One size does not fit all: Sex bias in pharmacologic venous thromboembolism prophylaxis.

BACKGROUND: The optimal enoxaparin dosing strategy to achieve venous thromboembolism (VTE) prophylaxis in trauma patients remains unclear. Current dosing guidelines often include weight, age, and renal function but still fail to achieve appropriate prophylactic anti-Xa levels in many patients. We hypothesized that additional patient factors influence anti-Xa response to enoxaparin in trauma patients. METHODS: This is a retrospective review of patients admitted to a Level 1 trauma center for ≥4 days from July 2015 to September 2020, who received enoxaparin VTE prophylaxis per protocol (50-59 kg, 30 mg/dose; 60-99 kg, 40 mg/dose; ≥100 kg, 50 mg/dose; all doses every 12 hours) and had an appropriately timed peak anti-Xa level. Multivariate regression was performed to identify independent predictors of prophylactic anti-Xa levels (0.2-0.4 IU/mL) upon first measurement. RESULTS: The cohort (N = 1,435) was 76.4% male, with a mean ± SD age of 49.9 ± 20.0 years and a mean ± SD weight of 82.5 ± 20.2 kg (males, 85.2 kg; females, 73.7 kg; p <0.001). Overall, 68.6% of patients (n = 984) had a prophylactic anti-Xa level on first assessment (69.6% of males, 65.1% of females). Males were more likely to have a subprophylactic level than females (22.1% vs. 8.0%, p <0.001), whereas females were more likely to have supraprophylactic levels than males (26.9% vs. 8.3%, p < 0.001). When controlling for creatinine clearance, anti-Xa level was independently associated with dose-to-weight ratio (odds ratio, 0.191 for 0.5 mg/kg; p < 0.001; confidence interval, 0.151-0.230) and female sex (odds ratio, 0.060; p < 0.001; confidence interval, 0.047-0.072). Weight and age were not significant when controlling for the other factors. CONCLUSION: Male patients have a decreased anti-Xa response to enoxaparin when compared with female patients, leading to a greater incidence of subprophylactic anti-Xa levels in male patients at all dose-to-weight ratios. To improve the accuracy of VTE chemoprophylaxis, sex should be considered as a variable in enoxaparin dosing models. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Protein Kinase D1 Regulates Cardiac Hypertrophy, Potassium Channel Remodeling, and Arrhythmias in Heart Failure.

Background Structural and electrophysiological remodeling characterize heart failure (HF) enhancing arrhythmias. PKD1 (protein kinase D1) is upregulated in HF and mediates pathological hypertrophic signaling, but its role in K+ channel remodeling and arrhythmogenesis in HF is unknown. Methods and Results We performed echocardiography, electrophysiology, and expression analysis in wild-type and PKD1 cardiomyocyte-specific knockout (cKO) mice following transverse aortic constriction (TAC). PKD1-cKO mice exhibited significantly less cardiac hypertrophy post-TAC and were protected from early decline in cardiac contractile function (3 weeks post-TAC) but not the progression to HF at 7 weeks post-TAC. Wild-type mice exhibited ventricular action potential duration prolongation at 8 weeks post-TAC, which was attenuated in PKD1-cKO, consistent with larger K+ currents via the transient outward current, sustained current, inward rectifier K+ current, and rapid delayed rectifier K+ current and increased expression of corresponding K+ channels. Conversely, reduction of slowly inactivating K+ current was independent of PKD1 in HF. Acute PKD inhibition slightly increased transient outward current in TAC and sham wild-type myocytes but did not alter other K+ currents. Sham PKD1-cKO versus wild-type also exhibited larger transient outward current and faster early action potential repolarization. Tachypacing-induced action potential duration alternans in TAC animals was increased and independent of PKD1, but diastolic arrhythmogenic activities were reduced in PKD1-cKO. Conclusions Our data indicate an important role for PKD1 in the HF-related hypertrophic response and K+ channel downregulation. Therefore, PKD1 inhibition may represent a therapeutic strategy to reduce hypertrophy and arrhythmias; however, PKD1 inhibition may not prevent disease progression and reduced contractility in HF.

Driving under the influence: a multi-center evaluation of vehicular crashes in the era of cannabis legalization.

BACKGROUND: Eleven states have instituted laws allowing recreational cannabis use leading to growing public health concerns surrounding the effects of cannabis intoxication on driving safety. We hypothesized that after the 2016 legalization of cannabis in California, the use among vehicular injury patients would increase and be associated with increased injury severity. METHODS: San Diego County's five adult trauma center registries in were queried from January 2010 to June 2018 for motor vehicle or motorcycle crash patients with completed toxicology screens. Patients were stratified as toxicology negative (TOX-), positive for only THC (THC+), only blood alcohol >0.08% (ETOH+), THC+ETOH, or THC+ with any combination with methamphetamine or cocaine (M/C). County medical examiner data were reviewed to characterize THC use in those with deaths at the scene of injury. RESULTS: Of the 11,491 patients identified, there were 61.6% TOX-, 11.7% THC+, 13.7% ETOH+, 5.0% THC+ETOH, and 7.9% M/C. THC+ increased from 7.3% to 14.8% over the study period and peaked at 14.9% post-legalization in 2017. Compared with TOX- patients, THC+ patients were more likely to be male and younger. THC+ patients were also less likely to wear seatbelts (8.5% vs 14.3%, p<0.001) and had increased mean Injury Severity Score (8.4±9.4 vs 9.0±9.9, p<0.001) when compared with TOX- patients. There was no difference in in-hospital mortality between groups. From the medical examiner data of the 777 deaths on scene, 27% were THC+. DISCUSSION: THC+ toxicology screens in vehicular injury patients peaked after the 2016 legalization of cannabis. Public education on the risks of driving under the influence of cannabis should be a component of injury prevention initiatives. LEVEL OF EVIDENCE: III, Prognostic.

Repeat head computed tomography for anticoagulated patients with an initial negative scan is not cost-effective.

BACKGROUND: Patients on antithrombotic medications presenting with blunt trauma are at risk for delayed intracranial hemorrhage. We hypothesized that clinically significant delayed intracranial hemorrhage is rare in patients presenting on antithrombotic medications and therefore routine, repeat head computed tomography imaging is not a cost-effective practice to monitor for delayed intracranial hemorrhage. METHODS: Patients presenting to our institution on antithrombotic (anticoagulant and antiplatelet) medications during a 5-y period from January 2014 through March 2019 who underwent a head computed tomography for blunt trauma were identified in our trauma registry. Patients with an initial negative head computed tomography underwent repeat imaging 6 h after their initial head computed tomography. Patient demographics, antithrombotic medication, international normalized ratio, Glasgow Coma Score, clinical change in neurologic status, and need for neurosurgical intervention were collected. RESULTS: Our institution evaluated 1,676 patients on antithrombotic therapy with blunt trauma. The initial head computed tomography was negative in 1,377 patients (82.0%). Of those with an initial negative head computed tomography, 12 patients (0.9%) developed an intracranial hemorrhage that was identified on the second head computed tomography. Delayed intracranial hemorrhage included 6 patients with intraventricular hemorrhage, 3 with subdural hematoma, 2 with subarachnoid hemorrhage, and 1 with an intraparenchymal hemorrhage. None of the patients with delayed intracranial hemorrhage developed a change in neurologic status, required an intracranial pressure monitor, or underwent neurosurgical intervention. The estimated total direct cost of the negative head computed tomography scans was $926,247. CONCLUSION: Clinically significant delayed intracranial hemorrhage is rare in trauma patients on antithrombotic therapy, with an initial negative head computed tomography. Routine repeat head computed tomography imaging in patients with a negative scan on admission is not cost-effective.

Oral ulcerations in a patient with autosomal dominant hyper-IgE syndrome (AD-HIES).

A 23-year-old woman with autosomal dominant hyper-IgE syndrome complicated by recurrent pneumonia and sinusitis presented with 1 week of multiple painful oral ulcers unresponsive to empiric antiviral and antifungal treatment. Her ulcers progressively worsened and she required hospitalisation for intravenous hydration and pain control. PCR swab of an ulcer was positive for varicella-zoster virus. Her symptoms never fully resolved despite antiviral therapy, and within 2 weeks, she relapsed with new and worsening ulcers. Biopsy revealed chronic active inflammation with no evidence of viral inclusion bodies or fungal hyphae. She was diagnosed with recurrent aphthous stomatitis and referred to a local dentist for CO2 laser treatments with rapid resolution of her symptoms. This case highlights the broad differential for recurrent oral ulcers in people with a primary immunodeficiency. It also raises awareness of the benefits of laser therapy for aphthous stomatitis treatment and the importance of partnering with our colleagues in dentistry.

Hyperglycemia regulates cardiac K+ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways.

Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K+ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K+ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K+ current (IK1), but reduces the amplitude and inactivation recovery time of the transient outward K+ current (Ito) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 amplitude and Ito recovery effects (but not Ito amplitude) were prevented by the Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. Ito reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both Ito and IK1 were reduced in line with the downregulated K+ channel expression. However, IK1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances IK1 and Ito recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K+ channel expression and function, which may further increase arrhythmia susceptibility.