Predictors of hospital length of stay and long-term care facility placement in aneurysmal subarachnoid hemorrhage.

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently associated with complications, extended hospital length of stay (LOS) and high health care related costs. We sought to determine predictors for hospital LOS and discharge disposition to a long-term care facility (LTCF) in aSAH patients. Methods: We performed a retrospective study of a prospectively collected cohort of consecutive patients with aSAH admitted to an academic referral center from 2016 to 2021. Multiple linear regression was performed to identify predictors for hospital LOS. We then created a 10-point scoring system to predict discharge disposition to a LTCF. Results: In a cohort of 318 patients with confirmed aSAH, mean age was 57 years (SD 13.7), 61% were female and 70% were white. Hospital LOS was longer for survivors (median 19 days, IQR 14-25) than for non-survivors (median 5 days, IQR 2-8; p < 0.001). Main predictors for longer LOS for this cohort were ventriculoperitoneal shunt (VPS) requirement (p < 0.001), delayed cerebral ischemia (p = 0.026), and pneumonia (p = 0.014). The strongest predictor for LTCF disposition was age older than 60 years (OR 1.14, 95% CI 1.07-1.21; p < 0.001). LTCF score had high accuracy in predicting discharge disposition to a LTCF (area under the curve [AUC] 0.83; 95% CI 0.75-0.91). Forty-one percent of patients who were discharged to a LTCF had significant functional recovery at 3 months post-discharge. Conclusions: VPS requirement and aSAH related complications were associated with longer hospital LOS compared to other factors. LTCF score has high accuracy in predicting discharge disposition to a LTCF.

Comparison of the Effects of Blood Pressure Parameters on Rebleeding and Outcomes in Unsecured Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Elevated systolic blood pressure (SBP) has been linked to preprocedural rebleeding risk and poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). This study seeks to compare the effects of SBP and mean arterial pressure (MAP) on rebleeding and functional outcomes in aSAH patients. METHODS: We performed a retrospective study of a prospectively collected cohort of consecutive patients with aSAH admitted to an academic center in 2016-2023. Binary regression analysis was used to determine the association between BP parameters and outcomes including rebleeding and poor outcome defined as modified Rankin Scale 4-6 at 3 months postdischarge. RESULTS: The cohort included 324 patients (mean age 57 years [standard deviation 13.4], 61% female). Symptomatic rebleeding occurred in 34 patients (11%). Higher BP measurements were recorded in patients with rebleeding and poor outcome, however, only MAP met statistical significance for rebleeding (odds ratio {OR} 1.02 for 1 mmHg increase in MAP, 95% confidence interval {CI}: 1.001-1.03, P = 0.043; OR 1 per 1 mmHg increase in SBP, 95% CI 0.99-1.01; P = 0.06)) and for poor outcome (OR 1.01 for 1 mmHg increase in MAP, 95% CI: 1.002-1.025, P = 0.025; OR 1 for 1 mmHg increase in SBP, 95% CI: 0.99-1.02, P = 0.23) independent of other predictors. CONCLUSIONS: MAP may appear to be slightly better correlated with rebleeding and poor outcomes in unsecured aSAH compared to SBP. Larger prospective studies are needed to identify and mitigate risk factors for rebleeding and poor outcome in aSAH patients.

An analysis of the inclusion of ear and hearing care in national health policies, strategies and plans.

Ear- and hearing-related conditions pose a significant global health burden, yet public health policy surrounding ear and hearing care (EHC) in low- and middle-income countries is poorly understood. The present study aims to characterize the inclusion of EHC in national health policy by analysing national health policies, strategies and plans in English, French, Spanish, Portuguese and Arabic. Three EHC keywords were searched, including ear*, hear* and deaf*. The terms 'human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)', 'tuberculosis' and 'malaria' were included as comparison keywords as these conditions have historically garnered political priority in global health. Of the 194 World Health Organization Member States, there were 100 national policies that met the inclusion criteria of document availability, searchable format, language and absence of an associated national EHC strategy. These documents mentioned EHC keywords significantly less than comparison terms, with mention of hearing in 15 documents, ears in 11 documents and deafness in 3 documents. There was a mention of HIV/AIDS in 92 documents, tuberculosis in 88 documents and malaria in 70 documents. Documents in low- and middle-income countries included significantly fewer mentions of EHC terms than those of high-income countries. We conclude that ear and hearing conditions pose a significant burden of disease but are severely underrepresented in national health policy, especially in low- and middle-income countries.

Translatability barriers between preclinical and clinical trials of AAV gene therapy in inherited retinal diseases.

Inherited retinal diseases (IRDs) are progressive degenerative diseases which cause gradual vision loss or complete blindness. As over 270 gene mutations have been identified in the underlying pathology of IRDs, gene therapy as a treatment modality has been an increasingly active realm of investigation. Currently, the most common vehicle of ocular gene delivery is the adeno-associated virus (AAV) vector. This is injected into the immune-privileged subretinal space to mediate transgene expression in retinal cells. Although numerous animal models of IRDs have demonstrated successful outcomes following AAV-mediated gene delivery, many of these studies fail to translate into successful outcomes in clinical trials. The purpose of this review is to A) comparatively assess preclinical and clinical IRD trials in which the success of AAV-mediated therapy failed to translate between animal and human participants B) discuss factors which may complicate the translatability of gene therapy in animals to results in humans.

Applying Representation Quotient Methodology to Racial, Ethnic, and Gender Trends of Applicants and Matriculants to Urology Residency Programs From 2010-2018.

OBJECTIVE: To accurately examine the trends in the racial and gender composition of medical students applying and matriculating to urology residency programs. METHODS: Reports on race/ethnicity and gender for medical school graduates, and urology residency applicants and matriculants were obtained for years 2010-2018. The proportions of individuals representing different racial and gender identities among urology applicants and matriculants were divided by a denominator of their proportion in medical school graduating classes to produce representation quotients (RQapp and RQmat, respectively). Linear regression models were performed on yearly RQs to estimate the RQ changes over time. Nonparametric testing was used to evaluate for differences in applicant to matriculant representation within each identity. ANOVA was performed separately on RQapp and RQmat values to assess differences in representation between identities in the applicant and matriculant populations. RESULTS: Asian men experienced increases in representation among urology applicants (RQapp: slope 2.04 × 10-2; P = .03) and matriculants (RQmat slope: 7.46 × 10-2; P = .0076) during the study period. Black men trended towards under-representation among applicants (RQapp slope -1.51 × 10-1; P = .03) and matriculants (RQmat slope: -1.71 × 10-1; P = .02). When examining genders, both men (RQapp=1.43 vs RQmat=1.44; P = .80) and women (RQapp=0.52 vs RQmat = 0.51; P = .67) had unchanged representation in the applicant and matriculant cohorts, but women severely underrepresented on average. CONCLUSIONS: Women and Black men are underrepresented in the urology workforce. These concerning findings demonstrate the dire need for initiatives regarding recruitment into urology to support and to ensure successful entry into the field for minority groups.

Association of asymptomatic cerebral vasospasm with outcomes in survivors of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Cerebral vasospasm (cVSP) is a common complication in aneurysmal subarachnoid hemorrhage (aSAH) and is associated with worse outcomes. However, clinical significance of asymptomatic cVSP is poorly understood. We sought to determine the association of asymptomatic cVSP with functional outcome and hospital length of stay (LOS). METHODS: We performed a retrospective study of a prospectively collected cohort of patients with aSAH who survived hospitalization at an academic center between 2016 and 2021. We defined cVSP based on transcranial Doppler criteria. Multivariate logistic and multiple linear regression analyses were used to determine the association of asymptomatic cVSP with poor functional outcome (defined as modified Rankin scale 3-6 at 3 months after discharge) and hospital length of stay (LOS). RESULTS: The cohort consisted of 201 aSAH patients with a mean age 54.9 years (SD 13.6) and 60% were female. One hundred nine patients (54%) experienced cVSP, of whom 43 patients (39%) were asymptomatic. Patients with asymptomatic cVSP were younger (mean 50.5 years [SD 10.6] vs 61 years [SD12.5]; p < 0.001) and had longer ICU LOS (median 13 days [IQR12-20] vs median 12 days [IQR9-15], p = 0.018) compared to those without cVSP. However, after adjusting with other variables asymptomatic cVSP was not associated with longer ICU or hospital LOS. Asymptomatic cVSP was not associated with poor outcome either (p = 0.14). CONCLUSION: Asymptomatic cVSP, which was more common in younger patients, was neither associated with poor functional outcome nor hospital LOS.  Larger prospective studies are needed to assess the significance of asymptomatic cVSP on long-term outcomes.

Association of pre-admission antihypertensive agents and outcomes in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Delayed cerebral ischemia (DCI) and poor functional outcome are common complications in patients who suffer from aneurysmal subarachnoid hemorrhage (aSAH). It has been proposed that pre-admission beta-blocker therapy may lower cerebral vasospasm (cVSP) risk after aSAH; however, this association with other antihypertensives is unknown. We sought to determine the association between antihypertensives and clinical outcomes in aSAH patients. METHODS: We performed a retrospective study on a prospectively collected cohort of consecutive patients with aSAH who were admitted to an academic center from 2016 to 2021. Association between pre-admission use of antihypertensives and patient outcomes was determined. Primary outcomes included DCI and poor functional outcome at 3 months after discharge defined as modified Rankin scale [mRS] 4-6. The secondary outcome was cVSP identified using transcranial Doppler (TCD). RESULTS: The cohort consisted of 306 aSAH patients with mean age 57.1 (SD 13.6) years with 187 females (61 %). Although pre-admission use of beta-blockers (OR 0.40, 95 % CI 0.21-80, p = 0.02), calcium channel blockers (OR 0.43, 95 % CI 0.19-0.93, p = 0.035), and thiazide (OR 0.31, 95 % CI 0.11-0.86, p = 0.025) were associated with lower risk of cVSP in univariate analysis, we did not find any association in a multivariate model after adjusting for age. There was no association between any class of antihypertensives and DCI or functional outcome. CONCLUSION: Pre-admission use of antihypertensive agents may affect TCD findings, however, none of them appear to be independently associated with DCI or functional outcome. Larger prospective studies are needed to establish any potential association.

Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

INTRODUCTION: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. METHODS: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. RESULTS: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Development of a large animal model of lethal polytrauma and intra-abdominal sepsis with bacteremia.

BACKGROUND: Trauma and sepsis are individually two of the leading causes of death worldwide. When combined, the mortality is greater than 50%. Thus, it is imperative to have a reproducible and reliable animal model to study the effects of polytrauma and sepsis and test novel treatment options. Porcine models are more translatable to humans than rodent models due to the similarities in anatomy and physiological response. We embarked on a study to develop a reproducible model of lethal polytrauma and intra-abdominal sepsis, which was lethal, though potentially salvageable with treatment. METHODS: Our laboratory has a well-established porcine model that was used as the foundation. Animals were subjected to a rectus crush injury, long bone fracture, liver and spleen laceration, traumatic brain injury and hemorrhage that was used as a foundation. We tested various colon injuries to create intra-abdominal sepsis. All animals underwent injuries followed by a period of shock, then subsequent resuscitation. RESULTS: All animals had blood culture-proven sepsis. Attempts at long-term survival of animals after injury were ceased because of poor appetite and energy. We shifted to an 8-hour endpoint. The polytrauma injury pattern remained constant and the colon injury pattern changed with the intention of creating a model that was ultimately lethal but potentially salvageable with a therapeutic drug. An uncontrolled cecal injury (n=4) group resulted in very early deaths. A controlled cecal injury (CCI; n=4) group had prolonged time prior to mortality with one surviving to the endpoint. The sigmoid injury (n=5) produced a similar survival curve to CCI but no animals surviving to the endpoint. CONCLUSION: We have described a porcine model of polytrauma and sepsis that is reproducible and may be used to investigate novel treatments for trauma and sepsis. LEVEL OF EVIDENCE: Not applicable. Animal study.

Valproic acid treatment rescues injured tissues after traumatic brain injury.

BACKGROUND: No agents that are specifically neuroprotective are currently approved to emergently treat patients with traumatic brain injury (TBI). The histone deacetylase inhibitor, high-dose valproic acid (VPA) has been shown to have cytoprotective potential in models of combined TBI and hemorrhagic shock, but it has not been tested in an isolated TBI model. We hypothesized that VPA, administered after isolated TBI, will penetrate the injured brain, attenuate the lesion size, and activate prosurvival pathways. METHODS: Yorkshire swine were subjected to severe TBI by cortical impact. One hour later, animals were randomized to VPA treatment (150 mg/kg delivered intravenously for 1 hour; n = 4) or control (saline vehicle; n = 4) groups. Seven hours after injury, animals were sacrificed, and brain lesion size was measured. Mass spectrometry imaging was used to visualize and quantitate brain tissue distribution of VPA. Sequential serum samples were assayed for key biomarkers and subjected to proteomic and pathway analysis. RESULTS: Brain lesion size was 50% smaller (p = 0.01) in the VPA-treated animals (3,837 ± 948 mm) compared with the controls (1,900 ± 614 mm). Endothelial regions had eightfold higher VPA concentrations than perivascular regions by mass spectrometry imaging, and it readily penetrated the injured brain tissues. Serum glial fibrillary acid protein was significantly lower in the VPA-treated compared with the control animals (p < 0.05). More than 500 proteins were differentially expressed in the brain, and pathway analysis revealed that VPA affected critical modulators of TBI response including calcium signaling pathways, mitochondria metabolism, and biosynthetic machinery. CONCLUSION: Valproic acid penetrates injured brain tissues and exerts neuroprotective and prosurvival effects that resulted in a significant reduction in brain lesion size after isolated TBI. Levels of serum biomarkers reflect these changes, which could be useful for monitoring the response of TBI patients during clinical studies.

Valproic acid decreases resuscitation requirements after hemorrhage in a prolonged damage-control resuscitation model.

BACKGROUND: Hemorrhage is the leading cause of preventable death in trauma. Future military conflicts are likely to be in austere environments, where prolonged damage-control resuscitation (p-DCR) may be required for 72 hours before evacuation. There is a need to demonstrate that p-DCR is feasible and to optimize its logistics. Dried plasma (DP) is a practical alternative to conventional blood products in austere settings, and valproic acid (VPA) improves survival in preclinical models of trauma and hemorrhage. We performed the current experiment to study the synergistic effects of VPA and DP and hypothesized that VPA treatment would decrease the fluid resuscitation requirements in p-DCR. METHODS: Female swine were subjected to 50% hemorrhage (associated with 20% survival using non-plasma-based p-DCR) and left unresuscitated for 1 hour to simulate medic response time. They were then randomized to receive VPA (150 mg/kg + DP 250 mL; DP-VPA group; n = 5) or DP alone (DP group; n = 6). All animals were resuscitated to a systolic blood pressure of 80 mm Hg with lactated Ringer according to the Tactical Combat Casualty Care Guidelines for 72 hours, after which packed red blood cells were transfused to simulate evacuation to higher levels of care. RESULTS: The DP-VPA group needed significantly (p = 0.002) less volume of lactated Ringer to reach and maintain the target systolic blood pressure. This would translate to a 4.3 L volume sparing effect for a 70-kg person. CONCLUSION: Addition of a single dose of VPA significantly decreases the volume of resuscitation required in a p-DCR model.

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

BACKGROUND: Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. METHODS: Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. RESULTS: This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups. CONCLUSION: A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.