This article describes a neural model of the anatomy, neurophysiology, and functions of intrinsic and extrinsic theta rhythms in the brains of multiple species. Topics include how theta rhythms were discovered; how theta rhythms organize brain information processing into temporal series of spatial patterns; how distinct theta rhythms occur within area CA1 of the hippocampus and between the septum and area CA3 of the hippocampus; what functions theta rhythms carry out in different brain regions, notably CA1-supported functions like learning, recognition, and memory that involve visual, cognitive, and emotional processes; how spatial navigation, adaptively timed learning, and category learning interact with hippocampal theta rhythms; how parallel cortical streams through the lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC) represent the end-points of the What cortical stream for perception and cognition and the Where cortical stream for spatial representation and action; how the neuromodulator acetylcholine interacts with the septo-hippocampal theta rhythm and modulates category learning; what functions are carried out by other brain rhythms, such as gamma and beta oscillations; and how gamma and beta oscillations interact with theta rhythms. Multiple experimental facts about theta rhythms are unified and functionally explained by this theoretical synthesis. The topic of hippocampal theta rhythms combines several basic themes about how our brains work. These themes include, in varying degrees of generality:•How theta rhythms were discovered;•How theta rhythms organize brain information processing into temporal series of spatial patterns;•How distinct theta rhythms occur within area CA1 of the hippocampus and between the septum and area CA3 of the hippocampus;•What functions theta rhythms carry out in different brain regions, notably CA1-supported functions like learning, recognition, and memory that involve visual, cognitive, and emotional processes;•How spatial navigation, adaptively timed learning, and category learning interact with hippocampal theta rhythms;•How parallel cortical streams through the lateral entorhinal cortex (LEC) and the medial entorhinal cortex (MEC) represent the end-points of the What cortical stream for perception and cognition, and the Where cortical stream for spatial representation and action;•How the neuromodulator acetylcholine interacts with the septo-hippocampal theta rhythm and modulates category learning;•What functions are carried out by other brain rhythms, such as gamma and beta oscillations; and•How gamma and beta oscillations interact with theta rhythms.per se, I will set the stage by discussing some of the main anatomical, neurophysiological, and functional properties of the hippocampus with which it interacts.Before discussing theta rhythms Brain circuits within the hippocampus (HC) interact with the MEC to regulate spatial learning and memory . ParticuThe classical article of Entorhinal grid cells provide inputs to place cells in hippocampal area CA3. They occur in the superficial layers of MEC and exhibit one of the most remarkable receptive fields of any cell type in the brain. Indeed, each grid cell can fire in multiple locations that may form a regular hexagonal grid . It is kCells in a population of grid cells at a given dorsoventral location in rat MEC exhibit receptive fields that are offset from each other . As the least common multiple of the grid cell scales that drive it  circuits automatically compute these co-occurrences to learn grid cell and place cell receptive fields, albeit at different levels of the learning hierarchy . SOMs ocAll the inputs that drive grid cell learning arise from ring attractor circuits, as noted in Section 1.4. One type of ring attractor circuit processes linear velocity inputs that input to stripe cells. The other ring attractor circuit processes angular velocity inputs that input to head direction cells, which modulate the directional selectivity of different stripe cells.Populations of stripe cells with a given spatial period that exhibit multiple directional preferences and spatial phases initially project with random adaptive weights to cells in the category learning layer of a SOM . LearninIn vivo, grid cells and place cells of increasing spatial scale are found along a dorsoventral gradient. The GridPlaceMap model explains how stripe cells of different spatial scales learn to activate different locations along the dorsoventral axis in layer II of MEC, thereby triggering learning of grid cells with increasing spatial scales. The selection of different grid cell spatial scales on the dorsoventral gradient is driven by a gradient in the rates at which cells respond along the dorsoventral gradient, from fast to slow. Cells that respond more quickly are active for shorter time intervals than cells that respond more slowly.A longer duration of sampling enables each grid cell to sample stripe cells over a larger spatial scale. The duration of sampling thus covaries with the spatial scale of the learned grid cells. Likewise, multiple entorhinal grid cell scales combine through learning to give rise to a dorsoventral gradient of hippocampal place cells, each of which can represent larger spaces than can an individual grid cell. Due to these temporal-to-spatial conversions, the SOM model shows how the dorsoventral gradient in response rates develops a spectrum of grid cell scales and place cell scales. It is thus called the Spectral Spacing model.population activity can learn to peak hundreds of milliseconds after their onset. That is why the GridPlaceMap model of grid cell learning is called a Spectral Spacing model. The rate gradient for spatial learning occurs in the MEC and its hippocampal projections. The rate gradient for temporal learning occurs in the LEC and its hippocampal projections.Remarkably, the response rate gradient for spatial learning is computationally homologous to a rate gradient that had, 20 years earlier, been used to explain hippocampal data about adaptively timed learning , 1996. Ttime cells in the hippocampus by One of the most striking properties of the Spectral Timing model is its Weber Law property whereby cells in the spectrum that respond at larger times also respond with longer durations. This prediction was strongly confirmed by the discovery, 20 years after it was made, of In summary, parallel dorsoventral gradients in the rates that cells respond within the entorhinal–hippocampal system may create multiple smaller spatial and temporal scales in the entorhinal cortex that can be fused into larger spatial and temporal scales in the hippocampal cortex, notably scales that are large enough to control adaptive behaviors during spatial navigation in large enclosures. The mechanistic homology between these spatial and temporal mechanisms suggests why they may occur side-by-side in MEC and LEC dorsoventral gradients through entorhinal cortex into the hippocampus.Spatial representations in the dorsal, or Where, cortical stream for spatial representation and action go through postrhinal cortex and MEC on their way to hippocampal cortex, whereas object representations in the ventral, or What, cortical stream for perception and object recognition go through perirhinal cortex and LEC on their way to hippocampal cortex , where tThese parallel and homologous spatial and temporal representations may clarify the role of hippocampus in supporting episodic learning and memory , since esequences of object and spatial information. The importance of sequential processing during both episodic learning and spatial navigation have led Episodic learning combines information about particular contextual cueing. For example, when we are in our kitchen and see a refrigerator and a stove at particular positions, we then expect to see our sink at a prescribed different position. The psychophysical literature about contextual cueing describes how sequentially experienced objects and positions contribute to such expectations, and guide efficient searches to discover and act upon desired goal objects , but that RSA was absent if the animals chewed food, washed their faces, etc. (automatic movement). The results also indicated that the mere repetition of the same motor act does not lead to a disappearance of hippocampal RSA, when such activity was initially present.”The article by Several articles also reported that the septal projection that drives the extrinsic theta rhythm is modulated by acetylcholine e.g., . Huerta The subsequent discussion will situate the above facts within a larger modeling context that mechanistically and functionally explains them and many others.The following facts and theoretical results clarify how cholinergic signals from the medial septum to the hippocampus influence the extrinsic theta rhythm. One measure of this effect is how disruption of the theta rhythm, or cholinergic modulation, or both influence the learned hexagonal spatial firing patterns of entorhinal grid cells.Experiments that reduce the theta rhythm by inactivating the septum cause a correlated reduction in the hexagonal spatial firing patterns of grid cells . Figure Does inactivation of the septum lead to grid cell disorganization because the theta rhythm collapses, or because cholinergic modulation of grid cells collapses, or both? Some authors, particularly those who have espoused that oscillatory interference causes grid cell receptive fields, have concluded from these data that “spatial coding by grid cells requires theta oscillations” and “support a role of neuronal oscillations in the coding of spatial information” . In othevigilance control , then the LTM trace w31 will learn that association, while the LTM trace w32 decreases because its abutting dendrite is then inactive.How does a winning activity trigger a teaching signal? In the READ circuit, the winning cells remain active long enough to trigger back-propagating action potentials in their dendrites , 13, whinormalized net activities in which the smaller activity is inhibited to zero and the larger activity is sensitive to the ratio of the inputs. The LTM traces can continue to learn these normalized net values throughout life, without ever saturating.Because the READ circuit is a recurrent on-center off-surround network whose cells obey shunting dynamics , the comout from a previously learned LTM weight occurs when a signal goes down a dendrite to its basal cell. Read-in of a new LTM weight value occurs when a teaching signal goes up the dendrite from its basal cell. A single cue-activated signal Si that persists for hundreds of milliseconds or seconds needs to be able to read-out its previously learned LTM weight and to read-in any new information with which it is associated. A cyclic rhythm of signaling down and up the sampled dendrites enables a sustained input signal to experience both associative read-in and read-out on its abutting dendrites, without incurring a noise-learning catastrophe. Such a dendritic rhythm is the price of avoiding noise-driven catastrophic forgetting of previously learned featural differences.An electrical signal cannot go both down a dendrite and up it at the same time. Read-In summary, the following cyclic processes are needed to dissociate associative read-out from read-in:1.out of cue-activated LTM-gated signals, as from the conditionable signals Siwij with adaptive weights wij, j = 1,2, in the READ circuit in Read-2.contrast-enhancing competition via the recurrent on-center off-surround feedback loop in 3.in of the contrast-enhanced and normalized activities into the adaptive weights wij in read-4.repeat.Such a recurring read-out/choice/read-in cycle is assumed to also occur in self-organizing maps, or SOMs, during perceptual, cognitive, and spatial category learning e.g., , not jusIn The cyclic nature of this process can now be better understood mechanistically. As noted above, the first reason for cyclic learning is that an electrical signal cannot go both down a dendrite  and up igated dipole field  in The proposed answer, briefly stated, is by designing the competition that interpolates intervals of read-out and read-in as a le field ,b, 1984.F2 of the network. This recurrent competition chooses the category that receives the largest total input from the currently active bottom-up feature pattern , such as a light or tone, shuts off hundreds of milliseconds before a rewarding or punishing unconditioned stimulus (US), such as a shock or food, turns on. This requires that a CS-activated memory trace be sustained during the inter-stimulus interval in order to learn an adaptively timed association between CS and US that enables the CS to elicit a CR. As these categories are learned, the hippocampus maintains inhibition of the orienting system (not shown), so that motivated attention can be maintained throughout the adaptively timed category learning interval. The prefrontal cortex can also, at the same time, learn to activate adaptively timed actions via the cerebellum. When category learning and performance is complete, the hippocampus is disengaged, memory consolidation has occurred, and the CS alone can elicit an adaptively timed conditioned response (CR). Data about theta modulation have been reported in autistic individuals . The imbThis article summarizes neural models of cortico-hippocampo-cerebellar dynamics and of the gamma, beta, and theta rhythms that underlie these dynamics during both normal and abnormal conditions.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To identify priorities for administrative, epidemiologic and diagnostic research in sepsis.As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis.Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process.The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis?There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care. As a consequence of the findings from the methodologies used by the Sepsis-3 Task Force and the 2016 Surviving Sepsis Campaign Guidelines [As part of a modified Delphi consensus process, members of the Research Committee deliberated research questions to be prioritized. Each member initially submitted five research questions on whatever sepsis topic they thought most important. Through a voting prioritization process , these qEach question was assigned to a subcommittee member for further elaboration. Each elaborating author was asked to provide further background to the research question by addressing what is known, what is not known/gaps in knowledge, and provide future directions for research priorities. These contributions were circulated among the group and harmonized into a single document. Editing was managed by all members and further input given by the committee co-chairs. We present the results of this process. The findings presented pertain to the adult sepsis guidelines, but many be relevant to pediatric sepsis too.The Surviving Sepsis Campaign supports a structured approach to sepsis care that is based on process measures and care bundles. Such structure might raise awareness about the problem and provide a consensus approach to its diagnosis and treatment, emphasizing measures that are supported by existing science. To realize the guidelines’ full potential, science supporting the recommendations must clarify not only the benefits and risks of individual interventions, but how these interventions, in combination and applied in a complex clinical environment, improve the process of care to realize better outcomes.Sepsis is a time-dependent condition in which hourly delays in diagnosis or in the initiation of effective treatments are associated with adverse outcomes and higher costs –10. UnfoEducation about best practices in sepsis has benefitted the clinical approach to patient care . IrrespeBest practices and goals are sometimes controversial, and incentivizing timely implementation can introduce trade-offs. For example, improvements associated with the early provision of antibiotics may increase the risk of administering the wrong drug . The setMandatory quality improvement programs improved sepsis bundle compliance and enhanced sepsis care , 26–29. Locally directed protocols that used standard criteria and outcomes enhanced multi-professional involvement and coordination  and imprIneffective communication and coordination of care may lead to adverse consequences and patient harm. Medical lapses, misadventures, delays, conflicting information, repeated tests, polypharmacy, higher costs, increased workload, and reduced confidence in decisions can result from suboptimal professional interactions, either through uncoordinated activity or poor shared situational awareness –42. StruKey points:Timely application of appropriate therapies is associated with improved outcomes in sepsis care.Improvement programs can have unwanted effects, such as the delivery of unnecessary therapies when the diagnosis is uncertain.Effectiveness of quality improvement programs correlates with enhancing clinical judgment, speeding delivery of care, establishing clear responsibilities, and facilitating coordination between clinicians.Although bundles are associated with improved outcomes, there is limited understanding about sources of effectiveness or how to test them. Key questions exist for the roles of coordination, teamwork and group cognition. An important knowledge gap concerns the roles for standardization and flexibility to account for local and patient-specific conditions. Endpoints, their measurement, and how results influence performance need further explanation.A knowledge gap exists regarding strategies for health care modeling in different environments. Educational research is lacking to define and address gaps in understanding about best practices. Using care standardization as an endpoint requires ongoing measurement against an evolving evidence base, as standards and best practices change over time. Local factors that might drive variability are inadequately described. How knowledge gaps lead to variability in implementation of sepsis care is largely unknown.Current detection strategies emphasize rapid identification of patients at risk of further clinical deterioration. The time-dependence of detection and interventions could be better described. Uncertainty in sepsis research investigating the timing of care delivery relates to an inconsistent approach to “time zero” for therapies. Controversies about timing trade-offs for therapies such as antibiotics persist, and are informed by limited data that illustrate either risks or benefits, but not both. Tradeoffs may vary by location and situation.Studies of out-of-hospital antibiotic administration do not adequately address severity of illness, which might influence the benefits of timely administration. Although protocols are appealing to standardize care, they require validation, due to a lack of understanding of the factors that make them optimal –45. The Improvements in the administration of sepsis care will come from a stronger foundation in education, organizational and cognitive sciences. Cost-effectiveness, delivery efficiencies and unwanted trade-offs should be compared. Means of improving situational awareness, interdisciplinary collaboration and communication are objectives for investigation. Cognitive and social research exploring interventions that enhance collaboration could provide useful information for the creation of more effective quality improvement strategies. Identifying key metrics, ways to measure them and provide feedback to participants might improve program effectiveness. As more effective programs result from such investigations, another future target for systems research should be a better understanding of how to enhance the willingness of healthcare professionals to adopt sepsis performance improvement programs.Various cognitive artifacts, objects or cues that help clinicians think, might improve group consensus and sense-making. Sepsis bundles were developed as a cognitive strategy for implementing guideline recommendations, and future efforts are needed to build a better working knowledge of how bundles work and how to improve upon them to facilitate better care. Electronic medical record data management and alerting could support the early detection and efficient and timely delivery of high-quality interventions to patients with sepsis , 48, 49.What impacts, positive and negative, occur as a consequence of standardized sepsis care, taking into consideration timing, appropriateness  and effectiveness?What interventions enhance coordination and communication, and how can these activities be measured?What devices can help clinicians manage complex decision-making in the setting of sepsis?A goal of epidemiology is to infer biological rationales from population-based observations . In sepsApplying different sepsis definitions leads to variable assessments of sepsis epidemiology. For example, while overlap is quite high , Sepsis-Using epidemiologic data like gender, ethnicity, nationality, resource availability, age, and comorbid conditions in sepsis research is difficult, in large part because of confusion arising in the criteria used to link outcomes to independent clinical variables. For example, the effects of age or coexisting illness on outcome can overwhelm the contribution of other variables. One approach to this problem is to use available data to create sepsis “subtypes”. Clinical presentation, progression, response to treatment, and risk of mortality may be affected by variations in the response of each unique host –65. BiomKey points:Changing sepsis criteria lead to varying estimates of incidence and mortality.The prevalence of comorbidities and access to health care resources in different populations contribute to different estimates in sepsis epidemiology,Creation of “types” using multiple data sources enhances diagnosis and prognosis estimates.The lack of consensus on definitions/clinical criteria and on the appropriate source of data makes quantifying the global burden of sepsis challenging . ConfirmUntil definitive classification criteria are developed, estimating epidemiologic trends and identifying appropriate endpoints will remain challenging. Classifying sepsis on the basis of clinical or molecular phenotypes/endotypes must be refined if the classifications are to identify high-risk patients or evaluate therapies . In spitIn order to better apply population data to sepsis research, further efforts must be made to disentangle the effects of multiple independent variables on susceptibility and treatment responses. Isolating the effects of gender, race/ethnicity, nationality, and resource availability should be an explicit goal of future epidemiologic and therapeutic investigations. Investigations should determine if separating patients into subgroups could be useful earlier in the disease, affecting prognostic prediction, use of ICU resources, or guiding treatment , 83. ProHow can investigators disentangle complex interactions to isolate important clinical factors when investigating sepsis therapies?What factors identify subgroups for diagnostic or prognostic enrichment of study cohorts?How can datasets be managed to reduce confounding or the dominance of one factor over other important ones when trying to describe sepsis subsets?Sepsis is defined as “life-threatening organ dysfunction caused by a dysregulated host response to infection” . Thus, oAt times, it is difficult to identify organ dysfunction, or to differentiate it from the other defining characteristics of sepsis, infection and a dysregulated host response. For example, organ dysfunction may be dependent on the host response, and dysregulation of the host response may in turn depend on the infecting organism. Further complicating matters is terminology; dysfunction, injury and failure are often used interchangeably. For convenience, failure may be thought of as an irreversible process, while dysfunction denotes the possibility that the process can be reversed –88. HoweBiomarkers for sepsis-induced dysfunction have been validated for several organ systems , 89, 90.Objective criteria exist to denote lung and kidney dysfunction , 90. HowKey points:Many markers for organ dysfunction are nonspecific.Combinations of markers may improve the ability to detect organ dysfunction.Dysfunction and injury are separate processes, but frequently confused.In most cases, the relationship between most biomarkers and actual organ dysfunction has remained elusive. The deficit in knowledge reflects the absence of gold standards, and is also a comment on the lack of studies truly validating many biomarkers. Pathobiology of organ dysfunction is not well described. In addition, the descriptors of organ dysfunction change as sepsis progresses. The relationship between dysfunction and injury in specific organ systems is poorly characterized. When testing and applying criteria for organ dysfunction, investigators and clinicians need to account for changes that reflect infection itself versus the effects of other pathologic states  or insults . Counting dysfunction by organ systems does not adequately explain the concept of sepsis-associated dysfunction, nor does it explain the interrelations between different dysfunctions.In the future, clinical criteria for sepsis should be informed by patterns that reflect a disease state with expected outcomes whose trajectory can be corrected with proper therapies. Clinicians and researchers should disentangle dysfunction caused by new-onset sepsis, by sepsis perturbations  or by pre-existing sepsis. A better approach to melding indices of cell damage with those of impaired organ function is fundamental. Efforts are needed to explore the relationship between mechanisms of injury and dysfunction. For example, both microcirculation changes and mitochondrial aberrancies are invoked as causes of injury. It is likely, however, that both are induced by sepsis, and their relationship to each other is unclear. Therapeutic targets of interest include prognosis markers and correction of organ dysfunction. Investigators should look for better markers that can provide actionable information before injury has already developed, and indicate a process whose culmination is sepsis-induced organ dysfunction. A key gap in understanding the pathobiology of sepsis could be addressed by efforts to integrate measureable data qualifying function and dysfunction.A major obstacle to research is circular logic. By defining sepsis as organ dysfunction from a dysregulated response to infection but lacking a way to establish that dysfunction is sepsis-related (because sepsis is defined by organ dysfunction in the first place), clinicians and researchers constantly contend with establishing which came first. The proposed paths we have cited offer an opportunity to solve this problem and conceive of interventions to prevent further morbidity.Understanding the ways dysfunction can be detected will aid in identifying patients for therapies. Integrating studies that measure and combine imaging, molecules and assess function into more specific patterns could help fulfill the goal of establishing validated signals of how a dysregulated response evolves. Investigation of phenotypic variation might yield useful information about individual susceptibilities to dysfunction, or help determine patterns specific to sepsis. All investigations must contend with the reality that sepsis outcomes depend on patients’ responses, comorbid conditions and baseline status, sources of infection and appropriateness of therapies. Being able to measure function and dysfunction is a way to disentangle these variables and a route to therapeutic insights.What is the pathobiology of organ dysfunction?What is the relationship between dysfunction and injury?How can dysfunction from sepsis be differentiated from that caused by other coexisting pathologic states ?While epidemiologic study helps determine sepsis susceptibility and response to therapy in populations, insights can be used to identify patients for clinical care. Better description and categorization of patients supports clinical diagnosis and effective therapies. A lack of clinical criteria that effectively screen for sepsis is a major challenge. This defect has repercussions for epidemiology, treatment, quality improvement initiatives and research efforts.Absent a diagnostic gold standard, outcome proxies such as mortality or ICU admission are generally used to identify patients with sepsis. These proxies calibrate a screening model, but they can be influenced by factors such as standards of care, setting and inequities. For Sepsis-3, using a SOFA score leverages available but imperfect proxies for organ dysfunction as criteria for sepsis . ImproveElements of the systemic inflammatory response syndrome (SIRS) criteria  have beeThe Sepsis-3 Task Force criteria propose the quick Sepsis-Related Organ Failure Assessment (qSOFA) score as a prompt for clinicians to look for underlying organ dysfunction and sepsis in non-ICU patients , 55. PreUsing the full SOFA score as a screening tool is appealing in that it incorporates the concept of organ dysfunction, albeit in a limited way. Derivation and validation studies suggest it is useful in the ICU setting and that an increase in score of 2 or more is highly predictive of hospital mortality . The eSOClinical deterioration models and early warning scores, such as the National Early Warning Score (NEWS) or the Modified Early Warning Score (MEWS) , 116, maIn resource-limited settings, screening is mostly based on available data and cannot count on costly diagnostics or the deployment of response teams. The routine monitoring of vital signs and vigilance for infection can raise suspicion of sepsis, but vital sign abnormalities can be seen in many non-sepsis conditions .Predictive analytics can currently produce robust, adaptive models to sort patients by risk for various outcomes, and models exist to predict outcomes highly correlated with sepsis –122. To Rapid acquisition of actionable data is crucial. Screening too early erodes specificity. Screening too late reduces the ability to mitigate deterioration and organ dysfunction. The original qSOFA validation study considered data from 48 h before to 24 h after the onset of infection . This peKey points:Sepsis identification is based on proxies for dysfunction that are used in combination .qSOFA was conceived as a quick tool to prompt further clinical assessment for sepsis.Warning systems may enhance sepsis screening, but must be tuned to optimize alarm volume and effectiveness. These factors can be setting-dependent.The best screening tool for each setting has not been determined. SOFA was developed in cohorts receiving care in high-resource environments, mostly in the United States, and may not perform as well elsewhere. The scale includes outdated therapies and measurements that may not correlate well with true organ dysfunction. An aggregate SOFA score of 2 might represent mild abnormalities in 2 organ systems or more significant abnormalities in one. It is unclear that these are equivalent states in the setting of infection. Existing proxies for organ dysfunction are limited. Linkages to important outcomes not influenced by other external variables are lacking. There are few studies of sepsis screening that take into account the mechanics of how the screening affects work flow and how the work flow changes outcomes. Currently, there is an opportunity to better harmonize definitions, diagnostics and treatments to improve sepsis outcomes. Tradeoffs in different approaches are not characterized, in particular those involving sensitivity and false positive rates, model consistency versus generalizability, detection-focused versus action-focused constructs, and targeting early cases versus all cases.Until better markers for organ dysfunction are identified and validated, screening for sepsis based on organ dysfunction will be limited. Suspecting infection is still a good first step in screening, but there are currently limited tools to enhance the suspicion that infection is present. Although the calculation of a SOFA score as a screening tool appears reasonable, it lacks prospective validation of its usefulness at the bedside. Deterioration models currently do not use markers of deterioration that are unique to sepsis. Predictive analytics systems have performed adequately in detecting sepsis cases retrospectively, but there is no clear demonstration that their use effectively changes relevant clinical outcomes.Better screening for sepsis would include improved screening for organ dysfunction. Selecting better proxies for organ dysfunction and, more problematically, for a dysregulated host response, and validating their predictive abilities in a variety of settings are imperatives for improving screening. These proxies would ideally be easily available, capture dysfunctions early and be specific for sepsis-induced organ dysfunction. Identification of common variables  across a variety of settings would enhance the ability to screen and treat the disease, and to study the effects of screening. Operationally, improved descriptions of relevant outcomes, and the linkage between screening tools, therapeutic responses to the screens and outcomes would help guide clinical recommendations.Tools using data from the electronic medical records might, using algorithms, be adapted to predict cases of sepsis. There is a need to explore how algorithms could trigger appropriate diagnostic and therapeutic measures. The relevance of these algorithms may depend on the resources available and it will be important to assess whether they hold promise in lower income settings. Finding better ways to use the data available to clinicians in a variety of settings is an important focus for future research.What markers identify a dysregulated host response to infection?How can screening tools lead to actions that improve clinical outcomes?How can screening be implemented in resource-limited environments?Shock has long been viewed as an extreme form of circulatory insufficiency whose association with mortality is validated –125. TheCharacterizing shock of any etiology becomes problematic when trying to determine how low the blood pressure must be for an entity to be called “shock”. In most forms, the blood pressure is deemed to be sufficiently low to be considered shock if it is associated with a clinically apparent change in organ function, e.g., an altered mental status. Other characteristics used to identify organ dysfunction include oliguria, nausea/vomiting or shortness of breath. In sepsis, organ dysfunction often precedes the development of hypotension. By definition, it has to manifest in order to diagnose sepsis. Thus, conventional criteria for identifying shock may not apply. Indeed, it is tempting to consider “septic shock” as simply “sepsis where the sepsis-induced organ dysfunction lies in the cardiovascular system”. An additional difficulty arises when considering the underlying cause of hypotension. In most forms of shock, the primary defect is known. This knowledge identifies a rational approach to therapy. In sepsis, however, the underlying defect is unknown. Indeed, virtually all the abnormalities that lead to hypotension in other shock states are present in sepsis Table —but thesTo revise the definition of septic shock the Sepsis-3 task force sought to reconcile these different considerations. Given that sepsis-associated mortality is affected by what organ systems are dysfunctional, considering septic shock as a unique entity might not be justified. The view of shock as a state of cellular, and not organ system, dysfunction removed the requirement for hypotension. After debate, the task force arrived at a compromise. Thus, septic shock is defined as “a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially raise mortality”. This formulation encompasses both circulatory and cellular abnormalities while acknowledging that, at this time, the main distinction between sepsis and septic shock lies in the rate of survival.In Sepsis-1, septic shock is defined as “sepsis with hypotension, despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status”. Sepsis-Perhaps the most important issue, however, is that both Sepsis-1 and Sepsis-2 are products of expert opinion. The choice of the variables used as clinical criteria  was made by task force members.The clinical criteria for septic shock enumerated in Sepsis-3 were identified based on expert opinion, but the process was more refined. A literature search identified 44 studies reporting septic shock mortality that contributed to a list of the clinical criteria for septic shock. This list was used to inform a Delphi process among the task force members , 102. ThSince the publication of Sepsis-3, a limited number of studies examining septic shock have confirmed the findings . The SepIn perhaps the most comprehensive study to date, data from 205,632 patients identified as having sepsis using either Sepsis-1/2 or Sepsis-3 criteria were extracted from the national critical care database in England . In thisKey points:Criteria for septic shock were produced by a consensus process and are nonspecific.Sepsis-3 criteria for septic shock reflect a more refined process and perform better at discriminating a high-mortality cohort while missing few cases.The most readily explored open questions include validation of established criteria and evaluation of hemodynamics. Septic shock variables, alone or in combination, have not been verified prospectively. Areas for study include prospective validation of Sepsis-3 clinical criteria for septic shock, further evaluation of the criteria in resource challenged populations and environments, and investigation of the use of serum lactate levels to improve discrimination. The impact of added proxies that involve non-routine and potentially expensive tools  on the validity of Sepsis-3 criteria is unknown. It is important to examine the cost–benefit ratio of any added criteria. Other clinical questions include: When, relative to fluid administration, should vasopressors be initiated? and: Is there a better “vasopressor of choice” than norepinephrine?It remains unclear if there are tangible pathobiological difference between sepsis and septic shock. Such a dichotomy would demonstrate that septic shock is an entity distinct from sepsis and not just “sepsis with CV dysfunction”. It also would eliminate mortality from the definition. Septic shock should be more than merely a subset of sepsis where mortality is substantially increased. In the current state of knowledge, we lack a “gold standard” that can be used to evaluate clinical criteria, biomarkers and other proxies. If septic shock is indeed a unique disorder, are there biomarkers that identify it without also identifying sepsis? If so, does it require treatment that is different from what is used to treat sepsis and support the circulation? Answers to these questions would support the clinical use of the term “septic shock”.Regarding the concept of shock, a better characterization of pathobiology could inform diagnosis and therapeutics. Is shock a macroscopic or microscopic phenomenon? Is there a spectrum—from biochemical to sub-cellular  to cellular to tissue/organ system to systemic manifestations ? Are there ways to differentiate between these possibilities? In other forms of shock, the initiator is known.Another unanswered question is whether there is a chronological progression from infection to sepsis to septic shock, or if it is possible to transition from infection directly to septic shock. This should be the case if the underlying pathobiology of sepsis and septic shock are different.New definitions or identifying criteria would be expected to disentangle “septic shock” from “sepsis with dysfunction of the cardiovascular system”. If septic shock is to be a separate entity, the diagnostic approach to it should differ from that used for sepsis absent septic shock and efforts should seek to progress towards a “gold standard” for diagnosis and study. Obtaining insight as to whether underlying factors mediate the transition from simple infection to sepsis or to septic shock and justify designating septic shock as a unique entity is fundamental. Future research would specify therapeutic targets for septic shock that are independent of those attacked when treating sepsis.Is septic shock a distinct entity from sepsis?What is the pathobiology of septic shock?How can the presence of shock be confirmed independent of the diagnosis of sepsis?When should specific interventions be initiated in the setting of shock that would not otherwise be used in sepsis without shock?Treating sepsis should improve clinical outcomes, but addressing what constitutes an important outcome is a challenge. Viable construct criteria for sepsis should associate with whatever outcomes are selected. Ideally, treating some or all criteria improves these outcomes, but this relationship cannot be assumed. The presumed pathobiology of sepsis suggests that most criteria serve as markers rather than drivers of disease. These criteria should have clinically relevant outcomes validity. Whereas pursuit of a definition might improve the description of what sepsis is, clinical needs focus more on the parameters that can trigger therapies that improve outcomes.Absent defining features, sepsis is either inferred subjectively  or apprThe current identification paradigm for sepsis (Sepsis-3) makes use of established criteria (SOFA) . This apThere are three essential elements to the concept of sepsis: infection, a dysregulated host response, and organ (cellular) dysfunction. Defining infection might be the least problematic, but it is imperfect. Defining a dysregulated host response implies a sound understanding of a regulated host response, but the understanding is incomplete. A stress response to injury has multiple descriptions , 142. ItUse of proxies leads to a compounding problem. As one proxy for organ dysfunction is combined with others, and then attributed as a part of a dysregulated host response resulting from infection, inaccuracies of each proxy multiply, such that the model’s performance is degraded even if each component by itself is reasonably accurate. Linking proxies and outcomes, one sees a related problem. Assume a marker picks up 90% of patients with sepsis. We want to correlate this marker with an outcome like ICU length of stay. If 90% of patients with sepsis have an increased length of stay, only 81% of those selected by the marker will have the outcome we are using to validate our model.Sepsis does not occur in a clinical vacuum, and patient comorbidities, susceptibilities and responses (regulated and dysregulated) are expected to vary. A neutropenic or immunosuppressed patient will have a different response to bacteremia than someone with “normal” immune function. It may not be one disorder. Data suggest that there may be different phenotypes or endotypes for sepsis .Outcomes validity for any scoring model is sensitive to the outcomes chosen. Sepsis-3 criteria use mortality and intensive care unit (ICU) stay of 3 days or longer , and manKey points:Sepsis-3 criteria leverage a scoring system to identify patients likely to benefit from sepsis therapies.Most clinical information guiding the diagnosis of sepsis depends on proxies that may be markers rather than drivers of the dysregulated host response.Sepsis-3 criteria are validated against outcomes that may not be directly related to sepsis.Available data inconclusively describe the relative beneficial and harmful effects of biologic perturbations, blurring the definitions of regulated and dysregulated. Clinical information consists of inflammatory biomarkers, endocrine abnormalities, altered metabolic signals and evidence of organ dysfunction, but the significance of each of these findings is unclear. Constructing a formulation of sepsis based on proxies doesn’t necessarily specify the direction of the abnormality. For example, elevated stimulating hormones might reflect central overstimulation or peripheral underactivity, requiring different treatments. Clinicians and scientists struggle to separate dysfunctions driving a dysregulated host response from those caused by the host response. Available scoring systems lack organ-specificity. Improvements from the addition of data need further validation.We still know very little about which patterns in clinical information can identify patients requiring specific care to improve outcomes. Gaps include separating drivers from markers, injury from dysfunction, identifying infection and finding better characteristics for regulated and dysregulated host responses. We lack sufficient grasp of what should be important outcomes. Clinical research depends on uncovering patterns that identify patients at risk for clinically relevant outcomes and for whom interventions can change clinical trajectories. Available markers approximate interactions at a cellular and intracellular level. These proxies have yet to be mapped in a way that enables characterization of the whole organism response. We lack sufficient insight into model performance in both clinical construct validity (does the formulation approximate sepsis?) and outcome validity .Patterns in response may be helpful ways to improve models and link them to valid outcomes, but key elements of these patterns are unexplained. In the example of the direction problem, sampling a panel of hormone function , rather than a single value , helps specifiy what the abnormality means. This is not as clear with sepsis. Recognizing patterns of clinical improvement or deterioration validates clinical suspicions. This approach only works if mechanisms are understood, an ongoing limitation. Efforts to quantify intensity  or cliniInvestigations into isolated organ dysfunctions would inform characterizations that could then be assessed in terms of causality, providing much needed insight into the mechanisms of sepsis. A focus on cellular dysfunction rather than nonspecific markers may help validate what relevant criteria establish a diagnosis whose treatment would be expected to improve outcomes. Further inquiry should explore clinical outcomes that approximate what a clinician would hope to improve by treating sepsis, such as by reversing organ dysfunctions (when they can be measured) or their effects.Investigating the long-term effects and trajectories of organ dysfunctions could inform discussions about their nature and meaning. Interactions and more subtle data patterns  can be investigated and may provide insight about integrated host responses to infection. How patient factors influence clinical data outcomes prediction deserves further study. The interactions of neurologc, endocrine and immune systems with critical functions such as metabolism, coagulation, and cell death, need characterization. Investigations should aim to build mechanistic models that help explain how complementary clinical data relate to each other and describe the benefits and harms of adaptation patterns. Finally, future investigations should address clinical criteria construct validitiy and outcome validity.Important research questions:How can markers of a dysregulated host response be distinguished from drivers of that response?How do cellular-level processes interact to produce organism-level responses?What is the best way to characterize a dysregulated response to infection, optimizing clinical criteria, construct validity and outcomes validity?The six questions addressed by this paper identify important issues about how to define, categorize, assess, predict, diagnose and treat sepsis. Subcommittee members, representing a broad group of clinicians from different parts of the world, addressed these considerations from a variety of perspectives. However, although the process used the common Delphi standard, it is based on the consensus of experts and is therefore subjective and prone to bias.The accounts of what is known, the identified knowledge gaps, and the future directions for research serve as an important and prioritized resource for future sepsis investigations. Addressing these key gaps will lead to better understanding of disease epidemiology, pathobiology and individual patient heterogeneity, which will facilitate timely and accurate sepsis patient identification to deliver effective therapies, building on the progress made by the Sepsis-3 Task Force and the Surviving Sepsis Campaign.


Gestational diabetes mellitus (GDM) is a common disorder of pregnancy with short- and long-term consequences for mother and baby. Pre-eclampsia is of major concern to obstetricians due to its sudden onset and increased morbidity and mortality for mother and baby. The incidence of these conditions continues to increase due to widespread maternal obesity. Maternal obesity is a risk factor for GDM and pre-eclampsia, yet our understanding of the role of adipose tissue and adipocyte biology in their aetiology is very limited. In this article, available data on adipose tissue and adipocyte function in healthy and obese pregnancy and how these are altered in GDM and pre-eclampsia are reviewed. Using our understanding of adipose tissue and adipocyte biology in non-pregnant populations, a role for underlying adipocyte dysfunction in the pathological pathways of these conditions is discussed. This suA systemised review of adipose tissue and adipocytes in GDM and pre-eclampsia was carried out. A search of published literature using PubMed and MEDLINE was conducted independently by two investigators using the keywords: “adipose” OR “adipocyte” OR “subcutaneous OR visceral OR omental OR ectopic NEAR fat” OR “lipolysis” combined with “pregnancy” OR “gestation” OR “maternal”, “gestational diabetes mellitus” OR “preeclampsia” OR “hypertens* NEAR pregnancy” using the operator AND. Duplicates were removed and all 2296 articles were screened by title and abstract for inclusion. Articles were excluded if: BMI was the only assessment of body fatness; there was a lack of healthy control group; an abstract could not be found or was a conference proceeding; only fetal outcomes were measured or the article was published in a language other than English. The number of total publications assessed was 176. This list was supplemented for the wider review with references that provided background information on non-pregnant adipose tissue function, healthy and obese adaptation to pregnancy and clinical features of healthy and complicated pregnancy. A maximum of 100 references could be cited in this article. Non-cited reference material is available as Adipose tissue is not a single, uniform organ but is organised and distributed throughout the body into distinct anatomical and functional depots which determine its role in energy homeostasis and its association with disease. Adipose tissues are divided into three subtypes: white, brown and beige. Whilst brown adipose tissue has an important role in thermogenesis and beige adipose tissue is of emerging interest as a site of fat oxidation, white adipose tissue (WAT) is the primary site of lipid storage and mobilisation in humans and is the focus of this review. WAT acts as a buffer against the toxic effects of excess circulating lipids by storing free fatty acids (FFA) in adipocytes and releasing them for use by peripheral tissues in times of relative energy depletion. Peripheral, subcutaneous adipose tissue (SAT) is the largest depot and is the primary storage site of fatty acids as triglyceride. SAT can be located in the upper and lower body; lower body SAT is more insulin sensitive and stores fatty acids securely, whereas upper body SAT is relatively insulin resistant and has a greater propensity to release fatty acids from storage. Central, visceral adipose tissue (VAT) is associated with the development of obesity-related disorders, probably via the release of fatty acids directly into the portal circulation. The extent and site of lipid storage in response to energy excess is regulated by endocrine function, the rate of lipid utilisation and the expansion capacity of WAT.Uptake of fatty acids is mediated via lipoprotein lipase (LPL) that is secreted by adipocytes and situated on the vascular endothelium of adipose tissue. LPL hydrolyses FFA from triglycerides contained in triglyceride-rich lipoproteins such as chylomicrons and Very low density lipoprotein (VLDL), allowing their uptake into adipocytes via fatty acid transporters in the adipocyte membrane. The release of FFA from adipose tissue is governed by lipolysis of triglyceride, regulated via a trio of enzymes in a stepwise manner: adipose triglyceride lipase, hormone sensitive lipase (HSL) and monoglyceride lipase. Insulin is a key hormone that inhibits adipocyte lipolysis and increases glucose uptake. Healthy adipose tissue displays metabolic flexibility, whereby lipolysis is carefully regulated by hormones, catecholamines and paracrine signals to facilitate physiological responses to changes in requirements for lipid storage versus mobilisation. FFA released from SAT are returned to the liver for oxidation or secretion in VLDL. Upper body SAT is estimated to be the source of 60% of circulating FFA, lower body SAT 15–20% and VAT 6–17% . While VAdipokines and cytokines secreted by adipocytes, adipose-resident immune cells, endothelial cells and other cellular compartments of the adipose tissue can have a diverse range of autocrine and paracrine effects which act to regulate insulin sensitivity, inflammation, cardiovascular function, behaviour and cell growth. Adiponectin, one of the most abundant adipokines in circulation, is anti-inflammatory, insulin sensitising and is inversely associated with increased adiposity. Leptin, the most well-characterised adipokine, correlates with fat mass and is increased post-prandially, regulating food intake and glucose and fat metabolism in healthy individuals. In contrast to adiponectin, leptin has pro-inflammatory actions and is associated with increased adiposity and insulin resistance. There are numerous other adipokines which are not the focus of this current review and are discussed elsewhere . ObesityBMI is a universally accepted measure of body fatness and biomarker of metabolic disease risk when used in conjunction with other risk factors and is routinely measured in clinical settings. However, because BMI does not measure either the quantity or quality of body fat or convey any information about its location (SAT or VAT), it is relatively indiscriminate in predicting cardio-metabolic risk in comparison to central obesity with high intra-abdominal VAT. BMI is thus a proxy marker of adiposity, which cannot distinguish individuals who store fat in SAT in a relatively benign way, from those who store fat in VAT, which is related to metabolic dysfunction and pathology. In addition, the site of fat storage is recognised to be influenced by ethnicity, age, smoking and diet, which strongly suggests that the efficacy of BMI as a risk discriminator will vary between different populations.Adipose tissue is comprised of adipocytes and stromal cells including pre-adipocytes and immune cells, which support the proliferation and differentiation of pre-adipocytes to adipocytes and secrete a variety of cytokines and growth factors facilitating this. When individuals become obese, excess calories are stored as triglyceride within the adipocytes of WAT. If there is insufficient capacity in mature adipocytes, new adipocytes are formed from pre-adipocytes in order to increase storage capacity. The formation of adipocytes (adipogenesis) occurs in two phases. The first phase is commitment to differentiation and involves the production of committed white pre-adipocytes from mesenchymal stem cells. Terminal differentiation forms mature adipocytes containing a lipid droplet that occupies almost all the space within the cell. In some individuals there appears to be a limited ability to produce mature adipocytes from pre-adipocytes (hyperplastic adipocyte expansion) and instead excess fatty acids are stored in existing mature adipocytes leading to an increase in their size (hypertrophic expansion) , 13. In Once SAT capacity is exceeded, lipids begin to accumulate in visceral and finally ectopic tissues . “SpilloAdipose tissue expansion is an adaptive response to healthy human pregnancy. Maternal body composition and metabolism undergo dramatic changes in order to provide the developing fetus with a continuous supply of nutrients and prepare the mother for lactation. The initial phase of gestation is anabolic when maternal fat stores increase to a peak towards the end of the second trimester due to adipocyte hyperplasia and increased adipose tissue lipogenesis. Metabolism switches to a catabolic state around mid-gestation, characterised by increased adipose tissue fatty acid turnover and increased levels of lipolysis. Gluteal SAT adipocytes increased in size and number by late pregnancy in healthy non-obese women and adipose tissue showed increased expression of genes involved in tissue remodeling, angiogenesis and inflammation . IncreasIn pregnancy there is a shift in fat distribution from the lower body towards the upper abdominal region. The increase in abdominal fat in pregnancy has been found to be attributable to accumulation of VAT rather than SAT and there is an increase in VAT accumulation throughout gestation even in healthy pregnancy. Regional differences in SAT function were observed in pregnancy, with LPL activity in adipocytes from the femoral region, but not the abdominal region, increasing in pregnant women , 24. Adi+ T cell cytokines, correlated with abdominal VAT but not SAT [Despite lean and obese women accumulating similar amounts of gestational fat, the distribution of adipose tissue storage varies dependent on pre-pregnancy BMI. Skinfold thickness measurements show that lean pregnant women gain significantly more fat in lower body compartments, whereas obese pregnant women gain more in upper body compartments . Further not SAT .Consistent with non-pregnant women, obesity in pregnancy is characterised by insulin resistance, dyslipidaemia and low-grade chronic inflammation , 32. SATThe higher levels of inflammation in obese compared to lean women suggest that adipokines may play a role in the pathophysiology of obesity-related pregnancy, possibly via endothelial dysfunction . There wAdipocytes in abdominal SAT at gestational weeks 8–12 were non-significantly larger in obese pregnant women (mean diameter 91 µm) than lean pregnant women (79 µm) . Obese wInsulin binding to SAT adipocytes was reduced by more than 50% in the third trimester of pregnancy compared to non-pregnant controls , 44, 45 Pre-pregnancy BMI and early GWG are potentially modifiable risk factors for gestational hypertensive disorders and GDM –50. AlthWomen with GDM had larger VAT adipocytes than normal glucose tolerant (NGT) controls and adipocyte size correlated with plasma glucose levels . SAT expInsulin receptor expression was found to be lower in both SAT and VAT from women with GDM compared to BMI-matched controls . In compIn a cohort matched for BMI, VAT, but not SAT, TNFα mRNA expression was higher in GDM compared to controls, whereas IL-6 expression was unchanged in both tissues . Leptin Published data on adipocyte function in pre-eclampsia is extremely limited. The size distribution of SAT and VAT adipocytes was altered in pre-eclampsia with more adipocytes in the lowest tertile of diameters compared to controls suggesting limited adipocyte differentiation . Women wIn VAT, there was increased activated macrophage infiltration in pre-eclampsia and ex vivo adipocytes isolated from women with pre-eclampsia had higher inflammatory cytokine release in response to a pro-inflammatory stimulus . NeutropAs described above, a failure of adipocyte expansion can lead to ectopic fat accumulation and development of insulin resistance and metabolic disease . There iImpairment of adipocyte expansion is related to development of T2DM in non-pregnant populations and an understanding of this pathway sheds light on adipocyte function in pregnancy. GWG can easily be accommodated by adipocyte hypertrophy in healthy pregnancy. The relatively limited insulin resistance induced by pregnancy hormones in health leads to a regulated increase in lipolysis to supply nutrients to the fetus. In obese pregnancy, women commence pregnancy with a relative degree of SAT and VAT adipocyte hypertrophy and insulin resistance. In response to pregnancy hormones, obese women develop a higher than normal insulin resistance which reduces the ability of insulin to switch off lipolysis resulting in increased delivery of fatty acids to VAT and the liver leading to increased liver VLDL production and increased plasma triglyceride concentrations. There are limited data on adipocyte function in GDM and pre-eclampsia but that which is available suggests a role for adipocyte dysfunction in these diseases of pregnancy. In women who develop GDM, one might hypothesise that there is reduced hyperplasia and SAT hypertrophy resulting in fatty acid spillover. These fatty acids are directed to VAT which also experiences adipocyte hypertrophy and a reduced ability to retain fatty acids. Once the capacity of both depots is exceeded, then ectopic fat may begin to collect in the liver and pancreas leading to reduced pancreatic insulin secretion and tipping maternal metabolism into overt GDM. In women with pre-eclampsia, one might hypothesise that there is an innate maternal insulin resistance perhaps induced by changes in placental hormones secreted by a dysfunctional placenta. This insulin resistance impairs adipocyte differentiation, limiting the number of mature adipocytes and hence severely limiting the capacity of SAT to store gestationally acquired fat. Fatty acid spillover will occur, resulting in increased plasma lipids and ectopic fat accumulation in liver and placenta exacerbating further maternal insulin resistance and placental dysfunction. Clearly the evidence to support these hypotheses is limited and more data that will provide an understanding of the function of adipose tissue in GDM and pre-eclampsia is required.Metabolic complications of obese pregnancy may share a common metabolic origin with those found in non-pregnant obesity, through the development of insulin resistance. Although the concepts of benign and visceral obesity are only just beginning to be addressed in obstetric medicine, recognition of these obese phenotypes could have a major impact on the ability to identify high risk pregnancy. Currently, the ability to predict the onset of gestational disorders is limited, despite robust associations with BMI. A more detailed understanding of the pathological pathways related to adiposity may identify new risk factors to predict, and potential new treatments to prevent, GDM and pre-eclampsia.Supplemental References


The COVID-19 pandemic created new challenges to delivering safe and effective health care while minimizing virus exposure among staff and patients without COVID-19. Health systems worldwide have moved quickly to implement telemedicine in diverse settings to reduce infection, but little is understood about how best to connect patients who are acutely ill with nearby clinical team members, even in the next room.To inform these efforts, this paper aims to provide an early example of inpatient telemedicine implementation and its perceived acceptability and effectiveness.Using purposive sampling, this study conducted 15 semistructured interviews with nurses , attending physicians , and resident physicians  on a single COVID-19 unit within Stanford Health Care to evaluate implementation outcomes and perceived effectiveness of inpatient telemedicine. Semistructured interview protocols and qualitative analysis were framed around the RE-AIM  framework, and key themes were identified using a rapid analytic process and consensus approach.All clinical team members reported wide reach of inpatient telemedicine, with some use for almost all patients with COVID-19. Inpatient telemedicine was perceived to be effective in reducing COVID-19 exposure and use of personal protective equipment (PPE) without significantly compromising quality of care. Physician workflows remained relatively stable, as most standard clinical activities were conducted via telemedicine following the initial intake examination, though resident physicians reported reduced educational opportunities given limited opportunities to conduct physical exams. Nurse workflows required significant adaptations to cover nonnursing duties, such as food delivery and facilitating technology connections for patients and physicians alike. Perceived patient impact included consistent care quality, with some considerations around privacy. Reported challenges included patient–clinical team communication and personal connection with the patient, perceptions of patient isolation, ongoing technical challenges, and certain aspects of the physical exam.Clinical team members reported inpatient telemedicine encounters to be acceptable and effective in reducing COVID-19 exposure and PPE use. Nurses adapted their workflows more than physicians in order to implement the new technology and bore a higher burden of in-person care and technical support. Recommendations for improved inpatient telemedicine use include information technology support and training, increased technical functionality, and remote access for the clinical team. The COVID-19 pandemic created new challenges to delivering safe and effective health care while minimizing virus exposure among staff and patients without COVID-19. Telemedicine has long been recognized as a potential solution to these challenges and was deployed in response to the Ebola, SARS, and H1N1 outbreaks ,3. HealtInpatient telemedicine adoption is also useful for personal protective equipment (PPE) conservation. For inpatients with known infections, the clinical team must don one-time-use PPE each time they enter the patients’ rooms to safely provide care and help prevent transmission. Increased demand for PPE has led to intermittent regional supply shortages that place millions of health workers at risk ,11. InpaHealth systems hoping to incorporate telemedicine must overcome several recognized barriers, including costs, training, resistance to change by clinical team members and staff, and patient characteristics associated with reduced comfort in using technology, such as older age or lower level of education ,14. The Despite the growing implementation of inpatient telemedicine, formal evaluations are limited. Telemedicine used to deliver care remotely has been shown to be effective in many clinical settings . In the This study conducted 15 semistructured interviews with attending  and resident  physicians and nurses  on a designated COVID-19 unit at Stanford Health Care as part of a qualitative process evaluation. To clarify, attending physicians  have completed all medical training and oversee resident physicians  who have recently graduated from medical school and are in years 1 to 3 of their hospital training. This evaluation sought to understand the implementation and perceived effectiveness of an inpatient telemedicine solution across multiple domains, including patient care, clinical workflow, and clinical team satisfaction.Beginning in March 2020, a large academic health center—Stanford Health Care, Palo Alto, California, USA—designated a single inpatient nonintensive care unit to treat all potential and confirmed patients with COVID-19 admitted to their hospital. To reduce clinical team and staff pathogen exposure and to conserve PPE, each patient received an iPad tablet (Apple Inc) with the ability to receive web-conference calls from computers in two private conference rooms on the unit. A patient’s unique web-conferencing link and a password were required to enter the privacy-compliant system; this information was available to any clinical team members on the unit. Each tablet in the patient rooms had the web-based teleconferencing software Zoom  installed in a “hub-and-spoke” configuration, such that a call from the “hub” tablet on the unit floor would trigger the “spoke” patient tablet to automatically turn on its audio and video functions. The inpatient telemedicine intervention aimed to reduce clinical team in-person encounters and allowed the primary and specialist physician team, nurses, and extended care team members  to provide patient care remotely in the on-unit conference rooms throughout the day.Semistructured interview protocols explored the implementation and perceived effectiveness of inpatient telemedicine in reducing pathogen exposure and PPE use. The interviews also captured perceptions of the appropriateness of inpatient telemedicine use in various settings and its impact on clinical team satisfaction. Interview protocols were developed using RE-AIM , an implementation science framework most commonly used to support effective implementation of interventions, but that is also valuable in structuring the evaluation of key implementation outcomes -28. InteThe target population for interviews included nurses and resident and attending physicians who were part of the clinical team and had used telemedicine since its launch within the organization in March 2020. The evaluation team contacted the medical director and nursing manager on the COVID-19 unit and received a list of clinical team member names from which to contact potential participants and request an interview. Interviews were conducted between May and June 2020 and reflect technical capabilities and workflows used during this period. Purposive sampling methods were used to recruit participants until thematic saturation was reached. Recruitment was challenging due to the small pool of clinical team members working on the COVID-19 unit and their demanding responsibilities in the context of the pandemic. Saturation was reached, by role, when new themes no longer emerged during interviews .a priori categories informed by interview question categories  and RE-AIM constructs (Interviews were audio recorded and transcribed verbatim using Rev (Rev.com Inc). A qualitative health services researcher (NS) and a physician health services researcher (SV) independently reviewed and summarized key themes across all interview transcripts using a rapid analytic process structured around nstructs  30]. Ke. Kea pria priori coding framework for analysis, the following themes emerged: (1) implementation setting and climate, (2) clinical team workflows around inpatient telemedicine, (3) clinical team satisfaction with inpatient telemedicine, (4) perceived impacts on patients, (5) limitations of inpatient telemedicine, and (6) anticipated future uses of inpatient telemedicine. Using RE-AIM, as defined above, and categories drawn from the semistructured interview guide as an Implementation setting and climate subthemes addressed adoption, information sharing, and training.Adoption of inpatient telemedicine was reported to be near universal across attending and resident physicians and nurses who cared for patients on the COVID-19 designated inpatient unit. Web-conferencing was also used to replace morning rounds for patients with COVID-19, which would otherwise take place with the full physician team (both residents and attendings) and nurses, when available.Information sharing and training about the intervention were reported to be informal. The novelty of the inpatient telemedicine system also led to variations in the terminology used to describe it. Clinical team members called it “video visits,” “virtual rounding,” “inpatient telemedicine,” “telemedicine,” “video chat,” “Zoom visits,” or “Zoom.” There were no consistent terms used within interviewee roles, and no miscommunications resulting from variation in terminology were reported.Most clinical team members learned about the inpatient telemedicine system through word of mouth, though some did participate in a technical training session, and instructions for initiating inpatient telemedicine visits were posted on the computers in the designated web-conferencing rooms. Most physicians reported learning about the technology from either the nursing team or from a physician coming off a previous shift. Most nurses also reported learning about inpatient telemedicine through their peers, though one had received training from an information technology (IT) representative. Though instructions were posted, nurses shared that they regularly received an influx of questions and requests for help initiating visits from physician team members and others. Nurses reported that these questions and requests did not seem to diminish in the months following implementation.Clinical team workflow subthemes addressed the relative stability of physician workflows compared to the period before the COVID-19 pandemic, the significant adaptations of nurse workflows to account for additional responsibilities associated with COVID-19 restrictions and inpatient telemedicine, workflows for extended care team members hinging on call coordination and availability of translators, and a need for improved technology support workflows.Attending physicians and senior residents shared that they entered patient rooms less frequently due to the availability of inpatient telemedicine and, as a result, they reduced their PPE use and exposure to COVID-19. Junior residents did not enter the rooms at all per trainee program guidelines.Clinical team members reported that a baseline physical exam was typically conducted in person by the senior resident or attending physician. Any additional in-room examinations were conducted by the nurse, senior resident, or attending and took place anywhere from daily to every few days, depending on the patient’s clinical needs. When asked how they decided whether or not to enter a room for an in-person assessment, physicians considered patient acuity of illness, opting to forgo low-value in-person encounters that could otherwise be addressed via video. Any decrement in clinical status also triggered an in-person exam. Rounding activities typically included daily telemedicine conversations between the patient and the physician team , as long as patients were clinically stable.Patients continued to receive regular, in-room nursing care multiple times each day. In addition to their usual responsibilities, nurses reported being tasked with additional responsibilities outside their standard work. These included delivering food multiple times per day, changing linens, and disinfecting patient rooms due to room entry restrictions barring housekeeping and cafeteria staff from entering the rooms of patients with COVID-19. Nurses reported “batching” their entrances to complete several tasks at once to reduce PPE use, and they used inpatient telemedicine when they wanted to check on patients but deemed an in-room encounter unnecessary. Nurses shared that inpatient telemedicine was primarily used for hourly assessments of each inpatient, which is considered best practice in nursing care, and was often a satisfactory alternate to an in-person encounter.Most notably, nurses reported expending significant time to facilitate team use of inpatient telemedicine, including scheduling the virtual meetings and circulating web-conferencing links and passwords to all participants . The coordination of a single call was reported to take up to 20 minutes of a nurse’s time to complete. While some attendings and residents reported setting up calls themselves, some corroborated their ongoing reliance on nursing support to facilitate calls.Nurses also reported being asked to don PPE and enter patient rooms during inpatient telemedicine visits to turn the tablet screen or increase tablet volume to optimize the interaction with the physician or extended team member in the conference, as patients frequently moved the tablet or adjusted its settings between visits. These situations negated any reduction in PPE consumption that the inpatient telemedicine system may have facilitated and transferred potential exposure from the caller to the nurse. While nurses did not express dissatisfaction with these changes directly, some nurses shared concern that time spent facilitating telemedicine encounters for other team members pulled them away from their own patient care responsibilities.Nurse-led adaptations of the technology that supported patient care included the following: (1) acquiring an extra tablet at the nursing station through IT to be able to monitor and provide 24/7 visualization of a delirious patient with dementia who was a fall risk and (2) facilitating communication between patients and family members, particularly in acute care situations, if they had time to coordinate the conference room and the family member and patient schedules.On-site extended care team members, such as respiratory therapists, dietitians, psychiatrists, social workers, research coordinators, and other team members, were not physically permitted on the unit and could, therefore, not initiate inpatient telemedicine visits through on-site conference rooms. Given these limitations, nurses were also sometimes asked to conduct respiratory therapy activities or fulfill other clinical needs on behalf of their remote care team members.Call coordination via inpatient telemedicine was reported to rely on nurses to coordinate and required each relevant team member to be available simultaneously in their own confidential setting for the telemedicine visit to take place effectively. Many patients with COVID-19 did not speak English as their first language, and it was particularly challenging to schedule remote interpreters on telemedicine visits. Interpreters worked virtually in multiple settings using multiple technical platforms, often producing a 5- to 10-minute delay while the physician and patient waited in the teleconference room.The logistics of using and maintaining tablets in patient rooms created new workflows for the clinical team. Each tablet was mounted on a cart to the side of the patient bed and nurses mentioned that the placement of the tablet sometimes interfered in patient care, specifically in conducting physical exams or providing treatment that required access to that side of the bed. Additionally, tablet maintenance meant that updates automatically pushed by the technology companies or a dead battery could put a tablet out of commission, without reported backup machines available on the inpatient unit that could immediately address the issue.Satisfaction subthemes highlighted high attending and resident physician satisfaction specific to reduced infection exposure and improved efficiency in daily workflows, resident physician concerns with reduced educational opportunities, and no stated change in satisfaction for nurses.Most physicians perceived inpatient telemedicine to have a positive impact on their daily work and reported that the platform was intuitive to use, given their experience with the technology in nonclinical settings. Physicians also perceived having additional time to check in on patients given the reduction in time spent walking between patient rooms. These factors, in addition to reduced PPE use and in-room COVID-19 exposure, were reported to contribute to improved job satisfaction and reduce feelings of anxiety around infection among attending and resident physicians.In-room physical exams prior to the pandemic typically included attending physicians and senior and junior residents; however, during the pandemic, attending physicians and senior residents primarily conducted in-room physical exams with patients with COVID-19 alone. Junior residents mentioned missing educational aspects of the physical exam due to this reduction in training at the bedside, though they appeared to accept the small trade-off on education to prioritize their safety and were still able to engage with patients through inpatient telemedicine.Nurses did not report a change in job satisfaction or anxiety, as they perceived that their in-room exposure stayed at similar, if not increased, levels following the implementation of inpatient telemedicine due to the increased housekeeping and care responsibilities described above. As fewer members of the primary physician team and extended care team were allowed to enter patient rooms, these additional tasks fell on the nursing team to complete.Perceived patient impact subthemes included consistent quality of care, privacy considerations, and limitations of inpatient telemedicine, particularly with respect to communication, physical exams, and patient–clinical team connection.Overall, inpatient telemedicine was perceived to be effective in reducing COVID-19 exposure and PPE use without significantly compromising quality of care. Patient outcomes, specifically around quality of care, were perceived to be of similar quality to in-person visits. Physicians and nurses reported that inpatient telemedicine facilitated improved care by allowing the clinical team to “eyeball” a patient’s physical status remotely throughout the day without donning PPE. Additionally, all physicians reported that the inpatient telemedicine system allowed for higher-quality care than care delivered via phones available at the patient’s bedside, as physicians were able to assess patients’ physical statuses and capture facial expressions otherwise missed through audio alone.Physicians and nurses felt that patient privacy was protected, as calls could only be made in the designated conferencing rooms through the secure system. Some clinical team members mentioned feeling concerned about the auto-activation of video in the patient’s room and would call the patient by phone just before initiating a web-conferencing visit to alert the patient. However, some physicians felt the auto-accept feature was critical to provide timely care if patients were unable to activate video by themselves.The clinical team reported that patients sometimes turned the tablet screen away from themselves for privacy reasons and reduced the volume, especially at nighttime when the screen brightness and sound might interrupt their sleep. This allowed patients to rotate the screen toward themselves when they were ready for the visit, but it also meant that sometimes calls from the clinical team were missed, as the patient did not notice or could not hear the team initiating the call. It was at these points that a physician might ask a nurse to don PPE and enter the room to turn the tablet screen toward the patient and increase the audio volume.Some residents acknowledged concern that the lack of physical presence may compromise care, particularly for vulnerable patients with an altered mental status and hearing challenges as well as for non-English speakers. At the same time, a resident also acknowledged that telemedicine opened up new care possibilities for a deaf patient who was admitted with COVID-19 and could only read lips. Whereas PPE would have covered the resident’s mouth during an in-person exam, telemedicine allowed a conversation to take place.Additional use cases where inpatient telemedicine was thought to be inappropriate around prognosis included when sharing bad news or communicating complex information in another language. Several nurses reported concerns of less appropriate use by the extended care team, such as a psychiatric evaluation completed over telemedicine for a patient with known dementia or a physical therapy evaluation for a patient who had trouble standing. Other adaptations made to adjust to virtual patient care were also reported as less ideal, such as directing patients to identify complex medical instruments or asking nurses to conduct exams typically done by a resident. Some physicians and nurses also noted the loss of in-person connection, worrying that it may inadvertently lead to worse outcomes or at least reduce patient satisfaction. One nurse felt that this loss of interpersonal connection went against her training.Loss of connection was reported to be felt by the patients as well. The clinical team reported that few patients had commented on their inpatient telemedicine experience, though those who had received feedback shared that some patients were confused as to why physicians and nurses were not entering the room as often. Some clinical team members perceived that inpatient telemedicine made their patients feel more isolated.Clinical team members agreed that inpatient telemedicine might expand beyond use in patients with COVID-19 in future use cases. Contexts favorable to telemedicine use included those with patients who were comfortable with the technology and were clinically stable and mentally coherent. When asked what percentage of daily encounters they prefer to conduct via inpatient telemedicine in the future, clinical team members shared preferences ranging from 0% to 80%. Suggested uses included leveraging inpatient telemedicine to allow remote  access to patients throughout the day and to connect patients with remote visitors.used in the context of an infectious disease may be uniquely more favored by the clinical team than its past uses, which predominantly focused on connecting patients to remote providers. In the infectious disease setting, inpatient telemedicine provides both an additional layer of defense against an infectious pathogen and an opportunity to visually connect “face-to-face”  with vulnerable patients in need of care.This is the first qualitative analysis of inpatient telemedicine used to improve infection control using established implementation science frameworks that the authors are aware of. Findings suggest that telemedicine used as an infection control tool in a nonintensive care inpatient setting was generally accepted and adopted among attending physicians, resident physicians, and nurses. Clinical team members agreed that quality of patient care remained largely unchanged, particularly given the ever-present option to convert a telemedicine assessment to an in-person exam if clinical deterioration was suspected. Recognized limitations included challenges around clinical team communication and personal connection with the patient, perceptions of patient isolation, ongoing technical challenges, and certain aspects of the physical exam. Such barriers have been previously reflected in the literature alongside concerns of technical costs and unfavorable reimbursement ,32,33. HInvestigations to augment key aspects of the physical exam and others with a “remote hospital system,” such as a connected stethoscope, are ongoing in the institution. In addition, the institution is implementing solutions to the challenges around the patient–clinical team connection; ease of communication, particularly with the timeliness of incorporating interpreters, is in the process of being improved, following rapid feedback of these findings. These findings also point to the possibility of incorporating a calendar system for patients who are hospitalized who may see their schedules filled with procedures, specialist consults, and family conference calls. A series of remote but human connections throughout the day may ease reported feelings of patient isolation and simplify challenges related to multi-party scheduling.While stakeholders perceived that inpatient telemedicine is effective in preventing COVID-19 exposure and reducing PPE use for most clinical team members, perceptions varied by role. Physicians, especially junior residents, reported having the lowest degree of in-room exposure, as attendings and senior residents conducted the majority of in-person assessments. In-room exposure was reportedly highest among the bedside nursing team who spent more time in the room, as their responsibilities shifted to include ancillary duties  that would have otherwise been conducted by the extended care team; their experience is consistent with those in other health systems and countries that have highlighted the critical roles nurses have played in the COVID-19 response . The oveLiterature suggests this major shift in clinical workflow may not be without cost. Nursing interruptions are dangerous and have been shown to compromise patient safety and quality of care, particularly around wrong medication or wrong dose -39. In tMany have pointed out that for health care institutions to become learning health care systems, they must pair rapid innovation with rapid evaluation . PerhapsThese interviews with clinical stakeholders point to a set of key opportunities to improve inpatient telemedicine, including clinical team education, IT support and training during the transition phase, technical functionality around audio volume and video privacy, and remote access for staff. Recommendations for improved inpatient telemedicine use are outlined in This study was conducted within a single academic medical center undergoing operational changes in response to the COVID-19 pandemic, and learnings are, therefore, not generalizable to other institutions or time periods. The use of qualitative methods provided a more nuanced assessment of facilitators and barriers to inpatient telemedicine implementation and adoption; however, this study was limited by a small sample size representing each role, as the hospital appropriately restricted nonclinical staff on the COVID-19 unit of interest. While the evaluation team felt that thematic saturation for each population was attained, unexpected viewpoints from a broader population may have been missed. Additionally, though efforts were made to include patient voices in this evaluation, the authors were unable to complete a sufficient number of patient interviews to draw meaningful conclusions from this perspective. An exploration of the patient perspective and a quantitative analysis of inpatient telemedicine’s impact on patient outcomes are important areas of future work.In this evaluation of an inpatient telemedicine system deployed as an infection control measure, attending and resident physicians and nurses reported virtual encounters as acceptable and effective in reducing COVID-19 exposure and PPE use for certain clinical team members. Additionally, the clinical team perceived quality of patient care to remain unchanged, though challenges were identified around the following: increased burden of technical implementation borne disproportionately by nurses, technology support, integration of remote extended care team members, patient–clinical team communication and connection, and conducting physical exams. Ongoing optimization of the technical and team workflow aspects of inpatient telemedicine is needed to deliver safe, effective care during the current and future pandemics.


Mucosal tissues in the human female reproductive tract (FRT) are primary sites for both gynecological cancers and infections by a spectrum of sexually transmitted pathogens, including human immunodeficiency virus (HIV), that compromise women's health. While the regulation of innate and adaptive immune protection in the FRT by hormonal cyclic changes across the menstrual cycle and pregnancy are being intensely studied, little to nothing is known about the alterations in mucosal immune protection that occur throughout the FRT as women age following menopause. The immune system in the FRT has two key functions: defense against pathogens and reproduction. After menopause, natural reproductive function ends, and therefore, two overlapping processes contribute to alterations in immune protection in aging women: menopause and immunosenescence. The goal of this review is to summarize the multiple immune changes that occur in the FRT with aging, including the impact on the function of epithelial cells, immune cells, and stromal fibroblasts. These studies indicate that major aspects of innate and adaptive immunity in the FRT are compromised in a site‐specific manner in the FRT as women age. Further, at some FRT sites, immunological compensation occurs. Overall, alterations in mucosal immune protection contribute to the increased risk of sexually transmitted infections (STI), urogenital infections, and gynecological cancers. Further studies are essential to provide a foundation for the development of novel therapeutic interventions to restore immune protection and reverse conditions that threaten women's lives as they age. A review of immune changes in the female reproductive tract of women after menopause reveals that while there is a general decline in immune protection, specific immune aspects are upregulated or remain unchanged in a compartmentalized manner. Understanding how immune protection changes in the reproductive tract in the years following menopause is essential to protect women from sexually transmitted infections and gynecological cancers as they age. Little is known about how FRT epithelial functions change with age in postmenopausal women, since most studies focus on younger reproductive‐aged women.3.1hlamydia trachomatis  is 25–50 layers thick with superficial, parabasal, and basal layers  and retinoic acid inducible gene (RIG)‐like receptors (RLR), which recognize conserved moieties known as pathogen‐associated molecular patterns (PAMPs) characteristic of broad classes of pathogens. PRR expression varies within the FRT by anatomical location and cell type  and stromal‐derived factor‐1 (SDF‐1α) , which remain in tissues without recirculating, thereby providing first line local defense against reinfection and reactivation  cells represent 10–30% of FRT immune cells (Givan et al., BRIGHT cells, increased CD56‐CD16+ cells (Solana et al., The extent to which phenotype and numbers of FRT NK cells change in the postmenopausal FRT remains unknown; however, blood NK cells undergo profound changes with aging (Hazeldine & Lord, 7.2The density and distribution of B cells varies within the premenopausal FRT, with IgA‐, IgG‐, or IgM‐producing cells predominantly found in the vagina, ectocervix, endocervix, and fallopian tubes, but minimal numbers in the endometrium and ovary (Crowley‐Nowick et al., Endometrial secretions contain IgG and IgA, with IgG present at higher levels (Schumacher et al., in vitro (Ghosh et al., Immunoglobulins present in FRT secretions are essential components of immune protection. IgG and IgA neutralize incoming pathogens and prevent their entry into target cells (Lamm et al., ,8The mucosal immune system in the human FRT has uniquely evolved to meet the challenges of an external environment as well as support new life. Across multiple anatomical compartments, mucosal immunity is precisely regulated to protect against sexually transmitted pathogens while accommodating allogeneic spermatozoa and an immunologically distinct semi‐allogeneic fetus. While much is known about the mucosal immune system in the FRT during the reproductive years, little is known about the changes that occur after menopause as women age. Limited studies into innate and adaptive immune functions in the FRT following menopause indicate that immune protection by epithelial cells, stromal fibroblasts, T cells, and DC in the FRT are compromised, with limited compensation. Much remains to be learned about the impact of age following menopause on immune protection in the FRT. Understanding the impact of age on mucosal immune protection in the FRT is crucial given the challenges women face in terms of urogenital infections, exposure to sexually transmitted pathogens, and gynecological cancers that threaten the lives of women worldwide. This review emphasizes the need for additional studies to provide a foundation for the development of age‐appropriate therapeutic interventions that increase protection in older women, the fastest growing segment of the population in developed countries.The authors declare no conflict of interest.MRG and CRW wrote the introduction section; MVP wrote epithelial cell, fibroblast, and other cells sections; MRG, CRW, and ZS wrote the T‐cell section; MRG wrote the DC section. All authors edited and approved the manuscript.