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A heavily modified Ford Mustang Mach One, Shadow ultimately ended up boasting many parts and tweaks worthy of the fastest Boss and Shelby racing Mustangs of the era-- as well as a few outlaw devices to boot. Dark Horse offers readers enough information to build their own modern clone of the car if they wish. Feedback from readers indicates that certain of Shadow's innovations from decades back are being added to some 21st century race and rally cars today. At least until an unusual mugging on the streets of Boston leaves him badly incapacitated one day.

In the aftermath, he suffers a temporary relapse to a state of derangement he'd suffered only once before, some years previous. After regaining his senses, Staute realizes that he now recollects all new and astonishing experiences from his college days, 18 years past.

Staute fears he's losing his mind; or else someone now has the scary ability to inject false memories into a person's head and selected him as their first victim. Desperate to find some clue to who had done this to him and why and confirm he wasn't simply losing his marbles , Staute begins examining his new memories of events he is sure never happened, and soon finds himself enraptured by the tale he finds there. Staute has been coached in advanced space-time physics by accidental time-travelers, who believe him to be a younger version of the 21st century genius who first conceived of their core technologies.

If the travelers are correct as to his identity, perhaps Staute can resolve the problem which has set them adrift across time, and enable them to reach home again. But Staute's efforts soon lead them into a future war instead, and Staute finds himself under siege from both within and without. While they cannot change history and free the victims, they must never-the-less send Staute and an android companion into the living nightmare to obtain data critical to their continued journey through time.

There, the duo must contend with war bots, monsters, and mythological gods brought to life. All rights reserved. What is known Clinical criteria for sepsis in the Sepsis 3 definition are based on a model where the outcome variables are either mortality or a composite of mortality and increased length of ICU stay [ 1 , , ]. These clinical constructs are based on objective measurements that are easily obtained and are linked to outcomes that can be the result of clinical decision making i.

Relatively little is known, however, about the pathobiology of dysfunction in individual organ systems that is associated with these outcomes. Clinical identification is based largely on surrogates e. In contrast, a diagnosis such as myocardial infarction correlates serum markers troponins, creatinine kinase subgroups to functional studies wall shortening on echocardiography, changes in electrocardiogram pattern and anatomy angiography, histology. Absent such a standard, clinical criteria must be used to construct predictive models for sepsis.

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In the current state, these criteria are limited in their ability to differentiate a septic patient from a patient with other disorders. In addition, current predictive models are based on outcomes mortality, length of stay that themselves may be biased by subjective clinical decisions. Future directions Studies that address the lack of gold standards for sepsis-associated organ dysfunction are needed.

This will likely require translation of animal models of organ dysfunction or human markers with specific indicators of organ function.


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Some possible examples include myocardial wall motion on imaging, renal tubular ion pump function, hepatic synthetic pathways, real-time assessment of host immune status, histopathology, and omics-based expression patterns. The short-term translational goal will be to correlate functional findings with existing clinical markers.

Ideally multiple independent assessments of organ function would be used to try to provide a comprehensive assessment of whole organ function. Gold standards for each organ would correlate with available clinical findings laboratory, imaging, functional assessment which would then be correlated with clinical outcomes. Clinical criteria for sepsis definitions could then be adapted to provide more precise identification of organ dysfunction.

Long-term, markers of organ dysfunction that either do not exist currently or exist only in the research domain would ideally make the diagnosis of organ dysfunction more mechanistic and precise. Finally, although it is reasonable to assume that prevention or early treatment of organ dysfunction improves outcome in sepsis, clinical studies should test this supposition.

What is known Sepsis is managed in a variety of settings, including high, low and middle-income countries, differently-equipped facilities and in and out of hospital, including pre-hospital transport. Absent a diagnostic gold standard, screening tools must either predict important outcomes or correlate with the development of a recognizable entity, as a generally agreed clinical picture of sepsis.

The need to avoid missing at-risk patients is an important consideration, especially in environments where a missed opportunity to intervene may have a strong effect on outcomes. Over-triage of patients who may not have sepsis or progress to develop sepsis risks wasting resources and exposing patients to the risks of unnecessary interventional therapies.

At the same time, under-triage of patients runs the risk of late identification, which is associated with increased risk of death. Both of these issues are likely exacerbated in resource-limited environments. The purpose of a good screening tool is to identify populations at risk and compel further assessment and treatment while ideally excluding those not at risk.

Subsequent studies appear to validate the criteria in both low-middle and developing countries [ , , ], although this is relatively limited in scope. There are also two large prospective evaluations of the predictive model in the literature from the United States and Australia [ , ]. In addition, goals for a screening tool may vary by setting, as high-resource environments might potentially trade under-triage for better accuracy, whereas low-resource environments might benefit from initial over-triage, so as not to miss high-risk cases.

Finally, the purpose of the screen—to compel further assessment and treatment—has not been adequately studied. Future directions Existing models for sepsis screening should be refined. As such, the efficacy of screening tools should be tested in different environments.

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Ideally, this would take the form of prospective studies linked to clinically meaningful outcomes, although numerous study designs could potentially yield important information. These studies should look at triggered clinical actions which could be diagnostic or therapeutic, and whose correlation to a variety of clinically important outcomes would be determined. Research should characterize construct or predictive validity of any screening tool including sensitivity, specificity, positive predictive value and negative predictive value.

Studies should consider a variety of clinically important outcomes. What is known Septic shock occurs in the setting of a physiologic state of hypoperfusion. While lactate typically correlates with perfusion abnormalities, it may also be associated with abnormal metabolism. Further, while Sepsis 3 and previously Sepsis 1 and 2 includes definitions without recommendations for management, the Surviving Sepsis Campaign Guidelines give differential antibiotic recommendations for sepsis as compared to septic shock, often based on very low certainty of evidence [ 3 ].

Although many clinicians characterize shock by perfusion indices, this does not provide a clear definition based on mechanisms. Further, the clinical criteria in Sepsis 3, while based upon large database analysis, were not unanimously agreed upon by the taskforce. In addition, many locations throughout the world cannot measure lactate, which leads to the question of how one identifies septic shock at the bedside if a clinician cannot measure lactate.

Further, there is limited evidence comparing the metabolic and circulatory abnormalities between sepsis and septic shock, and it remains unsettled whether septic shock is truly a unique entity or simply a manifestation of a greater severity of sepsis. Future directions Research should address the fundamental question of whether septic shock is a disorder that is distinct from sepsis.

If it is, efforts should address proxies for septic shock that have predictive validity for important outcomes or construct validity for a helpful clinical entity. These proxies could be correlated to clinical presentation in an effort to identify a unique group of high risk patients.

Models could be created from large databases and then prospectively validated in larger groups of patients. The impacts for diagnosis, treatment and outcomes should be prospectively assessed. Importantly, investigation should address the question of whether septic shock needs to be treated differently than sepsis outside of the institution of vasopressors. Investigation should not rely on an outcome mortality that is both the independent variable used when creating the definitions to differentiate the two entities and the dependent variable the most common outcome used in clinical intervention studies.

Finally, the clinical criteria for septic shock in Sepsis 3 should be prospectively validated. What is known Clinical criteria used to identify sepsis in patients with suspected infection are derived from the association between mortality, length of ICU stay, and a discharge diagnosis of sepsis. At the bedside, clinicians draw on a larger collection of data to make diagnostic and therapeutic decisions.

Lack of appropriate data

Ultimately, practitioners make clinical decisions, such as limiting life-sustaining therapies and deciding to transfer patients into or out from an ICU, based on an impression of prognosis. In addition, qSOFA has fairly robust validity in predicting mortality and prolonged stay in patients prior to ICU admission although its accuracy is lower in the ICU [ , , , ]. However, both mortality and increased length of ICU stay are themselves influenced by clinical decision making.

Many important clinical outcomes, such as cognitive dysfunction and lasting organ dysfunctions, have not been studied. It is also unclear if the variables or specific elements in SOFA need updating. The pathobiology of many if not most adverse outcomes in the ICU is not described. Future directions Research is needed both in improving which clinical information is utilized and in assessing patient-centric outcomes beyond mortality and length of ICU stay understanding that these continue to be critically important outcomes.

Answering the two components of this research question will therefore require studies ranging from but not limited to a animal modeling, b new study designs, c big data approaches, d creation of new technologies, and e survey and face-to-face meetings to understand what outcomes are most valued. Measures should be assessed individually and as multiple, interactive variables, to establish relationships between different organ dysfunctions.

What is known The way in which ICUs and their larger hospitals and healthcare systems are organized and managed affects quality and efficiency in sepsis care. Further, both early recognition and early intervention in sepsis saves lives.

Performance improvement efforts for sepsis are associated with improved patient outcomes. An example of this is the Surviving Sepsis Campaign bundles, in which rapid antibiotic administration and fluid resuscitation are associated with lower mortality [ 4 , , , , ].

Sepsis performance improvement programs should optimally have multiprofessional representation physicians, nurses, advanced practice providers, pharmacists, respiratory therapists, nutrition support specialists, administrators. Successful programs should include protocol development and implementation, targeted metrics to be evaluated, data collection, and ongoing feedback to facilitate continuous performance improvement. While it is known that adaptation of process of care to different health care systems around the globe is highly variable, there is a lack of understanding both in the extent of this variability and its causes.

Within bundles, even if beneficial in aggregate, this does not mean that each component has equivalent efficacy or any efficacy and whether other critical elements are missing entirely that would potentially change outcome. Future directions Research towards understanding which systems of sepsis screening and care delivery are most beneficial and cost-effective in a wide variety of patient care environments is critical.

This should not be limited to the ICU but include the emergency department and the wards and potentially both pre-hospital emergency care and outpatient facilities for sepsis screening as well [ , ]. These can be intra-location delivery systems i. ICU-specific, ED-specific , intra-hospital, intra-health care system or regionalized such as in trauma care in many countries. Methods of determining and then tracking optimal communication, transitions of care, and multidisciplinary coordination of care will likely be critical to this effort.