Delay of fixation increases 30-day complications and mortality in traumatic pelvic ring injuries.

PURPOSE: While decreased time to fixation in femur fractures improves mortality, it remains unclear if the same relationship exists for pelvic fractures. The National Trauma Data Bank (NTDB) is a data repository for trauma hospitals in the United States (injury characteristics, perioperative data, procedures, 30-day complications), and we used this to investigate early, significant complications after pelvic-ring injuries. METHODS: The NTDB (2015-2016) was queried to capture operative pelvic ring injuries in adult patients with injury severity score (ISS) ≥ 15. Complications included medical and surgical complications, as well as 30-day mortality. Multivariable logistic regression was used to investigate the association between days to procedure and complications after adjusting for demographic characteristics and comorbidities. RESULTS: 2325 patients met inclusion criteria. 532 (23.0%) sustained complications, and 72 (3.2%) died within the first 30 days. The most common complications were deep vein thrombosis (DVT) (5.7%), acute kidney injury (AKI) (4.6%), and unplanned intensive care unit (ICU) admission (4.4%). In a multivariate analysis, days to procedure was independently significantly associated with complications, with an adjusted odds ratio (95% confidence interval) of 1.06 (1.03-1.09, P < 0.001), best interpreted as a 6% increase in the odds of complication or death for each additional day. CONCLUSION: Time to pelvic fixation is a significant and modifiable risk factor for major complications and death. This suggests we should prioritize time to pelvic fixation on trauma patients to minimize mortality and major complications.

Radiographic bladder shift is a harbinger of intraoperative blood loss in acetabular surgical fixation.

PURPOSE: The purpose of this study was to characterize the relationship between a novel radiographic measurement on initial AP pelvis radiograph (termed "bladder shift," BS) to intraoperative blood loss (IBL) during acetabular surgical fixation. METHODS: All adult patients receiving unilateral acetabular fixation (Level 1 academic trauma; 2008-18) were reviewed. AP pelvis radiographs were reviewed for visible bladder outlines and then measured to determine the percentage deformation toward the midline. Hemoglobin & hematocrit data were then used to calculate quantitative blood loss between pre- and post- operative blood counts for data analysis. RESULTS: 371 patients with unilateral traumatic acetabular fractures requiring fixation were reviewed; 99 of these had visible bladder outlines, complete blood count and transfusion data (2008-2018; 66% associated patterns). Median bladder shift (BS) was 13.3%. Every 10% of bladder shift was associated with 123 mL greater IBL. Patients with full bladder shift to midline sustained a median 1.5L IBL (interquartile range [IQR] 0.8 to 1.6). Associated patterns had a threefold greater median BS (associated: 16.5% [15.4 to 45.9] vs. elementary: 5.6% [1.1 to 15.4], p < 0.05) and received intraoperative pRBC twice as frequently (57% vs. 24%, p < 0.01). CONCLUSIONS: Radiographic bladder shift is an easily available visual marker, in patients sustaining acetabular fractures, that may predict intraoperative hemorrhage and need for transfusions.

Risk of Revision and Complications After Total Hip Arthroplasty for Acute Treatment of Acetabular Fracture.

BACKGROUND: Total hip arthroplasty (THA) for the treatment of acute acetabular fractures may be indicated where there is high risk for failure of open reduction and internal fixation. This study aimed to determine risks of revision and rates of major complications of THA for acute acetabular fractures. METHODS: A retrospective review was performed (all-claims data files of a large national database) by querying International Classification of Disease, 10th revision procedure codes for THA within 14 days of acetabular fracture. We identified all-cause revision and surgical complications including dislocations, mechanical failures (loosenings or broken prostheses), infections, as well as medical complications. Demographic data collected included age, sex, obesity, and Charlson Comorbidity Index (CCI). Multivariate analyses evaluated the association of revision and major surgical complications after adjusting for demographic characteristics and comorbidities. We identified 956 THAs for the treatment of acute acetabular fracture from 2015 to 2020. Of all acute acetabular fractures treated with THA, 241 were concomitant with open reduction and internal fixation (ORIF), and 715 were THA-alone. RESULTS: All-cause revision risk was 18.2%, overall major surgical complication rate 26.9%, and medical complication rate was 13.2%. Women were associated with increased risk of revision (adjusted odds ratio (aOR) 1.8; confidence interval (CI) 1.3 to 2.6, P = .001), dislocation (aOR 2.0; CI 1.5 to 3.1, P < .001), mechanical complication (aOR 2.1; CI 1.4 to 3.2, P < .001), and infection (aOR 1.6; CI 1.0 to 2.5, P = .044). CONCLUSION: We noted risk of all-cause revision of 18.2%, overall major surgical complication rate of 26.9%, and overall major medical complication rate of 13.2% for THA as the treatment of acute acetabular fracture. We caution against broad expansion of THA for treatment of acute acetabular fractures. Furthermore, increased risks of revision and complications in women warrant additional investigation into patient and fracture characteristics that may contribute to this finding.

Distribution of Bacterial Species and Resistance Patterns in Surgical Site Infection after Prior Administration of Vancomycin and Tobramycin Intrawound Powdered Antibiotic Prophylaxis.

OBJECTIVE: Evaluate the species distribution and resistance patterns of bacterial pathogens causing surgical site infection (SSI) after operative fracture repair, with and without the use of intrawound powdered antibiotic (IPA) prophylaxis during the index surgery. DESIGN: Retrospective cohort study. SETTING: Academic, level 1 trauma center, 2018-2020. PATIENTS/PARTICIPANTS: Fifty-nine deep SSIs were identified in a sample of 734 patients with 846 fractures (IPA [n = 320], control [n = 526]; open [n = 157], closed fractures [n = 689]) who underwent orthopaedic fracture care. Among SSIs, 28 (48%) patients received IPA prophylaxis and 25 (42%) of the fractures were open. INTERVENTION: Intrawound powdered vancomycin and tobramycin. MAIN OUTCOME MEASUREMENTS: Distribution of bacterial species and resistance patterns causing deep surgical site infections requiring operative debridement. RESULTS: Zero patients developed infections caused by resistant strains of streptococci, enterococci, gram-negative enterics, Pseudomonas , or Cutibacterium species. The only resistant strains isolated were methicillin resistance (19%) and oxacillin-resistant coagulase-negative staphylococci (16%). There was no associated statistical difference in the proportion of bacterial species isolated, their resistance profiles, or rate of polymicrobial infections between the IPA and control group. Most (93%) cases using IPAs included vancomycin and tobramycin powders. There were 59 SSIs; 28 (9%) in the IPA cohort and 31 (6%) in the control cohort ( P = 0.13). CONCLUSION: The use of local antibiotic prophylaxis resulted in no measurable increase in the proportion of infections caused by resistant bacterial pathogens after operative treatment of fractures. However, the small sample size and limited time frame of these preliminary data require continued investigation into their role as an adjunct to SSI prophylaxis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Role of single-dose intravenous iron therapy for the treatment of anaemia after orthopaedic trauma: protocol for a pilot randomised controlled trial.

INTRODUCTION: Orthopaedic trauma and fracture care commonly cause perioperative anaemia and associated functional iron deficiency due to a systemic inflammatory state. Modern, strict transfusion thresholds leave many patients anaemic; managing this perioperative anaemia is an opportunity to impact outcomes in orthopaedic trauma surgery. The primary outcome of this pilot study is feasibility for a large randomised controlled trial (RCT) to evaluate intravenous iron therapy (IVIT) to improve patient well-being following orthopaedic injury. Measurements will include rate of participant enrolment, screening failure, follow-up, missing data, adverse events and protocol deviation. METHODS AND ANALYSIS: This single-centre, pilot, double-blind RCT investigates the use of IVIT for acute blood loss anaemia in traumatically injured orthopaedic patients. Patients are randomised to receive either a single dose infusion of low-molecular weight iron dextran (1000 mg) or placebo (normal saline) postoperatively during their hospital stay for trauma management. Eligible subjects include adult patients admitted for lower extremity or pelvis operative fracture care with a haemoglobin of 7-11 g/dL within 7 days postoperatively during inpatient care. Exclusion criteria include history of intolerance to intravenous iron supplementation, active haemorrhage requiring ongoing blood product resuscitation, multiple planned procedures, pre-existing haematologic disorders or chronic inflammatory states, iron overload on screening or vulnerable populations. We follow patients for 3 months to measure the effect of iron supplementation on clinical outcomes (resolution of anaemia and functional iron deficiency), patient-reported outcomes (fatigue, physical function, depression and quality of life) and translational measures of immune cell function. ETHICS AND DISSEMINATION: This study has ethics approval (Oregon Health & Science University Institutional Review Board, STUDY00022441). We will disseminate the findings through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT05292001; ClinicalTrials.gov.

Motivation and family communication in hereditary prostate cancer genetic testing: Survey of patients from a US tertiary medical center.

Identification of a hereditary prostate cancer in an affected individual can guide treatment and may also impact cancer screening and surveillance for patients and their relatives. This study aimed to determine the factors that are associated with the decision-making process of individuals with prostate cancer regarding whether to pursue genetic testing as well as how, why, and with whom genetic test results are shared. We surveyed 113 patients diagnosed with prostate cancer who received cancer genetic counseling through a United States tertiary medical center, inquiring about genetic testing motivations and family communication about results. Among those who pursued genetic testing, (1) learning about my family's possible cancer risk (98%), (2) learning information that may guide cancer treatment (93%), and (3) learning if I am at risk for future cancers (92%) were most frequently identified as slightly or very important factors in their decision. Participants shared their genetic test results in a higher proportion to male first-degree relatives than female first-degree relatives; however, no significant difference was found (p = 0.103). Our study may suggest sex differences related to family communication about genetic testing results. Such findings indicate a critical need for genetic counselors to clearly communicate the impact of genetic test results on both male and female relatives. Further research on motivation and family communication about genetic test results in diverse cohorts is needed.

Platelet reactivity and platelet count in women with iron deficiency treated with intravenous iron.

Background: Iron deficiency anemia (IDA) and heavy menstrual bleeding are prevalent, interrelated issues impacting over 300 million premenopausal women worldwide. IDA is generally associated with increased platelet counts; however, the effects of IDA and its correction on platelet function in premenopausal women remain unknown. Objectives: We sought to determine how IDA and intravenous iron affect platelet count and platelet function in premenopausal women. Methods: Hematologic indices were assessed in a multicenter, retrospective cohort of 231 women repleted with intravenous iron. Pre- and postinfusion blood samples were then obtained from a prospective cohort of 13 women to analyze the effect of intravenous iron on hematologic parameters as well as platelet function with flow cytometry and platelet aggregation assays under physiologic shear. Results: Following iron replacement, anemia improved, and mean platelet counts decreased by 26.5 and 16.0 K/mm3 in the retrospective and prospective cohorts, respectively. Replacement reduced baseline platelet surface P-selectin levels while enhancing platelet secretory responses to agonists, including collagen-related peptide and ADP. Platelet adhesion and aggregation on collagen under physiologic shear also significantly increased following repletion. Conclusion: We find that intravenous iron improves anemia while restoring platelet counts and platelet secretory responses in premenopausal women with iron deficiency. Our results suggest that iron deficiency as well as iron replacement can have a range of effects on platelet production and function. Consequently, platelet reactivity profiles should be further examined in women and other groups with IDA where replacement offers a promising means to improve anemia as well as quality of life.

Electrical Impedance as a Noninvasive Metric of Quality in Allografts Undergoing Normothermic Ex Vivo Lung Perfusion.

Ex vivo lung perfusion (EVLP) increases the pool of suitable organs for transplant by facilitating assessment and repair at normothermia, thereby improving identification of quality of marginal organs. However, there exists no current objective approach for assessing total organ edema. We sought to evaluate the use of electrical impedance as a metric to assess total organ edema in lungs undergoing EVLP. Adult porcine lungs (40 kg) underwent normothermic EVLP for 4 hours. To induce varying degrees of lung injury, the allografts were perfused with either Steen, a modified cell culture media, or 0.9% normal saline. Physiologic parameters (peak airway pressure and compliance), pulmonary artery and left atrial blood gases, and extravascular lung water measurements were evaluated over time. Wet-to-dry ratios were evaluated postperfusion. Modified Murray scoring was used to calculate lung injury. Impedance values were associated with lung injury scores ( p = 0.007). Peak airway pressure ( p = 0.01) and PaO 2 /FiO 2 ratios ( p = 0.005) were both significantly associated with reduced impedance. Compliance was not associated with impedance ( p = 0.07). Wet/dry ratios were significantly associated with impedance and Murray Scoring within perfusion groups of Steen, Saline, and Modified Cell Culture ( p = 0.0186, 0.0142, 0.0002, respectively). Electrical impedance offers a noninvasive modality for measuring lung quality as assessed by tissue edema in a porcine model of normothermic EVLP. Further studies evaluating the use of impedance to assess organ edema as a quality marker in human clinical models and abdominal organs undergoing ex vivo perfusion warrant investigation.

Treatment of Persistent Erythema Multiforme With Janus Kinase Inhibition and the Role of Interferon Gamma and Interleukin 15 in Its Pathogenesis.

IMPORTANCE: Persistent erythema multiforme (PEM) is poorly understood and lacks effective therapies other than glucocorticoids. OBJECTIVE: To report outcomes following treatment of PEM with Janus kinase (JAK) inhibition and to elucidate cytokine drivers of erythema multiforme (EM). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective case series of 4 patients with PEM treated with tofacitinib and/or upadacitinib in 2015 to 2021 at the dermatology clinics of 2 major tertiary referral centers. Four consecutive patients with PEM refractory to multiple treatment approaches were treated. In 1 patient, skin biopsy specimens were obtained for RNA sequencing and proteomic analysis before and during treatment. Molecular findings were validated through RNA in situ hybridization analysis of cytokine expression in biopsy specimens from a total of 12 patients with EM (3 treated with tofacitinib in this study and 9 historic samples). INTERVENTIONS: Treatment with tofacitinib, 5 to 10 mg, twice daily or upadacitinib, 15 mg, once daily. MAIN OUTCOMES AND MEASURES: Change in PEM activity was assessed in all 4 patients treated with a JAK inhibitor. Median (range) follow-up was 20.5 months (10.0-36.0 mo). RESULTS: The study population of 4 female patients had a mean (SD) age of 46.2 (13.7) years and a mean (SD) disease duration of 21.75 (11.30) years. Marked clinical improvement was noted in all 4 patients. In 1 patient with a robust improvement following treatment with tofacitinib, RNA sequencing identified interferon gamma (IFN-γ) and interleukin 15 (IL-15) as cytokines with activity both highly upregulated at baseline in lesional skin and subsequently suppressed following tofacitinib treatment. Measurement of IFNG- and IL15-positive cells in additional EM biopsy specimens of 12 patients showed significant upregulation of IFNG (8.72 cells per mm; 95% CI, 2.60-14.84) and IL15 (14.13 cells per mm; 95% CI, 0.14-28.11) compared with normal skin (P = .008 and P = .045, respectively). CONCLUSIONS AND RELEVANCE: The results of this case series study suggest that JAK inhibition may be effective in treating PEM and that IFN-γ and IL-15 may be important cytokine mediators of the disease.

Treatment of granuloma annulare and suppression of proinflammatory cytokine activity with tofacitinib.

BACKGROUND: Granuloma annulare (GA) is a common cutaneous inflammatory disorder characterized by macrophage accumulation and activation in skin. Its pathogenesis is poorly understood, and there are no effective treatments. The potential health implications of severe GA are unknown. OBJECTIVE: We sought to better understand GA pathogenesis and evaluate a molecularly targeted treatment approach for this disease. METHODS: We used single-cell RNA sequencing to study the immunopathogenesis of GA and also evaluated the efficacy of tofacitinib (a Janus kinase 1/3 inhibitor) in 5 patients with severe, long-standing GA in an open-label clinical trial. RESULTS: Using single-cell RNA sequencing, we found that in GA lesions IFN-γ production by CD4+ T cells is upregulated and is associated with inflammatory polarization of macrophages and fibroblasts. In particular, macrophages upregulate oncostatin M, an IL-6 family cytokine, which appears to act on fibroblasts to alter extracellular matrix production, a hallmark of GA. IL-15 and IL-21 production appears to feed back on CD4+ T cells to sustain inflammation. Treatment of 5 patients with recalcitrant GA with tofacitinib inhibited IFN-γ and oncostatin M, as well as IL-15 and IL-21, activity and resulted in clinical and histologic disease remission in 3 patients and marked improvement in the other 2. Inhibition of these effects at the molecular level paralleled the clinical improvement. Evidence of systemic inflammation is also present in some patients with severe GA and is mitigated by tofacitinib. CONCLUSIONS: The Janus kinase-signal transducer and activator of transcription pathway is activated in GA, likely in part through the activity of IFN-γ and oncostatin M, and Janus kinase inhibitors appear to be an effective treatment.

Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2.

OBJECTIVE: Elevated serum phosphate has emerged as a major risk factor for vascular calcification. The sodium-dependent phosphate cotransporter, PiT-1, was previously shown to be required for phosphate-induced osteogenic differentiation and calcification of cultured human vascular smooth muscle cells (VSMCs), but its importance in vascular calcification in vivo and the potential role of its homologue, PiT-2, have not been determined. We investigated the in vivo requirement for PiT-1 in vascular calcification using a mouse model of chronic kidney disease and the potential compensatory role of PiT-2 using in vitro knockdown and overexpression strategies. APPROACH AND RESULTS: Mice with targeted deletion of PiT-1 in VSMCs were generated (PiT-1(Δsm)). PiT-1 mRNA levels were undetectable, whereas PiT-2 mRNA levels were increased 2-fold in the vascular aortic media of PiT-1(Δsm) compared with PiT-1(flox/flox) control. When arterial medial calcification was induced in PiT-1(Δsm) and PiT-1(flox/flox) by chronic kidney disease followed by dietary phosphate loading, the degree of aortic calcification was not different between genotypes, suggesting compensation by PiT-2. Consistent with this possibility, VSMCs isolated from PiT-1(Δsm) mice had no PiT-1 mRNA expression, increased PiT-2 mRNA levels, and no difference in sodium-dependent phosphate uptake or phosphate-induced matrix calcification compared with PiT-1(flox/flox) VSMCs. Knockdown of PiT-2 decreased phosphate uptake and phosphate-induced calcification of PiT-1(Δsm) VSMCs. Furthermore, overexpression of PiT-2 restored these parameters in human PiT-1-deficient VSMCs. CONCLUSIONS: PiT-2 can mediate phosphate uptake and calcification of VSMCs in the absence of PiT-1. Mechanistically, PiT-1 and PiT-2 seem to serve redundant roles in phosphate-induced calcification of VSMCs.

Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without Receptor for Advanced Glycation End-products (RAGE).

HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-ß and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-ß1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-ß1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression.

Initial surgical and pain management outcomes after Nuss procedure.

PURPOSE: The purpose of this article was to report surgical and pain management outcomes of the initial Nuss procedure experience at the Children's Hospital of Wisconsin (Milwaukee) and to place this experience in the context of the published literature. METHODS: The initial 118 consecutive Nuss procedures in 117 patients were retrospectively reviewed with approval of the Children's Hospital of Wisconsin human rights review board. Patient, surgical, complication, and pain descriptors were collected for each case. Statistical methods for comparison of pain strategies included the Kolmogorov-Smirnov test for normality, 1-way repeated measures analysis of variance, and paired t tests. RESULTS: Patient, surgical, and complication descriptors were comparable to other large series. Complication rates were 7% early and 25% late. Epidural success rate was 96.4%. There was 1 episode of recurrence 2 years postbar removal (n = 114). CONCLUSIONS: The institution of the Nuss procedure provides a highly desired result with significant complication rates. The ideal approach would deliver this result with lower risk. A pain service-driven epidural administration of morphine or hydromorphone with local anesthetic provides excellent analgesia for patients after Nuss procedure. The success of epidural analgesia is independent of catheter site and adjunctive medications. Ketorolac was an effective breakthrough medication.

Comparative proteomic analysis of PAI-1 and TNF-alpha-derived endothelial microparticles.

Endothelium-derived microparticles (EMPs) are small vesicles released from endothelial cells in response to cell injury, apoptosis, or activation. Elevated concentrations of EMPs have been associated with many inflammatory and vascular diseases. EMPs also mediate long range signaling and alter downstream cell function. Unfortunately, the molecular and cellular basis of microparticle production and downstream cell function is poorly understood. We hypothesize that EMPs generated by different agonists will produce distinct populations of EMPs with unique protein compositions. To test this hypothesis, different EMP populations were generated from human umbilical vein endothelial cells by stimulation with plasminogen activator inhibitor type 1 (PAI-1) or tumor necrosis factor-alpha (TNF-alpha) and subjected to proteomic analysis by LC/MS. We identified 432 common proteins in all EMP populations studied. Also identified were 231 proteins unique to control EMPs, 104 proteins unique to PAI-1 EMPs and 70 proteins unique to TNF-alpha EMPs. Interestingly, variations in protein abundance were found among many of the common EMP proteins, suggesting that differences exist between EMPs on a relative scale. Finally, gene ontology (GO) and KEGG pathway analysis revealed many functional similarities and few differences between the EMP populations studied. In summary, our results clearly indicate that EMPs generated by PAI-1 and TNF-alpha produce EMPs with overlapping but distinct protein compositions. These observations provide fundamental insight into the mechanisms regulating the production of these particles and their physiological role in numerous diseases.