For patients suffering with chronic neuropathic pain the need for suitable novel therapies is imperative. Over recent years a contributing factor for the lack of development of new analgesics for neuropathic pain has been the mismatch of primary neuropathic pain assessment endpoints in preclinical vs. clinical trials. Despite continuous forward translation failures across diverse mechanisms, reflexive quantitative sensory testing remains the primary assessment endpoint for neuropathic pain and analgesia in animals. Restricting preclinical evaluation of pain and analgesia to exclusively reflexive outcomes is over simplified and can be argued not clinically relevant due to the continued lack of forward translation and failures in the clinic. The key to developing new analgesic treatments for neuropathic pain therefore lies in the development of clinically relevant endpoints that can translate preclinical animal results to human clinical trials. In this review we discuss this mismatch of primary neuropathic pain assessment endpoints, together with clinical and preclinical evidence that supports how bidirectional research is helping to validate new clinically relevant neuropathic pain assessment endpoints. Ethological behavioral endpoints such as burrowing and facial grimacing and objective measures such as electroencephalography provide improved translatability potential together with currently used quantitative sensory testing endpoints. By tailoring objective and subjective measures of neuropathic pain the translatability of new medicines for patients suffering with neuropathic pain will hopefully be improved. Neuropathic pain arises from lesions or diseases affecting the somatosensory component of the nervous system at any level of the peripheral or central nervous system . NeuropaNeuropathic pain is mechanistically heterogenous encompassing degrees of neurogenic sensitization, deafferentation and/or neurogenic inflammation. Signs and the symptoms of neuropathic pain include allodynia, hyperalgesia and paresthesia. One mechanism can underlie many different symptoms, the same symptom in two patients may be caused by different mechanisms, more than one mechanism can operate in a single patient, and these mechanisms may change with time . Many meSeverity of neuropathic pain is a primary predictor of the negative health impact on patients . Hence tCurrent systemic and topical pharmacological treatments of neuropathic pain have substantial limitations in terms of the level of efficacy provided and/or the side effect profile. This means the management of neuropathic pain is unsatisfactory in both preventing its development and in halting or modifying its progression . A key tThe primary focus of this review is to examine the industry standard measures of neuropathic pain and analgesia in animal models and patients in combination with how bidirectional research is implementing ways to measure spontaneous ongoing chronic pain and associated QoL in animals to further improve forward translation. As will be discussed, currently industry standard markers of neuropathic pain in humans and animals are distinct and subjective. In humans this is not a problem as pain is an individual experience and subjective markers such as questionnaires accurately measure a human’s pain level, although can lead to significant variability. However industry standard stimulus evoked pain markers in animals, such as static allodynia (von Frey) are often a poor representation of the animal’s spontaneous neuropathic pain and rely on human interpretation. Translatability between these distinct and subjective industry standard markers is poor as shown by the lack of current translational success. An improvement would be to compliment simple stimulus evoked markers with an objective marker in animals such as burrowing which removes human subjectivity, but cannot be directly translated to a marker in humans. An ideal marker for neuropathic pain (and chronic pain per se) is likely one that is objective in both humans and animals and can be directly translated between the two, such as data from Electroencephalography (EEG) recordings, which can be conducted in both species with no human subjectivity involved.Most neuropathic pain conditions are clinically managed with a choice of four licenced or recommended medicines, amitriptyline, duloxetine, gabapentin, or pregabalin whilst carbamazepine is specifically licenced for trigeminal neuralgia . These mPainful peripheral diabetic neuropathy is a widely studied condition in RCTs to assess neuropathic pain therapies as it is a leading cause of chronic peripheral neuropathic pain affecting between 25 and 50% of patients . To dateWe have summarized in The gold standard treatment pregabalin, is sometimes portrayed as an exemplar forward translational success story for the use of animal models in the neuropathic pain field. As seen in The chemical ingredient in chilli pepper, capsaicin, has been available since the 1980s in various formulations as lotions, creams or patches in low concentrations of 0.025–0.075% over the counter to treat neuropathic pain, such as diabetic neuropathy. Clinical efficacy therefore was recognized long before identification of its molecular target in 1997 . CapsaicFor the past two decades rational drug discovery efforts have been mechanistically driven addressing targets arising from a better understanding of the mechanism of existing analgesic drugs e.g. TRPV1 (capsaicin patch), α2δ-1 (gabapentinoids) or novel mechanisms arising from biological, human pathophysiological, or genomic studies e.g. Nav1.7, Neurokinin 1 (NK-1) . DespiteConus magus, a cone snail SNX-111 that blocks the N-type (CaV2.2) neuronal voltage gated calcium channel. Ziconotide produced striking analgesia in reflexive pain animal models and RCTs for cancer and AIDS related neuropathic pain when administered intrathecally . Many oIn contrast other novel mechanisms, such as substance P (NK-1) antagonists have failed in the clinic despite convincing evidence of analgesic efficacy in animal models. NK-1 receptor antagonists, such as the antiemetic aprepitant at clinically safe and tolerable doses, occupying and engaging >90% of its central target are inefficacious in relieving ongoing pain in postherpetic neuralgia patients despite convincing analgesic efficacy in animals . The lacand physical sensations  stimuli delivered by an experimenter to assess loss and gain of function of different afferent fiber classes   Figure . PrimariStimulus evoked sensory endpoints are robust, reproducible, high throughput measures, with face  and predictive validity . Since the presence or absence of analgesia in animals can only be inferred from observations made by humans  and cannot be self-reported  this preAlternative preclinical assessments can be used to infer signs of not just the classical reflex hypersensitivity but also spontaneous pain measurements along with the other comorbidities such as anxiety, depression, sleep issues and cognitive deficits so often found associated with chronic pain patients . Here weBecause pain is an internal, private experience, self-report remains the gold standard for its measurement in the clinic  and the An excellent example of cross-species use of assessment tools has been the use of the numerical rating scale (NRS) in the assessment of pregabalin efficacy in dogs. In human clinical trials, pregabalin efficacy in peripheral neuropathy has been evaluated with success using patients’ daily pain scores . In the Whilst subjective measures of pain in humans does not present the same challenges as subjective measures in preclinical species there is still room for improvement. Subjective measures in humans still introduce variability and limit the translational potential of markers used preclinically to clinical trials, through using different endpoints. Whilst an important improvement to forward translatability would be to use objective preclinical endpoints with the current subjective clinical ones. Using the same objective endpoint in both is the ideal goal for markers of neuropathic pain.Rodents possess several naturalistic/innate characteristics within their behavioral repertoire and suppression of these characteristics can be observed in a similar way to the assessment of QoL measures in neuropathic pain patients. These include wheel running , nestingAnalysis of burrowing behaviors in rodent pain models has become increasingly popular over the last 10 years  and demonstrates reproducible results across laboratories . Rodent This emotional contagion whereby burrowing behavior of STZ type-1 diabetic rats increased if they burrowed with their cage partner  and their individual burrowing increased if they were socially housed with a control partner not in pain , these may improve the translatability potential of preclinical data.Changes in facial features of humans convey a wide range of states and emotions which have been extensively studied in the context of pain, particularly in neonates  and non-Despite the extensive amount of literature , the useUSV would seem an ideal pain stimulated behavior which can be detected using an inexpensive bat detector , recorded, and quantified  for reviAs already discussed, neuropathic pain in the clinic is characterized by disturbances of both sensory and affective components. These frequently encountered comorbidities which include appetite decrease, depression, anhedonia and disruptions to sleep cycles present behaviors that can influence pain directly within the preclinical setting . AnxietySucrose preference can measure anhedonia, a key feature of depression  which isNon-evoked ongoing (spontaneous) pain along with the motivational/affective component of spontaneous pain can be assessed using conditioned place avoidance (CPA), conditioned place preference (CPP)  and placSynonymous with the time reliant changes observed with anxiety/depression-like behaviors the use of CPP has proved useful in demonstrating the temporal nature in the development of spontaneous ongoing neuropathic pain . AdditioChronic neuropathic pain patients can produce poor performance in tasks requiring cognitive flexibility even when taking commonly prescribed analgesics . CognitiStudies investigating cognitive dysfunction that can occur during chronic neuropathic pain have been able to dissociate the effects of gabapentin from that of the anti-diabetic drug metformin on cognition  and the Using the same mono-neuropathic model, Currently the most promising advances toward objective measures of neuropathic pain have been made using microneurography, neuroimaging and EEG. These techniques can be conducted on both preclinical species and on humans and thus data from these techniques can be directly translated between species providing a key opportunity for the development of objective markers for neuropathic pain.in vivo) provides the opportunity to study the pathophysiology of sensory and axonal abnormalities in pain processing; abnormalities which may underlay the phenomenon of spontaneous pain , positron emission tomography (PET), and magnetoencephalography (MEG), have contributed substantially to our understanding of the perception and processing of pain in humans. The use of PET and MRI for assessment of the brain response to pain, in man, particularly neuropathic pain have been reviewed previously . Their aFunctional magnetic resonance imaging (fMRI) is often viewed as the gold standard for longitudinal studies because it is non-invasive. This technique typically uses the blood oxygen level dependent (BOLD) methodology to identify changes in hemoglobin oxygenation which indicates alterations in neural metabolism over time. Although fMRI possesses good spatial resolution it provides only an indirect measure of neuronal activity associated with a task or stimulus and is associated with poor temporal resolution. PET is hampered by both poor spatial and temporal resolution but its advantage over fMRI is that via glucose metabolism, using fluodeoxyglucose (FDG)-PET, it is a more direct measurement of neuronal activity than the BOLD signal. Well-known major confounds associated with rodent brain imaging are the methods used to secure the subject during the scan. Unquestionably, anesthetic agents and restraint techniques impact the results obtained from rodent studies and must be taken into consideration in their design and interpretation . Some PEPET scanning using translocator protein (TSPO)-binding radioligands (e.g. [11C]PBR28) is a promising option for studies of neuroinflammation . TSPO isUnder healthy baseline conditions TSPO is expressed constitutively at low levels by multiple cell types including neurones and glial cells . During in vivo is a challenge and extrapolation of TSPO biology from rodent to human myeloid cells should be done with caution  inflammation . Owen et caution .Despite the innate challenges associated with the various imaging techniques this technology is still commonly used in rodents and considerable progress is continuing to be made in this field. As such, this has led to the identification of a core pattern of nociceptive-evoked events and brain regions activated in human pain imaging studies  that are also activated in the majority of the rodent studies . MoreoveEEG, first conducted in humans by Hans Berger in 1924, is the technique used to study the electrical currents produced in the brain . It is rEarly evidence showed neuropathic pain patients had an increased theta (4–8 Hz) power, decreased alpha (8–12 Hz) power and increased rhythmicity of theta oscillations termed thalamocortical dysrhythmia . EvidencFindings in humans that spinal cord stimulation (SCS) reduces neuropathic pain have now been replicated in rodents through using EEG patterns as a marker. This procedure involves a surgically implanted device applying an electrical stimulation to the spinal cord of patients to alter neuronal activity . SCS hasOther than the potential of data generated through EEG recordings as a translatable marker, it also has uses in neuropathic pain treatments that avoid the use of animals, by being applied directly to humans. One such method is neurofeedback modulation (NFB) which uses a real time EEG display, to allow patients to monitor and regulate their brain oscillations . After tIn SCI, EEG signals have been used to classify  and evenThe use of data produced by EEG as a marker of neuropathic pain has solid potential; however, it does come with limitations. One key example is the different methods of EEG electrode placement in humans and rodents . The skuAn important consideration when using EEG to investigate neuropathic pain is whether the changes seen in the brain or spinal cord are most important. Whilst it is important to continue work in both areas, the current understanding that pain is a combination of both sensory and emotional aspects leads to the likelihood that EEG recordings focusing on changes in the brain will have a greater ability to analyze the true pain experience. However, the changes seen in the spinal cord may provide a more accessible target as shown by SCS where the effects of neuropathic pain are not clouded by additional factors such as mental state and previous experiences.EEG is a technique that provides a promising way of producing data that can be used as a biomarker of neuropathic pain as it is both translatable and unbiased. Further development is needed to fully characterize the changes produced by individual neuropathic pain causes and identify specific EEG patterns that translate between animals and humans.In this review, we have discussed how bidirectional research is attuning animal models closer to the human condition, by refining neuropathic pain assessment outcome measures to aid translation of preclinical results to the clinic. Alternative behavioral measures outlined in this review provide a means by which preclinical researchers can study not only the development of neuropathic pain but the analgesic response to clinical candidates in a more comprehensive manner. However, the very nature of moving away from simple reflex based measures does mean that behavioral measures may be more easily perturbed by subtle changes relating to environmental events e.g. housing conditions and minor protocol variations that can result in inter-laboratory and inter-group variability. For example, short term social isolation has been shown to suppress burrowing behavior in STZ type-1 diabetic but not control rats . Given t


Despite growing research demonstrating the potential for shared decision making (SDM) to improve health outcomes, patient preferences—including financial trade-offs—are still not routinely incorporated into health care decision making. As the US health care delivery system transitions to rewarding value-based care, the question of “value to whom?” assumes greater importance. To achieve the goals of value-based care, the patient voice must be incorporated into clinical decision making by embedding SDM as a routine part of clinical practice. Identified as a priority by the Centers for Medicare & Medicaid Services (CMS), SDM-related measures and initiatives have already been integrated into CMS’ Center for Medicare and Medicaid Innovation (Innovation Center) demonstration projects  and value-based payment programs  to incentivize more proactive SDM engagement between patients and their providers. Furthermore, CMS has also integrated formal shared decision-making encounters into coverage and reimbursement policies , demonstrating a growing interest in SDM and its potential for eliciting and promoting the integration of patient preferences into the clinical decision-making process. In addition to increasing policy efforts to promote SDM, we need more research investments aimed at understanding how to optimize the science and practice of meaningful SDM. The current landscape and proposed road map for next steps in research, outlined in this review article, will help ensure the transition of pilots and research projects regarding the implementation of SDM into sustainable solutions. Therefore, the success of value-based payment models requires that providers incorporate patient preferences into routine clinical decision making. Virtually all assessment of value, however, presumes a set of benefits that remains constant from one patient to the next, failing to account for how individualized preferences shape the value equation. In fact, decades of research demonstrate that no singular correct answer exists for many health care decisions because so many of them involve a series of trade-offs. The side effect of neuropathy may have a profoundly different impact on a concert pianist than a theoretical physicist.In the race toward an emerging health care system that rewards providers for the value they provide, the question of “value to whom?” holds great significance. Ultimately, we should measure the impact of the care delivered by health care providers on the basis of improvement in outcomes that matter to their patients relative to the costs of achieving those results. Patients will not accept a The transition to new care delivery and payment models provides incentives for providers to change behavior. Those models are gradually encouraging more attention to meeting patients’ diverse needs and preferences, but greater opportunity exists for us to shape that future, especially in the care of people with cancer. This paper provides context for the need to better incorporate patient preferences into routine clinical decision making, presents an analysis of the policy landscape and a business imperative for doing so, and proposes a road map for next steps in research.Shared decision making (SDM) is “a process of communication in which clinicians and patients work together to make optimal healthcare decisions that align with what matters most to patients” ,2. The pCare found that cancer patients want their providers to understand and appreciate the effect treatment has on their lives, such as on their jobs, financial status, family and household responsibilities, access to transportation, and significant upcoming plans [However, the routine incorporation of patient preferences into clinical practice and decision making remains limited . Researcng plans . Howeverng plans .Care ’s survey, less than half of the respondents reported having adequate information on whether they would be able to work, the care they would need at home, and the out-of-pocket cost of treatment [Research also shows that cancer patients are at high risk for financial hardship, and financial trade-offs are an increasingly important part of decision making in oncology care . For exareatment . In PAF’reatment .As we drive toward the promotion of SDM as a means to incorporate the patient voice into clinical decision making, further research is required to optimize the practice and science of SDM and ensure that patients’ personal goals, needs, values, and expectations guide the decision-making process.The changing US payment environment provides direct and indirect incentives for providers to engage proactively in SDM. The Centers for Medicare & Medicaid Services (CMS) has explicitly identified SDM as a priority and has experimented with direct SDM reimbursement through a Center for Medicare and Medicaid Innovation (Innovation Center) demonstration. CMS has also created a set of requirements and expectations in some of its alternative payment models (APMs). CMS continues to develop performance measures related to SDM to drive more proactive SDM engagement among providers through its Quality Payment Program (QPP) that relies on an evolving set of performance measures and clinical practice improvement activities. Indirectly, CMS has identified SDM as a critical component in APMs and other value-based payment arrangements, encouraging providers to use SDM to succeed in achieving high-quality, cost-effective care that most appropriately meets beneficiaries’ expectations. Medicare is a federal health insurance program for individuals who are aged 65 years or older, certain younger individuals with disabilities, and those with end-stage renal disease. Medicaid is a joint federal and state program that provides medical cost assistance and coverage to some low-income and under-resourced individuals. Specifications of Medicaid programs vary by state, and some individuals are able to qualify and receive coverage under both Medicare and Medicaid programs .CMS promotes SDM through the Innovation Center. For example, the Innovation Center launched the Comprehensive Primary Care (CPC) Initiative, a 4-year multipayer initiative designed to strengthen primary care. CPC serves as the foundation for the Comprehensive Primary Care Plus (CPC+), a 5-year advanced primary care medical home model. Fundamental to this initiative and the practice redesign model are 5 CPC functions, including “Patient and Caregiver Engagement,” which promotes the integration of decision aids for preference-sensitive conditions into routine care for primary care practices .The Oncology Care Model (OCM)—which aims to provide high-quality and coordinated oncology care through an episode payment model—also promotes SDM by holding providers accountable for documenting a care plan. OCM specifies that the care plan must address the 13 components of the Institute of Medicine’s Care Management Plan for each participating beneficiary. The components include aspects of a patient’s care closely related to their preferences and goals, such as the following:Treatment goals Treatment benefits and harms, including common and rare toxicities and how to manage these toxicities, as well as short-term and late effects of treatmentInformation on quality of life and a patient’s likely experience with treatmentEstimated total and out-of-pocket costs of cancer treatmentA plan for addressing a patient’s psychosocial health needs, including psychological, vocational, disability, legal, or financial concerns and their managementThe Transforming Clinical Practice Initiative (TCPI) supports integration of SDM into the clinical workflow by supporting over 140,000 clinician practices across the United States in developing and sharing their quality improvement strategies to achieve large-scale health care transformation ,18. MayoIn 2016, the Innovation Center announced the Beneficiary Engagement and Incentives models, which included 2 new models focused on SDM: (1) the SDM Model focused on integrating a 4-step SDM process into routine clinical practice of accountable care organizations (ACOs) to better inform and engage beneficiaries  and (2) CMS, however, announced the cancellation of the SDM Model in 2017 followed by the DDS Model in the first half of 2018 as a result of technical issues and apparent lack of interest from qualifying ACOs. This cancellation signals there is still a long way to go in understanding how to appropriately hold providers accountable for SDM and construct models that integrate SDM into their existing workflows.As the Innovation Center continues to struggle with the best vehicles for achieving SDM accountability, CMS released a request for information in September 2017 for a new direction for the Innovation Center. The request for information focuses on promoting patient-centered care and testing new market-driven reforms that support SDM and engagement efforts by empowering beneficiaries as consumers and improving price transparency [CMS has also integrated SDM-related quality measures into several value-based payment programs, including the Merit-based Incentive Payment System (MIPS), the FY 2019 Medicare Hospital Inpatient Prospective Payment Systems (IPPS) Rule, and the Medicare Shared Savings Program (MSSP).Established by the QPP, MIPS is a value-based payment pathway for clinicians billing under Medicare part B, which broadly rewards value and outcomes. Most clinicians who are subject to the QPP are expected to participate in the MIPS pathway. For calendar year 2019, CMS estimates that 650,165 clinicians will be eligible to participate in MIPS .CMS calculates an MIPS score and associated payment adjustment based on 4 performance categories, 1 of which involves practice improvement activities, which comprises 15% of the final score for the 2019 reporting year. Providers select from an inventory of activities that include several related to SDM and beneficiary engagement :Engagement of patients, family, and caregivers in developing a plan of careImproved practices that engage patients previsitUse of evidence-based decision aids to support SDMAnother MIPS performance category focuses on quality measures, which comprises 45% of the final score for the 2019 reporting year. There are 2 SDM-related measures for the 2018 performance year :Total knee replacement—SDM: trial of conservative  therapyHepatitis C—discussion and SDM surrounding treatment optionsOn August 2, 2018, CMS released the FY 2019 IPPS final rule, which outlines CMS’ perspective and response to public comments on inclusion of 1 SDM-related process measure (NQF #2962)  in the PCMS’ policy changes to include SDM-related measures in value-based payment models demonstrate an increased commitment to incentivizing SDM and the incorporation of patient preferences into clinical decision making. However, fully assessing the extent to which patient and family preferences have been adequately elicited and integrated will require the development and use of more robust measures to assess the decision-making process of clinicians and beneficiaries.Another approach to deploying performance measurement as a lever to drive SDM involves the more broadly focused member experience measures, given the evidence linking SDM to greater patient satisfaction . The MSSHow well providers communicateHealth promotion and educationSDMStewardship of patient resources  There also exist several SDM-related measures that have been validated by their developers but not yet integrated into Medicare reporting and/or value-based programs. Although not all measures are developed with the intention for integration into Medicare programs, there still exists an opportunity for stakeholders to advocate for inclusion of these validated measures into CMS’ quality programs. For example, such measures include the American Academy of Neurology’s “Patient/Caregiver Nutritional Preferences”  and “PatMore recently, CMS has also taken steps to integrate SDM into a coverage and reimbursement policy. For example, CMS finalized changes to the implantable cardioverter defibrillator (ICD) national coverage determination (NCD). Specifically, the update requires a formal SDM encounter between the patient and a physician or qualified nonphysician practitioner  before ICD implantation for certain patient populations . This reIn August 2018, an advisory panel to CMS strongly recommended that CMS integrate patient-reported outcomes into future NCDs for Chimeric Antigen Receptor T-cell (CAR-T) therapies. The Medicare Evidence Development & Coverage Advisory Committee argued that coverage of CAR-T therapies should take into consideration a variety of patient-reported outcomes including assessments of how the clinical decisions account for individual patient preferences.The direction that CMS is taking to promote and incentivize greater SDM between patients and clinicians poses an opportunity for providers to engage in the practice of SDM and position themselves for greater success across an increasing number of value-based payment models. The increasing integration and promotion of SDM in CMS programs suggests that SDM has the potential to play a critical role in improving providers’ performance in value-based programs. However, this would require timely development and testing of strategies and tools to support meaningful SDM as well as more robust approaches to SDM payment models and provider accountability.As the policy environment begins to shift toward promoting a greater focus on placing the patient and family at the center of the care decision-making process, 3 key opportunities exist.First, we need to improve patient and provider engagement in SDM, that is, we need further research on appropriate tactics, approaches, and resources to better prepare patients and families to share their preferences  during clinical decision making. We also need best practices for educating and training providers on how to engage in SDM, so they can successfully elicit and integrate patient preferences in care decision making.Second, successful payment models will require the development and use of robust SDM performance measures. These measures need to assess whether a successful SDM encounter took place as well as its impact on key outcomes of interest, including patient satisfaction with care. In addition, given that some validated SDM measures have been developed but not yet integrated into Medicare quality programs, an opportunity exists for stakeholders to advocate for their inclusion in these programs. Value-based payment models, if well designed, over the long term will encourage SDM. But in the short-term, there may be a need to think about alternatives to promote SDM given the upfront investment of time, resources, and technology costs that are required to achieve meaningful SDM. Research is needed to assess how to ensure that we are not creating unnecessary burdens.Third, to succeed, SDM needs to be respectful of the demands that already exist on providers as well as on patients and caregivers. Further research should explore how to integrate SDM into the clinical workflow in ways that minimize provider burden and meet patients where they are. This will require consideration of the role of the multidisciplinary team and ideal points in patient’s care journey where SDM should be implemented. This will also require the development of resources, tools, and technologies (both patient- and provider-facing tools). For example, health information technology should be used to create new real-world evidence and better incorporate preferences into clinical decision making through dashboards. Such dashboards could pull information from patients and better capture and exchange information from providers’ clinical electronic data.Finally, patient contribution and participation should be built into the fabric of improving SDM tools, measures, resources and processes. That is, patients should be a key stakeholder included in and central to the development of solutions by, for example, using human-centered design principles to include the patients’ perspective in all aspects of the development of such, and ensuring that patients have a seat on advisory boards and other committees that guide this work.Despite research showing that SDM has the potential to improve health outcomes, patient preferences—including those regarding financial trade-offs—are still not routinely incorporated into health care decision making. Given the evidence that demonstrates how SDM can support more effective value-based care, the transition to an increasingly value-based payment environment has great potential to drive the routinization of SDM in standard care delivery over the long term. In the more immediate time frame, direct and indirect incentives for providers to engage in SDM, embedded in payment and delivery reform space, show promise for integrating patient preferences into the heart of clinical decision making. Moreover, the proposed road map for next steps in research will help ensure the transition of pilots and research projects regarding the implementation of SDM into sustainable solutions.


The origins of health and disease can be programmed during prenatal development caused by an unfavorable intrauterine environment, known as “fetal programming.” Intrauterine or fetal growth restriction (IUGR/FGR) describes a pathological condition in which the fetus fails to grow to its biological potential, primarily because of poor placental function. In turn, FGR is known to lead to short- and long-term consequences, like cardiovascular, renal, immunological and neurological disease that greatly impact on individuals and society. Adequate diagnostic approaches and therapeutic interventions are lacking. Thus, dissecting cellular and molecular mechanisms causing placental dysfunction, suboptimal fetal/offspring organ development, and disturbed genetic/epigenetic programming in the offspring are great challenges all required so that interventions can be explored. Defining individual causes for FGR will enable a better diagnosis and raise possible translational candidates for intervention to improve the health of the FGR offspring.in utero diagnosis, possible mechanisms initiating an adverse maternal environment, together with the consequences of fetal programming for neonatal and life-long health, plus discussion on potential interventions.The aim of the present collection “Causes and Consequences of Intrauterine Growth Restriction (IUGR)” was to bring together the many causes for fetal growth restriction, and to describe the consequences of predisposition toward various diseases in later life. The 21 contributions, both reviews and original research papers, include basic science and clinical studies to highlight the placental origins of growth restriction, difficulties associated with Salavati et al., one of the contributing authors, the guest editors of this collection would like to shift the term intrauterine growth retardation/restriction (IUGR), toward the term fetal growth restriction (FGR). As investigators in the field, we agreed that the term FGR more appropriately addresses that it is the individual rather than the environment that is at risk. Furthermore, we would like to encourage a shift away from using the terms small for gestational age (SGA) and FGR interchangeably—in past years both terms have described an estimated fetal weight/ birth weight <10th centile, but SGA should not be used as a synonym for FGR. Most importantly, the difference between SGA and FGR refers to the fact that FGR fetuses are pathologically growth-restricted and demonstrate a reduction in growth trajectory as placental function fails. SGA describes a fetus that is small, but with a normal growth trajectory and normal umbilical artery Doppler velocimetry that indicate the SGA fetus is growing constitutively small along its genetically determined size. In contrast, FGR fetuses do not reach their genetically determined potential size due a pathological interruption to normal growth, most often resulting from placental insufficiency. Thus, SGA defines a statistical deviation only of size but not the pathological condition. Moreover, it would be worthwhile to address a subdivision of early-onset FGR (<32 weeks), and late-onset FGR (≥32 weeks) in future investigations because the two different time intervals are probably due to different causes of placental dysfunction and certainly result in varied consequences for the growth restricted infant.In putting together this collection of studies we became even more aware how diverse this problem is, and that we remain far away from identifying molecular mechanisms in common, or to ascertain a simple concept about the origin of health and disease. After a short discussion with Woods et al. summarizes studies of common types of placental defects in established mouse mutants, which help to instruct us in gaining a better understanding of placental gene expression pattern with an impact on failures in human placentation. In addition, gene expression responsible for the development of the different placental structures is often modulated by epigenetic mechanisms.Besides genetic defects or intrauterine infections, FGR is primarily attributed to a dysfunctional placenta. Lessons from mutant mice demonstrate that defective placental structures are clearly related to FGR. The review of Salavati et al. show that screening of defective human placental development by morphometry could serve to identify FGR at early stages for a better clinical management.Identifying impairment of placental development is another challenge; Hayward et al. demonstrated that the placenta is able to compensate for the calcium transport by a decrease in calcium binding proteins, the parathyroid hormone-related protein and an increase in serum/glucocorticoid-regulated kinase. Another compensating mechanism is described by Schmidt et al. using a FGR rat model fed with low protein diet during pregnancy, which revealed that offspring showed significantly reduced levels of local corticosterone, probably a mechanism to sustain brain development. Endogenous compensation mechanisms are rarely investigated within FGR research but could help to identify novel treatment options in future. Placental infection during pregnancy is also a main cause FGR, and the review of Seitz et al. describes the molecular mechanisms of Plasmodium falciparum infection—still an important issue and reason for FGR in tropical/ subtropical regions—via a defined surface antigen. Deciphering such infection strategies might give rise to intelligent treatment options.Placental dysfunction and reduced nutrient transfer to the fetus is a primary mediator of reduced fetal growth, however the placenta may be able to compensate and thus sustain the health of the developing fetus. Using mouse mutants defective in IGF2, Vogtmann et al. presents an hs-Flt-1 overexpressing mouse model which evidenced that sFlt-1 is responsible for the development of FGR because of a reduced placental efficiency with changes in the maternal/fetal vasculature.The pregnancy disease preeclampsia is a primary complication associated with FGR, and with an increase in the anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) of the placenta. Feenstra et al. revealed that maternal vascular malperfusion contributes to FGR in late pregnancy. Maternal vascularization at the feto-maternal unit in humans and mice involves uterine vasodilation and vessel remodeling upon trophoblast invasion with the help of immune cells. Using a specific deletion of the progesterone receptor in mouse dendritic cell, Thiele et al. showed that impairment of the cross talk between progesterone and dendritic cells leads to a reduction of pregnancy-protective immune cells leading to a poor placentation and FGR. These findings are corroborated by studies on pregnant women from Dunk et al., where defective progesterone-mediated poor decidualization is associated with an elevated mature dendritic profile and the failure of utero-vascular remodeling in FGR.Several studies highlighted the often neglected maternal impact of FGR. A multicentre trial by This review opens discussion about functional connections between placental malformation/malfunction and cardiovascular as well as brain diseases in adults. At this point it needs to be mentioned that not only FGR infants could develop a cardiovascular disease later in life, but there are long term cardiovascular consequences for mothers who develop preeclampsia during pregnancy, a topic which is very interesting however, not highlighted in our collection.Langmia et al. summarize the effects of prolonged adverse maternal environment such as diabetic pregnancies as well as undernutrition and hypoxic conditions on placental genetic/epigenetic modifications, which in turn contribute to FGR combined with cardiovascular programming in rodents and humans. Malhotra et al. turn attention to consequences of growth restriction for the neonate after birth, and brings together a review of literature to show that FGR is associated with respiratory, cardiovascular, and neurological morbidities after birth that may require extra management in neonatal intensive care. The presence and severity of neonatal and longer term respiratory, cardiovascular, and neurological deficits reflect whether FGR is early- or late-onset, the severity of growth restriction, the degree of fetal cardiovascular adaptation, and the gestation at birth. Neonatal pathology is substantiated by Villamor-Martinez et al. who show that FGR but not SGA babies maintain a patent ductus arteriosus after birth which again emphasizes the importance to discriminate between SGA and FGR in clinical studies. The pulmonary consequences of FGR are examined by Allison et al. in FGR and appropriately-grown preterm lambs, together with the potential therapeutic effects of early intervention with umbilical cord blood stem cells.van Wyk et al.). When growth restriction is evoked by calorie restricted diet during rat pregnancy, intervention with lactoferrin ameliorates FGR, and has a neuroprotective effect as shown by van de Looij et al. Clinical investigations for health consequences of the offspring need to carefully discriminate between babies only with FGR, with FGR and premature birth, and babies defined as SGA babies. In this context Morsing et al. could demonstrate that reduced brain volumes as determined by MRI, normally judged as a consequence for FGR, are more likely due to premature birth.Obstetric management can improve catch-up growth of FGR babies and also neurodevelopmental and behavioral outcomes . Hartkopf et al. examined the origins of altered neurodevelopmental function in FGR offspring, and observed that fetal responses show early evidence of altered brain development, while at 2 years of age, children born FGR were found to have neurodevelopmental delays. Indeed the review by Vollmer and Edmonds describes that school-age children who were born growth restricted are more likely to demonstrate cognitive, behavioral, and/or attention deficits and this is particularly so when FGR and preterm birth are co-morbidities.Many studies deal with the consequences of an adverse maternal environment for brain development in growth restricted offspring. A good deal of those maternal insults summarized by Fleiss et al. summarizes research and clinical efforts to identify known pathogenic mechanisms that contribute to FGR and, in particular, neurodevelopmental compromise, and highlight knowledge gaps that require addressing. Quite sensibly, they demand a more concerted research focus and global networking on this complex topic. Yawno et al. examined the ontogeny of cerebellar development in the final trimester of fetal sheep FGR and showed that altered brain cerebellar growth is evident antenatally, and continued in utero compromise leads to progressive worsening in development of the cerebellum. Together, these preclinical and clinical studies provide good evidence that altered brain development begins in utero due to placental compromise, and therefore early diagnosis and early intervention to improve neurological function in FGR offspring are key research areas.The review of The collection of articles presented here in this special issue aimed to describe the various causes and many of the consequences for a baby developed in an adverse intrauterine environment wherein placental insufficiency leads to fetal growth restriction. We described the maternal insults or pregnancy compromise that may seriously affect fetal growth and well-being of the offspring including pregnancy diseases, eating disorders, infection/inflammation, and hormonal imbalance. It is however apparent that fetal growth restriction is primarily caused by placental dysfunction, leading to chronic fetal hypoxia and hypoglycaemia. It is these consequences of placental insufficiency that lead to reduced fetal growth overall, and suboptimal organ development. FGR is associated with lifelong burden of chronic diseases including metabolic, respiratory, cardiovascular and neurological deficits that greatly impact on individuals and society. At this time it remains that adequate diagnostic approaches as well as therapeutic interventions are lacking. The many studies in animals as well as in clinical trials reveal how complex and difficult it is to define a clear phenotype, and as a consequence, to implement an appropriate management strategy during pregnancy, a period which has high ethical limitations in treatment. Thus, in this topic we have described that FGR is strongly linked to altered neonatal and long-term outcomes, and research to improve outcomes must be based on an improved understanding of the pathophysiological mechanisms that alter organ development and growth. Herein our author contributors propose better collaborative research networks that will continue working toward standardized diagnosis and outcome assessments, and will continue research to increase our understanding of the complex changes that occur due to placental insufficiency, so that improved clinical management and treatment is implemented to reduce the burden of FGR.All authors contributed as editors of this Research Topic, and wrote and edited this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: The locus coeruleus (LC) is a nucleus in the human brainstem with a variety of noradrenaline-driven functions involved in cognition, emotions, and perception. Dementia with Lewy bodies (DLB) constitutes a neurodegenerative disease involving deposits of alpha-synuclein, first appearing in the brainstem. The goal of this narrative review is to delineate the relationship between the expression of psychiatric symptoms as an early-onset of DLB and the degeneration of the LC's noradrenaline system.Methods: We searched in PubMed for relevant articles concerning LC degeneration and psychiatric symptoms in prodromal DLB in this narrative review. We rely on the McKeith criteria for prodromal psychiatric DLB.Results: We found four studies that document neuronal loss, deposits of Lewy bodies and other hints for neurodegeneration in the LC in patients with DLB. Furthermore, we reviewed theories and studies on how the degenerated noradrenaline LC system contributes to psychiatric DLB's phenotype. We hypothesized how anxiety, hallucinations, delusions, and depressive symptoms might occur in DLB patients due to degenerated noradrenergic neurons entailing consecutive altered noradrenergic transmission in the LC's projection areas.Conclusions: LC degeneration in prodromal DLB might cause psychiatric symptoms as the first and non-motor manifestation of DLB, as the LC is affected earlier by degeneration than are dopaminergic structures such as the substantia nigra, which are impaired later in the disease course. The locus coeruleus (LC) is the small, bilaterally shaped structure in the brainstem located in the pons that contributes to cognitive functions  is a disorder hallmarked by a demential syndrome and underlying alpha-synucleinopathy with Lewy bodies. Several clinical core criteria must be fulfilled to diagnose DLB, ranging from symptoms of Parkinsonism, fluctuating attention and cognition, rapid eye movement (REM) sleep behavioral disorder, and visual hallucinations according to the McKeith criteria  was demonstrated to be higher in DLB than AD patients in cerebrospinal fluid, whereas peripheral blood level of MHPG was decreased in DLB compared to AD patients (Janssens et al., Concerning depressive symptoms, there is evidence that patients with depression reveal a reduced LC neuromelanin contrast signal (Shibata et al., There is another prodromal DLB subtype besides psychiatric prodromal DLB that is characterized by mild cognitive impairment (McKeith et al., Taken together, a hypothesis is provided for LC involvement in generating psychiatric symptoms such as depression, anxiety, and psychosis including delusions and hallucinations  that mayin vivo biomarkers and the psychopathology of prodromal DLB patients. Taking this approach, we believe it will be possible to optimize diagnostic tools for detecting prodromal DLB.Taken together, the LC noradrenaline system is a promising nucleus that should be targeted in future neuroimaging studies in prodromal DLB patients. Furthermore, investigations focusing on noradrenaline biomarkers in blood and cerebrospinal fluid should guide researchers to discover the relationship between the noradrenergic system's In vivo neuromelanin-sensitive imaging of the LC seems to be an adequate tool for this purpose, as it is known to be sensitive in neurodegenerative diseases such as PD or AD (Betts et al., via fMRI would be of merit in prodromal DLB patients to assess the LC system's functionality with its various connections relevant for LC function in prodromal DLB patients. LC neuroimaging is sensitive enough to depict the LC's integrity, as Hämmerer et al. (Via in vivo LC imaging, it would be possible to stratify patients such as prodromal DLB patients in clinical trials according to their noradrenergic dysfunction. Furthermore, we want to apply monoaminergic and molecular biomarkers to assess LC system degeneration that might be linked to neuropsychiatric symptoms in prodromal DLB [as is evident in patients with AD (Jacobs et al., Considered together, we provide a framework for the postulated relationship between early-appearing psychopathology and LC dysfunction due to Lewy body pathology in prodromal DLB patients. Future research should address the potential relationship between psychopathology and LC degeneration along with LC dysfunction in prodromal DLB patients. r et al.  showed iThe 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.


We also outline a research agenda based on our framework. Ultimately, we hope that this framework utilizing a “brain-as-predictor” approach generates novel insights about the neural underpinnings of message-induced behavior change among lower SES individuals, and helps to close the gap in SES-based health disparities by harnessing the power of neuroimaging.Socioeconomic status (SES)-related health disparities persist for numerous chronic diseases, with lower-SES individuals exhibiting greater risk of morbidity and mortality compared to their higher-SES counterparts. One likely contributor is disparities in health messaging efforts, which are currently less effective for motivating health behavior change among those lower in SES. Drawing on communication neuroscience and social neuroscience research, we describe a conceptual framework to improve health messaging effectiveness in lower SES communities. The framework is based on evidence that health-message-induced activity in the ventral striatum (VS) and subdivisions of the medial pre-frontal cortex (MPFC) predicts behavior change. Additionally, we draw from social neuroscience work showing that activity in these regions during valuation and the processing of self-related vs. social information, differs as a function of SES. Bringing together these previously disparate lines of work, we argue that health messages emphasizing the  This self-focused framing may not be effective among lower SES individuals, who tend to be more focused on the well-being and stability of their social network rather than focusing on personal goals and independence. As such, shifting health messages to be more interpersonally-focused may be more congruent with and instrumental for lower SES individuals. Indeed, past cross-cultural work has already demonstrated how tailoring health messages to match individuals' interpersonal orientations can enhance their effectiveness through shifting perceptions of persuasiveness and even improving health behaviors  that facilitate behavior change. Given its advantages, we suggest that neuroimaging techniques need to be harnessed to provide a more robust indicator of message persuasiveness and likelihood of the message leading to future behavior change among lower SES individuals. However, given the expense and difficulty of acquiring fMRI data, following initial “neural focus groups,” knowledge gained from brain imaging research can be extended into follow-up behavioral studies and broader dissemination efforts. In other words, neuroimaging research is foundational for and complementary to behavioral work on message effectiveness  and their hypothesized neurocognitive functions, given that activity in these regions in response to health messages has been shown to predict behavior change  may be tracking how valuable health information is to an individual and predicts subsequent behavior change, we propose that messages that focus on the personal vs. social value of adopting a healthier lifestyle will be associated with differential activity in this system depending on SES. We hypothesize that social-focused health messages, emphasizing the social value and benefits of engaging in chronic disease prevention behaviors for close others, will be associated with greater activity in the value system and future behavior change among lower SES individuals, given their tendency to value others. In contrast, we predict that self-focused messages highlighting the benefits of behavior change for the self will be associated with less activity in the value system and subsequent behavior change among lower SES individuals, given their tendency to place less emphasis on the self.So far as we are aware, no research has yet explored how the content of messages  influences activity in value-related neural regions among lower SES individuals. However, we will discuss the social and cultural neuroscience literature that inspires the conceptual framework and hypotheses outlined above. While a handful of studies have investigated how lower relative social standing in more local hierarchies  modulates activity in the value system during the processing of social cues , and provides insight into ways to create health messages that are uniquely valuable among lower SES populations. Future imaging work should design health messages that highlight the positive outcomes of behavior change for either the self (self-focused) or close others  to evaluate the extent to which they are differentially associated with activity in the value system and behavior change for lower SES individuals. Given that lower SES individuals tend to value the thoughts and feelings of others  will be associated with stronger activation in the AMPFC, thus inducing future behavior change. In contrast, we predict that health messages focusing on benefits to the self  will elicit less activity in the AMPFC, producing less downstream behavior change.One last neural region that is important in understanding message-induced health behavior change is the DMPFC, which is involved in a variety of social cognitive processes, such as perceiving and understanding the thoughts, feelings, and motivations of others  will be associated with greater activation in the DMPFC and greater behavior change among lower SES individuals, relative to health messages that focus on just benefits to the self .Based on the foregoing discussion, we ultimately predict that among lower SES individuals, social-focused health messages will elicit greater activation in the VS and sub regions of the MPFC , relative to self-focused health messages. Further, we predict that greater activation in these regions in response to the social-focused health messages will predict greater subsequent behavior change. To test these hypotheses, we suggest that future fMRI studies design and test a variety of message framing strategies to determine their effectiveness among lower SES participants. In keeping with prior conceptualizations of “low SES,” this would involve recruiting participants with less than a college degree, those living at or below the federal poverty line, and/or those working blue collar and/or service industry jobs. During the fMRI scan, participants can be randomly assigned to view health messages that focus either on how engaging in a variety of healthy behaviors  can benefit close others, or how they benefit the self. For example, a social-focused health message promoting a healthy diet could state, “Depend on a healthy diet, so your family can depend on you,” whereas a self-focused message could say, “Depend on a healthy diet to feel and look your best.” Similarly, a social-focused health message promoting cancer screenings could state, “Get regularly screened for cancer so you can grow old with your partner,” whereas a self-focused message could say “Get regularly screened for cancer to live a long and successful life.” In addition to altering the text as outlined above, health messages could also feature different images that are either social-focused  or self-focused . Message-induced neural activity within the VS and sub regions of the MPFC can then be compared between the two different assigned groups , relative to a control condition , to see which message framing type elicits the greatest activity in these regions of interest. To assess downstream behavior change, participants can complete follow-up behavior change assessments a few months following the fMRI scan. Further analyses can then test the extent to which message-induced activity in the regions of interest predict future behavior change, depending on the content of the message. Collecting participants' perceptions of the persuasiveness of health messages may also enable researchers to test whether self-reported measures or neural responses to the messages are better predictors of behavior change.Once these initial studies focused on lower SES individuals are carried out, it will be important for subsequent studies to recruit people across the entire SES gradient and examine similar processes. Comparing the effectiveness of different message framing strategies  among lower SES people vs. higher SES people will ensure that the effects are specific to lower SES. We predict that compared to higher SES individuals, lower SES individuals will show greater neural activity in the VS and sub regions of the MPFC in response to social-focused health messages (relative to self-focused messages). Conversely, we predict that compared to lower SES individuals, higher SES individuals will show greater neural activity in these regions in response to self-focused health messages . Further, greater activation in these regions of interest will predict downstream behavior change. Thus, social-focused health messages will be more effective for lower SES people, and self-focused health messages will be more effective among higher SES people.Beyond our main predictions and example paradigm, there are a myriad of other exciting directions that future imaging studies could take, such as testing the effectiveness of multiple types of social-focused health messages. For instance, in our examples above, we primarily focus on close others, such as interpersonal relationships, given the past literature in social psychology and sociology showing that lower SES individuals tend to have tight-knit social networks . Although focusing on specific social roles and identities could be effective, it is important to note that social identity can influence beliefs and attitudes about health behaviors and could even undermine motivations to change. For instance, lower SES Americans are more likely to view unhealthy behaviors as part of their in-group identity, and making their socioeconomic group membership salient influences fatalistic beliefs about improving health  evokes greater activity in a region included in the mentalizing network  and the AMPFC among more interdependent individuals  more generally tend to express an independent or individualistic view of the self, compared to individuals from Non-Western countries , who tend to adopt an interdependent view of the self  could then be rolled out specifically in lower SES communities. For example, billboards, advertisements at public transit stops, and even TV, radio, and social media public service announcements could be tailored to more effectively speak to and resonate with individuals in the communities where they reside. Second, results from these studies could be used to provide more cultural-tailored training for physicians, nurses, and other health-care professionals so that these providers can more effectively motivate health behavior change across the SES gradient. Along these lines, providers could receive information about how to frame behavior change messages in more socially-oriented terms, and thus more effectively motivate their lower SES patients to engage in behavior change. This could improve patient-provider communication in an effort to achieve health equity. Thus, results from the research agenda outlined here can (and should) ultimately be disseminated to public health and health-care professionals such that the knowledge gained can be implemented in lower SES communities to promote health equity.which health messages are most effective in inducing behavior change among lower SES individuals, and why such messages are particularly potent. This promising area of work can then be used to design more effective and targeted messaging campaigns that can be carried out at the population-level to help close the current gaps in chronic disease disparities and promote health equity.In conclusion, there are tremendous opportunities to harness both communication and social neuroscience perspectives to create effective and tailored messages that advance chronic disease prevention efforts among lower SES populations who are more susceptible to poor health outcomes. Our proposed framework serves as a path for future research to address SES disparities in health through improving health messaging effectiveness utilizing a brain-as-predictor approach. Future studies should use brain imaging to understand The original contributions generated for the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.SB and KM wrote the manuscript. PS and AL participated in the revision and proof-reading process of the manuscript. All authors have approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Millions of refugees worldwide are exposed to violence, family separation, culture loss and exile. The coronavirus disease 2019 (COVID-19) exposes these populations to a new threat, one that could prove to be more devastating than the events forcing them to flee their homelands.,Refugees are vulnerable to COVID-19,The refugees’ fear of being isolated in quarantines and separated from their families, or even killed to slow the pandemic, can explain why aid workers in Rohingya camps report minimal testing among residents with COVID-19 symptoms.While empirical studies are needed to understand the extent and nature of stigma in refugees with COVID-19, news media reports from refugee-sending countries, such as Iraq, indicate that stigma is a major barrier to prevention and treatment.Moreover, the COVID-19 pandemic has strained the finances of governments, nongovernmental organizations and humanitarian agencies that serve refugees. The economic crisis caused by efforts to contain the pandemic is worsening the refugees’ already precarious situation in informal labour markets. Without access to government support for unemployed citizens, many refugees rely on insufficient cash assistance from humanitarian agencies and many will not have jobs waiting for them when business reopens. The United Nations High Commissioner for Refugees reports that a recent survey in Jordan showed that only 35% of Syrian refugees said they had a secure job to return to after the lifting of COVID-19 restrictions.The Lancet’s guiding principle of public health networks leaving no one behind during the COVID-19 pandemic,The COVID-19 pandemic has exposed systems of inequality but was met with delayed responses by public health authorities to address the needs of the most vulnerable. Humanitarian agencies serving refugees emphasize the importance of global support for the receiving countries so they can continue their efforts of solidarity, medical care and economic support. Hence, we strongly endorse As resources are constrained, agencies and professionals serving refugees should consider giving priority to screening vulnerable subgroups  to manage comorbidities more effectively, encourage patients to reduce high-risk behaviour, provide treatment and reduce transmission rates.


These students, 41 females and 3 males, ranged in age from 20 to 25 yr, were provided a voluntary questionnaire seeking responses related to the perceived effectiveness and individual preferences of in-class lectures and in-person labs vs. remote online teaching practices. A similar questionnaire was offered on a volunteer basis to precollege students (n = 17). These students, female, high-school students from freshman to senior status (14–18 yr of age), were interested in equine science as a major at UC Davis in the future. This questionnaire evaluated their response to a 2-week remote synchronous online equine science course, which included multiple teaching methods, including lectures, mini labs, and full labs. Responses from both populations suggested that equine courses were perceived as effective when offered as online, remote courses. Live (synchronous) classes and labs offered on Zoom increased engagement and interaction, but students also appreciated the opportunity to access recorded materials. Students responded positively to online remote teaching and found courses to be effective for increasing their knowledge about equine science in an engaging manner, despite their continued preference for in-person instruction.The COVID-19 pandemic has challenged professors and students of all disciplines to adjust quickly to remote online teaching and education platforms. In this new era of remote teaching, a greater challenge has been presented in the field of equine science; how to effectively share knowledge that is most often demonstrated by providing students access to live, in-person animal examples. Historically, students and teachers believed skill sets, which are vital for future careers in the industry  must be learned through hands-on experience. However, in-person methods were not available, so students were taught through the Zoom platform. Students enrolled in various levels of equine science classes were invited to complete a short voluntary questionnaire measuring their response and perception to equine courses taught in an entirely online remote setting by the same professor. One group was comprised of undergraduates majoring in the field ( Spring brought a swift change across the field of education, due to varying responses to the COVID-19 pandemic from elementary schools to universities. Many responses from schools included mandated changes to pedagogy, which happened suddenly and somewhat unexpectedly for students and teachers. For example, at the University of California, Davis, all in-person classes were cancelled 9 d before the end of Winter quarter . ContextHowever, the idea of moving courses online and offering online education is nothing new. Since tThe objective of the study was to measure student responses to questionnaires completed after the conclusion of the course to learn more about student perceptions of course effectiveness. Along with student opinions about the class content and teaching methods, effectiveness was also measured through reported level of engagement in these courses that relied upon the instructional support of videos shown during class meetings. Reporting attendance  completed this questionnaire. Respondents ranged in age from 20 to over 25 yr of age, and all were Junior or Senior-level students, with a majority of their majors being Animal Science with an equine option.This case study focused on students enrolled in equine science courses, which would typically be offered in person, at both the undergraduate and high-school (precollege) level. All students were asked to voluntarily share their opinions and perception of the effectiveness of equine science courses offered synchronously online. Two online questionnaires concerning the effectiveness of remote online equine science courses were designed and offered for completion to the students enrolled in one of three equine science courses. The first questionnaire was comprised of 18 questions and was created using Google Forms. This questionnaire was offered on a voluntary basis to students enrolled in one of two upper division equine science courses, Advanced Equine Reproduction Physiology and Equine Enterprise. The response options were construct-specific in hopes of avoiding response bias often seen with agree/disagree response options . Forty-fn = 17), all high school females ranging in age from 14–18 yr. There were 17 questions in this questionnaire, which was created using Qualtrics.The second questionnaire was created specifically for completion by the precollege equine science students . Results from both questionnaires were compiled and checked for completion, and compatible questions, which allowed for comparison between questionnaires were identified and compared. Since questionnaires were on a volunteer basis and part of the courses IRB approval was not required.Statistical AnalysisIn the context of relatively limited sample sizes and given the failure to fulfill parametric assumptions , results from both groups were analyzed using Bayesian inference for ANOVA. Statistical differences in the mean of the possible answers for the questions reflected in Bayesian algorithms considered by SPSS and used in this analyses are described and publicly available in IBM SPSS Statistics Algorithms version 25.0 by IBM Corp.  was measured to quantify the strength of the evidence against null or alternative hypothesis when comparing hypothesis pairs. Both genders found online courses effective without showing a preference for synchronous online courses taught live on Zoom over the recordings of these live classes. However, females and males and precollege or undergraduate students indistinctly found it much easier to grasp concepts taught online when compared to in-person classes and found recorded sessions very useful.Despite the usefulness of recorded class sessions, female and male students mostly preferred to attend live (synchronous) courses. Indistinctly precollege or undergraduate students slightly preferred turning in assignments online. On average, precollege and undergraduate female and male students indistinctly found being asked questions combined with viewing supplemental videos from slightly to very helpful, with these videos being from slightly to very effective when helping to sustain attention. Precollege or undergraduate females or males found guests speakers very effective, slightly preferring seeing teachers and guest speakers live on Zoom. The most valued element of online course was the interactive and international element through guest speakers, while the lowest valued aspects were related to technical problems. Precollege and undergraduate either female or male students were in the same time zone and country on average and found Zoom easy to use. On average males and female students preferred lecture topics related to donkey science, behavior, nutrition, and reproduction physiology.According to the results, precollege and undergraduate female and male student both found content easy to access and found the professor to be very effective at online teaching, indicating they would like to repeat the course with the same professor if they had the option, or would recommend the class and teacher to their peers.Bayesian inference for ANOVA suggested no significant differences were found for any of the questions formulated across genders, except for “Did you prefer turning assignments in online?” for which a significant difference was found between female and male respondents, with females slightly preferring to hand in assignments online, while on average males prefer to hand in assignments in person. Bayesian inference for ANOVA suggested males belonged to the Animal Biology program while females belonged to the Animal Science program on average. Female age was significantly different from males’ age with females being 21 on average while males were 26, respectively.P < 0.05) slightly preferred in-person lessons while precollege students slightly preferred online lessons. When attendance was considered, significant differences were found with precollege students always attending live lectures while undergraduate students only attending half of the live lectures on average. For the attendance preference, precollege students significantly always preferred to attend live lectures while undergraduate students mostly prefer to attend live lectures. Precollege students found it (P < 0.05) slightly helpful being asked questions, while undergraduate students found it very helpful. Precollege students found supplemental videos slightly helpful (P < 0.05) while undergraduate students found them very helpful. Precollege students presented a neutral (P < 0.05) attitude towards seeing professor or guest speakers live as they taught, while undergraduate students reported a slight preference to see professor or guest lecturers live. On average precollege and undergraduate students differed in regards to what they disliked most due to their technical problems  while undergraduate students on average did not have anything notable to mention as a complaint or negative aspect of the course (P < 0.05). Undergraduate student significantly belonged to the animal science program on average. Undergraduate students (P < 0.05) were more specialized in equine diseases or equine science in general while precollege students’ favorites topics covered were Equine Behavior and Reproduction. Student age significantly differed, with precollege students being below the age of 18 while undergraduate students were 22–23 yr old on average.Bayesian inference for ANOVA suggested significant differences were found for the comparison between precollege students and undergraduate students. Specifically, undergraduate students (Educators were faced with a new and unexpected challenge in Spring of 2020; how to quickly adapt to unplanned emergency remote online teaching . InstrucThis quick adaptation could be linked to a generation of students whose ethos easily aligns with technology . PerhapsBased on student’s responses to our questionnaires, combining instructional videos focused on learning objectives with dedicated question and answer sessions this method seemed to increase engagement based on student participation. This method was used in all the courses examined in this case study, and students in both populations, undergraduates and precollege, found short instructional videos developed by the professor specifically for this purpose helpful and effective. Some video segments consisted of prerecorded sessions with experts on specific topics, which were shown and supplemented by providing a question and answer period with the guest lecturer and students. Based on the questionnaire results, overall the students found the courses to still be effective in terms of meeting their expectations, which aligns with reports that such methods were successful in other didactive teaching programs . Other eStudents enrolled in equine courses typically want to be future veterinarians, and gaining hands-on practical experience is still considered essential for their future professions. However, other fields which usually rely upon these hands-on courses are also beginning to use instrumentation videos. For example, example in one dental hygiene course, students were shown instructional videos on various procedures and then asked open-ended questions pertaining to the information shown . A similOne study with veterinary students found that live stream videos, case studies, and clinical cases are helping increase students’ ability to make important clinical decisions . In the Though educators in this field will continue to be challenged by certain aspects of remote teaching, the content and structure of classes remains in our control, as well as our method of delivering our message. Whether we find ourselves teaching in the physical brick and mortar classroom or in this new online classroom, the possibilities discovered in this new format should encourage all educators to reach new heights of creativity. What was initially perceived as detrimental to teaching in this field may spur innovation and the development of new teaching strategies to disseminate information in nontraditional formats, such as creating learning activities and evaluation methods that promote critical thinking and enhance student’s ability . AnotherBased on the responses from the questionnaires one could draw the conclusion that all equine science students in college and precollege during the pandemic have found online equine science courses to be a good idea, especially when taught with instructional methods that are geared toward capturing student attention and increasing engagement meaning increasing participation from students. Based on this case study, instructors may find it helpful to teach courses synchronous, have their video camera on during lecture and create short instructional videos to supplement one taught live hands on labs. Finally, methods developed for emergency online remote learning may prove useful when moving into regularly scheduled offerings of online classes, and perhaps in certain instances could even replace hands-on experiences when in-person classes resume. Although findings suggest students will continue to prefer in-person classes, the overall positive response to these methods suggests that online equine classes can be a good idea, even as we return to traditional classes.


The aim of this paper is to review all the up to date evidence, including experiences from China and Italy, to guide the safe management of such patients when undergoing gynaecological procedures.The worldwide impact of COVID-19 continues to be felt as hospitals in all countries reduce elective and non- urgent cases to allow staffing and resources to be deployed elsewhere. Urgent gynaecological and cancer procedures are continuing, and it is imperative all theatre staff are protected and risks of SARS-CoV-2 viral transmission reduced when operating on asymptomatic, suspected or confirmed COVID-19 patients. In particular, there are concerns relating to the transmission of COVID-19 during gynaecological laparoscopic surgery, arising from the potential generation of SARS-CoV-2 contaminated aerosols from CO Since the swift arrival of COVID-19, most national bodies and learned societies have advised the urgent suspension of elective surgery with the focus shifting to emergency and cancer surgery . This alSARS-CoV-2 virus is largely transmitted via respiratory droplets and the highest transmission risks arise when undertaking aerosol generating procedures (AGPs) i.e. medical and patient care activities that can result in the release of airborne particles (aerosols). AGPs can create a risk of airborne transmission of infections that are usually only spread by droplet transmission. Due to the high viral load in respiratory secretions, intubation and extubation remain one of the highest risk AGPs . The maiIn laparoscopic surgery, the creation of an artificial pneumoperitoneum may increase the risk of aerosol exposure to the whole operating team. Specific evidence relating to the presence of SARS-CoV-2 virus in the peritoneal cavity and thus its transmission during laparoscopic surgery is lacking, but theoretical risks may be extrapolated from previous pandemics and viral infections. For example, prior to COVID-19, previous studies have shown that other pathogens such as activated corynebacterium, human papillomavirus (HPV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) have been detected in surgical smoke .The presence of HPV DNA has been reported in approximately 40% of smoke plumes following loop excision biopsy of the cervix . An analBoth ultrasonic and electrosurgical devices have the propensity to create large surgical plumes thus potentially increasing the risks of viral transmission. Recent NHS pandemic Coronavirus Infection Prevention and Control guidance states that high speed surgical devices generate aerosol . UltrasoMost standard operating theatres have a positive pressure relative to the surrounding air (e.g. in corridors and adjacent areas) to prevent the flow of air from less sterile areas into a more sterile one. However, this positive pressure environment created within the operating theatre makes the spread of aerosols faster, posing an increased airborne viral transmission risk.A negative pressure environment is ideal to reduce dissemination of the virus beyond the operating theatre although such facilities are not widely available. A high frequency of filtered air exchanges may help reduce viral load within an operating theatre .It should be borne in mind that the risks of airborne viral transmission are not restricted to laparoscopic surgery because both open and laparoscopic surgery have the propensity to generate aerosols. However, the overall risk may be lower with open surgery  as an arAs this pandemic progresses, the need to continue operating in emergency situations such as ectopic pregnancies on suspected or confirmed COVID-19 patients will increase.Hypothetical risks of viral transmission must be balanced against the significant benefits of adopting a minimally invasive approach, namely reduced morbidity and mortality, shorter hospital stay and quicker return to daily activities .These advantages have gained even more significance in helping to maintain wider public health, in light of the pressure on health care resources imposed by this pandemic.The evidence so far does not suggest an increased risk of COVID-19 transmission during gynaecological laparoscopic surgery when personal protective equipment (PPE) is used.Molecular studies have detected viral RNA in a range of bodily specimens from COVID-19 patients, including upper and lower respiratory tract samples, faeces and blood, indicating the potential presence of infectious virus. SARS-CoV-2 virus has been detected in faeces in 29% of cases , presumaThe Royal College of Obstetricians and Gynaecologists (RCOG) along with the British Society for Gynaecological Endoscopists (BSGE) recently released a statement on gynaecological laparoscopic procedures and COVID-19. They recommended that laparoscopic approaches should be utilised when feasible in preference to laparotomy . These sIt is imperative all medical and theatre personnel are protected during this pandemic and full precautions are taken to reduce the transmission risks. Inadequate protection results in an increased infection rate amongst medical and nursing staff with significant morbidity and in some cases sadly mortality, placing a further strain on already struggling health services when resources are at a premium. It is important to follow both local and national  guidanceThere remains a paucity of evidence surrounding SARS-CoV-2 virus transmission particularly in laparoscopic gynaecological surgery, however these recommendation are based on national and international guidance and extrapolated data from other viral infections . These pNon-surgical treatments should be utilised where possible to reduce the risk of horizontal transmission of SARS-CoV-2 virus to health care workers, and reduce the need for hospital admission, provided they are a safe alternative.Patients should be risk assessed for potential SARS-CoV-2 viral infection. Consider universal SARS-CoV-2 virology screening in all patients undergoing surgery. Patients testing negative can proceed with the standard laparoscopic technique and routine surgical infection control procedures.If urgent surgery is required and testing is not possible, manage as suspected COVID-19 with precautions described.Hospitals should have clear pathways and make theatre allocations to separateCOVID-19 positive patientsClinical emergenciesClinically urgent casesTrauma patientsThe laparoscopic procedures should be undertaken by the most experienced surgeon available to ensure full knowledge of safe laparoscopic procedures are followed and to ensure that the procedure is performed in the shortest time possible.To protect operating staff:Enhanced PPE is mandatory for all theatre personnel In order to minimise possible exposure and to guard against depletion of PPE stock, ensure that only staff that are required for the procedure are present in theatreTheatre staff need to be versed in self-protection strategies against suction materials and blood contaminated areas in theatres and in laparoscopic suction in line with local protocolsTo aid artificial ventilationOperating pressures should be kept as low as possibleMinimise the amount of TrendelenburgTo prevent and manage aerosol dispersionCaution and care should be taken during insufflationSpecial attention should be paid to port sites to prevent explosive dispersion of body fluids both at the insertion/removal of trocars and specimen retrievalLimit the number of incisions where possible, although there should be enough port sites to allow safe and expeditious surgeryEnsure that incisions are of appropriate size to prevent leakage during the procedureMinimise exchange of instruments to minimise leakageCaution when using ultrasonic devices as the potential for aerosol generationmay be higher.Employ electrosurgical and ultrasonic devices in a manner that minimises surgical smoke production with low power settings and avoidance of prolonged activation2 pneumoperitoneum during surgery and (2) avoid explosive dispersion of body fluids when removing trocars and retrieving specimens.Suction devices, smoke evacuation filters, retrieval devices and swabs should be used to: (1) prevent aerosol transmission: remove smoke, aerosol and the COOnly evacuate surgical smoke via the tap on ports when attached to a smoke evacuation filter and / or by direct suction using a vacuum suction unit.Only evacuate the pneumoperitoneum via direct suction using a vacuum suction unit.Gynaecological operations that carry a risk of bowel involvement, however small should be performed by laparotomy.Standard laparoscopic practice is to remove all ports under vision and subsequently expel all the operative gas followed by removal of the laparoscope under direct vision. In view of the potential aerosol risks all ports used to release gas should have a suitable smoke extraction device attached. At the end of the procedure, gas should be removed using the combination of a suction device and releasing gas slowing via a filtered port. The accessory ports should be removed slowly and over a blunt probe, which is subsequently removed, to reduce the risk of hernia as removal under direct vision is not possible when avoiding inadvertent gas leakage.The primary port should still be removed under direct vision once the abdomen has been completely deflated.Ports larger than 5mm should be closed as per standard practice, however a J needle closure  is recommended rather than using an Endoclose device, which would increase the risk of gas escaping from the abdomen.Laparoscopic hysterectomies, in the context of malignancies, are likely to continue to be undertaken in this pandemic. Particular care must be taken during colpotomy and subsequent uterine extraction to minimise unfiltered gas leakage and sudden loss of blood and other body fluids. The abdomen should be emptied of gas using a suction device and filtered ports, as described above, prior to removal of the uterus. To minimise airborne droplet transmission consideration should be given to performing an open hysterectomy, on a case by case basis.


Sleep is mandatory in most animals that have the nervous system and is universally observed in model organisms ranging from the nematodes, zebrafish, to mammals. However, it is unclear whether different sleep states fulfill common functions and are driven by shared mechanisms in these different animal species. Mammals and birds exhibit two obviously distinct states of sleep, i.e., non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, but it is unknown why sleep should be so segregated. Studying sleep in other animal models might give us clues that help solve this puzzle. Recent studies suggest that REM sleep, or ancestral forms of REM sleep might be found in non-mammalian or -avian species such as reptiles. These observations suggest that REM sleep and NREM sleep evolved earlier than previously thought. In this review, we discuss the evolutionary origin of the distinct REM/NREM sleep states to gain insight into the mechanistic and functional reason for these two different types of sleep. Although a wealth of evidence suggests that sleep is related to many diverse processes such as memory consolidation, emotional stability and maintenance of brain homeostasis, the mechanisms by which sleep fulfills these functions are unclear . Even thBesides behavioral criteria, the standard method to define sleep in animals with a well-developed cerebral cortex, like mammals and birds, is the observation of a pattern of coordinated changes in electroencephalogram (EEG) and electromyogram (EMG) readings. However, in other animals, sleep is usually defined solely by behavioral criteria : (1) steIn humans and various other mammalian species, NREM sleep and REM sleep stages are defined behaviorally and can be separated by EEG/EMG scoring . REM sleObservations about the existence of REM sleep in cats, rats and other mammals have provided fundamental information for understanding the architecture of sleep. Recent technological advances in the field of neuroscience, such as optogenetics and pharmacogenetics, as well as neuronal tracing techniques have accelerated our knowledge-gathering capabilities about the neuronal mechanisms that control sleep/wakefulness states in mammals . Among mAt least in mammals and birds, during wakefulness, the EEG shows a pattern of low amplitude, high frequency fluctuations, and the EMG shows considerable amounts of muscle activity. During NREM sleep, the EEG shows large amounts of oscillation in the delta (0–4 Hz) frequency ranges. Prolonged periods of wakefulness are usually followed by increased amounts of NREM sleep with high delta activity, showing the existence of compensatory and homeostatic mechanisms in its regulation .After NREM sleep, the EEG starts to show abundant theta activity that arises from the dorsal hippocampus , which iSince the neuronal regulation and the associated characteristics are very different, REM sleep might be highly distinct from NREM sleep. In rodents, under certain circumstances, the pressure to enter NREM sleep or REM sleep can build up and dissipate separately .The respective functions of NREM sleep and REM sleep are poorly understood and it is therefore not clear why these distinct states emerged during evolution. NREM sleep has been shown to be involved in several “housekeeping” processes of the brain, such as homeostatic synaptic plasticity, memory consolidation, and clearance of brain metabolites . Recent Another prominent role of REM sleep might be to support brain maturation in the early stages of life. It is known that in humans and other mammals, REM sleep is most abundant in early development stage, in particular in the neonatal period . MoreoveThe time spent in REM sleep varies not only during an individual’s development but also among species, as has been reported at least in mammals and birds . For exaThe existence of two distinct sleep states only in endotherms has been thought to be the other clue to understanding the evolution of sleep . For exaNon–avian reptiles  are at key evolutionary positions, they are ectotherms, and share a common ancestor with mammals and birds, and thus can serve as precious model animals to decipher the evolution of neural functions – including sleep.Identifying sleep in reptiles is challenging mainly for two reasons. Firstly, they generally exhibit long periods of quiescence. Secondly, their cortical EEG does not allow unambiguous identification of sleep states . QuiescePogona vitticeps) exhibits a period of behavioral sleep rich in delta frequency (0.5–4 Hz) characterized by numerous negative high amplitude sharp waves  also exhibits high voltage sharp waves occurring during behavioral sleep in some brain regions including the DVR  located in the lateral hypothalamus are important in maintaining and generating REM sleep. In reptiles, MCH neurons reside in the periventricular and lateral hypothalamic area . In miceBrain temperature declines during NREM sleep and rises during REM sleep in endotherms . We stilIn zebrafish, sleep has been defined solely by behavioral criteria based on periods of quiescence associated with a specific posture  , as it iA recent study suggested that there are at least two sleep states in fish . The resMoreover, the authors reported that they observed two distinct sleep states in zebrafish by analyzing eye movement, heart and muscle activity, along with brain-wide activity imaging. The authors termed these two states “slow bursting sleep” and “propagating wave sleep,” which share similarities with mammalian NREM and REM sleep. Notably, propagating wave sleep was accompanied by increased variance in the distribution of inter-heartbeat intervals, showing similarity to mammalian REM sleep. These observations suggest that two states of sleep are found even in non-amniotic vertebrates. Furthermore, MCH was shown to regulate propagating wave sleep in zebrafish, similarly to the effect of MCH on REM sleep in mice, which also suggests similarity between propagating wave sleep and mammalian REM sleep. This study revealed that a REM sleep-like state exists even in distantly related vertebrates. Since REM sleep is thought to be important in the development of the brain, it is important to know whether adult fish also show a REM sleep-like state.Sepia Officinalis), one of the cephalopods that has the largest and most complex brain  is particularly useful to study at a molecular level. It is suitable for non-biased screens to decipher the genetic components underlying unidentified biological phenomena because of its short reproductive cycle and the availability of genetic tools. Consequently, many findings about sleep have been obtained through studies on flies. The fly sleep model is now widely accepted and has inspired the development of other genetic models of sleep, such as the nematode (C. elegans)  . The useIt is not clear whether flies and nematodes also display dynamic neuronal processes such as REM and NREM sleep because their sleep has been solely defined by behavioral criteria. Recently, it was reported that a gene coding salt-inducible kinase 3 (SIK3) positively regulates NREM sleep in mice . InteresIt is likely that some reptiles, teleosts, and even cuttlefish have two different electrophysiological sleep states, sharing some features with NREM and REM sleep in mammals. However, it should be noted that mammalian NREM and REM sleep have been defined based on measurable traits constrained by anatomical or physiological features specific to mammals . Thus, aRecent studies showing there are two distinct states of sleep in reptiles fish and cuttlefish have opened up avenues of research toward understanding REM sleep, although we are only half-way down this road. It remains to be elucidated why the brain needs two states of sleep, i.e., sleep with highly synchronous and de-synchronized firing of neurons.Sleep is essential in most animals that have the nervous system, and is universally observed in model animals ranging from nematodes to zebrafish to mammals. Mammals and birds exhibit two obviously distinct states of sleep, i.e., non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep, but it is unknown why sleep should be so segregated. In addition, it is unclear whether the different sleep states fulfill common functions and are driven by shared mechanisms in these different animal species. Studying sleep in other animal models might give us clues that could help solve this puzzle. Recent studies suggest that REM sleep or ancestral forms of REM sleep might be found in non-mammalian and non-avian species such as reptiles. These observations suggest that REM sleep and NREM sleep evolved earlier than previously thought. In this review, we discuss the evolutionary origin of the distinct REM/NREM sleep states to gain an insight into the mechanistic and functional reasons for these two different types of sleep.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.