Principles for management of hip fracture for older adults taking direct oral anticoagulants: an international consensus statement.

Hip fracture is a common serious injury among older adults, yet the management of hip fractures for patients taking direct oral anticoagulants remains inconsistent worldwide. Drawing from a synthesis of available evidence and expert opinion, best practice approaches for managing patients with a hip fracture and who are taking direct oral anticoagulants pre-operatively were considered by a working group of the Fragility Fracture Network Hip Fracture Audit Special Interest Group. The literature and related clinical guidelines were reviewed and a two-round modified Delphi study was conducted with a panel of experts from 16 countries and involved seven clinical specialities. Four consensus statements were achieved: peripheral nerve blocks can reasonably be performed on presentation for patients with hip fracture who are receiving direct oral anticoagulants; hip fracture surgery can reasonably be performed for patients taking direct oral anticoagulants < 36 h from last dose; general anaesthesia could reasonably be administered for patients with hip fracture and who are taking direct oral anticoagulants < 36 h from last dose (assuming eGFR > 60 ml.min-1.1.73 m-2); and it is generally reasonable to consider recommencing direct oral anticoagulants (considering blood loss and haemoglobin) < 48 h after hip fracture surgery. No consensus was achieved regarding timing of spinal anaesthesia. The consensus statements were developed to aid clinicians in their decision-making and to reduce practice variations in the management of patients with hip fracture and who are taking direct oral anticoagulants. Each statement will need to be considered specific to each individual patient's treatment.

Models of care that avoid or improve transitions to hospital services for residential aged care facility residents: An integrative review.

Care transitions for older people moving from residential aged care facilities (RACFs) to hospital services are associated with greater challenges and poorer outcomes. An integrative review was conducted to investigate models of care designed to avoid or improve transitions for older people residing in RACFs to hospital settings. Twenty-one studies were included in the final analysis. Models of care aimed to either improve or avoid transitions of residents through enhanced primary care in RACFs, promoting quality improvement in RACFs, instilling comprehensive hospital care, conducting outreach services, transferring information, or involved a combination of outreach services and comprehensive hospital care. As standalone interventions, standardised communication tools may improve information transfer between RACFs and hospital services. For more complex models, providing quality improvement and outreach to RACFs may prevent some types of hospital admissions.

OakEcol: A database of Oak-associated biodiversity within the UK.

Globally there is increasing concern about the decline in the health of oak Quercus trees. The impact of a decline in oak trees on associated biodiversity, species that utilize oak trees, is unknown. Here we collate a database of all known birds, bryophytes, fungi, invertebrates, lichens and mammals that use oak (Quercus petraea and Q. robur) in the UK. In total 2300 species are listed in the database. For each species we provide a level of association with oak, ranging from obligate (only found on oak) to cosmopolitan (found on a wide range of other tree species). Data on the ecology of each oak associated species was collated: part of tree used, use made of tree (feeding, roosting, breeding), age of tree, woodland type, tree form (coppice, pollarded, or natural growth form) and season when the tree was used. Data on use or otherwise by each of the 2300 species of 30 other tree species was also collated. A complete list of data sources is provided. For further insights into how this data can be used see Collapsing foundations: The ecology of the British oak, implications of its decline and mitigation options [1]. Data can be found at EIDC https://doi.org/10.5285/22b3d41e-7c35-4c51-9e55-0f47bb845202.

Enhanced sensitivity and responses to viologens from a whole-cell bacterial bioreporter treated with branched polyethyleneimines.

AIMS: Evaluate the use of polyethyleneimines (PEIs) as membrane permeabilizers to improve the responses and sensitivity of a bacterial bioreporter strain to viologens. METHODS AND RESULTS: The responses from E. coli str. EBS, i.e., E. coli BW25113 carrying plasmid pSDS, when exposed to five different viologens were characterized, as were the toxicities of seven different PEIS, including two linear and five branched species. Based on these results, benzyl viologen led to the greatest responses, and 0·8-kDa branched PEI (BPEI) was the least toxic of the PEIs tested and, therefore, both were selected for the subsequent tests. The bioluminescence and relative responses from E. coli str. EBS exposed to various concentrations of 0·8 kDa BPEI identified 400 mg l-1 as the optimal concentration. Using this concentration, tests were performed with all five of the viologens. CONCLUSIONS: The responses from E. coli str. EBS to the viologens were improved, with the maximum relative bioluminescence values increasing between 5·6 and 16·5-fold. The minimum detectable levels for four of the viologens were likewise improved 2- to 4-fold. SIGNIFICANCE AND IMPACT OF STUDY: Improving bacterial membrane permeability in a controlled manner using BPEIs can improve biosensing of toxic compounds, as well as be used in biofuel and bioenergy applications where membrane permeability to a solute is important.

Productivity and species richness in longleaf pine woodlands: resource-disturbance influences across an edaphic gradient.

This study examines the complex feedback mechanisms that regulate a positive relationship between species richness and productivity in a longleaf pine-wiregrass woodland. Across a natural soil moisture gradient spanning wet-mesic to xeric conditions, two large scale manipulations over a 10-yr period were used to determine how limiting resources and fire regulate plant species diversity and productivity at multiple scales. A fully factorial experiment was used to examine productivity and species richness responses to N and water additions. A separate experiment examined standing crop and richness responses to N addition in the presence and absence of fire. Specifically, these manipulations addressed the following questions: (1) How do N and water addition influence annual aboveground net primary productivity of the midstory/overstory and ground cover? (2) How do species richness responses to resource manipulations vary with scale and among functional groups of ground cover species? (3) How does standing crop (including overstory, understory/midstory, and ground cover components) differ between frequently burned and fire excluded plots after a decade without fire? (4) What is the role of fire in regulating species richness responses to N addition? This long-term study across a soil moisture gradient provides empirical evidence that species richness and productivity in longleaf pine woodlands are strongly regulated by soil moisture. After a decade of treatment, there was an overall species richness decline with N addition, an increase in richness of some functional groups with irrigation, and a substantial decline in species richness with fire exclusion. Changes in species richness in response to treatments were scale-dependent, occurring primarily at small scales (≤10 m2 ). Further, with fire exclusion, standing crop of ground cover decreased with N addition and non-pine understory/midstory increased in wet-mesic sites. Non-pine understory/midstory standing crop increased in xeric sites with fire exclusion, but there was no influence of N addition. This study highlights the complexity of interactions among multiple limiting resources, frequent fire, and characteristics of dominant functional groups that link species richness and productivity.

Estimating the human recovery costs of seriously injured road crash casualties.

Road crashes result in substantial trauma and costs to societies around the world. Robust costing methods are an important tool to estimate costs associated with road trauma, and are key inputs into policy development and cost-benefit analysis for road safety programmes and infrastructure projects. With an expanding focus on seriously injured road crash casualties, in addition to the long standing focus on fatalities, methods for costing seriously injured casualties are becoming increasingly important. Some road safety agencies are defining a seriously injured casualty as an individual that was admitted to hospital following a road crash, and as a result, hospital separation data provide substantial potential for estimating the costs associated with seriously injured road crash casualties. The aim of this study is to establish techniques for estimating the human recovery costs of (non-fatal) seriously injured road crash casualties directly from hospital separation data. An individuals' road crash-related hospitalisation record and their personal injury insurance claim were linked for road crashes that occurred in New South Wales, Australia. These records provided the means for estimating all of the costs to the casualty directly related to their recovery from their injuries. A total of 10,897 seriously injured road crash casualties were identified and four methods for estimating their recovery costs were examined, using either unit record or aggregated hospital separation data. The methods are shown to provide robust techniques for estimating the human recovery costs of seriously injured road crash casualties, that may prove useful for identifying, implementing and evaluating safety programmes intended to reduce the incidence of road crash-related serious injuries.

Following the transfer of DNA: How does the presence of background DNA affect the transfer and detection of a target source of DNA?

DNA transfer is of increasing importance in crime scene situations, partly due to analytical techniques detecting profiles in ever declining amounts of DNA. Whereas the focus has previously been DNA transfer of target sources, the effects of background DNA on transfer and detection of DNA after multiple contact situations have been much less investigated. This study measured the transfer and detection rates of a specific DNA source in the presence of background DNA sources. The presence of background DNA influenced the transfer of DNA differently depending on the combination of biological material and surface type. The detection of a profile from the target DNA decreased after multiple contact situations, due to the reduced total and relative quantity of target DNA, and the increasing complexity of the mixture. The results of this study contribute to a greater understanding of the effects of background DNA sources on DNA transfer and detection.

Injury risk for matched front and rear seat car passengers by injury severity and crash type: An exploratory study.

BACKGROUND: The risk of serious injury or death has been found to be reduced for some front compared to rear seat car passengers in newer vehicles. However, differences in injury severity between car occupants by seating position has not been examined. This study examines the injury severity risk for rear compared to front seat car passengers. METHOD: A retrospective matched-cohort analysis was conducted of vehicle crashes involving injured rear vs front seat car passengers identified in linked police-reported, hospitalisation and emergency department (ED) presentation records during 2001-2011 in New South Wales (NSW), Australia. Odds ratios were estimated using an ordinal logistic mixed model and logistic mixed models. RESULTS: There were 5419 front and 4588 rear seat passengers in 3681 vehicles. There was a higher odds of sustaining a higher injury severity as a rear-compared to a front seat car passenger, with a higher odds of rear seat passengers sustaining serious injuries compared to minimal injuries. Where the vehicle occupant was older, travelling in a vehicle manufactured between 1990 and 1996 or after 1997, where the airbag deployed, and where the vehicle was driven where the speed limit was ≥70km/h there was a higher odds of the rear passenger sustaining a higher injury severity then a front seated occupant. CONCLUSION: Rear seat car passengers are sustaining injuries of a higher severity compared to front seat passengers travelling in the same vehicle, as well as when travelling in newer vehicles and where the front seat occupant is shielded by an airbag deployed in the crash. Rear seat occupant protective mechanisms should be examined. Pre-hospital trauma management policies could influence whether an individual is transported to a hospital ED, thus it would be beneficial to have an objective measure of injury severity routinely available in ED records. Further examination of injury severity between rear and front seat passengers is warranted to examine less severe non-fatal injuries by car seating position and vehicle intrusion.

Comparison of novice and full-licenced driver common crash types in New South Wales, Australia, 2001-2011.

OBJECTIVE: To examine the circumstances of passenger vehicle crashes for novice licenced drivers aged 17-25 years and to compare the crash circumstances of the most common crash types for novices to a sample of full-licence drivers aged 40-49 years. METHOD: A retrospective analysis was conducted of passenger vehicle crashes involving novice and full-licenced drivers during 1 January 2001 to 31 December 2011 in New South Wales (NSW), Australia. RESULTS: There were 4113 injurious crashes of novice drivers. Almost half the novice driver crashes involved a single vehicle. Vehicle speed (33.2%), fatigue (15.6%) and alcohol (12.6%) were identified risk factors in novice driver crashes. Correspondence analysis for 4 common crash types for novice drivers revealed that the crash characteristics between novice and full-licenced drivers were similar. CONCLUSIONS: Similarities exist between novice driver and full-licenced driver crash risk for common crash types. Preventive strategies aimed at crash risk reduction for novice drivers may also benefit all drivers.

Risk factors associated with the severity of injury outcome for paediatric road trauma.

Road trauma is one of the most common causes of injury for children. Yet risk factors associated with different levels of injury severity for childhood road trauma have not been examined in-depth. This study identifies crash and injury risk factors associated with the severity of non-fatal injury outcome for paediatric road trauma. A retrospective analysis was conducted of paediatric road trauma identified in linked police-reported and hospitalisation records during 1 January 2001 to 31 December 2011 in New South Wales (NSW), Australia. The linkage rate was 54%. Injury severity was calculated from diagnosis classifications in hospital records using the International Classification of Disease Injury Severity Score. Univariate and multi-variable logistic regression was conducted. There were 2412 car occupants, 1701 pedestrians and 612 pedal cyclists hospitalised where their hospital record linked to a police report. For car occupants, unauthorised vehicle drivers had twice the odds (OR: 2.21, 95%CI 1.47-3.34) and learner/provisional drivers had one and a half times higher odds (OR: 1.54, 95%CI 1.15-2.07) of a child car occupant sustaining a serious injury compared to a minor injury. For pedal cyclists and pedestrians, there were lower odds of a crash occurring during school commuting time and higher odds of a crash occurring during the weekend or on a dry road for children who sustained a serious versus a minor injury. Injury prevention initiatives, such as restraint and helmet use, that should reduce injury and/or crash severity are advocated.

Residential mobility and the association between physical environment disadvantage and general and mental health.

BACKGROUND: Selective migration may influence the association between physical environments and health. This analysis assessed whether residential mobility concentrates people with poor health in neighbourhoods of the UK with disadvantaged physical environments. METHODS: Data were from the British Household Panel Survey. Moves were over 1 year between adjacent survey waves, pooled over 10 pairs of waves, 1996-2006. Health outcomes were self-reported poor general health and mental health problems. Neighbourhood physical environment was defined using the Multiple Environmental Deprivation Index (MEDIx) for wards. Logistic regression analysis compared risk of poor health in MEDIx categories before and after moves. Analyses were stratified by age groups 18-29, 30-44, 45-59 and 60+ years and adjusted for age, sex, marital status, household type, housing tenure, education and social class. RESULTS: The pooled data contained 122 570 observations. 8.5% moved between survey waves but just 3.0% changed their MEDIx category. In all age groups odds ratios for poor general and mental health were not significantly increased in the most environmentally deprived neighbourhoods following moves. CONCLUSIONS: Over a 1-year time period residential moves between environments with different levels of multiple physical deprivation were rare and did not significantly raise rates of poor health in the most deprived areas.

Safe system approach to reducing serious injury risk in motorcyclist collisions with fixed hazards.

Collisions with fixed objects in the roadway environment account for a substantial proportion of motorcyclist fatalities. Many studies have identified individual roadway environment and/or motorcyclist characteristics that are associated with the severity of the injury outcome, including the presence of roadside barriers, helmet use, alcohol use and speeding. However, no studies have reported the cumulative benefit of such characteristics on motorcycling safety. The safe system approach recognises that the system must work as a whole to reduce the net injury risk to road users to an acceptable level, including the four system cornerstone areas of roadways, speeds, vehicles and people. The aim of the present paper is to consider these cornerstone areas concomitantly, and quantitatively assess the serious injury risk of motorcyclists in fixed object collisions using this holistic approach. A total of 1006 Australian and 15,727 (weighted) United States motorcyclist-fixed object collisions were collected retrospectively, and the serious injury risks associated with roadside barriers, helmet use, alcohol use and speeding were assessed both individually and concomitantly. The results indicate that if safety efforts are made in each of the safe system cornerstone areas, the combined effect is to substantially reduce the serious injury risk of fixed hazards to motorcyclists. The holistic approach is shown to reduce the serious injury risk considerably more than each of the safety efforts considered individually. These results promote the use of a safe system approach to motorcycling safety.

A review of the use of human factors classification frameworks that identify causal factors for adverse events in the hospital setting.

Various human factors classification frameworks have been used to identified causal factors for clinical adverse events. A systematic review was conducted to identify human factors classification frameworks that identified the causal factors (including human error) of adverse events in a hospital setting. Six electronic databases were searched, identifying 1997 articles and 38 of these met inclusion criteria. Most studies included causal contributing factors as well as error and error type, but the nature of coding varied considerably between studies. The ability of human factors classification frameworks to provide information on specific causal factors for an adverse event enables the focus of preventive attention on areas where improvements are most needed. This review highlighted some areas needing considerable improvement in order to meet this need, including better definition of terms, more emphasis on assessing reliability of coding and greater sophistication in analysis of results of the classification. Practitioner Summary: Human factors classification frameworks can be used to identify causal factors of clinical adverse events. However, this review suggests that existing frameworks are diverse, limited in their identification of the context of human error and have poor reliability when used by different individuals.

The rising burden of serious thoracic trauma sustained by motorcyclists in road traffic crashes.

In many countries increased on-road motorcycling participation has contributed to increased motorcyclist morbidity and mortality over recent decades. Improved helmet technologies and increased helmet wearing rates have contributed to reductions in serious head injuries, to the point where in many regions thoracic injury is now the most frequently occurring serious injury. However, few advances have been made in reducing the severity of motorcyclist thoracic injury. The aim of the present study is to provide needed information regarding serious motorcyclist thoracic trauma, to assist motorcycling groups, road safety advocates and road authorities develop and prioritise counter-measures and ultimately reduce the rising trauma burden. For this purpose, a data collection of linked police-reported and hospital data was established, and considerable attention was given to establishing a weighting procedure to estimate hospital cases not reported to police and fatal cases not admitted to hospital. The resulting data collection of an estimated 19,979 hospitalised motorcyclists is used to provide detailed information on the nature, incidence and risk factors for thoracic trauma. Over the last decade the incidence of motorcyclist serious thoracic injury has more than doubled in the population considered, and by 2011 while motorcycles comprised 3.2% of the registered vehicle fleet, one quarter of road traffic-related serious thoracic trauma cases treated in hospitals were motorcyclists. Motor-vehicle collisions, fixed object collisions and non-collision crashes were fairly evenly represented amongst these cases, while older motorcyclists were over-represented. Several prevention strategies are identified and discussed.

The protective effect of roadside barriers for motorcyclists.

OBJECTIVE: Roadside barriers are often deployed between road users and fixed hazards to protect users from injury. However, the United States and Australian Roadside Design Guides do not consider motorcyclists in the risk-based decision process for the deployment of a barrier, because the severity indices for barriers and fixed hazards were developed for passenger vehicles. The aim of the present article is to quantify the protective effect of barriers with regards to motorcyclist injury and to thereby inform the Roadside Design Guides as to the relative severity of roadside hazards and infrastructure for motorcyclists. METHOD: A retrospective case series study, using linked police-reported road crash and hospital admission data in New South Wales, Australia, from 2001 to 2009 was performed. Crude and adjusted relative risks of motorcyclist serious injury were determined for various fixed objects compared to barriers, using serious injury rates and multiple variable logistic regression. Calculated relative risks compared with guardrail for motorcyclists were compared with those determined from the United States and Australian Roadside Design Guides for passenger vehicle occupants. RESULTS: The study identified 1364 motorcyclists injured as a result of single-vehicle collisions with roadside barriers, trees, utility poles, and other fixed roadside infrastructure. Trees, posts, and utility poles were shown to provide significantly higher risks of serious injury to motorcyclists compared to barriers. This was also found to be true for serious injuries to particular body regions, such as the head, spine, and torso. The results for motorcyclists were in reasonable agreement with those derived from severity indices in the United States and Australian Roadside Design Guides for passenger vehicle occupants. CONCLUSIONS: Roadside barriers provide a significant reduction in the risk of serious injury to motorcyclists compared to various roadside hazards. The provisions in the United States and Australian Roadside Design Guides for passenger vehicle occupants are generally applicable to motorcyclists and support the prior and ongoing use of such guides for designing roadsides that reduce the risk of injury to motorcyclists. However, a more realistic estimation might be derived by increasing the severity indices for barriers by around 25 percent for motorcyclists.

The effectiveness of helmets in bicycle collisions with motor vehicles: a case-control study.

There has been an ongoing debate in Australia and internationally regarding the effectiveness of bicycle helmets in preventing head injury. This study aims to examine the effectiveness of bicycle helmets in preventing head injury amongst cyclists in crashes involving motor vehicles, and to assess the impact of 'risky cycling behaviour' among helmeted and unhelmeted cyclists. This analysis involved a retrospective, case-control study using linked police-reported road crash, hospital admission and mortality data in New South Wales (NSW), Australia during 2001-2009. The study population was cyclist casualties who were involved in a collision with a motor vehicle. Cases were those that sustained a head injury and were admitted to hospital. Controls were those admitted to hospital who did not sustain a head injury, or those not admitted to hospital. Standard multiple variable logistic regression modelling was conducted, with multinomial outcomes of injury severity. There were 6745 cyclist collisions with motor vehicles where helmet use was known. Helmet use was associated with reduced risk of head injury in bicycle collisions with motor vehicles of up to 74%, and the more severe the injury considered, the greater the reduction. This was also found to be true for particular head injuries such as skull fractures, intracranial injury and open head wounds. Around one half of children and adolescents less than 19 years were not wearing a helmet, an issue that needs to be addressed in light of the demonstrated effectiveness of helmets. Non-helmeted cyclists were more likely to display risky riding behaviour, however, were less likely to cycle in risky areas; the net result of which was that they were more likely to be involved in more severe crashes.

Measured and modelled leaf and stand-scale productivity across a soil moisture gradient and a severe drought.

Environmental controls on carbon dynamics operate at a range of interacting scales from the leaf to landscape. The key questions of this study addressed the influence of water and nitrogen (N) availability on Pinus palustris (Mill.) physiology and primary productivity across leaf and canopy scales, linking the soil-plant-atmosphere (SPA) model to leaf and stand-scale flux and leaf trait/canopy data. We present previously unreported ecophysiological parameters (e.g. V(cmax) and J(max)) for P. palustris and the first modelled estimates of its annual gross primary productivity (GPP) across xeric and mesic sites and under extreme drought. Annual mesic site P. palustris GPP was ∼23% greater than at the xeric site. However, at the leaf level, xeric trees had higher net photosynthetic rates, and water and light use efficiency. At the canopy scale, GPP was limited by light interception (canopy level), but co-limited by nitrogen and water at the leaf level. Contrary to expectations, the impacts of an intense growing season drought were greater at the mesic site. Modelling indicated a 10% greater decrease in mesic GPP compared with the xeric site. Xeric P. palustris trees exhibited drought-tolerant behaviour that contrasted with mesic trees' drought-avoidance behaviour.

Obesity, overweight and liver disease in the Midspan prospective cohort studies.

OBJECTIVES: To analyse the relationship between body mass index (BMI) and liver disease in men and women. DESIGN: The Midspan prospective cohort studies. PARTICIPANTS: The three studies were: Main study, screened in 1965-1968, workplaces across Scotland, the general population of the island of Tiree and mainland relatives; Collaborative study, conducted from 1970 to 1973, 27 workplaces in Glasgow, Clydebank and Grangemouth; Renfrew/Paisley general population study, screened in 1972-1976. After exclusions there were 16 522 men and 10 216 women, grouped by BMI into under/normal weight (< 25 kg m(-2)), overweight (25 to < 30 kg m(-2)) and obese (>or=30 kg m(-2)). MEASUREMENTS: Relative rates (RRs) of liver disease mortality, subdivided into liver cancer and all other liver disease, by BMI category and per s.d. increase in BMI, followed-up to end 2007. RRs of liver disease from any diagnosis on the death certificate, hospital discharge records or cancer registrations (Collaborative and Renfrew/Paisley studies only 13 027 men and 9328 women). Analyses adjusted for age and study, then other confounders. RESULTS: In total, 146 men (0.9%) and 61 women (0.6%) died of liver disease as main cause. There were strong associations of BMI with liver disease mortality in men (RR per s.d. increase in BMI=1.41 (95% confidence interval 1.21-1.65)). Obese men had more than three times the rate of liver disease mortality than under/normal weight men. Adjustment for other risk factors had very little effect. No substantial or robust associations were observed in women. In all, 325 men (2.5%) and 155 women (1.7%) had liver disease established from any source. Similar positive associations were observed for men, and there was evidence of a relationship in women. CONCLUSIONS: BMI is related to liver disease, although not to liver disease mortality in women. The current rise in overweight and obesity may lead to a continuing epidemic of liver disease.

Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT).

1. Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue. 2. Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites. 3. Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats. 4. Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats.

Coordinated evolution of the hepatitis C virus.

Hepatitis C virus is a genetically heterogeneous RNA virus that is a major cause of liver disease worldwide. Here, we show that, despite its extensive heterogeneity, the evolution of hepatitis C virus is primarily shaped by negative selection and that numerous coordinated substitutions in the polyprotein can be organized into a scale-free network whose degree of connections between sites follows a power-law distribution. This network shares all major properties with many complex biological and technological networks. The topological structure and hierarchical organization of this network suggest that a small number of amino acid sites exert extensive impact on hepatitis C virus evolution. Nonstructural proteins are enriched for negatively selected sites of high centrality, whereas structural proteins are enriched for positively selected sites located in the periphery of the network. The complex network of coordinated substitutions is an emergent property of genetic systems with implications for evolution, vaccine research, and drug development. In addition to such properties as polymorphism or strength of selection, the epistatic connectivity mapped in the network is important for typing individual sites, proteins, or entire genetic systems. The network topology may help devise molecular intervention strategies for disrupting viral functions or impeding compensatory changes for vaccine escape or drug resistance mutations. Also, it may be used to find new therapeutic targets, as suggested in this study for the NS4A protein, which plays an important role in the network.