Minimal Clinically Important Difference (MCID) for the Short Musculoskeletal Function Assessment (SMFA) in Severe Lower Extremity Trauma: Pooled Data from 7 Multicenter, Prospective Clinical Trials.

BACKGROUND: The Short Musculoskeletal Function Assessment (SMFA) is a well validated, widely used patient-reported outcome (PRO) measure for orthopaedic patients. Despite its widespread use and acceptance, this measure does not have an agreed upon minimal clinically important difference (MCID). The purpose of the present study was to create distributional MCIDs with use of a large cohort of research participants with severe lower extremity fractures. METHODS: Three distributional approaches were used to calculate MCIDs for the Dysfunction and Bother Indices of the SMFA as well as all its domains: (1) half of the standard deviation (one-half SD), (2) twice the standard error of measurement (2SEM), and (3) minimal detectable change (MDC). In addition to evaluating by patient characteristics and the timing of assessment, we reviewed these calculations across several injury groups likely to affect functional outcomes. RESULTS: A total of 4,298 SMFA assessments were collected from 3,185 patients who had undergone surgical treatment of traumatic injuries of the lower extremity at 60 Level-I trauma centers across 7 multicenter, prospective clinical studies. Depending on the statistical approach used, the MCID associated with the overall sample ranged from 7.7 to 10.7 for the SMFA Dysfunction Index and from 11.0 to 16.8 for the SMFA Bother Index. For the Dysfunction Index, the variability across the scores was small (<5%) within the sex and age subgroups but was modest (12% to 18%) across subgroups related to assessment timing. CONCLUSIONS: A defensible MCID can be found between 7 and 11 points for the Dysfunction Index and between 11 and 17 points for the Bother Index. The precise choice of MCID may depend on the preferred statistical approach and the population under study. While differences exist between MCID values based on the calculation method, values were consistent across the categories of the various subgroups presented. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma.

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Evaluation of potency and metabolic stability of diphyllin-derived Vacuolar-ATPase inhibitors.

Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing.

Impact of Ebola virus nucleoprotein on VP40 virus-like particle production: a computational approach.

Ebola virus (EBOV) matrix protein VP40 can assemble and bud as virus-like particles (VLPs) when expressed alone in mammalian cells. Nucleoprotein (NP) could be recruited to VLPs as inclusion body (IB) when co-expressed, and increase VLP production. However, the mechanism behind it remains unclear. Here, we use a computational approach to study NP-VP40 interactions. Our simulations indicate that NP may enhance VLP production through stabilizing VP40 filaments and accelerating the VLP budding step. Further, both the relative timing and amount of NP expression compared to VP40 are important for the effective production of IB-containing VLPs. We predict that relative NP/VP40 expression ratio and time are important for efficient production of IB-containing VLPs. We conclude that disrupting the expression timing and amount of NP and VP40 could provide new avenues to treat EBOV infection. This work provides quantitative insights into EBOV proteins interactions and how virion generation and drug efficacy could be influenced.

Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment. METHODS: We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand. RESULTS: We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models. CONCLUSIONS: Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation. TRIAL REGISTRATION NUMBER: NCT00068003, NCT01174121, and NCT03412877.

Minor electrostatic changes robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles.

Ebola virus (EBOV) is a filamentous negative-sense RNA virus, which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus lifecycle to illuminate new drug targets. EBOV encodes for the matrix protein, VP40, which regulates assembly and budding of new virions from the inner leaflet of the host cell plasma membrane (PM). In this work, we determine the effects of VP40 mutations altering electrostatics on PM interactions and subsequent budding. VP40 mutations that modify surface electrostatics affect viral assembly and budding by altering VP40 membrane-binding capabilities. Mutations that increase VP40 net positive charge by one (e.g., Gly to Arg or Asp to Ala) increase VP40 affinity for phosphatidylserine and phosphatidylinositol 4,5-bisphosphate in the host cell PM. This increased affinity enhances PM association and budding efficiency leading to more effective formation of virus-like particles. In contrast, mutations that decrease net positive charge by one (e.g., Gly to Asp) lead to a decrease in assembly and budding because of decreased interactions with the anionic PM. Taken together, our results highlight the sensitivity of slight electrostatic changes on the VP40 surface for assembly and budding. Understanding the effects of single amino acid substitutions on viral budding and assembly will be useful for explaining changes in the infectivity and virulence of different EBOV strains, VP40 variants that occur in nature, and for long-term drug discovery endeavors aimed at EBOV assembly and budding.

Fix or Replace? Patient Preferences for the Treatment of Geriatric Lower Extremity Fractures: A Discrete Choice Experiment.

Introduction: When considering treatment options for geriatric patients with lower extremity fractures, little is known about which outcomes are prioritized by patients. This study aimed to determine the patient preferences for outcomes after a geriatric lower extremity fracture. Materials and Methods: We administered a discrete choice experiment survey to 150 patients who were at least 60 years of age and treated for a lower extremity fracture at a Level I trauma center. The discrete choice experiment presented study participants with 8 sets of hypothetical outcome comparisons, including joint preservation (yes or no), risk of reoperation at 6 months and 24 months, postoperative weightbearing status, disposition, and function as measured by return to baseline walking distance. We estimated the relative importance of these potential outcomes using multinomial logit modeling. Results: The strongest patient preference was for maintained function after treatment (59%, P < .001), followed by reoperation within 6 months (12%, P < .001). Although patients generally favored joint preservation, patients were willing to change their preference in favor of joint replacement if it increased function (walking distance) by 13% (SE, 66%). Reducing the short-term reoperation risk (12%, P < .001) was more important to patients than reducing long-term reoperation risk (4%, P = .33). Disposition and weightbearing status were lesser priorities to patients (9%, P < .001 and 7%, P < .001, respectively). Discussion: After a lower extremity fracture, geriatric patients prioritized maintained walking function. Avoiding short-term reoperation was more important than avoiding long-term reoperation. Joint preservation through fracture fixation was the preferred treatment of geriatric patients unless arthroplasty or arthrodesis provides a meaningful functional benefit. Hospital disposition and postoperative weightbearing status were less important to patients than the other included outcomes. Conclusions: Geriatric patients strongly prioritize function over other outcomes after a lower extremity fracture.

Effect of Aspirin Versus Low-Molecular-Weight Heparin Thromboprophylaxis on Medication Satisfaction and Out-of-Pocket Costs: A Secondary Analysis of a Randomized Clinical Trial.

BACKGROUND: Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin. METHODS: This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) twice daily or 81 mg of aspirin twice daily for thromboprophylaxis. The duration of the thromboprophylaxis, including post-discharge prescription, was based on hospital protocols. The study outcomes included patient satisfaction with and out-of-pocket costs for their thromboprophylactic medication measured on ordinal scales. RESULTS: The trial enrolled 12,211 patients (mean age and standard deviation [SD], 45 ± 18 years; 62% male), 9725 of whom completed the question regarding their satisfaction with the medication and 6723 of whom reported their out-of-pocket costs. The odds of greater satisfaction were 2.6 times higher for patients assigned to aspirin than those assigned to low-molecular-weight heparin (odds ratio [OR]: 2.59; 95% confidence interval [CI]: 2.39 to 2.80; p < 0.001). Overall, the odds of incurring any out-of-pocket costs for thromboprophylaxis medication were 51% higher for patients assigned to aspirin compared with low-molecular-weight heparin (OR: 1.51; 95% CI: 1.37 to 1.66; p < 0.001). However, patients assigned to aspirin had substantially lower odds of out-of-pocket costs of at least $25 (OR: 0.15; 95% CI: 0.12 to 0.18; p < 0.001). CONCLUSIONS: Use of aspirin substantially improved patients' satisfaction with their medication after orthopaedic trauma. While aspirin use increased the odds of incurring any out-of-pocket costs, it protected against costs of ≥$25, potentially improving health equity for thromboprophylaxis. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Does Topical Vancomycin Powder Use in Fracture Surgery Change Bacteriology and Antibiotic Susceptibilities? An Analysis of the VANCO Trial.

OBJECTIVE: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens. DESIGN: Secondary analysis of phase III, prospective, randomized clinical trial. SETTING: Thirty-six US trauma centers. PATIENT SELECTION CRITERIA: Patients who became infected after fixation of tibial plateau or pilon fracture. OUTCOME MEASURES AND COMPARISONS: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room. RESULTS: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus. CONCLUSIONS: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Skin Antisepsis before Surgical Fixation of Extremity Fractures.

BACKGROUND: Studies evaluating surgical-site infection have had conflicting results with respect to the use of alcohol solutions containing iodine povacrylex or chlorhexidine gluconate as skin antisepsis before surgery to repair a fractured limb (i.e., an extremity fracture). METHODS: In a cluster-randomized, crossover trial at 25 hospitals in the United States and Canada, we randomly assigned hospitals to use a solution of 0.7% iodine povacrylex in 74% isopropyl alcohol (iodine group) or 2% chlorhexidine gluconate in 70% isopropyl alcohol (chlorhexidine group) as preoperative antisepsis for surgical procedures to repair extremity fractures. Every 2 months, the hospitals alternated interventions. Separate populations of patients with either open or closed fractures were enrolled and included in the analysis. The primary outcome was surgical-site infection, which included superficial incisional infection within 30 days or deep incisional or organ-space infection within 90 days. The secondary outcome was unplanned reoperation for fracture-healing complications. RESULTS: A total of 6785 patients with a closed fracture and 1700 patients with an open fracture were included in the trial. In the closed-fracture population, surgical-site infection occurred in 77 patients (2.4%) in the iodine group and in 108 patients (3.3%) in the chlorhexidine group (odds ratio, 0.74; 95% confidence interval [CI], 0.55 to 1.00; P = 0.049). In the open-fracture population, surgical-site infection occurred in 54 patients (6.5%) in the iodine group and in 60 patients (7.3%) in the chlorhexidine group (odd ratio, 0.86; 95% CI, 0.58 to 1.27; P = 0.45). The frequencies of unplanned reoperation, 1-year outcomes, and serious adverse events were similar in the two groups. CONCLUSIONS: Among patients with closed extremity fractures, skin antisepsis with iodine povacrylex in alcohol resulted in fewer surgical-site infections than antisepsis with chlorhexidine gluconate in alcohol. In patients with open fractures, the results were similar in the two groups. (Funded by the Patient-Centered Outcomes Research Institute and the Canadian Institutes of Health Research; PREPARE ClinicalTrials.gov number, NCT03523962.).

Deep Surgical Site Infection after Fracture Has a Profound Effect on Functional Outcomes.

Background: Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods: This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results: After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions: This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function. Level of evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Composite Assessment Using Intestinal Ultrasound and Calprotectin Is Accurate in Predicting Histological Activity in Ulcerative Colitis: A Cohort Study.

BACKGROUND: Beyond endoscopic remission, histological remission in ulcerative colitis (UC) is predictive of clinical outcomes. Intestinal ultrasound (IUS) may offer a noninvasive surrogate marker for histological activity; however, there are limited data correlating validated ultrasound and histological indices. AIM: Our aim was to determine the correlation of IUS activity in UC with a validated histological activity index. METHODS: Twenty-nine prospective, paired, same-day IUS/endoscopy/histology/fecal calprotectin (FC) cases were included. Intestinal ultrasound activity was determined using the Milan Ultrasound Criteria, histological activity using the Nancy Histological Index, endoscopic activity using Mayo endoscopic subscore and Ulcerative Colitis Endoscopic Index of Severity, and clinical activity using the Simple Clinical Colitis Activity Score. RESULTS: Histological activity demonstrated a significant linear association with overall IUS activity (coefficient 0.14; 95% CI, 0.03-0.25; P = .011). Intestinal ultrasound activity was also significantly associated with endoscopic activity (0.32; 95% CI, 0.14-0.49; P < 0.001), total Mayo score (0.31; 95% CI, 0.02-0.60; P = .036) but not FC (0.10; 95% CI, -0.01 to 0.21; P = .064) or clinical disease activity (0.04; 95% CI, -0.21 to 0.28; P = .768). A composite of IUS and FC showed the greatest association (1.31; 95% CI, 0.43-2.18; P = .003) and accurately predicted histological activity in 88% of cases (P = .007), with sensitivity of 88%, specificity 80%, positive predictive value 95%, and negative predictive value 57%. CONCLUSIONS: Intestinal ultrasound is an accurate noninvasive marker of histological disease activity in UC, the accuracy of which is further enhanced when used in composite with FC. This can reduce the need for colonoscopy in routine care by supporting accurate point-of-care decision-making in patients with UC.

Risk-stratified thromboprophylaxis effects of aspirin versus low-molecular-weight heparin in orthopedic trauma patients: A secondary analysis of the PREVENT CLOT trial.

BACKGROUND: The PREVENT CLOT trial concluded that thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin (LMWH) in preventing death after orthopedic trauma. However, it was unclear if these results applied to patients at highest risk of thrombosis. Therefore, we assessed if the effect of aspirin versus LMWH differed based on patients' baseline risk of venous thromboembolism (VTE). METHODS: The PREVENT CLOT trial enrolled 12,211 adult patients with fractures. This secondary analysis stratified the study population into VTE risk quartiles: low (<1%) to high (>10%) using the Caprini score. We assessed stratum-specific treatment effects using the win ratio method, in which each patient assigned to aspirin was paired with each assigned to LMWH. In each pair, we compared outcomes hierarchically, starting with death, then pulmonary embolism, deep vein thrombosis, and bleeding. The secondary outcome added patients' medication satisfaction as a fifth composite component. RESULTS: In the high-risk quartile (n = 3052), 80% had femur fracture, pelvic, or acetabular fractures. Thoracic (47%) and head (37%) injuries were also common. In the low risk quartile (n = 3053), most patients had a tibia fracture (67%), 5% had a thoracic injury, and less than 1% had head or spinal injuries. Among high risk patients, thromboembolic events did not differ statistically between aspirin and LMWH (win ratio, 0.94; 95% confidence interval [CI], 0.82-1.08, p = 0.42). This result was consistent in the low (win ratio, 1.15; 95% CI, 0.90-1.47, p = 0.27), low-medium (win ratio, 1.05; 95% CI, 0.85-1.29, p = 0.68), and medium-high risk quartiles (win ratio, 0.94; 95% CI, 0.80-1.11, p = 0.48). When medication satisfaction was considered, favorable outcomes were 68% more likely with aspirin (win ratio, 1.68; 95% CI, 1.60-1.77; p < 0.001). CONCLUSION: Thromboembolic outcomes were similar with aspirin or LMWH, even among patients at highest risk of VTE. Aspirin was favored if medication satisfaction was also considered. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Practical application of the Crohn's disease exclusion diet as therapy in an adult Australian population.

There is demand from patients and clinicians to use the Crohn's disease exclusion diet (CDED) with or without partial enteral nutrition (PEN). However, the therapeutic efficacy and nutritional adequacy of this therapy are rudimentary in an adult population. This review examines the evidence for the CDED in adults with active luminal Crohn's disease and aims to provide practical guidance on the use of the CDED in Australian adults. A working group of nine inflammatory bowel disease (IBD) dietitians of DECCAN (Dietitians Crohn's and Colitis Australian Network) and an IBD gastroenterologist was established. A literature review was undertaken to examine (1) clinical indications, (2) monitoring, (3) dietary adequacy, (4) guidance for remission phase, and (5) diet reintroduction after therapy. Each diet phase was compared with Australian reference ranges for food groups and micronutrients. CDED with PEN is nutritionally adequate for adults containing sufficient energy and protein and meeting > 80% of the recommended daily intake of key micronutrients. An optimal care pathway for the clinical use of the CDED in an adult population was developed with accompanying consensus statements, clinician toolkit, and patient education brochure. Recommendations for weaning from the CDED to the Australian dietary guidelines were developed. The CDED + PEN provides an alternate partial food-based therapy for remission induction of active luminal Crohn's disease in an adult population. The CDED + PEN should be prioritized over CDED alone and prescribed by a specialist IBD dietitian. DECCAN cautions against using the maintenance diet beyond 12 weeks until further evidence becomes available.

Does Fracture Pattern Really Predict Displacement of LC1 Sacral Fractures?

BACKGROUND: Operative management of minimally displaced lateral compression type-1 (LC1) pelvic ring injuries remains controversial. We aimed to assess the proportion of LC1 pelvic fractures that displaced following nonoperative management as a function of specific ring fracture patterns, and we quantified the magnitude of this displacement. METHODS: A retrospective review of the billing registry of a level-I trauma center was performed. Two hundred and seventy-three patients with a high-energy LC1 pelvic ring fracture and <5 mm of sacral displacement were included. The fracture pattern was characterized with use of computed tomography (CT) scans and radiographs. Absolute and interval pelvic ring displacement were quantified with use of previously described methodology. RESULTS: Thirty-five pelvic ring injuries (13%) were displaced. The rate of displacement was 31% (15 of 49) for LC1 injuries involving a complete sacral fracture and bilateral ramus fractures, 12% (7 of 58) for injuries involving a complete sacral fracture and a unilateral ramus fracture, and 10% (5 of 52) for injuries involving an incomplete sacral fracture and bilateral ramus fractures. In displaced injuries, the average interval displacement was 4.2 mm (95% confidence interval [CI], 1.8 to 6.8) and the final displacement was 9.9 mm ± 4.2 mm. CONCLUSIONS: Our study suggests that fracture characteristics can be used to predict the likelihood of displacement of LC1 fractures that are treated without surgery. To our knowledge, the present study is the first to describe the magnitude of displacement that may occur in association with LC1 pelvic ring injuries that are treated nonoperatively; however, further studies are needed to determine the clinical impact of this displacement. LEVEL OF EVIDENCE: Diagnostic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Quitline usage does not improve rates of smoking cessation in orthopaedic trauma patients unless combined with nicotine replacement therapy.

PURPOSE: The negative effects of smoking following traumatic orthopaedic injury can lead to serious complications and decreased quality of life. The widely available quitline could be easily implemented in the orthopaedic postoperative period to improve outcome, but the effectiveness of this intervention in this population is unknown. The goal of this study was to determine if active referral to a quitline would improve rates of smoking cessation in this population. METHODS: This is a secondary analysis of a randomized control trial assessing the effectiveness of an inpatient intervention with varying intensities to promote smoking cessation. Participants were actively referred to the quitline as part of their intervention. Participants were surveyed at 6 weeks, 3 months and 6 months following their injury for 7-day abstinence, chemically confirmed with exhaled carbon monoxide monitoring. RESULTS: Smoking quitline use alone does not independently improve 7-day abstinence. Quitline and nicotine use are synergistic (OR, 5.6 vs. 2.3 at 3 months in patients who used nicotine patch and quitline vs. patch; OR, 7.8 vs. 2.1 at 3 months in patients who used any NRT and quitline vs. NRT alone). CONCLUSIONS: NRT use improves smoking cessation rates in orthopaedic trauma patients. Although smoking quitline use might not independently improve cessation rates in orthopaedic trauma patients postoperatively, concomitant use of NRT with quitline improves quit rates over NRT alone. Patients referred to quitline should be encouraged to use NRT.

Predicting Which Species of Bacteria Will Cause an Infection After Fracture Surgery.

The aim of this study was to develop and validate risk prediction models for deep surgical site infection (SSI) caused by specific bacterial pathogens after fracture fixation. A retrospective case-control study was conducted at a level I trauma center. Fifteen candidate predictors of the bacterial pathogens in deep SSI were evaluated to develop models of bacterial risk. The study included 441 patients with orthopedic trauma with deep SSI after fracture fixation and 576 control patients. The main outcome measurement was deep SSI cultures positive for methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), gram-negative rods (GNRs), anaerobes, or polymicrobial infection within 1 year of injury. Prognostic models were developed for five bacterial pathogen outcomes. Mean area under the curve ranged from 0.70 (GNRs) to 0.74 (polymicrobial). Strong predictors of MRSA were American Society of Anesthesiologists (ASA) classification of III or greater (odds ratio [OR], 3.4; 95% CI, 1.6-8.0) and time to fixation greater than 7 days (OR, 3.4; 95% CI, 1.9-5.9). Gustilo type III fracture was the strongest predictor of MSSA (OR, 2.5; 95% CI, 1.6-3.9) and GNRs (OR, 3.4; 95% CI, 2.3-5.0). ASA classification of III or greater was the strongest predictor of polymicrobial infection (OR, 5.9; 95% CI, 2.7-15.5) and was associated with increased odds of GNRs (OR, 2.7; 95% CI, 1.5-5.5). Our models predict the risk of MRSA, MSSA, GNR, anaerobe, and polymicrobial infections in patients with fractures. The models might allow for modification of preoperative antibiotic selection based on the particular pathogen posing greatest risk for this patient population. [Orthopedics. 2024;47(1):e19-e25.].

Technical Factors Contributing to Nonunion in Supracondylar Distal Femur Fractures Treated With Lateral Locked Plating: A Risk-Stratified Analysis.

OBJECTIVE: To identify technical factors associated with nonunion after operative treatment with lateral locked plating. DESIGN: Retrospective cohort study. SETTING: Ten Level I trauma centers. PATIENT SELECTION CRITERIA: Adult patients with supracondylar distal femur fractures (OTA/AO type 33A or C) treated with lateral locked plating from 2010 through 2019. OUTCOME MEASURES AND COMPARISONS: Surgery for nonunion stratified by risk for nonunion. RESULTS: The cohort included 615 patients with supracondylar distal femur fractures. The median patient age was 61 years old (interquartile range: 46 -72years) and 375 (61%) were female. Observed were nonunion rates of 2% in a low risk of nonunion group (n = 129), 4% in a medium-risk group (n = 333), and 14% in a high-risk group (n = 153). Varus malreduction with an anatomic lateral distal femoral angle greater than 84 degrees, was associated with double the odds of nonunion compared to those without such varus [odds ratio, 2.1; 95% confidence interval (CI), 1.1-4.2; P = 0.03]. Malreduction by medial translation of the articular block increased the odds of nonunion, with 30% increased odds per 4 mm of medial translation (95% CI, 1.0-1.6; P = 0.03). Working length increased the odds of nonunion in the medium risk group, with an 18% increase in nonunion per 10-mm increase in working length (95% CI, 1.0-1.4; P = 0.01). Increased proximal screw density was protective against nonunion (odds ratio, 0.71; 95% CI, 0.53-0.92; P = 0.02) but yielded lower mRUST scores with each 0.1 increase in screw density associated with a 0.4-point lower mRUST (95% CI, -0.55 to -0.15; P < 0.001). Lateral plate length and type of plate material were not associated with nonunion. ( P > 0.05). CONCLUSIONS: Malreduction is a surgeon-controlled variable associated with nonunion after lateral locked plating of supracondylar distal femur fractures. Longer working lengths were associated with nonunion, suggesting that bridge plating may be less likely to succeed for longer fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Autologous Faecal Microbiota Transplantation to Improve Outcomes of Haematopoietic Stem Cell Transplantation: Results of a Single-Centre Feasibility Study.

Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual's own stool (autologous FMT) to mitigate the risks of disease transmission from a donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. The stool was collected prior to starting first line therapy. Patients who progressed to HSCT were offered FMT via 3 × retention enemas before day +5 (HSCT = day 0). The feasibility was determined by the recruitment rate, number and volume of enemas administered, and the retention time. Longitudinally collected stool samples were also collected to explore the influence of auto-FMT using 16S rRNA gene sequencing. n = 4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25 (1-3) enemas 43.67 (25-50) mL total, retained for an average of 60.78 (10-145) min. No adverse events (AEs) attributed to the FMT were identified. Although the minimum requirements were met for the volume and retention of auto-FMT, the recruitment was significantly impacted by the logistical challenges of the pretherapy stool collection. This ultimately undermined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.