SnapShot: S-Phase Entry and Exit.

S-phase entry and exit are regulated by hundreds of protein complexes that assemble "just in time," orchestrated by a multitude of distinct events. To help understand their interplay, we have created a tailored visualization based on the Minardo layout, highlighting over 80 essential events. This complements our earlier visualization of M-phase, and both can be displayed together, giving a comprehensive overview of the events regulating the cell division cycle. To view this SnapShot, open or download the PDF.

SnapShot: Phosphoregulation of Mitosis.

During mitosis, a cell divides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see http://www.cell.com/cell/enhanced/odonoghue2.

Cep55 regulation of PI3K/Akt signaling is required for neocortical development and ciliogenesis.

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3ß/ß-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3ß. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss.

Charcot-Marie-tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model.

Charcot-Marie-Tooth (CMT) is a commonly inherited, non-fatal neurodegenerative disorder that affects sensory and motor neurons in patients. More than 90 genes are known to cause axonal and demyelinating forms of CMT. The p.R158H mutation in the pyruvate dehydrogenase kinase 3 (PDK3) gene is the genetic cause for an X linked form of axonal CMT (CMTX6). In vitro studies using patient fibroblasts and iPSC-derived motor neurons have shown that this mutation causes deficits in energy metabolism and mitochondrial function. Animal models that recapitulate pathogenic in vivo events in patients are crucial for investigating mechanisms of axonal degeneration and developing therapies for CMT. We have developed a C. elegans model of CMTX6 by knocking-in the p.R158H mutation in pdhk-2, the ortholog of PDK3. In addition, we have developed animal models overexpressing the wild type and mutant form of human PDK3 specifically in the GABAergic motor neurons of C. elegans. CMTX6 mutants generated in this study exhibit synaptic transmission deficits, locomotion defects and show signs of progressive neurodegeneration. Furthermore, the CMTX6 in vivo models display energy deficits that recapitulate the phenotype observed in patient fibroblasts and iPSC-derived motor neurons. Our CMTX6 animals represent the first in vivo model for this form of CMT and have provided novel insights into the cellular function and metabolic pathways perturbed by the p.R158H mutation, all the while closely replicating the clinical presentation observed in CMTX6 patients.

The convexity condition of density-functional theory.

It has long been postulated that within density-functional theory (DFT), the total energy of a finite electronic system is convex with respect to electron count so that 2Ev[N0] ≤ Ev[N0 - 1] + Ev[N0 + 1]. Using the infinite-separation-limit technique, this Communication proves the convexity condition for any formulation of DFT that is (1) exact for all v-representable densities, (2) size-consistent, and (3) translationally invariant. An analogous result is also proven for one-body reduced density matrix functional theory. While there are known DFT formulations in which the ground state is not always accessible, indicating that convexity does not hold in such cases, this proof, nonetheless, confirms a stringent constraint on the exact exchange-correlation functional. We also provide sufficient conditions for convexity in approximate DFT, which could aid in the development of density-functional approximations. This result lifts a standing assumption in the proof of the piecewise linearity condition with respect to electron count, which has proven central to understanding the Kohn-Sham bandgap and the exchange-correlation derivative discontinuity of DFT.

Loop gain response to increased cerebral blood flow at high altitude.

PURPOSE: To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep. METHODS: Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 µg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR). RESULTS: A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P < 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1). CONCLUSION: Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change.

A Mathematical Framework for Modelling the Metastatic Spread of Cancer.

Cancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network, they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer. To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner-a multigrid, hybrid, individual-based approach. This framework accounts for the spatiotemporal evolution of mesenchymal- and epithelial-like cancer cells, membrane-type-1 matrix metalloproteinase (MT1-MMP) and the diffusible matrix metalloproteinase-2 (MMP-2), and for their interactions with the extracellular matrix. Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix-degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs such as MMP-2.

Eligibility for anti-fibrotic treatment in idiopathic pulmonary fibrosis depends on the predictive equation used for pulmonary function testing.

BACKGROUND AND OBJECTIVE: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for example Australian patients must have a forced vital capacity ≥50% (%FVC), transfer factor of the lung for carbon monoxide ≥ 30% (%TLco) and forced expiratory volume in 1 s (FEV1 )/FVC ratio > 0.7. Despite defined cut-off values, no jurisdiction prescribes a reference equation for use; multiple equations exist. We hypothesized that access to subsidized treatment varies depending on the chosen equation. The %FVC and %TLco from different commonly used reference equations across general respiratory patients, and IPF-specific patients, were compared. METHODS: FVC and TLco measurements from a large general respiratory laboratory and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR) database were analysed using multiple equations. Differences between %FVC and %TLco for each equation were calculated, with particular interest in classification of patients (%) at the threshold for subsidized treatment. RESULTS: A total of 20 378 general respiratory database results were analysed. The %FVC ≥ 50% increased from 86% with the Roca equation to 96% with Quanjer (European Coal and Steal Community, ECSC) and %TLco≥30% increased from 91% with Paoletti to 98% with Thompson. However, overall increase in eligibility for subsidized treatment was modest, varying from 48.2% to 49.2%. A total of 545 AIPFR database results were analysed. The %FVC ≥ 50% increased from 73% with Roca to 94% with Quanjer (ECSC) and %TLco≥30% increased from 87% with Paoletti to 96% with Miller. Overall eligibility for subsidized treatment in the AIPFR group varied from 73.6% to 82.8% between surveyed interstitial lung disease (ILD) centres based entirely on the equation used. CONCLUSION: Substantial variability exists between reference equations, impacting access to subsidized treatment. Treating clinicians should be aware of this when assessing patients around public funding thresholds.

Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer.

OBJECTIVE: Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4. DESIGN: Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens). RESULTS: Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach. CONCLUSION: This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells.

Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL; however, it is not currently understood what deactivates MASTL and how this is achieved. In this study, we identified that PP1 is associated with, and capable of partially dephosphorylating and deactivating, MASTL during mitotic exit. Using mathematical modelling, we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and, hence, create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a strong switch-like activation of phosphatase activity during mitotic exit.

Mechanisms regulating phosphatase specificity and the removal of individual phosphorylation sites during mitotic exit.

Entry into mitosis is driven by the activity of kinases, which phosphorylate over 7000 proteins on multiple sites. For cells to exit mitosis and segregate their genome correctly, these phosphorylations must be removed in a specific temporal order. This raises a critical and important question: how are specific phosphorylation sites on an individual protein removed? Traditionally, the temporal order of dephosphorylation was attributed to decreasing kinase activity. However, recent evidence in human cells has identified unique patterns of dephosphorylation during mammalian mitotic exit that cannot be fully explained by the loss of kinase activity. This suggests that specificity is determined in part by phosphatases. In this review, we explore how the physicochemical properties of an individual phosphosite and its surrounding amino acids can affect interactions with a phosphatase. These positive and negative interactions in turn help determine the specific pattern of dephosphorylation required for correct mitotic exit.

Examining the role of individual movement in promoting coexistence in a spatially explicit prisoner's dilemma.

The emergence of cooperation is a major conundrum of evolutionary biology. To unravel this evolutionary riddle, several models have been developed within the theoretical framework of spatial game theory, focussing on the interactions between two general classes of player, "cooperators" and "defectors". Generally, explicit movement in the spatial domain is not considered in these models, with strategies moving via imitation or through colonisation of neighbouring sites. We present here a spatially explicit stochastic individual-based model in which pure cooperators and defectors undergo random motion via diffusion and also chemotaxis guided by the gradient of a semiochemical. Individual movement rules are derived from an underlying system of reaction-diffusion-taxis partial differential equations which describes the dynamics of the local number of individuals and the concentration of the semiochemical. Local interactions are governed by the payoff matrix of the classical prisoner's dilemma, and accumulated payoffs are translated into offspring. We investigate the cases of both synchronous and non-synchronous generations. Focussing on an ecological scenario where defectors are parasitic on cooperators, we find that random motion and semiochemical sensing bring about self-generated patterns in which resident cooperators and parasitic defectors can coexist in proportions that fluctuate about non-zero values. Remarkably, coexistence emerges as a genuine consequence of the natural tendency of cooperators to aggregate into clusters, without the need for them to find physical shelter or outrun the parasitic defectors. This provides further evidence that spatial clustering enhances the benefits of mutual cooperation and plays a crucial role in preserving cooperative behaviours.

Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs.

Entry into mitosis is driven by the coordinated phosphorylation of thousands of proteins. For the cell to complete mitosis and divide into two identical daughter cells it must regulate dephosphorylation of these proteins in a highly ordered, temporal manner. There is currently a lack of a complete understanding of the phosphorylation changes that occur during the initial stages of mitotic exit in human cells. Therefore, we performed a large unbiased, global analysis to map the very first dephosphorylation events that occur as cells exit mitosis. We identified and quantified the modification of >16,000 phosphosites on >3300 unique proteins during early mitotic exit, providing up to eightfold greater resolution than previous studies. The data have been deposited to the ProteomeXchange with identifier PXD001559. Only a small fraction (∼ 10%) of phosphorylation sites were dephosphorylated during early mitotic exit and these occurred on proteins involved in critical early exit events, including organization of the mitotic spindle, the spindle assembly checkpoint, and reformation of the nuclear envelope. Surprisingly this enrichment was observed across all kinase consensus motifs, indicating that it is independent of the upstream phosphorylating kinase. Therefore, dephosphorylation of these sites is likely determined by the specificity of phosphatase/s rather than the activity of kinase/s. Dephosphorylation was significantly affected by the amino acids at and surrounding the phosphorylation site, with several unique evolutionarily conserved amino acids correlating strongly with phosphorylation status. These data provide a potential mechanism for the specificity of phosphatases, and how they co-ordinate the ordered events of mitotic exit. In summary, our results provide a global overview of the phosphorylation changes that occur during the very first stages of mitotic exit, providing novel mechanistic insight into how phosphatase/s specifically regulate this critical transition.

Importance of Pelvic Radiography for Initial Trauma Assessment: An Orthopedic Perspective.

BACKGROUND: Many institutions have abandoned the routine for selective pelvic x-ray (PXR) for initial imaging in blunt trauma patients undergoing computed tomography (CT) scanning. OBJECTIVE: Our aim was to examine the association between selective use of PXR and time to diagnosis of (major) pelvic fractures, as well as prioritization of key immediate interventions (including hip reduction and pelvic arterial embolization). METHODS: We conducted a 1-year review of early management of pelvic fracture patients undergoing pelvic CT scanning. Time interval and sequence of initial imaging and key immediate interventions were recorded. RESULTS: Of 218 pelvic fracture patients, 79 (36%) had no initial PXR, and instead had an initial CT scan. Time to first pelvic imaging in those patients was 48 min (standard deviation [SD] = 47 min vs. 2 min [SD = 6 min] with PXR; p < 0.001). Of 40 hip dislocations, 15 (38%) were detected first on CT scan. Overall, 22 (55%) required a second CT scan after reduction in the emergency department. No initial PXR was performed in 42 of 120 (35%) pelvic ring fracture patients and in 16 of 61 (26%) unstable pelvic ring fractures. Time to pelvic arterial embolization was longer in 4 patients without initial PXR than in 14 patients with PXR (296 min [SD = 206 min] vs. 170 min [SD = 76 min], respectively, p = 0.038). CONCLUSIONS: Selective PXR was associated with a significant delay in recognition of (major) pelvic fractures, including those with associated hip dislocations and (potential) pelvic bleeding. PXR remains a useful screening tool to rapidly determine the need for immediate interventions and to allow early planning before CT scanning.

Impact of Etanercept Therapy on Disease Activity and Health-Related Quality of Life in Moderate Rheumatoid Arthritis Patients Population from a National British Observational Cohort.

OBJECTIVES: To describe a population with moderate rheumatoid arthritis (RA) before biologic initiation and assess change in disease status, health-related quality of life (HRQOL), and adverse events in etanercept (ETN)-treated patients. METHODS: Data on adult patients with moderate RA (3.2 < Disease Activity Score in 28 Joints [DAS28] ≤ 5.1) were retrospectively analyzed from the British Society for Rheumatology Biologics Register comparing a nonbiologic-treated group (nBG) using at least one traditional disease-modifying antirheumatic drug to a biologic group (BG) treated with ETN. The HRQOL was assessed by using the Health Assessment Questionnaire disability index score. To mitigate confounding, we controlled for drivers of progression. Appropriate univariate, multivariate, and regression analyses were used. RESULTS: A total of 1754 patients with RA were assessed (211 BG and 1543 nBG). Compared with the nBG, the BG tended toward higher disease activity, such as significantly higher tender joints and DAS28. The BG compared with the nBG had 1) a greater reduction in DAS28 and Health Assessment Questionnaire scores; 2) disease remission occurring more often (odds ratio = 2.7; P = 0.006); and 3) progression occurring in fewer patients (odds ratio = 0.3; P = 0.002). BG patients had a higher incidence of "other serious infection" and "other central nervous system-related events," with no significant differences in associated hospitalization rates or deaths. CONCLUSIONS: Among patients with moderate RA from a clinical practice registry, ETN-treated patients had significantly higher disease activity at the time of biologic initiation but significantly reduced disease activity and better HRQOL after 6 months compared with nBG patients, although the possibility of unmeasured confounding remains. The ETN group reported significantly higher incidences of "other serious infections" and "other central nervous system-related events" without higher hospitalization rates.

Observation may be an inadequate approach for injured extremities with single tibial vessel run-off.

INTRODUCTION: Trauma patients with sudden loss of distal perfusion due to tibial injuries are frequently not offered vascular interventions if a single vessel retains patency. We hypothesized that sudden loss of either all or some tibial vasculature would result in increased non-operative failure and higher amputation rates. METHODS: In this retrospective observational study, all traumatically injured patients from 2009 to 2012 with CT-angiogram-confirmed anterior tibial, posterior tibial, or peroneal artery injuries were included. RESULTS: From 2009 to 2012, 437 patients were admitted with arterial extremity injury of which 234 (53%) were lower extremity. From this group, 84 (36%) patients were identified with CT-angiogram-confirmed limited or no flow in the tibial arteries. A total of 44% (4/9) with 0 or 1 tibial vessel failed observation while only 8% (2/27) failed if they had 2 or 3 patent vessels (p < 0.05). Amputation rate was inversely related the number of open tibial vessels. There were 2.7 open tibial vessels in the limb salvage group compared to 1.1 in the amputation group (p < 0.05). CONCLUSION: Patients who failed an initial trial of observation were significantly more likely to have 0 or 1 tibial vessels patent. The number of open tibial vessels is significantly associated with limb salvage.

Greatwall maintains mitosis through regulation of PP2A.

Greatwall (GW) is a new kinase that has an important function in the activation and the maintenance of cyclin B-Cdc2 activity. Although the mechanism by which it induces this effect is unknown, it has been suggested that GW could maintain cyclin B-Cdc2 activity by regulating its activation loop. Using Xenopus egg extracts, we show that GW depletion promotes mitotic exit, even in the presence of a high cyclin B-Cdc2 activity by inducing dephosphorylation of mitotic substrates. These results indicate that GW does not maintain the mitotic state by regulating the cyclin B-Cdc2 activation loop but by regulating a phosphatase. This phosphatase is PP2A; we show that (1) PP2A binds GW, (2) the inhibition or the specific depletion of this phosphatase from mitotic extracts rescues the phenotype induced by GW inactivation and (3) the PP2A-dependent dephosphorylation of cyclin B-Cdc2 substrates is increased in GW-depleted Xenopus egg extracts. These results suggest that mitotic entry and maintenance is not only mediated by the activation of cyclin B-Cdc2 but also by the regulation of PP2A by GW.

Smoking cessation and the risk of cardiovascular disease outcomes predicted from established risk scores: results of the Cardiovascular Risk Assessment among Smokers in Primary Care in Europe (CV-ASPIRE) study.

BACKGROUND: Smoking is a major risk factor for cardiovascular disease (CVD). This multicenter, cross-sectional survey was designed to estimate the cardiovascular (CV) risk attributable to smoking using risk assessment tools, to better understand patient behaviors and characteristics related to smoking, and characterize physician practice patterns. METHODS: 1,439 smokers were recruited from Europe during 2011. Smokers were ≥40 years old, smoked > 10 cigarettes/day and had recent measurements on blood pressure and lipids. CV risk was calculated using the SCORE system, Framingham risk equations, and Progetto CUORE model. The CV risk attributable to smoking was evaluated using a simulated control (hypothetical non-smoker) with identical characteristics as the enrolled smoker. Risks assessed included CV mortality, coronary heart disease (CHD), CVD and hard CHD. Demographics, comorbidities, primary reasons for consultation, behavior towards previous attempts to quit, and interest in smoking cessation was assessed. Dependence on nicotine was evaluated using the Fagerström Test for Nicotine Dependence. GP practice patterns were assessed through a questionnaire. RESULTS: The prediction models consistently demonstrated a high CV risk attributable to smoking. For instance, the SCORE model demonstrated that this study population of smokers have a 100% increased probability of death due to cardiovascular disease in the next 10-years compared to non-smokers. A considerable amount of patients would like to hear from their GP about the different alternatives available to support their quitting attempt. CONCLUSIONS: The findings of this study reinforce the importance of smoking as a significant predictor of long-term cardiovascular events. One of the best gains in health could be obtained by tackling the most important modifiable risk factors; these results suggest smoking is among the most important.

Pelvic fractures: part 1. Evaluation, classification, and resuscitation.

Pelvic fractures range in severity from low-energy, generally benign lateral compression injuries to life-threatening, unstable fracture patterns. Initial management of severe pelvic fractures should follow Advanced Trauma Life Support protocols. Initial reduction of pelvic blood loss can be provided by binders, sheets, or some form of external fixation, which serve to reduce pelvic volume, stabilize clot formation, and reduce ongoing tissue damage. Persistently unstable patients may benefit from angiography with selective embolization, pelvic packing, or a combination of these interventions. Open pelvic fractures involving the perineum or bowel injury benefit from fecal diversion by colostomy. Trauma team coordination facilitates efficient resuscitative efforts and may affect definitive management by optimizing incision, ostomy, or catheter placement. Established protocols for both open and closed pelvic fractures help to standardize care.

Pelvic fractures: part 2. Contemporary indications and techniques for definitive surgical management.

Once the patient with pelvic fracture is resuscitated and stabilized, definitive surgical management and anatomic restoration of the pelvic ring become the goal. Understanding injury pattern by stress examination with the patient under anesthesia helps elucidate the instability. Early fixation of the unstable pelvis is important for mobilization, pain control, and prevention of chronic instability or deformity. Current pelvic fracture management employs a substantial amount of percutaneous reduction and fixation, with less emphasis placed on pelvic reconstruction proceeding from posterior to anterior, and most reduction and fixation of unstable pelvic fractures done with the patient supine. Compared with control subjects with acetabular fracture or pelvic fracture alone, patients with combined injury have a significantly higher Injury Severity Score, lower systolic blood pressure, and higher mortality rates; they are also transfused more packed red blood cells. Even with anatomic restoration of the pelvis, long-term outcomes after severe pelvic trauma are below population norms. The most common chronic problems relate to sexual dysfunction and pain. Regardless of fracture type, neurologic injury is a universal harbinger of poor outcome.