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Open-source climate risk assessment platforms allow for accessible and efficient estimation of current and future climate risk by combining information about hazard, exposure and vulnerability. Such assessments require making a number of choices, such as which hazard data source to use, and the data and approach taken to represent the exposure and vulnerability. As these choices are, to some extent, subjective, when assessing risk and informing adaptation decisions, alternative options should be considered to understand the uncertainty and sensitivity of risk to uncertain input data and assumptions. We present a novel approach to quantify the uncertainty and sensitivity of risk estimates, using the CLIMADA open-source climate risk assessment platform. This work builds upon a recently developed extension of CLIMADA, which uses statistical modelling techniques to model and stochastically simulate alternative realisations of climate risk, allowing for a richer quantification of climate model ensemble uncertainty. Here, we further analyse the propagation of hazard, exposure and vulnerability uncertainties by varying a number of input factors based on a discrete, scientifically justified set of options. We explore the uncertainty and sensitivity of risk to these variations, using the PAWN (PiAnosi and WagNer) method for global sensitivity analysis, allowing for an attribution of uncertainty to different drivers of the total uncertainty budget. We demonstrate the approach through an application to assess heat-stress risk to outdoor physical working capacity in the UK. In this application, we demonstrate how the risk estimated across plausible input settings better captures uncertainty and extreme outcomes (important for decision making); that all uncalibrated/non-bias-adjusted climate data sources underestimate risk in the recent past (highlighting the need for data calibration); and that when a global warming level framing is used it is the choice of global warming level that this risk is most sensitive to (2 C or 4 C warmer than pre-industrial), particularly in the south of the UK. This highlights the importance of mitigating climate change to reduce heat-stress risk.

We examine two scenarios of global greenhouse gas emissions developed to inform the Committee on Climate Change’s advice on the level of the UK’s Sixth Carbon Budget - focusing on the uncertainty in the global temperature outcomes associated with new estimates for the Earth’s equilibrium climate sensitivity. The first scenario is a rapid global decarbonisation scenario and the second follows an interpretation of pre-2021 current national commitments to reduce emissions prior to 2030. Updated estimates of equilibrium climate sensitivity have little impact on the median global temperature response, resulting in peak temperature values between 1.7°C to 1.9°C for the scenario aligned with the Paris Agreement, compared to estimated peak warming based on the assessment of IPCC Special Report on Global Warming of 1.5°C. Under all climate sensitivity distributions considered the scenario has a greater than 66% likelihood of limiting peak global mean temperatures to under 2°C throughout the century. The choice of equilibrium sensitivity distribution has greater impact at higher percentiles with differences of up to 0.5°C and 0.8°C in the 95th percentile outcome for the Paris Agreement aligned and current policy scenarios respectively. These differences can bring forward the timing of reaching dangerous levels of global warming by up to a decade.

The incidence of periprosthetic fractures is expected to rise increase by 4.6% every 10 years between 2015 and 2060. There are few large series examining optimal fixation constructs or the influence of early ambulation on outcome. The purpose of this narrative review is to investigate the published biomechanical considerations for periprosthetic fracture fixation, with specific consideration of early postoperative weightbearing. A literature review was performed to identify fracture incidences, etiology, and current trends in weightbearing after fixation. Benefits of early weightbearing, current constructs, and biomechanics are reviewed. The limited data available support medical benefits and increased union rates with early mobilization. Optimal fixation constructs are not agreed upon, but mechanical studies suggest that dual implant constructs can support physiologic weightbearing loads. Further clinical trials are required to investigate fracture union and hardware complications in dual implant construct

Objectives Describe the incidence of venous thromboembolism (VTE) in patients with pelvic and lower extremity long bone trauma in the setting of modern prophylaxis. Design Retrospective health-system database study. Setting Multi-center health care system. Patients Database query from 2010 to 2017 identified 11,313 adult trauma patients who received open reduction internal fixation of pelvic, acetabular, femoral neck, or intertrochanteric fractures, or received intramedullary nailing (IMN) of the femoral or tibial shaft. Patients with incomplete prophylaxis, prior history of VTE, coagulopathy, or concomitant lower extremity fracture were excluded. Intervention Mechanical and chemical VTE prophylaxis following pelvic or lower extremity fracture fixation. Main outcome measurements VTE rates. Results The overall VTE rate was 0.82% [0.39% deep venous thromboses (DVT); 0.43% pulmonary emboli (PE)]. By procedure, pelvic open reduction and internal fixation (ORIF) and femoral IMN had the highest VTE rates 1.70% (0.98% DVT; 0.78% PE) and 1.33% (0.75% DVT; 0.58% PE), whereas tibial IMN had the lowest incidence of VTE 0.34% (0.17% DVT; 0.17% PE). Among hip fractures, femoral neck ORIF had a VTE rate of 0.98% (0.59% DVT; 0.39% PE), whereas intertrochanteric ORIF had lower rates of 0.59% (0.20% DVT; 0.39% PE). Conclusions Despite adherence to modern VTEp protocols, nonpreventable VTE occur in 0.82% of pelvic and lower extremity orthopaedic trauma patients. Incidence ranged between 0.34% and 1.70% depending on injury/fixation method with the highest rate observed in pelvis ORIF followed by femoral IMN. In the era of pay for quality performance, it is important for health systems and auditing agencies to reconcile the difference between preventable and nonpreventable VTEs. Level of evidence Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Today’s climate policies will shape the future trajectory of emissions. Consumption is the main driver behind recent increases in global greenhouse gas emissions, outpacing savings through improved technologies, and therefore its representation in the evidence base will impact on the success of policy interventions. The IPCC’s Special Report on Global Warming of 1.5 °C (SR1.5) summarises global evidence on pathways for meeting below-2 °C targets, underpinned by a suite of scenarios from integrated assessment models (IAMs). We explore how final energy demand is framed within these, with the aim to making demand-related assumptions more transparent, and evaluating their significance, feasibility, and use or underutilisation as a mitigation lever. We investigate how the integrated assessment models compensate for higher and lower levels of final energy demand across scenarios, and how this varies when mitigating for 2 °C and 1.5 °C temperature targets through an analysis of (1) final energy demand projections, (2) energy-economy relationships and (3) differences between energy system decarbonisation and carbon dioxide removal in the highest and lowest energy demand pathways. We look across the full suite of mitigation pathways and assess the consequences of achieving different global carbon budgets. We find that energy demand in 2100 in the highest energy demand scenarios is approximately three to four times higher than the lowest demand pathways, but we do not find strong evidence that 1.5 °C-consistent pathways cluster on the lower end of demand levels, particularly when they allow for overshoot. The majority of demand reductions happen pre-2040, which assumes absolute decoupling from economic growth in the near-term; thereafter final energy demand levels generally grow to 2100. Lower energy demand pathways moderately result in lower renewable energy supply and lower energy system investment, but do not necessarily reduce reliance on carbon dioxide removal. In this sense, there is more scope for IAMs to implement energy demand reduction as a longer-term mitigation lever and to reduce reliance on negative emissions technologies. We demonstrate the need for integrated assessments to play closer attention to how final energy demand interacts with, relates to, and can potentially offset supply-side characteristics, alongside a more diverse evidence base.

OBJECTIVES To evaluate unilateral sacral fractures and compare those treated operatively versus nonoperatively to determine indications for surgery. DESIGN Prospective, multicenter, observational study. SETTING Sixteen trauma centers. PATIENTS/PARTICIPANTS Skeletally mature patients with pelvic ring injury and unilateral zone 1 or 2 sacral fractures and without anteroposterior compression injuries. MAIN OUTCOME MEASUREMENTS Injury plain anteroposterior, inlet, and outlet radiographs and computed tomography scans of the pelvis were evaluated for fracture displacement. RESULTS Three hundred thirty-three patients with unilateral sacral fractures and a mean age of 41 years with a mean Injury Severity Score of 15 were included. Ninety-two percent sustained lateral compression injuries, and 63% of all fractures were in zone 1. Thirty-three percent of patients were treated operatively, including all without lateral compression patterns. Operative patients were more likely to have zone 2 fractures (54%) and to have posterior cortical displacement (29% vs. 6.2%), both with P < 0.001. Over 60% of all patients had no posterior displacement. Mean rotational displacements comparing the injured side versus the intact side were no different for patients treated operatively compared with those treated nonoperatively. CONCLUSIONS Most unilateral sacral fractures are minimally or nondisplaced. Many patients with radiographically similar fractures were treated operatively and nonoperatively by different surgeons. This suggests an opportunity to develop consistent indications for treatment. LEVEL OF EVIDENCE Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Hysterectomy is one of the most commonly performed surgeries in women. Surgical-site infections (SSI) after hysterectomy can lead to increased morbidity and mortality as well as readmission, which is associated with increased costs for health systems. The aim of the project was to improve standardization of preoperative education on infection prevention and incorporate the use of preoperative chlorhexidine (CHG) bathing for patients undergoing hysterectomy to decrease rates of SSI. Data on SSI after hysterectomy were reviewed. Tracer methodology was used to identify gaps in the preoperative process by comparing the current process to the Council on Patient Safety in Women's Health Care Patient Safety Bundle "Prevention of Surgical Site Infection after Gynecologic Surgery." After implementation, survey data were collected on adherence to the washing protocol, and SSI data were monitored. Survey results reflected high compliance with the CHG washing protocol, provision of patient education, and overall patient satisfaction with the process. Before implementation in 2016, we reported 8 deep or organ/space SSI to the National Healthcare Safety Network. After implementation in 2018, we reported 3 deep or organ/space SSI. Standardizing infection prevention processes to align with safety bundles improves the quality of care provided to patients.

Radiologists should be familiar with basic principles of fracture fixation and the normal imaging appearances of implant constructs and their complications. The surgeon's selection of external fixation, intramedullary nail fixation, open reduction and internal fixation, or some combination depends on patient factors, fracture configuration, injury to the soft tissue envelope, and surgeon experience. Complications including loss of fixation with resultant malalignment, nonunion, infection, and posttraumatic osteoarthritis present additional challenges for the surgeon as well as the radiologist. This article reviews the rationale behind fracture fixation in fractures of the lower leg, ankle, and foot. Examples of postoperative complications are also reviewed.

Good outcomes following treatment of pelvic ring injuries, acetabular fractures, and femur fractures rely on restoration of native pelvic or limb alignment, anatomical reduction and rigid stability of articular fractures, and early postoperative mobilization. Multiple surgical approaches, reduction aids, and orthopaedic implants are available to stabilize these fractures. Despite best practices, complications including hardware failure, nonunions, malunions, and infections occur. This article discusses common fracture classification systems, implants, and imaging findings associated with unwanted complications in fractures of the pelvis, acetabulum, and femur.

The purpose of this prospective double-blinded positive control study was to compare the efficacy of 2.5% polyacrylamide hydrogel (2.5% PAAG) in the management of middle carpal joint lameness in Thoroughbreds against treatments of triamcinolone acetonide (TA) or sodium hyaluronate (HA). A total of 31 flat-racing Thoroughbreds with lameness (grade 1-3/5) localized to the carpus by intra-articular analgesia were selected. Following a radiological assessment of the carpi confirming the absence of fragment/fracture, the horses were randomly assigned for intra-articular treatment with either 2 ml of 2.5% PAAG, 12 mg TA or 20 mg HA (followed by two further intravenous treatments of 40 mg, at weekly intervals in the HA group only), by a treating veterinarian. All horses were rested for 48 hours post-treatment and then re-entered an unaltered training regimen. Subsequent examinations at 2, 4, and 6 weeks were performed by a blinded examining veterinarian for all groups, while horses treated with 2.5% PAAG were monitored for 12 weeks for recurrence of lameness. Significantly more joints treated with 2.5% PAAG were lame free (83%) at 6 weeks compared to TA (27%; P = .007) and to HA (40%; P = .04). There was no significant difference between TA and HA groups at any time. All the joints treated within 2.5% PAAG that were lame free at 6 weeks (10/12) were still lame-free at 12 weeks. In conclusion, treatment with 2.5% PAAG led to statistically superior results compared to TA and HA in the management of selected middle carpal joint lameness in flat-racing Thoroughbreds, with therapeutic effects persisting up to 12 weeks.

There is clear evidence that, even with the most favourable emission pathways over coming decades, there will be a need for society to adapt to the impacts of climate variability and change. To do this regional, national and local actors need up-to-date information on the changing climate with clear accompanying detail on the robustness of the information. This needs to be communicated to both public and private sector organisations, ideally as part of a process of co-developing solutions.EUCP is an H2020 programme that began in December 2017 with the aim of researching and testing the provision of improved climate predictions and projections for Europe for the next 40+ years, and drawing on the expertise of researchers from a number of major climate research institutes across Europe. It is also engaging with users of climate change information through a multiuser forum (MUF) to ensure that what we learn will match the needs of the people who need if for decision making and planning.The first big issue that EUCP seeks to address is how better to use ensembles of climate model projections, moving beyond the one-model-one-vote philosophy. Here, the aim is to better understand how model ensembles might be constrained or sub-selected, and how multiple strands of information might be combined into improved climate change narratives or storylines. The second area where EUCP is making progress is in the use of very high-resolution regional climate simulations that are capable of resolving aspects of atmospheric convection. Present day and future simulations from a new generation of regional models ae being analysed in EUCP and will be used in a number of relevant case studies. The third issue that EUCP will consider is how to make future simulations more seamless across those time scales that are most relevant user decision making. This includes generating a better understanding of predictability over time and its sources in initialised forecasts, and also how to transition from the initialised forecasts to longer term boundary forced climate projections.This presentation will provide an overview of the challenges being addressed by EUCP and the approaches the project is using.

UK Climate Projections 2018 (UKCP18) included land and marine projections and were published in 2018 to replace UKCP09. The land projections had three components, and all were designed to provide more information on future weather compared to UKCP09. The first component updated the UKCP09 probabilistic projections by including newer CMIP5 data and focussing on seasonal means from individual years rather than 30-year averages. The probabilistic projections represent the wider uncertainty. The second two components (global and regional projections) both had the aim of providing plausible examples of future climate, but at different resolutions.The global projections were a combination of 13 CMIP5 models and a 15-member perturbed parameter ensemble (PPE) of coupled simulations for 1900-2100 using CMIP5 RCP8.5 from 2005 onwards. The PPE was provided at 60km atmosphere, quarter degree ocean and the large-scale conditions from twelve of the members were used to drive the regional model at both 12km and 2.2km resolution. These plausible examples are more useful for providing information about weather in a future climate to support a storyline approach for decision making.The talk will present examples of new ways to use UKCP18 compared to UKCP09. We will show how the global projections can be used to understand that the recent record winter daily maximum temperature in the UK in 2019 had a large contribution from internal variability and what this means for breaking the record in a warming climate. We also use an example from China to demonstrate one way to exploit information at different time scales, looking at how a circulation index, which is predictable and related to tropical cyclone landfall, changes in a future climate.Finally, we show that while the enhanced resolution of the global and regional projections has improved our capability to provide climate information linked to the better representation of circulation, they lack diversity in some of the key drivers of future climate. Therefore, a key way forward will be to find an appropriate balance between the need for better diversity (e.g. multiple ensembles such as CMIP or PPEs) and the need for an appropriate resolution to retain this new capability.

Objective:To determine whether percutaneous transiliac–transsacral screw fixation improves pain, ambulation, length of stay, and the rate of disposition to home in patients with sacral fragility fractures.Design:Retrospective cohort study.Setting:Single academic Level 1 trauma center.Patients/Partic

Copyright © 2018 by the American Society of Plastic Surgeons. Background: Soft-tissue complications often dictate the success of limb salvage and the overall outcome of open fractures. Based on prior work at the R Adams Cowley Shock Trauma Center, the authors hypothesize that wounds larger than 200 cm2 are associated with a greater likelihood of both flap-related reoperation and wound complications among patients requiring soft-tissue reconstruction with a rotational flap or free tissue transfer. Methods: This study was a secondary analysis of Fluid Lavage in Open Wounds trial data that included all patients who received a rotational or free tissue flap transfer for an open fracture. The primary outcome was flap-related reoperation within 12 months of injury. The secondary outcome was wound complication, which included events treated operatively or nonoperatively. Multivariable logistic regression was used to assess the association between wound size and outcomes, adjusting for confounders. Results: Seventeen percent of the 112 patients required a flap-related reoperation. A wound size greater than 200 cm2 was not associated with reoperation in an unadjusted model (p = 0.64) or adjusting for Gustilo type (p = 0.70). The sample had an overall wound complication rate of 47.3 percent. Patients with a wound size of greater than 200 cm2 were three times more likely to experience wound complications (OR, 3.05; 95 percent CI, 1.08 to 8.62; p = 0.04) when adjusting for moderate to severe wound contamination and wound closure in the operating room. Conclusion: The findings of this study demonstrate that wound surface area is an integral determinant for wound complication following soft-tissue flap treatment, but found no association between wound surface area and flap-related reoperation rates.

OBJECTIVES Low serum albumin levels (hypoalbuminemia) have classically been used to identify malnutrition. The effect of increasing severity of malnutrition on postoperative outcomes in patients undergoing hip fracture surgery has not been well delineated on a large scale. DESIGN Retrospective. SETTING Multicenter. PATIENT/PARTICIPANTS A total of 12,373 patients undergoing hip fracture surgery from 2006 to 2013 National Surgery Quality Improvement Project data were identified. INTERVENTION Patient demographic, comorbidity, and preoperative laboratory data and complication, reoperation, and readmission data were collected. MAIN OUTCOME MEASUREMENTS Multivariate logistic regression was used to determine the effect of increasing severity of malnutrition on rates of 30-day postoperative complications, readmissions, and reoperations. RESULTS A total of 12,373 hip fractures met inclusion criteria. A total of 6506 (52.6%) patients had normal albumin levels (albumin ≥3.5 g/dL), 3205 (25.9%) patients were mildly malnourished (albumin 3.1-3.49 g/dL), 2265 (18.3%) were moderately malnourished (albumin 2.4-3.1 g/dL), and 397 (3.2%) patients were severely malnourished (albumin

Objectives To determine if topical vancomycin and tobramycin powder reduces the incidence of surgical site infection after pelvic ring and acetabulum fracture surgery. Design Retrospective cohort study. Setting University of Alabama at Birmingham, Academic Level I Trauma Center. Patients/participants Two hundred nineteen patients (140 meeting inclusion criteria) with pelvic and acetabular fractures who underwent open reduction and internal fixation from March 2012 to November 2013. Intervention One gram vancomycin and 1.2 g tobramycin powder applied deep in the surgical wound of the treatment group. Main outcome measurements Postoperative infection rate. Results One hundred forty patients were included. Control group (n = 69) and treatment group (n = 71) were similar for sex, age, ethnicity, and body mass index. There was no difference between groups with regards to renal function postoperative day 2 (P = 0.24). The risk of infection was 14.5% and 4.2% (P = 0.04) for the control and treatment groups, respectively. No significant effect of antibiotic treatment was observed overall after adjusting for EBL (odds ratio 0.20, 95% confidence interval, 0.02-1.06). Of note, a nonsignificant 71% increase was observed among those with ≥1 L EBL (odds ratio 1.71, 95% confidence interval, 0.02-147.02). Conclusions Topical antibiotics possibly reduce the incidence of surgical site infection after open pelvic and acetabulum fixation without increasing risk of renal impairment. The protective effect of topical antibiotics may be limited to patients with minimal intraoperative blood loss. Level of evidence Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Clavicle fractures' treatment recommendations are based on displacement. The goal of this paper is to determine upright clavicle radiographs at initial presentation changes timing and method of treatment. Retrospective study in a level 1 trauma center. 356 patients with clavicle fractures were reviewed. Patients with only supine radiographs (Group 1, 285 patients) were compared to patients with supine and upright radiographs (Group 2, 71 patients). Higher proportion of fractures in the upright vs supine radiographs were displaced 100% or more of the clavicle width, (52.1% vs. 33.5%, p =0.004). Treatment assignment changed from nonoperative to operative treatment more commonly in the Group 2 compared to Group 1 (43.7% vs 21.9%, p =0.019). The most common reason for surgery in Group 1 was presence of continued pain or failure to develop radiographic evidence of callus on serial radiographs (17, 53.1%) as compared to Group 2 (2, 14.2%, p =0.014). In Group 2 the most common cause for treatment change was displacement (12, 85.7%) as compared to Group 1 (15, 46.9%, p =0.014). Patients with upright x-rays are more likely to have a change in treatment because of displacement while patients that had supine x-rays have more delayed/nonunion.

The "handoff" phase of patient care is frequently associated with the genesis of adverse events. Patient handoffs in anesthesia care remain poorly studied. By reviewing archived video of anesthesia handoffs taking place in a simulated environment, we aimed to identify latent conditions and their impact on the quality and nature of handoffs occurring during surgical anesthesia care. Four trained coders assessed 58 handoffs occurring in 58 different simulated cases, for the presence or absence of 4 latent conditions: distractions, production pressure, noninteractive communication, and inappropriately timed handoff. Latent hazards frequently jeopardized handoff quality. Distractions and interruptions were conditions observed in 82% of cases; independently these did not appear to degrade handoff quality. The latent condition noninteractive communication was the greatest predictor of poor handoff scores (

Osteoarthritis is one of the most common disease processes effecting equine athletes, causing up to 60% of all lameness. This prospective longitudinal study reports on the effect of treatment of carpal and metacarpophalangeal joint lameness with 2.5% cross-linked polyacrylamide hydrogel (PAAG). A total of 49 flat-racing Thoroughbreds at a single training facility were included in the study. The results show a significant improvement in lameness grades at weeks 1 (P < .01), 4 (P < .001), 12 (P < .001), and 24 (P < .001) when compared to baseline lameness at week 0. This pilot study suggests that 2.5% cross-linked PAAG is a safe and effective joint treatment for managing joint lameness in Thoroughbred racehorses and warrants further blinded and controlled studies to fully evaluate the efficacy of the 2.5% cross-linked PAAG and its mode of action.

Percutaneous sacral screw fixation is the mainstay of posterior pelvic ring fixation. This study quantifies the accuracy of fluoroscopic screw placement using post-operative CT scans and redefines the fluoroscopic safe zone using a mathematical calculation obtained from Inlet and outlet images. The authors hypothesized that a mathematical calculation of screw placement within the ala will improve accuracy of screw placement. A retrospective review of consecutive patients admitted to a level 1 trauma center with pelvic fractures fixed with iliosacral screws from January 2011 to December 2014 was performed. Accuracy of screw placement was determined by comparing fluoroscopy to post-operative CT scans. A mathematical calculation of screw position within the sacral ala was applied to determine assess screw position and compared to CT findings. Ninety-four patients with 156 screws met inclusion criteria, of which 50 (32.0%) had a cortical breech on CT. The sensitivity and specificity of the inlet-outlet safe zone using mathematical calculation were 97.1% and 84.0%, respectively. The positive and negative predictive values were 92.7% and 93.3%, respectively. Overall accuracies of the radiographic inlet-outlet and lateral safe zones were 92.9% and 70.0%, respectively (p-value = 0.004). Sacral dysmorphism was not found to be associated with sacral cortical breech. A Simple mathematical calculation (screw position relative to percentage of bone width) on the inlet-outlet provides an accurate way to predict the accuracy of sacroiliac screws. The method is easy to implement, part of the surgery work-flow, and provides higher accuracy than relying on subjective interpretation of inlet, outlet, and lateral images. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1478-1484, 2017.

Background Zone 2 sacral fractures account for 34% of sacral fractures with reported neurological deficit in 21−28% of patients. The purpose of this study was to examine the risk factors for neurological injury in zone 2 sacral fractures. The authors hypothesized that partially thread iliosacral screws did not increase incidence of neurologic injury. Methods A retrospective review of consecutive patients admitted to a level 1 trauma center with zone 2 sacral fractures requiring surgery from September 2010 to September 2014 was performed. Patients were excluded if no neurologic exam was available after surgery. Fractures were classified according to Denis and presence/absence of comminution through the neural foramen was noted. Fixation schema was recorded (sacral screws or open reduction and internal fixation with posterior tension plate). Any change in post-operative neurological exam was documented as well as exam at last clinic encounter. Results 90 patients met inclusion criteria, with zone 2 fractures and post-operative neurological exam. No patient with an intact pre-operative neurologic exam had a neurological deficit after surgery. 86 patients (95.6%) were neurologically intact at their last follow-up examination. Four patients (4.4%) had a neurological deficit at final follow-up, all of them had neurological deficit prior to surgery. 81 patients were treated with partially threaded screws of which 1 (1.2%) had neurological deficit at final follow-up. Fifty-seven fractures (63.3%) were simple fractures and 33 fractures (36.7%) were comminuted. All four patients with neurological deficit had comminuted fractures. The association between neurologic deficit in zone 2 sacral fracture and fracture comminution was found to be statistically significant (p-value = 0.016). No nonunion was observed in this cohort. Conclusions The use of partially threaded screws for zone 2 sacral fractures is associated with low risk for neurologic injury, suggesting that compression through the fracture does not cause iatrogenic nerve damage. The low rate of sacral nonunion can be attributed to compression induced by the use of partially threaded compression screws. There is a strong association between zone 2 comminution and neurologic injury.

Protocol changes prompted by the Joint Commission mandating intravenous (IV) fluid bags to be used within 1 hour of spiking because of possible bacterial contamination have sparked clinical and economic concerns. This study investigated the degree of bacterial growth in which samples were obtained from spiked IV fluid bags at the time of spiking and 1, 2, 4, and 8 hours after spiking. No bacterial growth occurred in any of the 80 bags of Lactated Ringer's (LR) IV solutions sampled. This study demonstrated that LR IV bags do not support any bacterial growth for up to 8 hours after spiking.

Activating mutations in RAS proteins occur in ~1/3 of human cancers. These mutations impair the ability of the protein to hydrolyze GTP to GDP. As a result, mutant RAS proteins exist predominantly in the GTP-bound state, which directly activates aberrant downstream signaling via interaction with effectors such as RAF. Most RAS mutations occur at glycine 12 of the KRAS isoform. One such mutation, KRAS G12C, is particularly common in non-small cell lung cancer where it is found in ~15% of lung adenocarcinomas. Recent efforts have targeted KRAS G12C in the GDP-bound state; however, direct pharmacologic inhibition of active, GTP-bound KRAS G12C has proved challenging. Here, we deployed a novel SMARTTM (Small Molecule Assisted Receptor Targeting) platform to advance covalent compounds that selectively inhibit GTP-bound KRAS G12C. Using a mechanism reminiscent of the natural products rapamycin and cyclosporine, these compounds promote formation of a novel inhibitory ternary complex consisting of cyclophilin A (CypA, an abundant immunophilin present in all human cells), the SMART inhibitor, and GTP-KRAS G12C. Structure-based design of the SMART inhibitor yielded potent covalent inhibitors of GTP-KRAS G12C that exhibit >100-fold selectivity for mutant KRAS G12C over WT KRAS. Structural analysis of the ternary complex revealed that the covalent linkage between the SMART inhibitor and the mutant cysteine of KRAS occurred in the context of extensive interactions between CypA, the SMART inhibitor, and GTP-KRAS G12C that provide significant binding affinity (KI = 2.5 μM). The GTP-KRAS G12C|Inhibitor|CypA complex directly occluded effector binding, and as such, the compounds disrupted the KRAS-RAF interaction in biochemical assays. This activity was dependent on CypA, underlining the importance of the KRAS G12C| CypA protein-protein interaction in driving target engagement. In cell-based studies, SMART inhibitors crosslinked KRAS G12C and potently inhibited ERK phosphorylation and cell growth in G12C mutant tumor cell lines but had no effect on non-G12C bearing tumor cells. CRISPR knockout of cellular CypA confirmed that these activities were dependent on the presence of endogenous CypA. Importantly, SMART inhibitors bind directly to active, GTP-KRAS G12C and thus, their activity does not rely on trapping KRAS G12C in the inactive GDP-bound state. As a result, the cellular potency of SMART inhibitors with respect to crosslinking, pERK inhibition, and growth inhibition was maintained in the presence of growth factor treatments that reduce the cellular GDP-KRAS G12C pool. In contrast, we found that the activity of a previously described GDP-KRAS G12C targeting inhibitor was attenuated by growth factor treatment. To our knowledge, these are the first examples of mutant-selective KRAS inhibitors that target the active, GTP-bound state of KRAS G12C. We are currently optimizing the drug-like properties of these SMART inhibitors and evaluating their activity in in vivo models. Citation Format: Michelle L. Stewart, Nicholas R. Perl, Seung-Joo Lee, Linlong Xue, Minyun Zhou, Jonah Simon, Kathryn M. Luly, Siminia Grigoriu, Alex Yuzhakov, Alec Silver, Jason T. Lowe, Cindy C. Benod, Alan S. Mann, Gregory L. Verdine, Alan C. Rigby, Mark J. Mulvihill, Earl W. May, Anna Kohlmann, Sharon A. Townson, Roy M. Pollock, Meizhong Jin. Development of inhibitors of the activated form of KRAS G12C [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B37.

The Acute Care for Elders (ACE) Unit model improves cognitive and functional outcomes for hospitalized elders but reaches a small proportion of patients. To disseminate ACE Unit principles, we piloted the "Virtual ACE Intervention" that standardizes care processes for cognition and function without daily geriatrician oversight on two non-ACE units. The Virtual ACE Intervention includes staff training on geriatric assessments for cognition and function and on nurse-driven care algorithms. Completion of the geriatric assessments by nursing staff in patients aged 65 years and older and measures of patient mobility and prevalence of an abnormal delirium screening score were compared preintervention and postintervention. Postintervention, the completion of the assessments for current functional status and delirium improved (62.5% vs. 88.5%, p < .001) and (4.2% vs. 96.5%, p < .001). In a subsample analysis, in the postintervention period, more patients were up to the chair in the past day (36.4% vs. 63.5%, p = .04) and the prevalence of an abnormal delirium screening score was lower (13.6% vs. 4.8%, p = .16). The Virtual ACE Intervention is a feasible model for disseminating ACE Unit principles to non-ACE Units and may lead to increased adherence to care processes and improved clinical outcomes.

Identify risk to neurovascular structures around the knee with placement of skeletal traction pins.Kirchner wires were inserted into cadaveric limbs followed by layer dissecting of each leg. Correlations between weight, height, BMI, and distance were determined after calculating the average distance with deviation between each anatomic structure and the Kirschner wire.Insertion of traction pins around the knee did not result in injury to neurovascular structures. Both weight and BMI positively correlated with distance between implants and neurovascular structure. Data collected suggests similar trends for all other anatomic structures.

OBJECTIVES To examine the characteristics of high-energy geriatric trauma over time. DESIGN Retrospective chart review. SETTING Level 1 trauma center. PATIENTS Demographic, injury, and clinical characteristics were compared between 34,017 patients with geriatric and nongeriatric high-energy trauma from 2005 to 2014 using t test, χ analysis, and negative binomial regression for annual trend in injuries. RESULTS Geriatric high-energy trauma composed 11.2% of all trauma activations. Patients with geriatric high-energy trauma nearly doubled from the study period of 2005-2014 to previous 10 years (P = 0.0004). Compared with patients with nongeriatric trauma, geriatric high-energy traumas were twice as likely to be due to a fall from height (P < 0.0001), had higher Injury Severity Scores (P < 0.0001), fewer abdominal injuries (P = 0.0011), and have head trauma (P < 0.0001). Fracture patterns were similar between groups. Mortality was higher for all geriatric patients (odds ratio [OR], 4.76; 95% confidence interval [CI], 4.00-5.67), and high-energy mechanisms (OR, 4.71; 95% CI, 3.90-5.68) compared with low-energy mechanisms (OR, 3.00; 95% CI, 2.48-3.62). CONCLUSION The number of geriatric high-energy traumas has doubled over 10 years. Patients with geriatric trauma are sicker on presentation, based on the Injury Severity Score, and high-energy geriatrics have a 4-fold increase in mortality. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.

Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons. We determine the crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface. Analysis of the cryo-EM spliceosome Bact complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action. Collectively, we propose that PHF5A–SF3B1 forms a central node for binding to these splicing modulators., A number of natural occurring small-molecule splicing modulators are known. Here, the authors combine chemogenomic, structural and biochemical methods and show that these compounds also target the spliceosome-associated protein PHF5A and propose a potential modulator binding site in the PHF5A–SF3B1 complex.

Percutaneous sacral screw fixation is the mainstay of posterior pelvic ring fixation. This study quantifies the accuracy of fluoroscopic screw placement using post-operative CT scans and redefines the fluoroscopic safe zone using a mathematical calculation obtained from Inlet and outlet images. The authors hypothesized that a mathematical calculation of screw placement within the ala will improve accuracy of screw placement. A retrospective review of consecutive patients admitted to a level 1 trauma center with pelvic fractures fixed with iliosacral screws from January 2011 to December 2014 was performed. Accuracy of screw placement was determined by comparing fluoroscopy to post-operative CT scans. A mathematical calculation of screw position within the sacral ala was applied to determine assess screw position and compared to CT findings. Ninety-four patients with 156 screws met inclusion criteria, of which 50 (32.0%) had a cortical breech on CT. The sensitivity and specificity of the inlet-outlet safe zone using mathematical calculation were 97.1% and 84.0%, respectively. The positive and negative predictive values were 92.7% and 93.3%, respectively. Overall accuracies of the radiographic inlet-outlet and lateral safe zones were 92.9% and 70.0%, respectively (p-value = 0.004). Sacral dysmorphism was not found to be associated with sacral cortical breech. A Simple mathematical calculation (screw position relative to percentage of bone width) on the inlet-outlet provides an accurate way to predict the accuracy of sacroiliac screws. The method is easy to implement, part of the surgery work-flow, and provides higher accuracy than relying on subjective interpretation of inlet, outlet, and lateral images. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1478-1484, 2017.

The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.

Tibial plateau fractures are challenging to treat due to the high incidence of postoperative infections. Treating physicians should be aware of risk factors for postoperative infection in patients who undergo operative fixation.A retrospective review was undertaken to identify all patients with tibial plateau fractures over a 10 year period (2003-2012) who underwent open reduction internal fixation. A total of 532 patients were identified who met the inclusion criteria. Several patient and clinical characteristics were recorded, and those variables with a significant association (p0.05) with postoperative infection after a univariate analysis were further analyzed using a multivariate analysis.Fifty-nine (11.1%) of the 532 patients developed a deep infection. The average length of follow-up for patients was 19.5 months. Methicillin-resistant Staphylococcus aureus was the most common species, and it was isolated in 26 (44.1%) patients. Open fractures, the presence of compartment syndrome, and a Schatzker type IV-VI were found to be independent risk factors for deep infection.The rate of deep infection remains high after operative fixation of tibial plateau fractures. Patients with risk factors for infection should be counseled on the possibility of reoperation, and surgeons should consider MRSA prophylaxis in those patients who are at higher risk.

Treatment of infected long bone fractures or nonunions requires stability for bony union, yet retained implants can lead to persistent infection. Antibiotic cement intramedullary nails, in addition to external fixation, are commonly used to deliver intramedullary antibiotics in infected long bone fractures and provide temporary stability. However, the retrieval of these nails can result in debonding of antibiotic cement, which can require significant time and effort to remove. A variety of methods, including intramedullary hooks, reverse curettes, flexible osteotomes, and stacked guide rods, are commonly used to remove cement fragments. When these methods fail to allow access to the entire length of the canal, the Reamer Irrigator Aspirator system (Synthes, Paoli, PA) serves as an effective method for removing retained intramedullary cement. The surgical technique is described, and three cases illustrate the successful use of the Reamer Irrigator Aspirator system for removal of an antibiotic cement intramedullary nail.

An aldol-based ‘build/couple/pair’ (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti- aldol reactions were performed to produce four stereoisomers of a Boc protected γ-amino acid. In addition both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes, namely: nucleophilic aromatic substitution (SNAr), Huisgen [3+2] cycloaddition and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on solid-phase to yield a 14,400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships (SSAR) was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

For decades, the basic tenets of managing displaced femoral neck fractures have not changed, but the optimal treatment choice continues to be highly debated. The contemporary controversies associated with the treatment principles of displaced femoral neck fractures are distinct between young and old patients and are considered individually in this article about the current evidence. Although fixation constructs all seem to have similar complication rates, there is increasing evidence suggesting that total hip replacement improves patient functional outcomes for healthy, independent, elderly patients compared with hemiarthroplasty and should be considered as the treatment of choice for these patients.

A technical benefit of the reamer-irrigator-aspirator (RIA) system (Synthes, Paoli, PA) is the ability to harvest large volumes (40-90 cm3) of autogenous bone graft. Early evaluations of this technique have reported few problems, all of which were attributed to technical error. This case series reviews 6 RIA-associated complications including 4 fractures and their contributing risk factors. Cases were collected from 4 independent orthopaedic centers, and all patients underwent RIA bone graft harvesting in a lower extremity long bone injuries. In this population, 2 patients experienced acute RIA-associated events, necessitating an additional procedure or altered postoperative rehabilitation, whereas 4 patients fractured through their donor site in the early postoperative period. This series suggests that surgeons should (1) preoperatively assess cortical diameters at long bone harvest sites, (2) carefully monitor intraoperative reaming, and (3) avoid RIA bone graft harvesting in patients with a history of osteoporosis or osteopenia unless postharvest intramedullary stabilization is considered.

Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.

Through its control on the marine ITCZ, future changes in the tropical Atlantic meridional sea-surface temperature gradient (TAG) could have important impacts, on regional to global scales. We study the inter-model spread of projected TAG trends in response to increasing CO2, using results from 19 coupled GCMs which took part in the IPCC fourth assessment. Some models project substantial changes, with the smallest changes being in boreal autumn. There is substantial uncertainty, with no consistency even in the sign of change, and an ensemble mean close to zero. However, a strong statistical relationship is found between the simulated magnitudes of TAG trends and unforced TAG variability. Models with larger unforced variability in December–February show larger magnitude trends. We speculate that this relationship may be due to an underlying system of feedbacks whose strength varies considerably from model to model (the unforced variability ranges by a factor of 3 amongst these models, and the models exhibit large differences in mean state). We present evidence from further analysis and the literature to suggest which physical mechanisms may be involved. In particular, models projecting larger(smaller) magnitude TAG trends have larger(smaller) SST variability and cooler(warmer) mean SST in not just the Atlantic, but all three tropical/sub-tropical oceans, especially in the southern hemisphere near eastern coasts. These results could assist efforts to understand model errors in present and future tropical climate, and to develop observational constraints on future tropical projections.

An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction) is employed to afford the protected macrocycle.