Mean platelet volume and cardiac-surgery-associated acute kidney injury: a retrospective study.

PURPOSE: Increased mean platelet volume (MPV) may indicate platelet activation, platelet aggregation, and a resulting prothrombotic state. Such changes in the postoperative period have been associated with organ injury and adverse outcomes. We hypothesized that changes in MPV after cardiac surgery are associated with both a higher risk of acute kidney injury (AKI) and mortality. METHODS: In this retrospective study, we evaluated consecutive patients undergoing adult cardiac surgery patients between 12 December 2011 and 5 June 2018. The change in MPV was derived by calculating the difference between the baseline MPV before surgery and the average postoperative MPV just prior to the occurrence of AKI. We defined postoperative AKI according to Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury as either a ≥ 50% increase in serum creatinine in the first ten postoperative days, or an increase of ≥ 0.3 mg·dL-1 during any 48-hr window across the ten-day postoperative period. Multivariable logistic regression analysis was used to examine the association between MPV change and postoperative AKI and mortality. RESULTS: Of the 4,204 patients studied, 1,373 (32.7%) developed postoperative AKI, including 83 (2.0%) and 38 (0.9%) who developed stages II and III AKI, respectively. Compared with patients who had an increase in median postoperative MPV of 0.2 femtolitre (fL), those with an increase of 0.8 fL had an 80% increase in the odds of developing AKI (adjusted odds ratio [aOR], 1.80; 95% confidence interval [CI],1.36 to 2.38; P < 0.001) and were almost twice as likely to progress to a higher severity AKI (aOR, 1.66; 95% CI, 1.28 to 2.16; P < 0.001). Change in MPV was not associated with mortality (aOR,1.32; 95% CI, 0.92 to 1.89; P = 0.14). CONCLUSION: Increased MPV change in the postoperative period was associated with both increased risk and severity of AKI, but not mortality.

RéSUMé: OBJECTIF: Un volume plaquettaire moyen (VPM) augmenté peut être indicatif d'une activation plaquettaire, d'une agrégation plaquettaire, et de l'état prothrombotique qui en résulte. De tels changements en période postopératoire ont été associés à des lésions aux organes et à des devenirs défavorables. Nous avons émis l'hypothèse que des changements du VPM après une chirurgie cardiaque seraient associés à un risque plus élevé d'insuffisance rénale aiguë et de mortalité. MéTHODE: Dans cette étude rétrospective, nous avons évalué des patients adultes consécutifs subissant une chirurgie cardiaque entre le 12 décembre 2011 et le 5 juin 2018. Le changement de VPM a été dérivé en calculant la différence entre le VPM de base avant la chirurgie et le VPM postopératoire moyen juste avant la survenue de l'IRA. Nous avons défini une IRA postopératoire sur la base des Directives Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury (Les maladies rénales: Guide d'exercice clinique pour améliorer les devenirs globaux pour l'insuffisance rénale aiguë) en tant qu'une augmentation ≥ 50 % de la créatine sérique au cours des dix premiers jours postopératoires, ou une augmentation de ≥ 0,3 mg·dL−1 pendant toute fenêtre de 48 h au cours des dix premiers jours postopératoires. Une analyse multivariée de régression logistique a été utilisée pour examiner l'association entre le changement de VPM et l'IRA postopératoire et la mortalité. RéSULTATS: Parmi les 4204 patients à l'étude, 1373 (32,7 %) ont souffert d'IRA postopératoire, y compris 83 (2,0 %) et 38 (0,9 %) qui ont développé des IRA de stade II et III, respectivement. Par rapport aux patients ayant manifesté une augmentation du VPM postopératoire médian de 0,2 femtolitre (fL), ceux affichant une augmentation de 0,8 fL ont démontré une augmentation de 80 % de la probabilité d'IRA (rapport de cotes ajusté [RCA], 1,80; intervalle de confiance [IC] 95 %, 1,36 à 2,38; P < 0,001) et couraient un risque pratiquement deux fois plus élevé de voir leur IRA progresser à un stade plus grave (RCA, 1,66; IC 95 %, 1,28 à 2,16; P < 0,001). Les changements de VPM n'étaient pas associés à la mortalité (RCA, 1,32; IC 95 %, 0,92 à 1,89; P = 0,14). CONCLUSION: Une augmentation accrue du VPM en période postopératoire a été associée à un risque et une gravité accrus d'IRA, mais pas à la mortalité.

Inhibition of EphA/Ephrin-A signaling using genetic and pharmacologic approaches improves recovery following traumatic brain injury in mice.

Primary Objective: Eph/Ephrin signaling is inhibitory for developing axons and blocking Eph pathways enhances regeneration after spinal cord injury. It was hypothesized that inhibition of Eph signaling promotes cellular and behavioral recovery after traumatic brain injury (TBI). Research design: Lateral fluid percussion (LFP) injury was performed on wildtype (WT) and EphA6 knockout (KO) mice. EphA6-Fc, Ephrin-A5-Fc fusion proteins, and sodium orthovanadate were used to alter the signaling pathway. Immunohistochemistry and tissue explants revealed cellular changes. Rotarod tests demonstrated vestibulomotor function. Outcomes: The EphA6 receptor expression is upregulated following LFP. Uninjured EphA6 KO mice exhibit greater neurite density and clustered Ephrin-A5-Fc causes growth cone collapse in vitro. After LFP, EphA6 KO mice demonstrate longer neurites and decreased neuronal cell death and astrocytosis compared to WT mice. Blocking EphA signaling by soluble EphA6-Fc fusion protein reduces cell death and improves motor function following LFP whereas clustered Ephrin-A5-Fc exacerbates cell death and neurodegeneration. Sodium orthovanadate rescues growth cone collapse in vitro as well as cell death and neurodegeneration in vivo. Conclusions: Eph/Ephrin signaling plays an inhibitory role following TBI. Targeting the Eph signaling pathway with Fc fusion proteins and pharmacological agents can be a novel strategy to counter the damaging effects of TBI. Abbreviations: LFP: lateral fluid percussion; TBI: traumatic brain injury; KO: knockout; WT: wildtype; PTP2: protein phosphotyrosine phosphatase 2; Tg: transgenic; YFP: yellow fluorescent protein; ATM: atmospheres; RT-qPCR: Real-time-quantitative PCR; dpi: days post injury; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; DAPI: 4',6-diamidino-2-phenylindole; PBS: phosphate buffered saline; GFAP: glial fibrillary acidic protein; FLJC: fluorojade C; CA: cornu ammonis; SEM: standard error of the mean; ANOVA: analysis of variance; PLSD: posthoc least significant difference.

Analysis of Faculty Gender and Race in Scholarly Achievements in Academic Neurology.

Background: Intersection of gender and race and/or ethnicity in academic medicine is understudied; we aim to understand these factors in relation to scholarly achievements for neurology faculty. Methods: Faculty from 19 US neurology departments completed a survey (2021-2022) to report rank, leadership positions, publications, funded projects, awards, and speaker invitations. Regression analyses examined effects of gender, race, and their intersectionality on these achievements. Women, Black/Indigenous/People of Color (BIPOC), and BIPOC women were comparator groups. Results: Four hundred sixty-two faculty responded: 55% women, 43% men; 31% BIPOC, 63% White; 21% BIPOC women, 12% BIPOC men, 36% White women, 31% White men. Men and White faculty are more likely to be full professors than women and BIPOC faculty. The number of leadership positions, funded projects, awards, and speaker invitations are significantly greater in White compared to BIPOC faculty. Relative to BIPOC women, the number of leadership positions is significantly higher among BIPOC men, White women, and White men. Publication numbers for BIPOC men are lower, number of funded projects and speaker invitations for White women are higher, and number of awards among White men and White women is higher compared to BIPOC women. Discussion: Our study highlights that inequities in academic rank, award number, funded projects, speakership invitations, and leadership roles disproportionately impacted BIPOC women. More studies are needed to evaluate gender and race and/or ethnicity intersectionality effects on faculty achievements, reasons for inequities, recognition, and potential solutions.

Teaching Trans-Centric Curricular Content Using Modified Jigsaw.

Introduction: Transgender (trans) individuals have unique medical needs and difficulty accessing quality health care, exacerbated by inadequate provider knowledge. Incorporation of trans health care into medical school curricula has increased recently to address this gap. Jigsaw activities emphasize positive interdependence through structured cooperative learning, resulting in increased interest and self-confidence. We implemented a voluntary 2-hour modified jigsaw exercise on trans health care with changes designed to optimize the structure for medical students. Methods: The session was implemented both in person and virtually over 2 years with preclerkship medical students at the end of their endocrine/reproduction physiology course. The session featured a knowledge test with answer discussion followed by a clinical correlation-either a case discussion or video discussion. A pre- and posttest design compared students' knowledge, attitudes, and beliefs. Results: Eighty-nine students participated. Their initial attitudes and beliefs regarding trans health care were highly positive and remained elevated. Participants showed increases in knowledge and self-confidence discussing gender identity and clinical care postsession. All expressed interest in further training and felt the session enhanced their understanding of trans health and reproductive physiology. On 1-year follow-up, students showed decreased knowledge and self-confidence in discussing trans health; however, scores remained higher than presession. Student surveys suggested formal integration of more trans health education into the curriculum. Discussion: Medical students increased their knowledge and self-confidence regarding trans medicine and felt the modified jigsaw exercise was an effective teaching method. The results suggest that ongoing education is an important tool in optimizing trans health care.

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes.

After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E (APOE) are known to increase risk for developing Alzheimer's disease, however there is controversy from human and rodent studies as to whether ApoE4 is a risk factor for worse outcomes after brain trauma. To resolve these conflicting studies we have explored the effect of the human APOE4 gene in a reproducible mouse model that mimics common human injuries. We have investigated cellular and behavioral outcomes in genetically engineered human APOE targeted replacement (TR) mice following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. Relative to injured APOE3 TR mice, injured APOE4 TR mice had more inflammation, neurodegeneration, apoptosis, p-tau, and activated microglia and less total brain-derived neurotrophic factor (BDNF) in the cortex and/or hippocampus at 1 and/or 21 days post-injury. We utilized a novel personalized approach to treating APOE4 susceptible mice by administering Bryostatin-1, which improved cellular as well as motor and cognitive behavior outcomes at 1 DPI in the APOE4 injured mice. This study demonstrates that APOE4 is a risk factor for poor outcomes after rmTBI and highlights how personalized therapeutics can be a powerful treatment option.

BDNF Val66Met Genetic Polymorphism Results in Poor Recovery Following Repeated Mild Traumatic Brain Injury in a Mouse Model and Treatment With AAV-BDNF Improves Outcomes.

Clinicians have long noticed that some Traumatic Brain Injury (TBI) patients have worse symptoms and take a longer time to recover than others, for reasons unexplained by known factors. Identifying what makes some individuals more susceptible is critical to understanding the underlying mechanisms through which TBI causes deleterious effects. We have sought to determine the effect of a single nucleotide polymorphism (SNP) in Brain-derived neurotrophic factor (BDNF) at amino acid 66 (rs6265) on recovery after TBI. There is controversy from human studies as to whether the BDNF Val66Val or Val66Met allele is the risk factor for worse outcomes after brain trauma. We therefore investigated cellular and behavioral outcomes in genetically engineered mice following repeated mild TBI (rmTBI) using a lateral fluid percussion (LFP) injury model. We found that relative to injured Val66Val carriers, injured Val66Met carriers had a larger inflammation volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post-injury (DPI). We therefore concluded that the Val66Met genetic polymorphism is a risk factor for poor outcomes after rmTBI. In order to determine the mechanism for these differences, we investigated levels of the apoptotic-inducing pro BDNF and survival-inducing mature BDNF isoforms and found that Met carriers had less total BDNF in the cortex and a higher pro/mature ratio of BDNF in the hippocampus. We then developed a personalized approach to treating genetically susceptible individuals by overexpressing wildtype BDNF in injured Val66Met mice using an AAV-BDNF virus. This intervention improved cellular, motor, and cognitive behavior outcomes at 21 DPI and increased levels of mature BDNF and phosphorylation of mature BDNF's receptor trkB. This study lays the groundwork for further investigation into the genetics that play a role in the extent of injury after rmTBI and highlights how personalized therapeutics may be targeted for recovery in susceptible individuals.