Objective Dementia and falls are strongly associated, yet few studies have investigated outcomes in patients with dementia after falling. We evaluated differences in mortality, defined as in-hospital mortality or discharge to hospice, and additional outcomes in ground-level fall (GLF) patients with and without dementia.Methods Patients ≥65 years old were identified from the National Trauma Data Bank (2019–2022). Preliminary analyses examined characteristics between patients with and without pre-existing cases of dementia, documented at hospital admission. Upon identifying GLFs as the leading cause of hospital admission in patients with dementia, 1:1 propensity score-matched (PSM) models were used to examine outcomes in GLF patients with and without dementia.Results A total of 1 789 794 patients were included in the preliminary sample and 286 648 (16.0%) had dementia. Of 286 648 patients with dementia, 53.6% were admitted for GLFs. The PSM population consisted of 151 577 matched pairs of GLF patients with and without dementia. After matching, patients with dementia had significantly greater mortality (9.8% vs 6.3%, absolute risk difference (ARD) (95% CI) 3.5 percentage points (3.3 to 3.7); p<0.001) compared with patients without dementia. The proportion of patients with in-hospital mortality no longer significantly differed, but discharge to hospice remained significantly greater in patients with dementia (6.2% vs 2.7%, ARD (95% CI) 3.5 percentage points (3.3 to 3.7); p<0.001) compared with those without dementia. A greater proportion of patients with dementia were discharged to skilled nursing facilities or long-term care hospitals (40.6% vs 37.5%, p<0.001) and less were discharged to inpatient rehab or short-term care facilities (12.2% vs 18.1%, p<0.001) compared with those without dementia.Conclusions Findings from this retrospective study provide strong evidence that GLFs pose a significant health risk to patients with dementia. Implementing routine cognitive, exercise and fall-risk assessments in this population is needed.Level of evidence III.

Background Prior research explored the effect of elevation on deep vein thrombosis (DVT) but primarily examined injuries at elevations <1000 or >4000 feet, excluding elevations in between, and focused on specific subsets of trauma patients. This study aimed to conduct a more detailed analysis of the relationship between elevation and DVT in all trauma admissions.Methods This retrospective cohort study at four level I trauma centers included adult trauma patients (October 1, 2022 to October 1, 2023). Injury zip codes were used to define elevation. High-elevation (H-ELV) injuries (≥5000 feet) were compared with low-elevation (L-ELV) injuries (<5000 feet). Elevation was further categorized into 1000-foot increments. An alpha of <0.0001 defined statistical significance.Results Of 8620 patients, 49% (4231) had L-ELV injuries and 51% (4389) had H-ELV injuries. Compared to patients with L-ELV injuries, those with H-ELV injuries were significantly older, had lower oxygen saturation and higher heart rate, suffered falls and sports injuries more often, and motor vehicle collisions less often, and had a higher rate of comorbidities, including alcohol use disorder and anticoagulant use. DVTs occurred significantly more often after H-ELV injuries than L-ELV injuries (1.9% vs. 0.5%, p<0.0001). For each 1000-foot increase in elevation, there was a corresponding 0.4% average increase in the rate of DVT (moderate R2=0.6). After adjustment for alcohol use disorder and oxygen saturation, H-ELV injuries were associated with a 3.8-fold increase (95% CI 2.3 to 6.4) in the risk of DVT when compared with L-ELV injuries.Conclusions Even after adjustment, H-ELV injuries were associated with 3.8 increased odds of developing a DVT compared with L-ELV injuries. There was a significant positive linear association between DVT and injury elevation, with the rate of DVT increasing with increasing elevation. This finding may suggest the need for enhanced screening or tailored DVT prophylaxis methods at higher elevation trauma centers to improve outcomes.Level of evidence Level IV.

Previous abdominal surgery (PAS) increases risk of small bowel obstruction (SBO) due to adhesions, and appendectomy (appy) is an independent risk factor for abdominal adhesion-related complications. Peritoneal inflammation, e.g., acute appendicitis (AA), causes formation of reactive ascitic fluid (rA) that activates peritoneum surface mesothelial cells (MCs) to form adhesions. Pathologic adhesions may arise if restoration of MC-regulated fibrinolysis and secretion of glycocalyx (GCX) are disrupted. Proteins affecting these processes may originate from peritoneal rA. This is a prospective observational IRB-approved study at three Level 1 trauma centers where rA is collected prior to surgical intervention for non-perforated AA or adhesiolysis for SBO. Samples from 48 appy and 15 SBO patients were used to treat human MCs and subjected to quantification of 85 inflammatory mediators. Results were compared between patients with surgically naïve abdomens (naïve) and patients with >1 PAS. Select rA caused MCs to form clusters of fibroblastic cells, extracellular matrix fibers (FIB), and secretion of GCX. PAS and naïve patient rA fluids were clustered into “fiber-GCX” (FIB-GCX) groups: highFIB-highGCX, highFIB-lowGCX, noFIB-highGCX, noFIB-lowGCX, and noFIB-noGCX. Between groups, 26 analytes were differentially abundant including innate immune response, wound healing, and mucosal defense proteins. Factors that contributed to the differences between groups were rA-induced highFIB and history of PAS. Overall, PAS patient rA showed a muted immune response compared to rA from naïve patients. Our data suggest that abdominal surgery may negatively impact future immune responses in the abdomen. Further, quantifying immunomodulators in peritoneal rA may lead to the development a personalized approach to post-surgical adhesion treatment and prevention.

The opioid crisis has highlighted the urgent need for alternative pain management strategies. This review explores novel non-opioid targets and pathways involved in pain modulation, highlighting advancements in understanding and therapeutic potential. Pain, a multifaceted phenomenon with nociceptive, neuropathic, and inflammatory components, involves intricate molecular signaling cascades. Key pathways reviewed include voltage-gated sodium channels (Nav1.7, Nav1.8, Nav1.9), inflammasome complexes (NLRP3), the kynurenine pathway, prostaglandins, and bradykinin-mediated signaling. Emerging therapeutics such as selective Nav channel blockers, NLRP3 inhibitors, kynurenine pathway modulators, EP receptor antagonists, and bradykinin receptor antagonists offer promising alternatives to opioids. Despite challenges in clinical translation, these developments signal a paradigm shift in pain management, with precision-focused therapies poised to address unmet needs. This review emphasizes the importance of integrating molecular insights into the development of safer, more effective analgesics, setting the stage for transformative advancements in non-opioid pain relief.

INTRODUCTION:Cutaneous wounds are susceptible to metabolic imbalances, via hypoxia and the "Warburg effect," which can lead to excessive lactate accumulation, potentially delaying healing. It is also accepted that lactylation of histones and other proteins is important in the epigenetic regulation of cells. Thus, a greater understanding of how lactate affects fibroblasts could lead to new therapeutic approaches. This study aimed to investigate how lactate impacts transforming growth factor β1 (TGF-β1)- and interleukin (IL)-1β-induced transcriptional programs in normal human dermal fibroblasts (NHDFs). METHODS:Quantitative real-time PCR was used to evaluate transcriptional changes in key remodeling markers in NHDFs treated with 40 to 100 mM of sodium lactate, 0.1 μM of dexamethasone-21-phosphate, 10 mM of 2-deoxy- d -glucose, 2.5 μM of oligomycin, 10 μM of lactoyl-coenzyme A (lactyl-COA), or 10 mM of sodium acetate and then activated with 10 ng/mL of TGF-β1 or 0.1 ng/mL of IL-1β for 24 hours. Total messenger RNA was then isolated, and ΔΔCp relative expression was calculated versus appropriate controls, normalized to the housekeeping gene, GAPDH . Fluorescent membrane integrity and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays were also conducted to assess toxicity and metabolic changes, respectively. RESULTS:We observed that lactate dose-dependently inhibited TGF-β1-induced collagen type 1α1 ( COL1a1 ) and elastin ( ELN-1 ), as well as IL-1β-induced matrix metalloproteinase 3 ( MMP3 ) and matrix metalloproteinase 12 ( MMP12 ). The anti-inflammatory glucocorticoid, dexamethasone-21-phosphate, also inhibited cytokine-induced ELN , MMP3 , and MMP12 . Parallel analysis with 2-deoxy- d -glucose, oligomycin, lactyl-COA, and sodium acetate inferred that chromatin modifications and metabolic reprogramming may contribute to the observed lactate response in our model. In addition, metabolic reprogramming was confirmed via detection of elevated NAD(P)H-dehydrogenase activity. CONCLUSION:These findings suggest that, because of a potential biphasic response, high lactate treatment of NHDFs exhibits immunosuppressive effects, indicating that metabolic regulation may help mitigate tissue damage. Additionally, pharmacological manipulation of histone modifications or metabolic rebalancing may serve as intriguing therapeutic interventions.

The aging US population has altered the epidemiology of traumatic injury, but there are few studies examining changing patterns of traumatic intracranial hemorrhage (tICH). We examined temporal changes in incidence, demographics, severity, management, and outcomes of tICH among trauma admissions at six US Level I trauma centers over 6 years (July 1, 2016-June 30, 2022). Patients with tICH (subdural, epidural, subarachnoid, and intracerebral hemorrhage) were identified by 10th revision of the International Statistical Classification of Diseases diagnosis codes. Temporal trends were examined over 12 six-month intervals using joinpoint regression and reported as biannual percent change (BPC); models without joinpoints are described as linear trends over time. There were 67,514 trauma admissions over 6 years and 11,935 (17.7%) patients had a tICH. The proportion of tICH injuries significantly increased 2.6% biannually from July 2016 to July 2019 (BPC = 2.6, p = 0.04), then leveled off through June 2022 (BPC = -0.9, p = 0.19). Similarly, the proportion of geriatric patients (>= 65 years old) increased 2.4% biannually from July 2016 to July 2019 (BPC = 2.4, p = 0.001) as did injuries due to falls (BPC = 2.2, p = 0.01). Three of the four most prevalent comorbidities significantly increased: hypertension linearly increased 2.1% biannually, functional dependence increased 25.5% biannually through June 2019, and chronic anticoagulant use increased 19.0% biannually through June 2019 and then 3.1% thereafter. There were no trends in the rates of neurosurgical intervention (BPC = -0.89, p = 0.40), ED Glasgow coma score 3-8 (BPC = -0.4, p = 0.77), or presence of severe extracranial injuries (BPC = -0.7, p = 0.45). In-hospital mortality linearly declined 2.6% biannually (BPC = 2.6, p = 0.05); however, there was a 10.3% biannual linear increase in discharge to hospice care (BPC = 10.3, p < 0.001). These results demonstrate the incidence of tICH admissions is temporally increasing, and the population is growing older with more comorbidities and injuries from falls. Yet, traumatic brain injury severity and neurosurgical management are unchanged. The shift from in-patient death to hospice care suggests an increased need for palliative care services.

Most cases of pneumoperitoneum with associated peritonitis are due to perforation of a hollow viscus. In cases where hollow viscus perforation is not the cause, the pneumoperitoneum is classified as spontaneous and typically can be further subcategorized into thoracic, abdominal, gynecologic, and idiopathic categories. Spontaneous pneumoperitoneum is classically seen in asymptomatic patients, however in a small number of cases patients can present with a concomitant peritonitis. This case report presents a patient that had signs of sepsis and peritonitis with moderate pneumoperitoneum on computed tomography (CT) imaging but was found to have no perforated hollow viscus after an extensive operative and non-operative work up.

Objective The perioperative management of patients on antiplatelet drugs is a rising challenge in orthopedic trauma because antiplatelet drugs are frequently encountered and carry an increased risk of hemorrhagic consequences. The study objective was to examine the effect of aspirin on bleeding outcomes for patients with lower extremity fractures.Methods This retrospective study included patients requiring surgical fixation of traumatic hip, femur, and tibia fractures from January 1, 2018, to March 1, 2020. Patients were excluded if they had a significant head injury, were on chronic anticoagulant therapy, or they did not receive venous thromboembolism chemoprophylaxis. Comparisons between aspirin users (patients on aspirin therapy preinjury) and non-aspirin users were examined using χ2 tests, Cochran-Mantel-Haenszel tests, and multivariate logistic regression. The primary outcome was an overt, actionable bleed (eg, blood transfusion for surgical site hemorrhage) within 24 hours postoperative.Results There were 864 patients with lower extremity long bone fractures and 24% were aspirin users. The incidence of postoperative bleeding was 8.8% and significantly differed for patients taking aspirin versus not (13.6% vs 7.3%, p=0.01). However, biological sex at birth (M/F) was a significant effect modifier (interaction p=0.04). Among women, there were significantly more postoperative bleeds for aspirin users (17.8% aspirin vs 7.4% no aspirin, adjusted OR (AOR): 2.48 (1.28–4.81), p=0.01). Among men, there were similar postoperative bleeding events by aspirin use (5.6% aspirin vs 7.2% no aspirin, AOR: 0.50 (0.14–1.82), p=0.30). Postoperative hemoglobin values <8 g/dL were more frequent among female aspirin users (21.5% aspirin vs 12.5% no aspirin, p=0.01), but this association was not observed in men (p=0.43).Conclusion Women taking aspirin who suffer lower extremity fractures have greater than twofold greater odds of a postoperative bleeding event. These findings suggest adequate perioperative planning to ensure blood availability, and increased awareness to monitor closely for hemorrhage in the 24-hour postoperative window for women taking aspirin preinjury.Level of evidence IV

Introduction:Dysphagia, a complication of traumatic brain injuries (TBIs), can lead to death. Cervical collar (c-collar) restriction may increase the risk for dysphagia. The objective was to determine how c-collars affect dysphagia rates.Methods:This retrospective cohort study included geriatric TBIs or cervical spine injuries (January 2016 to December 2018) at a Level 1 trauma center. Outcomes (dysphagia, aspiration, and respiratory failure) were compared by c-collar placement.Results:There were 684 patients: 21.5% had a c-collar and 78.5% did not. Demographics, injury severity score, and Glasgow Coma Scale were comparable. Dysphagia (53.7% vs. 39.3%, p = .002) and respiratory failure (17.0% vs. 6.9%, p = .0002) were more common among patients with c-collars. Aspiration rates (p = .11) were similar. After adjustment, patients with a c-collar had a significantly higher odds of dysphagia and respiratory failure. Among patients who did not receive swallow therapy, aspiration (p = .02) and respiratory failure (p < .0001) were more common for those with c-collars.Conclusions:C-collar placement increased the risk for dysphagia and respiratory failure. There was evidence that swallow therapy may modify the effect of c-collar placement. For patients who did not receive swallow therapy, aspiration was more common among those with a c-collar. Dysphagia screening among patients with a c-collar may improve patient quality.

Objective:Operative management of axis fractures (C2) usually depend on the stability and location of the break and individual patient characteristics. We sought to describe the epidemiology of C2 fractures and hypothesized that determinants for surgery would differ by fracture diagnosis. Methods:Patients with C2 fractures were identified from the US National Trauma Data Bank from January 1, 2017, to January 1, 2020. Patients were classified by C2 fracture diagnosis: odontoid type II, odontoid types I and III, and non-odontoid fracture (hangman's fracture or fractures through base of the axis). The primary comparison was C2 fracture surgery versus non-operative management. Multivariate logistic regression was used to identify independent associations with surgery. Decision tree-based models were developed to identify determinants for surgery. Results:There were 38 080 patients; 42.7% had an odontoid type II fracture; 16.5% had an odontoid type I/III fracture; and 40.8% had a non-odontoid fracture. All examined patient demographics, clinical characteristics, outcomes, and interventions differed by C2 fracture diagnosis. Overall, 5292 (13.9%) were surgically managed (17.5% odontoid type II, 11.0% odontoid type I/III, and 11.2% non-odontoid; p<0.001). The following covariates increased odds of surgery for all three fracture diagnoses: younger age, treatment at a level I trauma center, fracture displacement, cervical ligament sprain, and cervical subluxation. Determinants of surgery differed by fracture diagnosis: for odontoid type II, age ≤80 years, a displaced fracture, and cervical ligament sprain were determinants; for odontoid type I/III, age ≤85 years, a displaced fracture, and cervical subluxation were determinants; for non-odontoid fractures, cervical subluxation and cervical ligament sprain were the strongest determinants for surgery, by hierarchy. Conclusions:This is the largest published study of C2 fractures and current surgical management in the USA. Odontoid fractures, regardless of type, had age and fracture displacement as the strongest determinants for surgical management, whereas associated injuries were determinants of surgery for non-odontoid fractures. Level of evidence:III.

Myoendothelial junctions (MEJs) are structures that allow chemical signals to be transmitted between endothelial cells (ECs) and vascular smooth muscle cells, which control vascular tone. MEJs contain hemoglobin alpha (Hbα) and endothelial nitric oxide synthase (eNOS) complexes that appear to control the production and scavenging of nitric oxide (NO) along with the activity of cytochrome b5 reductase 3 (CYB5R3). The aim of this study was to examine how hypoxia affected the regulation of proteins involved in the production of NO in brain ECs. In brief, human brain microvascular endothelial cells (HBMEC) were exposed to cobalt chloride (CoCl2), a hypoxia mimetic, and a transcriptional analysis was performed using primers for eNOS, CYB5R3, and Hbα2 with ΔΔCt relative gene expression normalized to GAPDH. NO production was also measured after treatment using 4,5-diaminofluorescein diacetate (DAF-DA), a fluorescent NO indicator. When HBMEC were exposed to CoCl2 for 48 h, eNOS and CYB5R3 messenger RNA significantly decreased (up to −17.8 ± 4.30-fold and −10.4 ± 2.8, respectively) while Hbα2 increased to detectable levels. Furthermore, CoCl2 treatment caused a redistribution of peripheral membrane-generated NO production to a perinuclear region. To the best of our knowledge, this is the first time this axis has been studied in brain ECs and these findings imply that hypoxia may cause dysregulation of proteins that regulate NO production in brain MEJs.

Open fractures are at high risk of infection because of exposure of bone and tissue to the environment. Initiation of intravenous antibiotics is recommended within 1 hour of hospital arrival, although the presence of other severe injuries may lead to delays in fracture management. This retrospective study of adult patients with open long-bone fractures admitted to six level 1 trauma centers between January 1, 2018, and December 31, 2019, aimed to examine adherence to antibiotic recommendations. Associations between receiving recommendation-adherent antibiotics and patient and injury characteristics were investigated univariately and in adjusted regression analyses. The most common fracture locations among the 404 patients included were the tibia (43%) and fibula (26%). Fifty-eight percent of patients received recommendation-adherent antibiotics. After adjustment, patient demographics, comorbidities, cause of injury, and overall injury severity did not show significant associations with adherence to recommendations. Concomitant serious abdominal (adjusted odds ratio [AOR]=0.44) and spinal injuries (AOR=0.23) were associated with lower odds of receiving recommendation-adherent antibiotics. Additionally, fractures of certain locations were associated with increased odds of adherence (humerus: AOR=2.78; fibula: AOR=1.64), as were type 3 fractures (AOR=1.55). The overall infection rate was 4%, and adherence to antibiotic recommendations was not associated with infection (3% vs 5% for nonadherent, P=.34). Results suggest that although full recommendation adherence was somewhat low among this patient population, certain injury characteristics were predictive of adherence rates. Current antibiotic recommendations may benefit from consideration of how antibiotic initiation may fit into the prioritization of injury management, especially in patients with polytrauma with other severe injuries. [Orthopedics. 2023;46(1):54-58.].

BACKGROUND: The adverse impact of acute hyperglycemia is well documented but its specific effects on nondiabetic trauma patients are unclear. The purpose of this study was to analyze the differential impact of hyperglycemia on outcomes between diabetic and nondiabetic trauma inpatients. METHODS: Adults admitted 2018 to 2019 to 46 Level I/II trauma centers with two or more blood glucose tests were analyzed. Diabetes status was determined from International Classification of Diseases-10th Rev.-Clinical Modification, trauma registry, and/or hemoglobin Ale greater than 6.5. Patients with and without one or more hyperglycemic result >180 mg/dL were compared. Logistic regression examined the effects of hyperglycemia and diabetes on outcomes, adjusting for age, sex, Injury Severity Score, and body mass index. RESULTS: There were 95,764 patients: 54% male; mean age, 61 years: mean Injury Severity Score, 10; diabetic, 21%. Patients with hyperglycemia had higher mortality and worse outcomes compared with those without hyperglycemia. Nondiabetic hyperglycemic patients had the highest odds of mortality (diabetic: adjusted odds ratio, 3.11; 95% confidence interval, 2.8-3.5: nondiabetics: ad-justed odds ratio. 7.5; 95% confidence interval, 6.8-8.4). Hyperglycemic nondiabetics experienced worse outcomes on every measure when compared with nonhyperglycemic nondiabetics, with higher rates of sepsis (1.1 vs. 0.1%,p <0.001), more SSIs (1.0 vs. 0.1%, p < 0.001), longer mean hospital length of stay (11.4 vs. 5.0,p < 0.001), longer mean intensive care unit length of stay (8.5 vs. 4.0, p < 0.001), higher rates of intensive care unit use (68.6% vs. 35.1), and more ventilator use (42.4% vs. 7.3%). CONCLUSION: Hyperglycemia is associated with increased odds of mortality in both diabetic and nondiabetic patients. hyperglycemia during hos pitalization in nondiabetics was associated with the worst outcomes and represents a potential opportunity for intervention in this high-risk group. Copyright (C) 2022 American Association for the Surgery of Trauma.

Background Traumatic aortic injuries (TAIs) are rare but are associated with a high mortality. Prior studies have shown skiers and pilots, whose injuries occur at high altitudes, are at an increased risk for a TAI. The purpose of this study was to examine the effect of altitude on the incidence of TAIs across all causes of injury. Methods This retrospective cohort study at six Level I trauma centers (8/1/2016–1/1/2020) included adult blunt trauma patients with a chest or abdomen injury. High altitude injuries (> 5000 ft.) were compared to low altitude injuries (≤ 5000 ft.). The primary outcome was incidence of TAI. Results There were 8562 patients, 37% were at high altitude and 63% at low altitude. High altitude patients were older ( p < 0.01), more often Caucasian ( p < 0.01) and had a higher ISS ( p < 0.01). There was a significantly greater incidence of TAI at high altitude than low altitude (1.5% vs. 1.1%, p = 0.01). The median altitude was significantly higher for patients with a TAI than for patients without a TAI (5100 ft. vs. 1400 ft., p = 0.01). After adjustment, high altitude patients had 2-fold [OR: 2.4 (1.6, 3.7)] greater odds of having a TAI than low altitude patients. Conclusion TAIs were more prevalent among high altitude injuries. Providers should be aware of the increased incidence of TAIs at high altitudes particularly when there is a delay in diagnosis and transfer to a trauma center with appropriate resources to manage these critical injuries. TAI screening at high altitude trauma centers may improve survival rates.

Objectives Open fractures are at risk of infection because of exposure of bone and tissue to the environment. Facial fractures are often accompanied by other severe injuries, and therefore fracture management may be delayed until after stabilization. Previous studies in this area have examined timing of multiple facets of care but have tended to report on each in isolation (eg, antibiotic initiation). Methods This was a retrospective study of adult patients admitted to five trauma centers from January 1, 2017 to March 31, 2021 with open facial fractures. Variables collected included demographics, injury mechanism, details on facial and non-facial injuries, facial fracture management (irrigation and debridement (I&D), irrigation without debridement, open reduction internal fixation (ORIF), antibiotics), and other hospital events. The study hypothesized that the presence of serious non-facial injuries would be associated with delays in facial fracture management. The primary aims were to describe open facial fracture management practices and examine factors associated with early versus delayed fracture management. A secondary aim was to describe infection rates. Early treatment was defined as within 24 hours of arrival for I&D, irrigation without debridement, and ORIF and within 1 hour for antibiotics. Results A total of 256 patients were included. Twenty-seven percent had major trauma (Injury Severity Score ≥16). The presence of serious head injury/traumatic brain injury was associated with delayed I&D (ORearly=0.04, p<0.01), irrigation without debridement (ORearly=0.09, p<0.01), and ORIF (ORearly=0.10, p<0.01). Going to the OR within 24 hours was associated with early I&D (ORearly=377.26, p<0.01), irrigation without debridement (ORearly=13.54, p<0.01), and ORIF (ORearly=154.92, p<0.01). The infection rate was 4%. Conclusions In this examination of multiple aspects of open facial fracture management, serious injuries to non-facial regions led to delays in surgical fracture management, consistent with the study hypothesis. Level of evidence Level III, prognostic/epidemiological.

Salottolo, Kristin1; Lieser, Mark2; Nwafo, Nnamdi3; Madayag, Robert4; Tanner, Allen5; Carrick, Matthew6; Corrigan, Chad7; Banton, Kaysie8; Bar-Or, David9 Author Information

BACKGROUND:There is debate on the need to withhold chemical venous thromboembolism (VTE) prophylaxis in patients requiring major orthopedic surgery. We hypothesized that the incidence of clinically significant hemorrhage (CSH) does not differ by the timing of prophylaxis in such patients.METHODS:This was a multicenter, retrospective cohort study conducted at five US trauma centers that included trauma patients admitted between January 1, 2018, to March 1, 2020, requiring surgical fixation of the femoral shaft, hip, or tibia and received VTE chemoprophylaxis during the hospitalization. Exclusions were major and moderate head or spinal injuries, chronic anticoagulant use, or multiple long bone surgeries. Timing of VTE chemoprophylaxis was examined as four groups: (1) initiated preoperatively without interruption for surgery; (2) initiated preoperatively but held perioperatively; (3) initiated within 12 hours postoperatively; and (4) initiated >12 hours postoperatively. The primary outcome was incidence of CSH (%), defined as overt hemorrhage within 24 hours postoperative that was actionable. Multivariate logistic regression evaluated differences in CSH based on timing of VTE chemoprophylaxis.RESULTS:There were 786 patients, and 65 (8.3%) developed a CSH within 24 hours postoperatively. Nineteen percent of patients received chemoprophylaxis preoperatively without interruption for surgery, 13% had preoperative initiation but dose(s) were held for surgery, 21% initiated within 12 hours postoperatively, and 47% initiated more than 12 hours postoperatively. The incidence and adjusted odds of CSH were similar across groups (11.3%, 9.1%, 7.1%, and 7.3% respectively; overall p = 0.60). The incidence of VTE was 0.9% and similar across groups ( p = 0.47); however, six of seven VTEs occurred when chemoprophylaxis was delayed or interrupted.CONCLUSION:This study suggests that early and uninterrupted VTE chemoprophylaxis is safe and effective in patients undergoing major orthopedic surgery for long bone fractures.LEVEL OF EVIDENCE:Therapeutic/Care Management; Level IV.

From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.