic insult was infection/inflammation in South America, Asia, and the single African site but cardiac arrest in the remaining regions., Conclusions: Neurologic insults are a significant pediatric international health issue. They are frequent and contribute substantial morbidity and mortality. These data suggest a need for an increased focus on acute critical neurologic diseases in infants and children including additional research, enhanced availability of clinical resources, and the development of new therapies.

Objective: Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE., Methods: DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy., Results: Fourteen SNPs with minor allele frequency >0.2 were identified. Four SNPS rs2283261, rs3819521, rs2283258, and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR 2.45, p = 0.007; OR 2.95, p = 0.025; OR 3.00, p = 0.013), had higher mean (β = 3.13, p = 0.000; β = 2.95, p = 0.005; β = 3.20, p = 0.008), and peak ICP (β = 8.00, p = 0.001; β = 7.64, p = 0.007; β = 6.89, p = 0.034). The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR 0.47, p = 0.004)., Conclusions: This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective-potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.

The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.

Background: Disturbances in cerebral blood flow (CBF) and brain oxygenation (PbO 2 ) are present early after pediatric cardiac arrest (CA). CBF-targeted therapies improved neurological outcome in our CA model. To assess the therapeutic window for CBF- and PbO 2 -targeted therapies, we propose to determine if CBF and PbO 2 disturbances persist at 24 h after experimental pediatric CA., Methods: Regional CBF and PbO 2 were measured at 24 h after asphyxial CA in immature rats (n = 26, 6-8/group) using arterial spin label MRI and tissue electrodes, respectively., Results: In all regions but the thalamus, CBF recovered to sham values by 24 h; thalamic CBF was >32% higher after CA vs. sham. PbO 2 values at 24 h after CA in the cortex and thalamus were similar to shams in rats who received supplemental oxygen, however, on room air, cortical PbO 2 was lower after CA vs. shams., Conclusion: CBF remains increased in the thalamus at 24 h after CA and PbO 2 is decreased to hypoxic levels in cortex at 24 h after CA in rats who do not receive supplemental oxygen. Given the enduring disturbances in this model and the lack of routine CBF or PbO 2 monitoring in patients, our data suggest the need for clinical correlation., Competing Interests: None