COVID-19 vaccination initiation and completion in a multicenter cohort study of insured US transgender and cisgender adults.

PURPOSE: Transgender and gender-diverse (TGD) people may have been disproportionately impacted by the COVID-19 pandemic, yet little is known about vaccination status in this population. This multicenter cohort study of insured adults examined the rates of COVID-19 vaccine initiation and completion in TGD persons compared to matched cisgender persons. METHODS: A cohort of TGD persons and matched cisgender persons enrolled in Kaiser Permanente health plans in Northern and Southern California between 12/1/2020 and 7/31/2021 were analyzed. COVID-19 vaccination initiation and completion rates were compared across groups using Cox regression models. RESULTS: Among transmasculine persons, the HR (95 % CI) estimates for COVID-19 vaccination initiation and completion were, respectively, 1.35 (1.30-1.40) and 1.78 (1.71-1.85) compared with cisgender women and 1.34 (1.29-1.40) and 1.81 (1.73-1.88) compared with cisgender men. Among transfeminine persons, the corresponding HRs (95 % CIs) for vaccination initiation and completion were 1.35 (1.30-1.40) and 1.78 (1.71-1.85) compared with cisgender women and 1.34 (1.29-1.40) and 1.81 (1.73-1.88) compared with cisgender men. CONCLUSION: Findings from this cohort of insured adults demonstrated that TGD persons initiated and completed COVID-19 vaccination at higher rates compared to matched cisgender persons. Further work is needed to understand vaccination rates and determinants in the broader TGD populations.

Aberrant Oxygen Concentrations Induce Systemic Inflammation in a Murine Model.

INTRODUCTION: Hypoxia is a significant cause of secondary insult in the critically ill trauma or surgical patient. The cause of increased mortality following a brief period of hypoxia is not well understood. The aim of this study is to determine the effect of acute, isolated deviations in oxygen concentration on proinflammatory cytokine release and markers of endothelial stress in a murine model. METHODS: Mice were randomized to either control, hypoxia, or hyperoxia group. The control group was exposed to room air for 60 min, the hyperoxia group was exposed to 70% fraction of inspired oxygen, and the hypoxia group was exposed to 10% fraction of inspired oxygen for 60 min. Whole blood collection was completed via cardiac puncture. Serum concentrations of proinflammatory cytokines and endothelial stress markers were analyzed via enzyme-linked immunosorbent assay. RESULTS: Following exposure to hypoxic conditions, there was a significant increase in interleukin (IL)-1α (IL-1 α), IL-1 ß, IL-3, IL-4, IL-6, IL-10, tumor necrosis factor α . Following exposure to hyperoxic conditions, there was a significant increase in monocyte chemoattractant protein-1 and regulated upon activation normal T cell expressed and presumably secreted, as well as a significant decrease in IL-12, and IL-17. No clinically significant difference was noted in serum concentration of endothelial stress markers between the treatment groups. DISCUSSION: Exposure to oxygen extremes induces systemic inflammation as measured by proinflammatory cytokines in a murine model. Hyperoxia also demonstrates the ability to downregulate certain inflammatory pathways while inducing others. No effect on serum concentration of endothelial stress markers is observed following acute, isolated hypoxic or hyperoxic conditions.

Multisystemic factors predicting street migration of children in Kenya: A multilevel longitudinal study of families and villages.

BACKGROUND: Street-migration of children is a global problem with sparse multi-level or longitudinal data. Such data are required to inform robust street-migration prevention efforts. OBJECTIVE: This study analyzes longitudinal cohort data to identify factors predicting street-migration of children - at caregiver- and village-levels. PARTICIPANTS AND SETTING: Kenyan adult respondents (n = 575; 20 villages) actively participated in a community-based intervention, seeking to improve factors previously identified as contributing to street-migration by children. METHODS: At two time points, respondents reported street-migration of children, and variables across economic, social, psychological, mental, parenting, and childhood experience domains. Primary study outcome was newly reported street-migration of children at T2 "incident street-migration", compared to households that reported no street-migration at T1 or T2. For caregiver-level analyses, we assessed bivariate significance between variables (T1) and incident street-migration. Variables with significant bivariate associations were included in a hierarchical logistical regression model. For community-level analyses, we calculated the average values of variables at the village-level, after excluding values from respondents who indicated an incident street-migration case to reduce potential outlier influence. We then compared variables between the 5 villages with the highest incidence to the 15 villages with fewer incident cases. RESULTS: In regression analyses, caregiver childhood experiences, psychological factors and parenting behaviors predicted future street-migration. Lower village-aggregated depression and higher village-aggregated collective efficacy and social curiosity appeared significantly protective. CONCLUSIONS: While parenting and economic strengthening approaches may be helpful, efforts to prevent street migration by children should also strengthen community-level mental health, collective efficacy, and communal harmony.

Need for Blood Transfusion Volume Is Associated With Increased Mortality in Severe Traumatic Brain Injury.

INTRODUCTION: Many patients suffering from isolated severe traumatic brain injury (sTBI) receive blood transfusion on hospital arrival due to hypotension. We hypothesized that increasing blood transfusions in isolated sTBI patients would be associated with an increase in mortality. METHODS: We performed a trauma quality improvement program (TQIP) (2017-2019) and single-center (2013-2021) database review filtering for patients with isolated sTBI (Abbreviated Injury Scale head ≥3 and all other areas ≤2). Age, initial Glasgow Coma Score (GCS), Injury Severity Score (ISS), initial systolic blood pressure (SBP), mechanism (blunt/penetrating), packed red blood cells (pRBCs) and fresh frozen plasma (FFP) transfusion volume (units) within the first 4 h, FFP/pRBC ratio (4h), and in-hospital mortality were obtained from the TQIP Public User Files. RESULTS: In the TQIP database, 9257 patients had isolated sTBI and received pRBC transfusion within the first 4 h. The mortality rate within this group was 47.3%. The increase in mortality associated with the first unit of pRBCs was 20%, then increasing approximately 4% per unit transfused to a maximum mortality of 74% for 11 or more units. When adjusted for age, initial GCS, ISS, initial SBP, and mechanism, pRBC volume (1.09 [1.08-1.10], FFP volume (1.08 [1.07-1.09]), and FFP/pRBC ratio (1.18 [1.08-1.28]) were associated with in-hospital mortality. Our single-center study yielded 138 patients with isolated sTBI who received pRBC transfusion. These patients experienced a 60.1% in-hospital mortality rate. Logistic regression corrected for age, initial GCS, ISS, initial SBP, and mechanism demonstrated no significant association between pRBC transfusion volume (1.14 [0.81-1.61]), FFP transfusion volume (1.29 [0.91-1.82]), or FFP/pRBC ratio (6.42 [0.25-164.89]) and in-hospital mortality. CONCLUSIONS: Patients suffering from isolated sTBI have a higher rate of mortality with increasing amount of pRBC or FFP transfusion within the first 4 h of arrival.

Re-evaluating the Use of High Sensitivity Troponin to Diagnose Blunt Cardiac Injury.

INTRODUCTION: Blunt cardiac injury (BCI) can be challenging diagnostically, and if misdiagnosed, can lead to life-threatening complications. Our institution previously evaluated BCI screening with troponin and electrocardiogram (EKG) during a transition from troponin I to high sensitivity troponin (hsTnI), a more sensitive troponin I assay. The previous study found an hsTnI of 76 ng/L had the highest capability of accurately diagnosing a clinically significant BCI. The aim of this study was to determine the efficacy of the newly implemented protocol. METHODS: Patients diagnosed with a sternal fracture from March 2022 to April 2023 at our urban level-1 trauma center were retrospectively reviewed for EKG findings, hsTnI trend, echocardiogram changes, and clinical outcomes. The BCI cohort and non-BCI cohort ordinal measures were compared using Wilcoxon's two-tailed rank sum test and categorical measures were compared with Fisher's exact test. Youden indices were used to evaluate hsTnI sensitivity and specificity. RESULTS: Sternal fractures were identified in 206 patients, of which 183 underwent BCI screening. Of those screened, 103 underwent echocardiogram, 28 were diagnosed with clinically significant BCIs, and 15 received intervention. The peak hsTnI threshold of 76 ng/L was found to have a Youden index of 0.31. Rather, the Youden index was highest at 0.50 at 40 ng/L (sensitivity 0.79 and specificity 0.71) for clinically significant BCI. CONCLUSIONS: Screening patients with sternal fractures for BCI using hsTnI and EKG remains effective. To optimize the hsTnI threshold, this study determined the hsTnI threshold should be lowered to 40 ng/L. Further improvements to the institutional protocol may be derived from multicenter analysis.

Platelet Function is Independent of Sphingolipid Manipulation.

INTRODUCTION: Previous literature suggests that sphingolipids may impact systemic coagulation and platelet aggregation, thus modulating the risks of thrombotic events. The goal of this investigation was to evaluate the role of serum sphingolipids on intrinsic platelet function to assess whether pharmacologic manipulation of sphingolipid metabolites would impact platelet aggregability. METHODS: C57BL/6J mice were injected with either normal saline, 1 mg/kg FTY720 (synthetic sphingosine-1-phosphate [S1P] receptor analog), or 5 mg/kg SLM6031434 (sphingosine kinase two inhibitor). Mice were sacrificed at 6 h and whole blood (WB) was collected for impedance aggregometry assessing platelet responsiveness to arachidonic acid or adenosine diphosphate. Ex vivo studies utilized WB or platelet-rich plasma that was pretreated with S1P, FTY720, amitriptyline, or d-sphingosine then analyzed by aggregability and flow cytometry for platelet and platelet-derived microvesicle characteristics. RESULTS: FTY720 and SLM6031434 pretreated induced similar arachidonic acid and adenosine diphosphate-mediated platelet aggregation as controls. Ex vivo WB and platelet-rich plasma treatment with S1P, FTY720, amitriptyline and d-sphingosine did not impact platelet aggregation. The percentages of CD41+, CD62P+ and CD41+/ceramide+, CD62P+/ceramide + platelets, and platelet-derived microvesicle were not significantly different between amitriptyline-treated and normal saline-treated cohorts. CONCLUSIONS: Sphingolipid modulating agents, such as FTY720, SLM6031434, S1P, amitriptyline, ceramide, and d-sphingosine do not appear to independently impact platelet aggregation in murine models.

Changes in Blood Lipids Following Initiation of Gender Affirming Hormone Therapy: A Systematic Review and Meta-Analysis.

Aim: The aim of this study was to conduct a systematic review and meta-analysis of changes in low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides following initiation of feminizing or masculinizing gender affirming hormone therapy (GAHT). Methods: A search of Ovid MEDLINE, Embase, Web of Science, SCOPUS, and CINAHL databases identified potentially relevant articles published from 1990 through 2024. Both observational and randomized trials of adults receiving feminizing or masculinizing GAHT with baseline and follow-up measures were included. Articles were reviewed for eligibility using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. The risk of bias in each study was quantified using the NHLBI Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. Random effects models were used to compute the before-and-after meta-differences in mean values for each parameter along with the I2 statistic to assess heterogeneity of results. Results: Thirty-five studies met the criteria for inclusion in the meta-analysis. Masculinizing GAHT was associated with significant changes in serum lipids from baseline up through the 60-month timepoint with meta-difference of means (95% CI) estimates of 26.2mg/dL (23.3,29.0) for LDL-C, 26.1mg/dL (22.8,29.4) for total cholesterol, 30.7mg/dL (6.9,54.6) for triglycerides and -9.4mg/dL (-12.1, -6.7) for HDL-C. Studies evaluating the effects of feminizing GAHT on balance demonstrated no notable changes in HDL-C or triglycerides while the results for LDL-C and total cholesterol were inconsistent. Heterogeneity of results ranged from minimal (I2 = 0%) to substantial (I2 = 90%). Conclusions: While the results for transfeminine individuals on GAHT appear somewhat reassuring, transmasculine patients receiving testosterone may benefit from closer monitoring of lipid profiles.

Hypobaria During Aeromedical Evacuation and Systemic Inflammation after Porcine Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI)-related morbidity is caused largely by secondary injury resulting from hypoxia, excessive sympathetic drive, and uncontrolled inflammation. Aeromedical evacuation (AE) is utilized by the military for transport of wounded soldiers to higher levels of care. We hypothesized that the hypobaric, hypoxic conditions of AE may exacerbate uncontrolled inflammation following TBI that could contribute to more severe TBI-related secondary injury. STUDY DESIGN: Thirty-six female pigs were used to test TBI vs. TBI sham, hypoxia vs. normoxia, and hypobaria vs. ground conditions. TBI was induced by controlled cortical injury, hypobaric conditions of 12,000 feet were established in an altitude chamber, and hypoxic exposure was titrated to 85% SpO2 while at altitude. Serum cytokines, UCH-L1 and TBI biomarkers were analyzed via ELISA. Gross analysis and staining of cortex and hippocampus tissue was completed for glial fibrillary acidic protein (GFAP) and phosphorylated tau (p-tau). RESULTS: Serum IL-1b, IL-6, and TNFα were significantly elevated following TBI in pigs exposed to altitude-induced hypobaria/hypoxia, as well as hypobaria alone, compared to ground level/normoxia. No difference in TBI biomarkers following TBI or hypobaric, hypoxic exposure was noted. No difference in brain tissue GFAP or p-tau when comparing the most different conditions of sham TBI+ground/normoxia to the TBI+hypobaria/hypoxia group was noted. CONCLUSION: The hypobaric environment of AE induces systemic inflammation following TBI. Severe inflammation may play a role in exacerbating secondary injury associated with TBI and contribute to worse neurocognitive outcomes. Measures should be taken to minimize barometric and oxygenation changes during AE following TBI.

Association between gender-affirming hormone therapy and measures of glucose metabolism: A longitudinal study.

CONTEXT: The long-term effect of gender-affirming hormone therapy (GAHT) on glucose metabolism is an area of priority in transgender health research. OBJECTIVES: To evaluate the relation between GAHT and changes in fasting blood glucose (FG) and glycosylated hemoglobin (HbA1c) in transmasculine (TM) and transfeminine (TF) persons relative to the corresponding temporal changes in presumably cisgender persons (i.e. without any evidence of TGD status). DESIGN: Retrospective cohort study. SETTING: Three large integrated health systems. PARTICIPANTS: 2,425 TF and 2,127 TM persons compared with 33,995 cisgender males (CM) and 38,913 cisgender females (CF) enrolled in the same health plans. OUTCOMES/MEASURES: Temporal changes in FG and HbA1c levels examined using linear mixed models with main results expressed as ratios-of-ratios. RESULTS: The pre- versus post-GAHT ratios-of-ratio (95% confidence interval) estimates adjusted for age, race/ethnicity, study site, and body mass index in the model comparing TF and CM groups were 1.05 (1.01, 1.09) for FG and 1.03 (0.99, 1.06) for HbA1c. By contrast, the corresponding results in the models contrasting TM and cisgender cohort members were in the 0.99-1.00 range. The ratio-of-ratios comparing post-GAHT changes among transgender and cisgender persons were close to the null and without a discernable pattern. CONCLUSION: Though the within-transgender cohort data suggest an increase in the levels of FG and HbA1c following feminizing GAHT initiation, these changes were no longer evident when compared with the corresponding changes in cisgender referents. Based on these results, clinically important effects of GAHT on routine laboratory markers of glucose metabolism appear unlikely.

Direct red blood cell effect on thrombosis is dependent on the interaction of tissue factor and calcium with membrane phosphatidylserine.

BACKGROUND: Prior literature has implicated red blood cells (RBCs) in the initiation of thrombosis and suggests that posttransfusion hypercoagulability may occur secondary to the effects of RBCs. Elevated serum tissue factor is a known sequelae of acute trauma. Phosphatidylserine (PS) is a prothrombotic phospholipid present within the RBC cell membrane. We hypothesized that RBC aggregation is dependent on the interaction between RBC membrane bound (exposed) PS, extracellular calcium, and tissue factor. METHODS: Human whole blood (WB) was separated into components, including RBCs and platelet-rich plasma (PRP). Whole blood, PRP, and RBCs underwent impedance aggregometry utilizing arachidonic acid (AA), ADP, collagen, calcium, and tissue factor (TF)-based agonists. Red blood cells then underwent impedance aggregometry utilizing combined calcium and TF agonists. Red blood cells were pretreated with Annexin V, a known PS blocking agent, and underwent impedance aggregometry with combined calcium and TF agonists to determine if the mechanism of calcium/TF-induced RBC aggregability is dependent on PS. Red blood cells treated with calcium, TF, calcium+TF, and pre-treated with Annexin V followed by calcium+TF were perfused through an in vitro model of pulmonary microcirculatory flow. RESULTS: Red blood cell aggregation was significantly higher than that of WB and PRP when utilizing a TF agonist, an effect unique to TF. The combination of calcium and TF demonstrated significantly higher RBC aggregation than either agonist alone. Pretreatment with Annexin V resulted in a significantly reduced aggregability of RBC following treatment with TF + calcium. Red blood cells aged to 42 days did not exhibit significant change in aggregation. Exposure to calcium and TF significantly reduced time to thrombosis of RBCs perfused through a pulmonary microcirculatory model. CONCLUSION: Treatment with both TF and calcium synergistically induces RBC aggregation. Phosphatidylserine appears to play an integral role in the TF/calcium-based, age-independent RBC aggregation response. Red blood cells treated with TF + calcium exhibit more rapid thrombus formation in an in vitro model of pulmonary microcirculatory perfusion.

Whole blood storage duration alters fibrinogen levels and thrombin formation.

INTRODUCTION: Whole blood resuscitation for hemorrhagic shock in trauma represents an opportunity to correct coagulopathy in trauma while also supplying red blood cells. The production of microvesicles in stored whole blood and their effect on its hemostatic parameters have not been described in previous literature. We hypothesized that microvesicles in aged stored whole blood are procoagulant and increase thrombin production via phosphatidylserine. METHODS: Whole blood was obtained from male C57BL/6 male mice and stored in anticoagulant solution for up to 10 days. At intervals, stored whole blood underwent examination with rotational thromboelastography, and platelet-poor plasma was prepared for analysis of thrombin generation. Microvesicles were prepared from 10-day-old whole blood aliquots and added to fresh whole blood or platelet-poor plasma to assess changes in coagulation and thrombin generation. Microvesicles were treated with recombinant mouse lactadherin prior to addition to plasma to inhibit phosphatidylserine's role in thrombin generation. RESULTS: Aged murine whole blood had decreased fibrin clot formation compared with fresh samples with decreased plasma fibrinogen levels. Thrombin generation in plasma from aged blood increased over time of storage. The addition of microvesicles to fresh plasma resulted in increased thrombin generation compared with controls. When phosphatidylserine on microvesicles was blocked with lactadherin, there was no difference in the endogenous thrombin potential, but the generation of thrombin was blunted with lower peak thrombin levels. CONCLUSION: Cold storage of murine whole blood results in decreased fibrinogen levels and fibrin clot formation. Aged whole blood demonstrates increased thrombin generation, and this is due in part to microvesicle production in stored whole blood. One mechanism by which microvesicles are procoagulant is by phosphatidylserine expression on their membranes.

Challenging Norms: The Impact of Transgender and Gender-Diverse Realities on Work and School Participation.

IMPORTANCE: Disruption in school and the workplace are health concerns for transgender people. OBJECTIVE: To evaluate transgender individuals' thoughts and comfort with how others perceive their gender identity (social affirmation) and its association with outness in the workplace and mistreatment at work or school. DESIGN: Cross-sectional survey. PARTICIPANTS: Survey respondents older than age 18 yr from the Study of Transition, Outcomes & Gender cohort (N = 696; n = 350 assigned male at birth, n = 346 assigned female at birth [AFAB]). OUTCOMES AND MEASURES: Ever "out" to employer and treated unfairly at work or school or fired from job. Predictors were high social affirmation and comfort with how others perceive own gender identity. Descriptive statistics and logistic regression were used for analyses. RESULTS: Individuals reporting high social affirmation were less likely to experience mistreatment at work or school than those with low social affirmation (odds ratio [OR] = 0.57, 95% confidence interval [CI] [0.38, 0.86]). Individuals AFAB who felt comfortable with how others perceived their gender identity were less likely to be out to their employers than individuals AFAB who did not (OR = 0.45; 95% CI [0.20, 0.97]). CONCLUSIONS AND RELEVANCE: Individuals with high social affirmation were less likely to experience work or school mistreatment, and feeling comfortable with how others perceive their gender identity did not signify the need to be out. Plain-Language Summary: Occupational therapy practitioners can play a pivotal role when working with transgender individuals by assisting in creating new routines for self-presentation at work or school, navigating social environments, and providing guidance in self-advocacy skills. Individuals assigned male at birth may be in greater need because they report lower levels of social affirmation and acceptance at school and work than individuals assigned female at birth.

Low-dose Paclitaxel with Pembrolizumab Enhances Clinical and Immunologic Responses in Platinum-refractory Urothelial Carcinoma.

PURPOSE: Single-agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma; therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. MATERIALS AND METHODS: This was a prospective, single-arm phase II trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and Eastern Cooperative Oncology Group ≤1. Treatment was pembrolizumab 200 mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21-day cycle for up to eight cycles unless progression or unacceptable adverse events (AE). The primary endpoint was overall response rate (ORR) with overall survival (OS), 6-month progression-free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma, and urinary miRs were evaluated. RESULTS: Twenty-seven patients were treated between April 2016 and June 2020, with median follow-up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic White. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with three complete responses. Six-month PFS rate was 48.1% [95% confidence interval (CI): 28.7-65.2] and median OS 12.4 months (95% CI: 8.7 months to not reached). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including two immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared with nonresponders. CONCLUSIONS: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory urothelial carcinoma. SIGNIFICANCE: We found that combining pembrolizumab with low-dose paclitaxel may be effective in patients with urothelial carcinoma progressing on platinum chemotherapy, with favorable safety profiles.

Microvesicles from stored red blood cells induce P-selectin and von Willebrand factor release from endothelial cells via a protein kinase C-dependent mechanism.

INTRODUCTION: The use of packed red blood cells (pRBCs) for resuscitation is limited by the red blood cell storage lesion, a series of biochemical and physiological changes that occur during the storage and aging of blood. Microvesicles (MVs) shed from pRBCs during this process are one component of the red blood cell storage lesion and lead to acute lung injury and pulmonary vascular microthrombi. We hypothesized that MVs from stored pRBCs lead to the release of P-selectin and von Willebrand factor (vWF) from endothelial cells and that this mechanism is mediated via activation of protein kinase C (PKC) or protein kinase A (PKA). METHODS: Leukoreduced, platelet-poor murine pRBCs were isolated from C57BL/6 8-12 week-old male mice via cardiac puncture, prepared via centrifugation using a Ficoll gradient, and stored for up to 14 days, the equivalent of 42 days of storage in humans. MVs were isolated from the stored pRBC units via sequential high-speed centrifugation. Murine lung endothelial cells (MLECs) were cultured and grown to confluence, then treated with MVs and either calphostin C, a PKC inhibitor (10 µg/mL), or PKI 14-22 amide, a PKA inhibitor (10 µM). The supernatant was collected after 1 h. P-selectin and vWF A2 concentrations were quantified via ELISA. Immunofluorescent staining for vWF was performed on MLECs. Statistical analysis was performed via unpaired t-test or ANOVA as indicated and reported as mean ± SD. Concentration is reported as pg/mL. RESULTS: MLECs treated with MVs isolated from stored pRBCs demonstrated increased release of P-selectin and vWF A2 in a dose-dependent fashion. MLECs treated with MVs prepared from stored as compared to fresh pRBCs demonstrated increased release of P-selectin (3751 ± 726 vs 359 ± 64 pg/mL, p < 0.0001) and vWF A2 (3141 ± 355 vs 977 ± 75 pg/mL, p < 0.0001) with increasing duration of storage. The treatment of MVs with calphostin C decreased the amount of P-selectin (1471 ± 444 vs 3751 ± 726 pg/mL, p < 0.0001) and VWF A2 (2401 ± 289 vs 3141 ± 355 pg/mL, p = 0.0017) released into the supernatant by MLECs compared to MVs alone. The treatment of MVs with PKI 14-22 increased the amount of P-selectin released compared to MVs alone (1999 ± 67 vs 1601 ± 135 pg/mL, p = 0.0018). CONCLUSIONS: MVs from stored pRBCs stimulate the release of P-selectin and VWF A2 from endothelial cells. The effect of MVs increases with both dose of MVs and age of stored pRBCs from which they are formed. This mechanism is dependent on activation of PKC and inhibition of this enzyme represents a potentially significant strategy to modulate the inflammatory response to resuscitation with stored pRBCs.

Just Say NO: Inhaled Nitric Oxide Effect on Respiratory Parameters Following Traumatic Brain Injury in Humans and a Porcine Model.

INTRODUCTION: The mechanism of post-traumatic brain injury (TBI) hypoxemia involves ventilation/perfusion mismatch and loss of pulmonary hypoxic vasoconstriction. Inhaled nitric oxide (iNO) has been studied as an adjunct treatment to avoid the use of high positive end-expiratory pressure and inspired oxygen in treatment-refractory hypoxia. We hypothesized that iNO treatment following TBI would improve systemic and cerebral oxygenation via improved matching of pulmonary perfusion and ventilation. METHODS: Thirteen human patients with isolated TBI were enrolled and randomized to receive either placebo or iNO with measured outcomes including pulmonary parameters, blood gas data, and intracranial pressure (ICP) /perfusion. To complement this study, a porcine model of TBI (including 10 swine) was utilized with measured outcomes of brain tissue blood flow and oxygenation, ventilator parameters, and blood gas data both after administration and following drug removal and clearance. RESULTS: There were no clinically significant changes in pulmonary parameters in either the human or porcine arm following administration of iNO when compared to either the placebo group (human arm) or the internal control (porcine arm). Analysis of pooled human data demonstrated the preservation of alveolar recruitment in TBI patients. There were no clinically significant changes in human ICP or cerebral perfusion pressure following iNO administration compared to controls. CONCLUSIONS: iNO had no significant effect on clinically relevant pulmonary parameters or ICPs following TBI in both human patients and a porcine model. The pressure-based recruitment of the human lungs following TBI was preserved. Further investigation will be needed to determine the degree of utility of iNO in the setting of hypoxia after polytrauma.

Desmopressin, Misoprostol, nor Carboprost Affect Platelet Aggregability Following Traumatic Brain Injury and Aspirin.

INTRODUCTION: Desmopressin (DDAVP) has been utilized clinically in patients taking aspirin (ASA) to improve drug-induced platelet dysfunction. Misoprostol and carboprost, prostaglandin analogs commonly used for postpartum hemorrhage, may also induce platelet aggregation. The aim of this study was to determine the effects of DDAVP, misoprostol, and carboprost administration on platelet aggregability following traumatic brain injury (TBI) in mice treated with ASA. METHODS: Male C57BL/6 mice were randomized into seven groups (n = 5 each): untouched, ASA only, Saline/TBI, ASA/TBI, ASA/TBI/DDAVP 0.4 µg/kg, ASA/TBI/misoprostol 1 mg/kg, and ASA/TBI/carboprost 100 µg/kg. TBI was induced via a weight drop model 4-h after ASA (50 mg/kg) gavage. Mice were given an intraperitoneal injection of DDAVP, misoprostol, or carboprost 10 minutes after TBI. In vivo testing was completed utilizing tail vein bleed. Mice were sacrificed 30-min posttreatment and blood was collected via cardiac puncture. Whole blood was analyzed via Multiplate impedance aggregometry, rotational thromboelastometry, and TEG6s. RESULTS: Mice receiving misoprostol after ASA/TBI demonstrated decreased tail vein bleeding times compared to ASA only treated mice. However, mice treated with misoprostol following ASA and TBI demonstrated decreased platelet aggregability compared to untouched mice and TBI only mice within the arachidonic acid agonist pathway. By contrast, DDAVP and carboprost did not significantly change platelet aggregability via adenosine diphosphate or arachidonic acid following ASA and TBI. However, DDAVP did decrease the platelet contribution to clot via rotational thromboelastometry. CONCLUSIONS: Reversal of medication-induced platelet inhibition has become increasingly controversial after TBI. Based on these results, DDAVP, misoprostol, nor carboprost consistently improve platelet aggregability following TBI in those also treated with ASA.

Preparing Community Health Workers to Empower Latino(a)s With Diabetes: A Real-World Implementation Study.

PURPOSE: The purpose of the study was to evaluate the delivery of diabetes self-management education (DSME) to Latino(a) adults by community health workers (CHWs). METHODS: Investigators developed an evidence-based, bilingual (Spanish/English) diabetes education curriculum and trained 10 CHWs on its content. CHWs then implemented the curriculum in 6-month diabetes group visit programs for low-income Latino(a)s with type 2 diabetes in nonacademic 501(c)3 community clinics. Investigators evaluated efficacy of the training through successful implementation, measured by participant group visit acceptance and attendance. RESULTS: Participants (n = 70) reported high levels of program satisfaction (3.8/4.0), improvement in quality of life (9.7/10), meeting of individual needs (3.8/4.0), and acceptability (9.7/10.0). Content analyses revealed that 87.1% of participants would not change the program or wanted to extend it. Participant attendance was 81.6%. CONCLUSIONS: Investigators demonstrated the ability to develop a training that nonmedical personnel (CHWs) successfully implemented in a real-world study. This study provides a curricular framework for CHW-led education that may serve as a template to extend to other diseases and populations.

Determinants of active surveillance uptake in a diverse population-based cohort of men with low-risk prostate cancer: The Treatment Options in Prostate Cancer Study (TOPCS).

BACKGROUND: Active surveillance (AS) is the preferred strategy for low-risk prostate cancer (LRPC); however, limited data on determinants of AS adoption exist, particularly among Black men. METHODS: Black and White newly diagnosed (from January 2014 through June 2017) patients with LRPC ≤75 years of age were identified through metro-Detroit and Georgia population-based cancer registries and completed a survey evaluating factors influencing AS uptake. RESULTS: Among 1688 study participants, 57% chose AS (51% of Black participants, 61% of White) over definitive treatment. In the unadjusted analysis, patient factors associated with initial AS uptake included older age, White race, and higher education. However, after adjusting for covariates, none of these factors was significant predictors of AS uptake. The strongest determinant of AS uptake was the AS recommendation by a urologist (adjusted prevalence ratio, 6.59, 95% CI, 4.84-8.97). Other factors associated with the decision to undergo AS included a shared patient-physician treatment decision, greater prostate cancer knowledge, and residence in metro-Detroit compared with Georgia. Conversely, men whose decision was strongly influenced by the desire to achieve "cure" or "live longer" with treatment and those who perceived their LRPC diagnosis as more serious were less likely to choose AS. CONCLUSIONS: In this contemporary sample, the majority of patients with newly diagnosed LRPC chose AS. Although the input from their urologists was highly influential, several patient decisional and psychological factors were independently associated with AS uptake. These data shed new light on potentially modifiable factors that can help further increase AS uptake among patients with LRPC.

Murine Traumatic Brain Injury Model Comparison: Closed Head Injury Versus Controlled Cortical Impact.

INTRODUCTION: Various murine models have been utilized to study TBI, including closed head injury (CHI) and controlled cortical impact (CCI), without direct comparison. The aim of our study was to evaluate these models to determine differences in neurological and behavioral outcomes postinjury. METHODS: Male C57B/6 mice (9-10 wk) were separated into six groups including: untouched, sham craniotomy (4 mm), CCI 0.9 mm depth of impact, CCI 1.6 mm, CCI 2.2 mm, and CHI. CCI was performed using a 3 mm impact tip at a velocity of 5 m/s, dwell time of 250 ms, and depth as noted above. CHI was completed with a centered 400 g weight drop from 1 cm height. Mice were survived to 14-d (n = 5 per group) and 30-d (n = 5 per group) respectively for histological analysis of p-tau within the hippocampus. These mice underwent Morris Water Maze memory testing and Rotarod motor testing. Serum was collected from a separate cohort of mice (n = 5 per group) including untouched, isoflurane only, CCI 1.6 mm, CHI at 1, 4, 6, and 24 h for analysis of neuron specific enolase and glial fibrillary acidic protein (GFAP) via ELISA. Laser speckle contrast imaging was analyzed prior to and after impact in the CHI and CCI 1.6 mm groups. RESULTS: There were no significant differences in Morris Water Maze or Rotarod testing times between groups at 14- or 30-d. P-tau was significantly elevated in all groups except CCI 1.6 mm contralateral and CCI 2.2 mm ipsilateral compared to untouched mice at 30-d. P-tau was also significantly elevated in the CHI group at 30 d compared to CCI 1.6 mm contralateral and CCI 2.2 mm on both sides. GFAP was significantly increased in mice undergoing CHI (9959 ± 91 pg/mL) compared to CCI (2299 ± 1288 pg/mL), isoflurane only (133 ± 75 pg/mL), and sham (86 ± 58 pg/mL) at 1-h post TBI (P < 0.0001). There were no differences in serum neuron specific enolase levels between groups. Laser doppler imaging demonstrated similar decreases in cerebral blood flow between CHI and CCI; however, CCI mice had a reduction in blood flow with craniotomy only that did not significantly decrease further with impact. CONCLUSIONS: Based on our findings, CHI leads to increased serum GFAP levels and increased p-tau within the hippocampus at 30-d postinjury. While CCI allows the comparison of one cerebral hemisphere to the other, CHI may be a better model of TBI as it requires less technical expertise and has similar neurological outcomes in these murine models.

Functional Outcomes After Localized Prostate Cancer Treatment.

Importance: Adverse outcomes associated with treatments for localized prostate cancer remain unclear. Objective: To compare rates of adverse functional outcomes between specific treatments for localized prostate cancer. Design, Setting, and Participants: An observational cohort study using data from 5 US Surveillance, Epidemiology, and End Results Program registries. Participants were treated for localized prostate cancer between 2011 and 2012. At baseline, 1877 had favorable-prognosis prostate cancer (defined as cT1-cT2bN0M0, prostate-specific antigen level <20 ng/mL, and grade group 1-2) and 568 had unfavorable-prognosis prostate cancer (defined as cT2cN0M0, prostate-specific antigen level of 20-50 ng/mL, or grade group 3-5). Follow-up data were collected by questionnaire through February 1, 2022. Exposures: Radical prostatectomy (n = 1043), external beam radiotherapy (n = 359), brachytherapy (n = 96), or active surveillance (n = 379) for favorable-prognosis disease and radical prostatectomy (n = 362) or external beam radiotherapy with androgen deprivation therapy (n = 206) for unfavorable-prognosis disease. Main Outcomes and Measures: Outcomes were patient-reported sexual, urinary, bowel, and hormone function measured using the 26-item Expanded Prostate Cancer Index Composite (range, 0-100; 100 = best). Associations of specific therapies with each outcome were estimated and compared at 10 years after treatment, adjusting for corresponding baseline scores, and patient and tumor characteristics. Minimum clinically important differences were 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, and 4 to 6 for bowel and hormone function. Results: A total of 2445 patients with localized prostate cancer (median age, 64 years; 14% Black, 8% Hispanic) were included and followed up for a median of 9.5 years. Among 1877 patients with favorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -12.1 [95% CI, -16.2 to -8.0]), but not worse sexual function (adjusted mean difference, -7.2 [95% CI, -12.3 to -2.0]), compared with active surveillance. Among 568 patients with unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -26.6 [95% CI, -35.0 to -18.2]), but not worse sexual function (adjusted mean difference, -1.4 [95% CI, -11.1 to 8.3), compared with external beam radiotherapy with androgen deprivation therapy. Among patients with unfavorable prognosis, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel (adjusted mean difference, -4.9 [95% CI, -9.2 to -0.7]) and hormone (adjusted mean difference, -4.9 [95% CI, -9.5 to -0.3]) function compared with radical prostatectomy. Conclusions and Relevance: Among patients treated for localized prostate cancer, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function at 10-year follow-up compared with radiotherapy or surveillance among people with more favorable prognosis and compared with radiotherapy for those with unfavorable prognosis. Among men with unfavorable-prognosis disease, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel and hormone function at 10-year follow-up compared with radical prostatectomy.