The free transverse rectus abdominis myocutaneous (fTRAM) flap is a frequently used option for autologous breast reconstruction, typically based on deep inferior epigastric vessels anastomosed to either the axillary or internal mammary systems. The distal portion of the fTRAM flap is routinely discarded prior to anastomosis, due to tenuous blood supply in the vascular territory most distal to the pedicle. This becomes problematic in cases that require use of the entire flap, such as in thin patients with large soft-tissue defects. We report a case where an additional “supercharged” venous microsurgical anastomosis was successfully performed to minimize adverse events while utilizing the entire fTRAM flap. Autologous breast reconstruction with the pedicled, free, and muscle-sparing transverse rectus abdominis myocutaneous (TRAM) flap has become a frequently used reconstructive option throughout its evolution, owing to its outstanding aesthetic outcome without the need for prosthesis, superior long-term result, and high patient satisfaction. The free TRAM (fTRAM) flap has traditionally been based on the deep inferior epigastric vessels anastomosed to either the axillary or internal mammary systems; however, this technique has been plagued with varying degrees of complications related to the unpredictable flap blood supply, including skin necrosis, fat necrosis, and partial and total flap loss . We presA 47-year-old female, with a history of left breast cancer and total mastectomy followed by neo-adjuvant radiation in 2009, presented to the Plastic and Reconstructive Surgery clinic in December 2014 to discuss options for breast reconstruction. Other significant past medical and surgical histories at the time of her initial presentation included a left posterolateral thoracotomy for complicated pneumococcal pneumonia, three cesarean sections, and 1 ppd tobacco use. Her disease status was closely monitored by her oncologic team and was deemed disease-free as evident in her then most up-to-date negative screening mammogram in 2013. Upon successful cessation of her tobacco use for a period of six months after the initial consultation, the patient was taken to the operating room in June 2015. With goals to recreate a full C-cup sized breast in a patient with a very thin body habitus (body mass index = 24), our team utilized a supercharged muscle-sparing fTRAM flap in order to safely utilize all four zones of the abdominal flap. Utilizing a two-team approach, the recipient site of the left chest was entered from her previous mastectomy incision, along with resection of the surrounding radiated fibrotic skin. A laterally based pectoralis flap was utilized to dissect up to the second rib, which was then partially resected to expose the left internal mammary artery and two veins. Simultaneously, the transversely oriented abdominal flap was elevated by the second surgeon, being particularly careful to preserve both the superior and inferior epigastric vessels on both hemi-abdominal flaps. Dissection proceeded in the prefascial plane above the anterior rectus sheath in a lateral to medial approach. After the favorable right-sided lateral row perforators were identified, the fascia was incised and the rectus muscle exposed, allowing us to trace the vessels down to the origin of the deep inferior epigastric artery and vein in the right lower quadrant. Care was taken to preserve both the superficial and deep inferior epigastric vessels on both sides of the flap during all steps of the dissection. Once the medial portion of the right-sided muscle-sparing TRAM flap was elevated in a MS-2 design, it was found to be quite thin, and so this portion of flap was folded on itself during the harvest. Once the flap was fully islandized, adequate perfusion and bleeding was seen along the entire flap, including zone 4 after the de-epithelization process  without mesh reinforcement given the minimal tension and healthy quality of her innate tissue. At the conclusion of the case, the flap exemplified excellent color and strong Doppler signals along the entire skin paddle. Three months after the initial reconstruction, the patient underwent a symmetrizing augmentation of the right breast with a subpectoral silicone implant, and revision of the left breast for improved superior medial fullness and reconstruction of the nipple using a C-Y trilobed flap Figure . The patThe traditional pedicle TRAM flap was first described by Hartrampf et al. in 1982, and has become a well-established form of autologous breast reconstruction in postmastectomy breast cancer patients [When the entire fTRAM flap is utilized through a single-sided vascular anastomosis, perfusion to the distal end becomes tenuous and prone to skin or fat necrosis, with a published incidence reaching as high as 32% of patients . Given tIn 1987, Harashina et al. developed a microvascularly augmented technique in which the pedicled flap was elevated on the superior deep epigastric pedicle along with the contralateral superficial or deep inferior epigastric vessels . The flaIn 1991, Beegle introduced the “supercharged” technique, where additional ipsilateral deep inferior epigastric vessels were anastamosed to either the internal mammary or thoracodorsal systems ,9. In 20In alignment with improving flap perfusion and outflow, our team effectively utilized the entire fTRAM flap in a folded fashion, by creating an additional venous anastomosis between the donor superficial inferior epigastric vein of zone 4 and the recipient medial internal mammary vein. This provided our patient with the optimal reconstructive procedure that maximized flap viability while minimizing donor site morbidity. The supercharged fTRAM flap was an excellent autologous reconstructive option in this case due to the necessity of harvesting a large flap in a thin patient with minimal subcutaneous fat.Currently, there is a plethora of reconstructive options for both implant and autologous based-breast reconstruction. To date, however, there have not been any studies comparing the supercharged fTRAM with other alternatives, such as the delayed technique or the turbocharged flap, where bilateral deep inferior epigastric pedicles are connected to recipient vessels. Our patient’s experience demonstrates how augmentation of the traditional fTRAM flap with additional blood supply can reduce the likelihood of flap necrosis when the entire fTRAM flap is used, which is often warranted in cases of thin patients presenting with large soft tissue defects. Further comparative studies are, however, necessary to optimize selecting the best reconstructive option for each individual patient.


Glioblastoma is an aggressive form of brain cancer that has seen only marginal improvements in its bleak survival outlook of 12–15 months over the last forty years. There is therefore an urgent need for the development of advanced drug screening platforms and systems that can better recapitulate glioblastoma’s infiltrative biology, a process largely responsible for its relentless propensity for recurrence and progression. Recent advances in stem cell biology have allowed the generation of artificial tridimensional brain-like tissue termed cerebral organoids. In addition to their potential to model brain development, these reagents are providing much needed synthetic humanoid scaffolds to model glioblastoma’s infiltrative capacity in a faithful and scalable manner. Here, we highlight and review the early breakthroughs in this growing field and discuss its potential future role for glioblastoma research. Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a dismal 5-year survival rate of 5% and median survival of just 14 months . The majPrimary GBM cell cultures have been crucial in understanding the biology of this disease by providing a widespread and accessible in vitro model. Following the successful isolation and characterization of glioblastoma stem cells (GSCs), that promote cancer progression and recurrence , 7, thisAnimal models have provided some solutions to the limitations of these in vitro cultures by providing a more holistic system for dissecting GBM molecular and cellular biology by incorporating tumor-host interactions . Of thesInitial efforts to improve ex vivo modelling of GBM focused on examining the role of extracellular matrix components in cancer growth dynamics  and wereCerebral Organoids (COs) are one of the most promising recent developments which attempt to provide an accurate microenvironment into which GSCs can infiltrate. These represent complex 3D cell aggregates derived from human pluripotent stem cells (hPSCs) which undergo neural differentiation and self-organize to form layered structures that resemble the developing human brain. COs have recently emerged as a model system for studying CNS disease within a human genetic background, as they appear to better recapitulate the cell diversity of the human cerebral cortex, including populations of neural progenitor cells, astrocyte precursor cells, oligodendrocyte precursor cells, excitatory neurons, inhibitory neurons and retinal cells , 26. WitWith the emergence of research pointing to GSCs being successfully used in more complex, fusion based culture protocols, recent studies have used human cerebral organoids as a model system to study GBM growth in a tridimensional human brain-like environment. These efforts can be broadly divided into two categories based on the method of inducing tumor formation in organoids. One is the use of genetically engineered organoid models, which are well suited for understanding genetic mechanisms of GBM induction within the 3D environment of healthy tissue that is present during in vivo tumorigenesis , 32. TheAfter initial indications of the possibility for organoids being receptive to fusion , da SilvA more recent study used stable lines of GFP tagged GSCs and co-cultured them with cerebral organoids to generate what authors called the “glioma cerebral organoid (GLICO)” model . This syA similar ex vivo approach was used in another study that explored the diverse cell type composition of GBM tumors . This stLastly, a recently published study compared different GBM models and their ability to reproduce cellular states found in primary tumors by single-cell RNA sequencing profiles sourced from four models: glioma spheres, tumor organoids, orthotopic PDXs, and GLICOs . These rG12V by homologous recombination [G12V mutation itself is not a common feature of GBM, through this manipulation the authors were able to experimentally simulate Ras pathway overactivation, a common molecular feature of GBM biology [As an alternative to using patient-derived tumor cells, some groups have opted to model GBM in cerebral organoids by using genetic manipulations to induce tumorigenesis , 32. Thi biology . As a pr biology , furtherOther examples of this approach include efforts by Bian et al. which combined transposon-mediated insertion of oncogenes with CRISPR-Cas9-mediated mutagenesis of tumor suppressor genes . Using tWhile organoid models have already begun addressing many of the long-standing limitations of existing GBM culture systems, they are not without challenges and limitations. High inter-organoid variability in both morphology and tissue identity remains a significant issue for CO-based disease models , 30. OngAnother important limitation, when compared to in vivo counterparts, is the lack of microglia or other critical immune cells in organoid-based models of GBM. The presence of microglia has been shown in cerebral organoids generated through certain protocols and can likely be further optimized to increase enrichment for these cells . HoweverAs discussed, there is a strong potential for the use of these hybrid organoid models in many areas ranging from basic research to clinical investigations. Of therapeutic interest, there are important prospects in the use of hybrid cerebral organoid/GBM systems as a platform for drug screening, including for targeting tumor invasion and therapy-resistant populations of glioma cells. Initial proof-of-principle experiments where these models were treated with well-established chemotherapy drugs , 36 showUp to now, published studies have had outputs focused on the genomic or transcriptional level of these new hybrid cell systems and have been successful in showing how they are distinctly different from earlier in vitro cultures of GBM. Importantly, studies have also shown that the profiles of GBM cells grown within such a system are closer to the molecular profiles of GBM cells isolated from primary tissue than to earlier culture protocols. Therefore, extending the outputs of this new model to other-omics technologies, such as proteomics and epigenomics, seems the natural step that could combine with functional studies to provide concrete candidates for therapeutics. Medium throughput chemical or CRISPR-based screens can also be leveraged towards the same goal. To this end, further optimizations such as the integration of tissue clearing and quantitative 3D imaging will likely continue to increase the potential throughput of this system . WhetherThe lack of significant improvement in GBM outcomes over recent decades spanning numerous breakthroughs in our understanding of the cellular and molecular mechanisms of cancer supports the continued search for alternative approaches to model and study this aggressive disease in the laboratory. Here we review the evolution and use of well-established stem cell protocols to generate tridimensional neuronal tissue with a cellular diversity similar to the human brain, particularly in the form of cerebral organoids. These dynamic cell aggregates are highly amenable to a wide array of experimental manipulations, including their ability to fuse with GSCs or engender a GBM-like cellular phenotype through genetic engineering. Initial studies have validated the distinct nature of these models and established them as a valuable and faithful platform for functional, multi-omic and drug screening initiatives. These hold significant potential for uncovering the underlying mechanisms of central features of GBM, such as infiltration and hypoxia. They also provide advanced systems for drug screening and the nomination of new targets for therapeutic efforts. In light of the highly plastic nature of GBM cells and the importance of the interactions within the tumor microenvironment , recent


As part of their professional role, healthcare providers enact multiple competing goal-directed behaviours in time-constrained environments. Better understanding healthcare providers’ motivation to engage in the pursuit of particular goals may help inform the development of implementation interventions. We investigated healthcare providers’ pursuit of multiple goals as part of a trial evaluating the effectiveness of an audit and feedback intervention in supporting appropriate adjustment of high-risk medication prescribing by physicians working in nursing homes. Our objectives were to determine whether goal priority and constructs from Social Cognitive Theory  predicted intention to adjust prescribing of multiple high-risk medications and to investigate how physicians in nursing homes prioritise their goals related to high-risk medication prescribing.Physicians in Ontario, Canada, who signed up for and accessed the audit and feedback report were invited to complete a questionnaire assessing goal priority, self-efficacy, outcome expectations, descriptive norms, and intention in relation to the three targeted behaviours  and a control behaviour (adjusting statin prescribing). We conducted multiple linear regression analyses to identify predictors of intention. We also conducted semi-structured qualitative interviews to investigate how physicians in nursing homes prioritise their goals in relation to appropriately adjusting prescribing of the medications included in the report: analysis was informed by the framework analysis method.Thirty-three of 89 (37%) physicians completed the questionnaire. Goal priority was the only significant predictor of intention for each medication type; the greater a priority it was for physicians to appropriately adjust their prescribing, the stronger was their intention to do so. Across five interviews, physicians reported prioritising adjustment of antipsychotic prescribing specifically. This was influenced by negative media coverage of antipsychotic prescribing in nursing homes, the provincial government’s mandate to address antipsychotic prescribing, and by the deprescribing initiatives or best practice routines in place in their nursing homes.Goal priority predicted nursing home physicians’ intention to adjust prescribing. Targeting goal priority through implementation interventions therefore has the potential to influence behaviour via increased motivation. Implementation intervention developers should consider the external factors that may drive physicians’ prioritization. Contributions to the literatureTime constraints introduce competition amongst healthcare providers’ multiple goals.After receiving audit and feedback, providers must prioritise their goals for practice change: how they do this is not fully understood.We found that the priority of a goal predicted nursing home physicians’ intention to adjust their prescribing of multiple high-risk medications after receipt of audit and feedback and that specific deprescribing goals were prioritised based on government policy, media coverage, and facility-level initiatives/routines.Our focus on multiple prescribing behaviours adds to recognised gaps in our understanding of how providers prioritise their goals in response to an implementation intervention.Individuals have and pursue multiple goals, where goals are conceptualised as the aims or objectives that an individual is trying to reach as a result of their behaviour . HealthcWe investigated healthcare providers’ pursuit of multiple goals as part of a trial evaluating the effectiveness of an audit and feedback (A&F) intervention. A&F involves measuring a provider’s practice, comparing it to a benchmark, and providing this information back to the provider to encourage change where appropriate . A CochrWe are evaluating the effectiveness of A&F in supporting appropriate adjustment of high-risk medication prescribing by physicians working in nursing homes . MedicatHowever, this does not fully account for the multiple behaviour perspective incorporated in the trial through the provision of feedback on multiple prescribing indicators. After receipt of feedback relating to many of their behaviours, providers likely must prioritise any practice change efforts that they deem to be appropriate. Previous research shows that healthcare providers’ behaviour in the context of multiple goals may be predicted in part by how those goals are perceived to compete with or facilitate each other , 20. AltIn addition, health behaviour theories tend to focus on understanding a single behaviour in isolation from others, and as a result, most health behaviour studies tend to take a single-behaviour focus –23. HoweMyPractice: Long-Term Care’ report  and is testing the impact of variations in (i) the comparator and (ii) feedback message framing, on the effectiveness of A&F to reduce prescribing of high-risk medications. The feedback focuses on the potential increased risk of falls related to medication use. Further details of the trial methods and A&F variants being evaluated are provided in the protocol  I don’t look so much at because I use a lot of antidepressants, and to me they are not as much of a danger as antipsychotics. I mean studies have shown that up to 80% of people in long-term care do have some form of depression… CNS active—a lot of things are CNS active, right?’ (P1)Prioritisation of the specified CNS-active medications indicator was rarely mentioned. One participant noted that this indicator included medications which were wide-ranging in relation to the potential for subsequent harm: they were therefore less likely to use this indicator to inform their clinical behaviour change efforts.Self-efficacy, outcome expectations, and descriptive norms did not predict physicians’ intention to appropriately adjust prescribing after receipt of A&F across any of the four prescribing behaviours  in the nursing home setting. However, goal priority consistently predicted intention across all four behaviours: the greater the priority it was for physicians to appropriately adjust their prescribing, the stronger was their intention to appropriately adjust their prescribing. Qualitative data helped to explore which factors may have played a role in determining how physicians prioritised their goals, showing that appropriate adjustment of antipsychotic prescribing was a priority, influenced by recent negative media coverage of antipsychotic prescribing in nursing homes, the Ministry’s mandate to address antipsychotic prescribing, and because deprescribing initiatives or best practice routines were already in place in their homes.To our knowledge, this is the first study to show that goal priority predicts healthcare providers’ intention. The evidence is further strengthened by the internal replication across four behaviours. That goal priority accounted for variability in intention to perform all of the prescribing behaviours, including those targeted and not targeted by the A&F, suggests that it may be a key component of physicians’ motivation relating to prescribing. This suggests that implementation interventions such as A&F which are explicitly designed to target goal prioritization have the potential to influence healthcare provider behaviour change via increased motivation.In their study of health behaviour, Conner et al.  found thOur qualitative findings provide further lessons for designing A&F to encourage prescribing behaviour change. It may be advantageous to design A&F to clearly align with external policy-driven targets. For example, the specific indicators included could be explicitly linked with relevant targets already prioritised. Since routines and workflows were described as exerting a strong influence over individual physicians’ prioritization, it may be beneficial to capitalise on this by developing and distributing nursing home-level A&F to drive team-level prioritization. This may be especially important in the context of nursing home care, since our demographic data indicate that physicians spend portions of their clinical time in different facilities and are therefore shifting between different routines and workflows and likely have significant constraints on their time in each facility. External targets, internal routines, and time pressures are key components of the context of nursing homes which can undermine the success of provider behaviour change initiatives, but interventions which involve multiple team members with a range of different roles can serve to unify the team and strengthen behaviour change efforts . HoweverFinally, our qualitative results also suggest that if an indicator aligns with an area of lower concern from a physician’s perspective (i.e. benzodiazepine prescribing), changing behaviour in response to the indicator will generally not be prioritised. It is therefore important to align A&F with areas of concern from the physician’s perspective, where feasible and appropriate. This may involve removing indicators for which performance is indeed less concerning or moving them to a less prominent position in the A&F. This could help to minimise cognitive load associated with interpreting feedback  and avoiWe have used theory-based quantitative measures and taken a multiple behaviour approach to investigate intention to appropriately adjust prescribing of multiple high-risk medications in nursing homes. Investigating multiple behaviours also allowed us to consider the relative priority of the different behaviours investigated. We incorporated qualitative methods to investigate contextual aspects of goal prioritization. However, a key limitation is that we have not included measures of behaviour. Nevertheless, the consistent relationship found between goal priority and intention highlights its importance as an aspect of motivation and aligns with previous work . Our surBuilding on these findings, future research could investigate the extent to which goal priority is a consistent predictor of intention across multiple different behaviours of healthcare providers in varying roles. It is also important to investigate the relationship between goal priority and provider behaviour, ideally using objective behavioural data; if a direct relationship is found, as for other goal constructs , this woUsing a multiple behaviour approach, goal priority was found to predict nursing home physicians’ intention to adjust prescribing. The greater the priority it was for physicians to adjust their prescribing, the stronger was their intention. Physicians prioritised their goals on the basis of government policy, media attention, and facility-level initiatives/routines. Further work to determine the role of goal prioritization in healthcare provider behaviour would inform the development and evaluation of implementation interventions targeting goal priority to facilitate behaviour change.Additional file 1. Good Reporting of A Mixed Methods Study (GRAMMS) Checklist.Additional file 2. Qualitative interview questions.


Tobacco use is the leading cause of preventable death and disease in the United States. Oregon’s coordinated care model for Medicaid provides an opportunity to consider novel ways to reduce tobacco use.We sought to evaluate the changes in tobacco cessation benefits, patient access to cessation interventions, and cigarette smoking prevalence before and after introduction of the statewide Coordinated Care Organization (CCO) cigarette smoking incentive metric for Medicaid members.Medicaid and public health collaborated to develop a novel population-level opportunity to reduce tobacco use. In 2016, an incentive metric for cigarette smoking was incorporated into Oregon’s CCO Quality Incentive Program, which holds Oregon’s CCOs accountable for providing comprehensive cessation benefits and for reducing tobacco use prevalence among members.We evaluated the changes in tobacco cessation benefits, patient–provider discussions of smoking cessation, and cigarette smoking prevalence before and after the introduction of the statewide CCO cigarette smoking incentive metric.All 15 CCOs now cover cessation counseling  and pharmacotherapy . The number of CCOs requiring prior authorization for at least 1 FDA-approved pharmacotherapy decreased substantially. From 2016 through 2018, the percentage of Medicaid members who reported that their health care providers recommended cessation assistance increased above baseline. The incentive metric and aligned interventions were associated with a reduction in cigarette smoking prevalence among Medicaid members, as indicated by the electronic health record metric. Thirteen of 15 CCOs demonstrated a reduction in smoking prevalence with the statewide prevalence rate decreased from 29.3% to 26.6%.Since incentive metric implementation, progress has been made to reduce tobacco use among CCO members. Cross-agency partnerships between Medicaid and public health contributed to these successes. Tobacco use can be reduced with evidence-based cessation strategies such as improving access to cessation counseling and medications as well as community-based interventions.We describe the efforts of a state health agency to improve access to cessation benefits and reduce tobacco use through the creation and implementation of a novel incentive metric for Oregon’s Medicaid delivery organizations.Medicaid and public health agencies can work together to reduce tobacco use through policy and systems levers both inside and outside of clinics.Tobacco use is the leading cause of preventable illness and death in the United States. In 2018, 19.7% of people used any tobacco product, and use was disproportionately higher among those who have Medicaid (27.8%) . The negThe term “cigarette smoking” in this article is used to describe the process of inhaling tobacco smoke from combustible cigarettes. “Tobacco use” is broader and generally includes the use of cigars, e-cigarettes, smokeless tobacco, and other tobacco and vaping products.Reducing tobacco use requires a multifaceted approach that prevents youth and young adults from initiating tobacco use, eliminates tobacco-related health disparities in all populations, minimizes exposure to secondhand smoke, and helps tobacco users quit . Key eleThe evidence-based clinical strategies that underpin this comprehensive approach, along with evidence of successful cross-sector collaboration between public health and health care, are well documented in the literature –9. The Uincentive metrics, for which they receive payment for performance if they meet certain benchmarks or targets (Oregon’s creation of coordinated care organizations (CCOs) in 2012  the history of related tobacco efforts that led to the creation of the incentive metric; 2) the current state and local policy and system infrastructure that supports CCO success on tobacco use reduction; and 3) the impact of these efforts on tobacco cessation benefits and cigarette smoking rates for Oregon’s Medicaid population.The introduction of the cigarette smoking incentive metric is grounded in a history of collaboration between public health and health care partners throughout the Oregon Health Authority (OHA). The Tobacco Prevention and Education Program (TPEP), housed in the Public Health Division, began operating in 1997 with the passage of Measure 44 , which iOHA currently leads tobacco reduction initiatives across multiple divisions that are responsible for both Medicaid and statewide public health outcomes. Since the inception of the TPEP program in 1997, cigarette smoking has decreased by more than 50% . TPEP’s The Medicaid program also has taken a comprehensive approach to reduce tobacco use among Medicaid members. In Oregon, the state legislature determines the Medicaid benefit package by drawing a funding line on the state’s Prioritized List of Health Services, with services “above the line” being covered and those “below the line” not being covered. The Health Evidence Review Commission (HERC) is a governor-appointed commission representing physicians, community members, and CCOs that manages Oregon’s unique Prioritized List, which emphasizes covering services that are evidence-based, maximize population health, and control costs. HERC has assigned a very high priority to tobacco cessation and since 2016 requires that all CCOs offer Medicaid patients the “gold standard” evidence-based cessation interventions, including FDA-approved pharmacotherapy and behavioral counseling .The Metrics and Scoring Committee, another statewide governor-appointed committee, is responsible for identifying incentive metrics for the CCO Quality Incentive Program . PerformCCO incentive metrics are selected each year by the Metrics and Scoring Committee. Throughout the year, the Committee considers proposals for new incentive metrics from various sources, including public testimony from community members, presentations from state agency staff and subject matter experts, recommendations from its Technical Advisory Workgroup, and in some years, a widely distributed stakeholder survey. The committee has adopted incentive metric selection and retirement criteria that it uses to determine which (and when) new metrics should be added or existing metrics removed from the CCO incentive metric set. Several key criteria that the committee considers include alignment with other metric sets and consistency with other state priorities.A tobacco prevalence metric was proposed for inclusion in the CCO incentive metric set soon after the establishment of CCOs in 2012; however, the only potential data source for a health plan–level, Medicaid-specific prevalence metric was the annual Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey, and stakeholders expressed concerns that the survey sample was insufficient to fairly capture quality improvement efforts by health plans to reduce prevalence. Throughout 2014 and 2015, potential incentive metric options — both process and outcome measures — were discussed. Before the committee approved a metric for the 2016 performance year, public health advocates provided expert testimony on the importance of focusing on tobacco use prevalence. The release of Oregon’s State Health Improvement Plan in 2015 identified the prevention and reduction of tobacco use as a top priority, which also helped to elevate and sustain interest in the issue.After the tobacco incentive metric was approved, the technical advisory workgroup developed the metric specifications based on Meaningful Use standards required for electronic health records (EHRs) and HERC requirements for tobacco cessation benefits.Since the introduction of the incentive metric in 2016, various OHA divisions and committees have been working together to ensure alignment across state-level programs, policies, and systems and to support CCOs in their efforts to reduce tobacco prevalence.Cross-agency alignment. Concurrent with the introduction of the incentive metric, HERC modified the Prioritized List of Health Services in 2015 to clarify the CCO requirement to cover effective clinical strategies, including behavioral health interventions  and FDA-approved pharmacotherapy. Public health and HERC also worked to ensure that comprehensive, gold-standard cessation benefits (as defined by both HERC and the 2010 Patient Protection and Affordable Care Act) (are Act)  were aliare Act) . This seMultisector Intervention Statements. Several years ago, HERC developed a concept of Multisector Intervention Statements to address the fact that improvement in health outcomes may sometimes be more efficiently achieved by using strategies that occur outside of a clinician–patient in-person visit  providing the minimum cessation benefit package, as defined by HERC, 2) reporting of EHR-based prevalence data, and 3) reducing cigarette smoking prevalence among CCO members .Each component of the cigarette smoking incentive metric is worth a certain percentage of the total metric calculation, and each year CCOs must meet a certain overall performance target to earn incentive dollars. The component percentages have shifted over time . In the When the cigarette smoking incentive metric was introduced in 2016, coverage of tobacco cessation benefits varied significantly across the CCOs. Embedding cessation benefit requirements into the metric specifications was intended to ensure that all Medicaid beneficiaries statewide would have access to a “benefit floor.” To meet the minimum cessation benefit requirement, each CCO must cover both counseling and FDA-approved cessation medications, as well as remove barriers to accessing the benefit . This reEHR-based reporting defines the cigarette smoking prevalence rate as the number of cigarette smokers among those who had an office visit with the provider during the year who have smoking and/or tobacco status recorded . The EHRThe comparison of CCO cessation benefits for 2014 (pre-incentive metric) and 2018 (post-incentive metric) is presented in In addition to benefit package improvements, Oregon also demonstrated a decline in its Medicaid cigarette smoking prevalence, as measured through EHRs between 2016 and 2018  . AlthougOther recent statewide evaluations through CAHPS  indicate that the CCO incentive metric has been successful in increasing provider attention to cessation. Since 2015, adult Medicaid tobacco users who reported that their doctors offered them cessation medications and other strategies to help quit has increased above baseline, with a high in 2017 and persistent gains above baseline through 2018  31)..31).This study has several key limitations. Although a focus on combustible cigarette use is critical, this metric did not focus on other forms of nicotine use that are also of concern: cigars, e-cigarettes, smokeless tobacco, and other tobacco and vaping products. Unmeasured confounders may exist, such as national trends that may have been the primary driver of the improvement in smoking cessation prevalence rather than Oregon’s CCO incentive metric alone. Despite this limitation, this novel outcome metric aligns public health and Medicaid to focus on a critical public health issue and improved access to evidence-based smoking cessation aids at a minimum. If the impact of this metric is smaller than reported, other benefits may still be derived from it, including holding health plans accountable to population health metrics and alignment between health plans and public health to improve outcomes with interventions spanning clinical and other sectors. Future studies could further triangulate key drivers of prevalence improvement by further investigating the use of pharmacotherapy, quitlines, counseling, and community-based interventions. The final limitation relates to generalizability. Other states and health plans may find it challenging to adopt metrics such as the Oregon smoking cessation metric. However, given the lack of viable comprehensive outcome measures on smoking cessation and the ongoing significant morbidity and mortality associated with smoking, it may be worthwhile for other systems to invest in adoption of a similar novel outcome metric.Oregon’s innovative work creating an incentive metric that requires health plans to cover comprehensive evidence-based tobacco cessation benefits and be held accountable for smoking prevalence has contributed to a substantial population decrease in smoking prevalence in Oregon and improved access to evidence-based cessation aids for OHP (Medicaid) members. This success depended on coordination and alignment across Medicaid and public health coupled with the use of financial incentives and effective data monitoring. Oregon has also worked effectively across sectors such as in the case of a statewide opioid initiative , and incIn addition to the statewide successes, the cigarette smoking incentive metric has created an unprecedented opportunity for local public health and health care partners to collaborate at the community level to implement effective strategies for preventing and reducing tobacco use. These efforts have led to CCOs investing time and resources in working on prevention strategies outside of the clinical setting, engaging more in their communities, and collaborating with local public health authorities.For health plans to truly be accountable for population health outcomes, those distal outcomes need to be measured and incentivized. Reliance on process-based metrics such as the proportion of primary care providers screening for tobacco use is arguably insufficient. Similarly, if the goal is accountability to improved population health, requiring health plans simply to provide a benefit or even measure the times patients received pharmacotherapy or counseling (standard smoking cessation metric measures) is not enough. Instead, requiring plans to be accountable for the health outcome  by using effective data reporting, concrete guidance and contractual requirements, required minimum coverage, and financial incentive metrics to drive the change, population health improvements are achievable. However, major barriers exist to health insurers addressing prevention activities at a clinical population level or community health level, including silos between public health and Medicaid health plans, lack of funding streams to facilitate delivery of nonclinical interventions, limited coordination between clinical systems and community resources, legal barriers to Medicaid paying for nontraditional services, and concerns about upfront costs of investing in additional services and strategies.As Oregon and other states continue to work to maximize population health with regard to tobacco use, continually promoting evidence-based strategies, regardless of the setting in which they are delivered, is important. What HERC seeks to do with the Multisector Intervention Statements is provide a menu of evidence-based options, some clinically focused and others exclusively based in the community, allowing plans to decide which of these interventions makes sense, given their priorities and community relationships and the cost–benefit ratio for each. To address the issue of tobacco in our communities, both prevention of tobacco initiation and effective treatment of tobacco use disorder are paramount to effectively reducing tobacco use prevalence.Oregon’s innovative work in developing an incentive metric that requires CCOs to address tobacco prevalence through evidence-based strategies extending beyond the clinical setting can be a model for other states and payers seeking to effect major population health change by increasing engagement and accountability of payers and health systems. Although CCOs have improved benefits since the adoption of the incentive metric and there is some indication of clinical providers improving their practice, room for improvement still exists using the strong foundation that HERC guidance, benefit requirements, and incentive metric strategies have set.


Immune cell activation and proliferation are closely linked to their metabolic programming. These activated immune cells share many features with tumor cells and are capable to respond to stimulations quickly and reprogram their metabolism to fight with invading pathogens. The corresponding changes in metabolism provide immune cells with energy and bio-precursors to match with necessity of immune functions. The major metabolic pathways utilized by immune cells for the purpose of protecting body from invading pathogens are glycolysis, glutaminolysis, fatty acid synthesis and oxidation, and mitochondria oxidative phosphorylation. These pathways play crucial roles in immune cell activation and differentiation. In this review, we describe how immune cells engage in certain metabolic processes according to their functional needs with a focus on T cells and macrophages. In steady stage, the cells in immune system are relatively quiescent with minimal activities and survival needs but they possess the ability to quickly respond to pathogens or environmental challenges and constantly orchestrate their effector functions . Once paDefense against invading infectious pathogens and noninfectious foreign substances is mediated by innate immunity and adaptive immunity. Innate immune responses are early reactions of immune system and carried out by innate immune cells including macrophages, neutrophils, and natural killer cells. They provide the first defense barrier and response of protection while adaptive immune responses offer more specific actions to the pathogens. There are two types of adaptive immune responses: antibody-based humoral immunity and cell-mediated cellular immunity. Humoral immunity is carried out by B-lymphocytes, also called B cells and provides specific and specialized attack to extracellular microbes and their toxin, facilitates the elimination of these pathogens. Cellular immunity by T-lymphocytes  with the function functions to eliminate intracellular microbes, such as virus and some bacteria residing inside host cells. The principal cell types in immune system consist of innate immune cells, T and B-lymphocytes, antigen-presenting cells, and effector cells.The major metabolic pathways that immune cells use to generate energy and biosynthesis materials are glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, fatty acid metabolism, and glutaminolysis.Glycolysis is a process that breaks down glucose and forms pyruvate with the production of two molecules of ATP. The pyruvate end product of glycolysis can be used in either anaerobic respiration if no oxygen is available or in aerobic respiration via the TCA cycle which yields much more usable energy for the cell.2, which can be used to generate ATP in mitochondria.The generated pyruvate from glycolysis has two fates. One is to import into the mitochondria and to be converted to acetyl-CoA, entering the TCA cycle to produce NADPH and FADH+ under hypoxic conditions. The generated NAD+ can be used in the process of generating pyruvate from glucose.The alternative fate of pyruvate is to be converted to lactate in the cytosol that is an important strategy to regenerate NAD2 generated from glycolysis and TCA cycles are passed along electron transport chain to oxygen and generate usable energy ATP.This is a process occuring in mitochondria that NADH and FADH2, which are used in oxidative phosphorylation to produce ATP. The other process is anabolic which is opposite to fatty acid oxidation, which is to creat fatty acid using Acetyl-CoA through actions of fatty acid synthase. This process is carried out during cytoplasm.Fatty acid metabolism includes two parts: one is catabolic process by which fatty acid is broken down by in mitochondria to generate Acetyl-CoA, which enters TCA cycle and NADH/FADHBefore T cells encounter any antigens and/or danger signals presented to them by antigen presenting cells (APC), they remain quiesent metabolically. In this state, naïve cells use IL-7 to maintain its homeostatic proliferation and survival, with a metabolical level similar to memory T cells –5. They Upon antigen and other danger signal stimulation, naïve T cells become highly proliferative and differentiated. They undergo massive clonal expansions and secret a large amount of cytokines, and differentate into Th1, Th2, Th17, and Treg cells in case of CD4 cells and cytotoxic T lymphocytes (CTL) in case of CD8 cells. The demands for energy and building blocks are very different from that of naïve T cells and require metabolic reprogramming . The proBesides glycolysis, glutaminolysis is also indispensable for T cell activation and proliferation for the purpose of supplying a fue source and biosynthetic precursors for protein and nucleic acid biosynthesis. When activated, T cells consume glutamine at a comparable rate to that of glucose . During Although less is known about lipid metabolism in T cell prolifeation and function, more and more evidence showed the importance and correlation between fatty acid metabolism and T cell proliferation. Firstly, it was reported that T cells switch to fatty acid synthesis from fatty acid oxidation upon activation and proliferation . SecondlMacrophages undergo profound metabolic reprogramming in response to danger signal or cytokine stimulation. These metabolic changes not only provide energy and biosynthesis power, but also directly regulate macrophage effector functions. In response to proinflammatory stimulation such as Lipopolysacharide (LPS), macrophages shift from oxidative phosphorlation and fatty acid oxidation toward glycolysis and fatty acid synthesis . The sigFirstly, it was found that macrophages stimulated with LPS utilized the Warburg effect to accumulate citrate, an intermediate in the cytric acid cycle. The accumulated citrate then contributes to the production of Nitric Oxide (NO), Reactive Oxygen Species (ROS), and prostaglandins, all of which play significant proinflammatory roles in LPS-activated macrophages . SecondlIn this review, we dicussussed the metabolic pathways immune cells adopt corresponding to their status and function a particular focus on T cells and macrophages. Although an increased and still increasing literature has enriched our understanding of the connections and switches between these two equally complicated processes, still a lot remains unknown. The biggest question is whether the metabolism change itself can serve as a trigger or signal to initiate downstream signalling pathways. The second question is how metabolism affects gene regulation in immune cells and from what levels. It is evident now that glycose and lipid metabolism can profoundly shape immune cell functions. Therefore, understanding the molecular pathways of these processes may offer a novel therapeutical treatment for inflammatory diseases.


Rapid eye movement sleep behavior disorder (RBD) contributes to injury due to the alteration of the expected atonia during rapid eye movement (REM) sleep. It occurs before the overt signs of Parkinson's disease (PD). The co-expression of PD and RBD is characterized by non-tremor predominant subtype and higher incidence of freezing. Freezing of gait (FOG) is a debilitating symptom seen in PD patients that lead to falls. While this phenomenon is understood poorly, the involvement of the pedunculopontine nucleus (PPN) and the neural circuits that control locomotion and gait have been examined. This network has also the same control for REM sleep and arousal. The close relationship between PD and RBD and FOG's consequences has led us to explore the relationship between RBD and PD with FOG. This review provides an overview of the neural connections that control gait, locomotion, and REM sleep. The neural changes were seen in PD with FOG and RBD, and sensory and motor changes observed in these two diseases. The functional neuroanatomy that controls REM sleep, arousal, and locomotion overlap significantly with multiple neural circuits affected in RBD and PD with FOG. Visual perception dysfunction and motor symptoms that primarily affect gait initiation are common to both patients with RBD and FOG in PD, leading to freezing episodes. Prospective studies should be conducted to elucidate the relationship of RBD and PD with FOG subtype and find innovative treatment approaches and diagnostic tools for PD with FOG. Rapid eye movement behavior sleep disorder (RBD) is characterized by a loss of normal muscle atonia and subsequent dream enactment . It occuPatients with both PD and RBD exhibit a non-tremor-predominant subtype of the disease, and a higher incidence of freezing of gait (FOG), leading to increased frequency of falls , 8. FOG Gait, locomotion, and REM sleep controlGait control, locomotion, and REM sleep share common pathways in which the PPN is central to all these functional neuroanatomic connectivities. Figure The PPN in the mesopontine tegmentum is involved in locomotor modulation, postural muscle tone, arousal, and REM sleep atonia . CholineChanges in the neural networks due to freezing of gait in PD and RBDNeural network changes as a result of FOG in PD and RBD have also been explored. A study by Pozzi et al. determined that the disruption in the communication in the cortical-subthalamic network in the hemisphere with decreased dopaminergic innervation led to gait freezing. This was observed during the transition from a well-executed gait cycle to the onset of gait freezing. Decoupling between the SMA and STN in the hemisphere with decreased dopaminergic innervation suggests asymmetry between the two hemispheres . AsymmetTwo studies also found a significant reduction in the cerebellar locomotor region (CLR) connection to the PPN in FOG patients , 29. FasSupraspinal control of gait is also affected in RBD and PD with FOG. One study revealed a decrease in PPN functional connectivity with the bilateral SMA proper, pre-SMA, and dentate nucleus in PD with impaired postural instability and RBD group. In particular, the PPN-SMA connectivity defect was seen in PD patients with a positive pull test and prolonged APA duration before gait initiation. PD with impaired postural instability and RBD patients also have decreased PPN functional connectivity with the bilateral medial prefrontal cortex (MPFC). This impaired connectivity is also evident in a study made by Wang et al., where patients with FOG have altered functional connectivity between the PPN and corticopontine-cerebellar pathways and visual temporal areas, including the tracts projecting to motor, sensory and cognitive regions. During tasks requiring high cognitive load, PD patients with FOG had weak activity in the pre-SMA . In contPatients with RBD were found to have altered functional connectivity between the bilateral PPN and the ventral posterior-anterior cingulate cortex (ACC), regions involved in arousal and alertness. The same structures, known as the functional associative network (ACC and SMA), serve as a compensation network in PD patients with faulty automatic control of sensorimotor networks . HoweverThe observed neural changes in these networks do not localize to a single neuroanatomic structure but rather reflect derangements of both spinal and supraspinal networks and, along with it, faulty compensatory mechanisms that worsen freezing. Figure Sensory and motor changes in RBD and FOGSensory ChangesThe integration of multiple environmental sensory inputs is necessary to execute a purposeful movement. Several studies have looked into these sensory interruptions that contribute to motor impairments in PD and RBD patients. FOG patients unresponsive to levodopa treatment have decreased visuospatial functioning performance as assessed using the Judgment of Line Orientation Test . This viInterestingly, idiopathic RBD (iRBD) patients also experience visuoperceptual dysfunction based on poor performance in the Biederman fragmented picture identification task. Results from this test reveal a lack of visual priming, which, when present, generally leads to a faster response to a stimulus as a result of prior exposure. This response seen in iRBD patients is consistent with impaired intermediate perceptive processing of visual information. The initial presentation of an image triggers identifying the overall structural representation of the image . MarquesOne study also reports auditory and audiovisual perception changes in PD patients. Specifically, there is a significant difference between auditory and visual reaction times in PD, with a more significant alteration observed in the FOG subtype. The responses to visual stimuli were significantly slower compared with the auditory modality . This fiMotor ChangesMotor manifestations in patients with RBD and PD have been described. A study by Postuma et al. has shown that PD with RBD are non-tremor predominant , had incGait parameters were analyzed in various studies. In one study, patients with probable RBD exhibited fewer steps, increased swing time, and step length variability with a tendency to decrease their velocity and cadence . PosturaIncreased muscle activity during REM sleep was found in PD with FOG and RBD patients. The tonic EMG activity, which generally should be low, considering that REM sleep is characterized by loss of muscle tone, increases PD with FOG than in PD without FOG patients . This elLimitationsThis review consisted mostly of cross-sectional studies and a few randomized controlled trials. Longitudinal studies to establish the relationship between RBD and FOG are lacking. In addition, only articles written in English were included in this review; hence, failing to include other studies that may have been relevant to the study.This review reveals that the functional neuroanatomy that controls REM sleep, arousal, and locomotion overlap significantly. There is no single neural structure localized that causes both RBD and FOG in PD. Instead, a decreased functionality was identified heterogeneously in these neural networks notably in the cortical-subthalamic network, connections between the PPN and cerebellar locomotor region, PPN and SMA, as well as in the PPN to MPFC and PNN to ACC connectivities. Sensory alterations, particularly visual perception dysfunction is evident in PD and RBD, which predisposes to increased motor symptoms in these patients. These motor symptoms that primarily affect gait initiation are common to both patients with RBD and FOG in PD, which subsequently leads to episodes of freezing. These findings are from cross-sectional studies published to date. Prospective studies are needed to establish all these findings' temporality and better understand the pathophysiology common to RBD and PD FOG. This approach allows better treatment approaches in PD patients with FOG and coexisting RBD and develop early diagnostic tools to diagnose PD with the FOG subtype.


Central to our subjective lives is the experience of different emotions. Recent behavioral work mapping emotional responses to 2,185 videos found that people experience upward of 27 distinct emotions occupying a high-dimensional space, and that emotion categories, more so than affective dimensions , organize self-reports of subjective experience. Here, we sought to identify the neural substrates of this high-dimensional space of emotional experience using fMRI responses to all 2,185 videos. Our analyses demonstrated that (1) dozens of video-evoked emotions were accurately predicted from fMRI patterns in multiple brain regions with different regional configurations for individual emotions; (2) emotion categories better predicted cortical and subcortical responses than affective dimensions, outperforming visual and semantic covariates in transmodal regions; and (3) emotion-related fMRI responses had a cluster-like organization efficiently characterized by distinct categories. These results support an emerging theory of the high-dimensional emotion space, illuminating its neural foundations distributed across transmodal regions.  •Dozens of video-evoked emotions were predicted from fMRI patterns in multiple regions•Categories better predicted cortical and subcortical responses than dimensions•Emotion-related responses had a cluster-like organization characterized by categories•Neural representation of emotion is high-dimensional, categorical, and distributed Neuroscience; Cognitive Neuroscience; Techniques in Neuroscience Emotions are mental states generated by the brain, constituting an evaluative aspect of our diverse subjective experiences. Traditionally, subjective emotional experiences have been described in theoretical and empirical studies using a limited set of emotion categories  as proposed in early versions of basic emotion theory  and by bTo elucidate the structure of diverse emotional experiences, The methodological criteria established in this study of emotion—the use of broad ranging stimuli sufficient to compare theoretical models of emotion—can be readily extended to the study of the neural basis of emotion. In addition, it is important for studies of the neural basis of emotion to consider activity across the whole brain, given that diverse psychological processes and distributed brain regions and functional networks are known to contribute to the representation of various emotional states . AlthougWe sought to understand the neural underpinnings of the high-dimensional space of diverse emotional experiences associated with a wide range of emotional stimuli using the experimental resources generated in the study by Using multiple analytical approaches, we investigated different facets of the neural representation of the emotional experiences associated with the videos. Neural decoding was used to examine whether and where individual features  are represented in the brain and provides a powerful way to identify mental states of subjects from brain activity patterns . Voxel-wHere, we first show that dozens of distinct emotions associated with videos were reliably predicted from activity patterns in multiple brain regions, which enabled accurate identification of emotional states. Although the brain regions representing individual emotions overlapped, configurations of regions proved to be unique to each emotion and consistent across subjects. We show that voxel activity in most brain regions was better predicted by voxel-wise encoding models trained on ratings of emotion categories than on ratings of affective dimensions. Comparisons with other models trained on visual or semantic features revealed that the emotion category model uniquely explained response modulations of voxels in transmodal regions, indicating that these regions encode either emotional experience or visual affordances for specific emotional experiences . Finally, unsupervised modeling of emotion-related neural responses showed that distributions of brain activity patterns associated with diverse emotional experiences (or affordances) were organized with clusters corresponding to specific emotion categories, which were bridged by continuous gradients. These results provide support for the theory that emotion categories occupy a high-dimensional space  and shedTo understand neural representations of diverse emotional experiences associated with rich emotional content, we recorded whole-brain fMRI signals from five subjects while they were freely viewing emotionally evocative short videos A. The stWe first used a neural decoding analysis to examine whether the emotions associated with presented videos could be predicted from brain activity patterns within specific regions and across the brain. We constructed a decoding model (decoder) for each emotion (34 emotion categories and 14 affective dimensions) to predict emotional experience ratings from the brain using multi-voxel activity patterns as input. The decoders of individual emotions were separately trained using activity patterns in each of multiple brain regions that include 360 cortical regions defined by a parcellation provided from the Human Connectome Project —typically, from many different regions as the color of individual dots (or brain regions) indicated. The results established that ratings of the 27 emotion categories that were reported to be reliably elicited by video stimuli  separately using the accuracies for the categories and dimensions. For most of the categories and dimensions, correlations between the same emotion pairs  were larger than correlations between different emotion pairs   from another subject using Pearson correlation coefficients (see ensions) E. Furthen = 2,180), and percentages of correct answers were used as an identification accuracy for one sample.Given that a complex emotional state can be represented by a blend or combination of multiple emotions , we next tested a decoding procedure that took into account multiple emotions simultaneously. To do so, we examined whether a specific video stimulus could be predicted, or identified, from the concatenated predictions of emotion categories or those of affective dimensions. The identification analysis was performed in a pairwise manner, in which a vector of predicted scores was compared with two candidate vectors  to test whether a correlation for the true video was higher than that for the false video . The results demonstrate how precisely different emotional states were decoded from brain activity and provide a useful means to visualize decoded emotional states.We first confirmed that the UMAP algorithm applied to the 34 emotion category scores replicated a similar two-dimensional map produced in the previous study , in whicWe next used voxel-wise encoding models to characterize how varying features associated with the presented videos modulate activities in each voxel. We constructed an encoding model for each voxel to predict activities induced by the emotionally evocative videos using a set of features , and model performance was evaluated by computing a Pearson correlation coefficient between measured and predicted activities  and the 14 affective dimensions  predicted brain activities induced by the presented videos  and also predicted 73.0% greater number of voxels with significant accuracies . In addition, when we constructed a joint encoding model by concatenating scores of 34 categories and 14 dimensions, the increase in the number of significantly predicted voxels was marginal when compared with the category model  but substantial when compared with the dimension model . Together, these findings suggest that the brain representation of affective dimensions is subsumed by, and can be inferred from, the brain representation of emotion categories.In comparing the model performances, we found that on average the category model outperformed the dimension model by a considerable margin . Notably, this tendency was even observed in ten subcortical regions, including the amygdala ,” which is estimated from functional connectivity patterns  and descp < 0.01). In terms of raw prediction accuracy, voxel activity was better predicted by both the emotion and semantic models at low and high values of the first PG than at the midpoint. However, at low/high values of the first PG, the semantic/emotion model outperformed the emotion/semantic model, respectively . Because emotional responses are correlated with semantic features high in emotional affordance , any brain regions predicted better by the emotion model than by the semantic model, even marginally, should be considered to encode emotional experience . Hence, the present findings suggest that brain regions high along the first gradient axis—that is, transmodal regions—are central to the brain's representation of emotion.Here, we tested empirically whether the PGs could account for the spatial arrangement of voxels preferentially representing visual object, semantic, and emotion information using encoding performances of models constructed from those different features. We plotted voxels predicted with significant accuracy by the visual object, semantic, or emotion models within the two-dimensional space defined by their values along the first and second PGs  can be reduced to the encoding of few broad affective dimensions such as valence, arousal, and certainty is an active area of debate that informs theories of emotion . Our encAs done in previous studies using voxel-wise modeling in specific sensory regions , we compOne issue worth noting is that, because each stimulus was presented only once, we were unable to estimate the proportion of systematic variance in voxel responses that was left unexplained by our models. Many voxel-wise encoding modeling studies have relied on repeated stimulus presentations to determine the upper bound of model prediction accuracies . HoweverOn this point, it is worth considering how investigations of brain representations of emotion may depend on the richness of the experimental stimuli used. The 2,181 videos studied here captured a wide spectrum of psychologically significant contexts. By contrast, most previous work has investigated neural underpinnings of emotion using a far narrower range of eliciting stimuli and a small set of emotions . Only reThis approach allowed rich and nuanced emotion categories to be accurately predicted from brain activity patterns A and 2B A critical question in neuroscience is where emotions evoked by different modalities of sensory input are encoded in the brain . AlthougOne limitation of the present study was that the emotion ratings we used were averages from multiple raters and not from the subjects of our fMRI experiment. Although our decoding and encoding models were able to establish systematic statistical relationships between those ratings and the brain activity patterns of our subjects, the reported feelings of those raters may not completely match those of our subjects. Hence, to the extent that neural representations of emotion are subject to individual differences in culture, demographic variables , and personality, future studies might uncover more robust neural representations by incorporating these variables.Another potential concern regarding the present investigation is the confounding of first-person and third-person emotions. The brain regions in which the category model outperformed the visual object and semantic models  overlapped with brain regions that have been implicated in a “theory of mind network” . It is pFinally, as we allowed the subjects to freely view presented video stimuli, differential gaze patterns for each emotional experience might have some influence on our brain data. Although the neural representation of gaze is known to be highly localized in specific brain regions , modelinAll methods can be found in the accompanying


The role of stress, trauma, and adversity particularly early in life has been identified as a contributing factor in both drug and food addictions. While links between traumatic stress and substance use disorders are well documented, the pathways to food addiction and obesity are less established. This review focuses on psychosocial and neurobiological factors that may increase risk for addiction-like behaviors and ultimately increase BMI over the lifespan. Early childhood and adolescent adversity can induce long-lasting alterations in the glucocorticoid and dopamine systems that lead to increased addiction vulnerability later in life. Allostatic load, the hypothalamic-pituitary-adrenal axis, and emerging data on epigenetics in the context of biological embedding are highlighted. A conceptual model for food addiction is proposed, which integrates data on the biological embedding of adversity as well as upstream psychological, social, and environmental factors. Dietary restraint as a feature of disordered eating is discussed as an important contextual factor related to food addiction. Discussion of various public health and policy considerations are based on the concept that improved knowledge of biopsychosocial mechanisms contributing to food addiction may decrease stigma associated with obesity and disordered eating behavior. Nutrition Transition theory describes a global trend toward consumption of processed foods that are low in fiber and high in added sugars and fats [The quest to discover the precise mechanisms of hedonic overeating began decades ago. While many theories have been proposed, none have been widely accepted, and the obesity epidemic continues to grow. The and fats . The chaand fats . Severaland fats . Soon afand fats . It was and fats . To dateand fats . HoweverBart Hoebel pioneered the concept of food addiction (FA) research using animal models, showing evidence of bingeing, withdrawal, craving, and concomitant changes in dopaminergic and opioidergic systems in response to overeating sugar ,12,13,14In humans, various forms of ELA are associated with illicit drug use later in life ,22,23. IThe purpose of this review is to focus on literature from FA as well as obesity in the context of exposure to trauma, stress, and adversity, in an effort to answer three questions: (1) is FA a biologically plausible explanation for a life course association between ELA and obesity? (2) how might other relevant psychological, social, and environmental factors contribute to FA and to obesity? see  and finaEcosocial Theory which emphasizes the social production of disease over biomedical individualism, describing “embodiment” as the biological incorporation of social and ecological circumstances into everyday life [Life Course Perspective is used to link ELA to adult health [Developmental Psychology perspective views human development as relational, pertaining to dynamics  which require individuals to be contextually situated into multidirectional and reciprocating ecological systems [Social and biological processes overlap and are inextricably linked. However, research methods are often incapable of capturing all features of an observed phenomenon, such as the various drivers of obesity see . Anotherday life . A Life t health ,37,38. F systems ,40,41. Yale Food Addiction Scale (YFAS) in 2009 [With the validation of the  in 2009  and the  in 2009 , FA in h in 2009 . It is w in 2009  yet it r in 2009 . For exa in 2009 . FA prev in 2009  compared in 2009 . It has  in 2009 .Among those with an ED diagnosis, Brewerton (2017) proposed that the presence of FA be conceptualized as a meaningful correlate of post-traumatic stress disorder (PTSD) severity and symptoms . For exaA frequent criticism of FA data in clinical settings is that the measure itself does not account for restrained eating  discuss. AnotherNeurobiological overlaps between obesity and addiction have been described within the mesolimbic pathway between the ventral tegmental area (VTA) and the ventral striatum, with further projection to limbic  and cortical regions  . Recent Among patients with obesity (n = 224), FA is more closely correlated with psychological factors  than with metabolic parameters  . In a smThe proposed pathways in Innovative methods that assess food environments include examining the (1) ratio of fast-food to full-service restaurants (2) ratio of bars/pubs to liquor stores and (3) presence of markets . MultileGiven the inverse relationship between SES and BMI ,102, obeTo illustrate further, a recent study showed that individuals with higher ACE scores were more likely to report not finishing high school, unemployment, and living below the poverty level . SustainThe fetal and infant origins of adult disease was proposed by Barker in 1990 . This foIt has been suggested that inflammatory mediators act on cortico-amygdala (threat) and cortico-basal ganglia (reward) circuits in a manner which predisposes individuals to “self-medicating” behaviors such as drug use, smoking, and the excess consumption of highly palatable foods . Such beA meta-analysis of 1781 people documented significantly decreased hippocampal volumes following ELA, with weaker evidence of increased amygdala volumes . AlteratEpigenetics is the study of how the environment regulates the genome, best described as changes in gene function without changes in gene sequence. DNA methylation is an enzymatically-catalyzed modification of DNA and is one plausible mechanism through which early life exposures  become biologically embedded . MethylaA milestone study confirmed what had been previously shown in animal models: human parental care impacts epigenetic regulation of hippocampal glucocorticoid receptor gene (NR3C1) expression . Such epEpigenetic control of the expression of opioid receptor genes  has been reviewed in the context of SUDs . While mIn a sample of 206 women with bulimic symptomatology, there was evidence of increased methylation of the DA-D2 gene promoter, compared to controls . Taq1A pWhile a PTSD diagnosis is associated with an altered stress response, chronic stress can exist in the absence of PTSD, and has been the focus of several investigations related to eating behavior. Multiple pathways have been described which link stress to obesity, including (1) interference with cognitive processes  (2) behavior  (3) physiological changes  and (4) production of biochemical hormones and peptides  . At a baTo illustrate further, individual differences in neural response to food cues under stress have been observed in human neuroimaging studies , lendingGiven the established links between stress and obesity, these links can be used to conceptualize relationships between stress and FA. The phenomenon of stress-induced reinstatement of drug-seeking is generalizable to other substances, including food . To illuIt has also been suggested that increased CRF alters serotonin release in the brain which facilitates DA in the accumbens . ProlongA recent review of preclinical data suggests three mechanisms by which DA and GCs interact: (1) GCs upregulate tyrosine hydroxylase (rate-limiting enzyme in DA synthesis) (2) GCs down-regulate monoamine oxidase  and (3) GCs are hypothesized to decrease DA uptake subsequently increasing synaptic DA . ClearlyThus far we have highlighted several social and environmental factors associated with STA and addiction-like eating. We have reviewed emerging data on the biological embedding of adversity, which may increase an individual’s susceptibility to FA, and potentially lead to obesity over time. Based on the overlap between FA and EDs as well as SUDs, we have recommended including these variables into statistical models which investigate weight outcomes. Finally, we have proposed a comprehensive conceptual framework to further contextualize these relationships by including two psychological  correlates of FA, EDs, and obesity: dietary restraint and weight stigma.Restrained eating is generally defined as a cognitive effort to eat less in order to lose weight , which hA dieting intervention on 121 females which included monitoring and restricting showed that monitoring increases perceived stress, while restricting increases the cortisol output . DietingThere is considerable debate on how to approach FA from a nutritional standpoint, including incorporating FA data into the traditional ED landscape . Meule hWeight stigma has been described as a “vicious cycle” where weight stigma begets weight gain . SimilarIn a large national sample (n = 5129), weight discrimination was associated with overeating  and less regular meal timing . IndividResearch on biological programming attempts to identify the most critical and sensitive periods that underlie the developmental origins of later childhood and adult disease . It has A recent study of New Orleans children showed that neighborhood stress exerts a direct influence on obesity, after adjusting for diet and activity . Such fiA “systems thinking” multilevel approach will be critical to reverse obesity trends. For example, trauma-informed treatment and stress management curriculum should be made available in underserved communities, starting with schools . MobilizThis paper has reviewed evidence to suggest that improving the early childhood environment might impact obesity risk and therefore should be a public health priority. Meanwhile, if reward-related neuroadaptations associated with addiction persist over time, addressing only the underlying factors may fail to create lasting changes in eating behavior, suggesting that policies targeting the food environment will also be important. Given that the food environment in the US promotes easy access to foods with addictive potential  it is noThere is mounting evidence of the harmful effects of processed foods in contemporary diets. A recent trial comparing the caloric intake of those on ultra-processed foods  compared to unprocessed/whole foods for two weeks found ad libitum intake was increased by approximately 500 kcal/day on the ultra-processed diet . Not surPublic health interventions to increase access to healthy foods in lower SES communities have been unsuccessful in reducing obesity, therefore new approaches are needed. Identifying certain foods to be addictive may encourage collective efforts to avoid them  and is aThe biological underpinnings of addictions strongly imply a role for ELA in the development of FA and obesity. Importantly, ELA can alter the physiological response to various forms of psychosocial STA across multiple body systems, which can have a cumulative impact on health behaviors over the lifespan. FA research which began in animal models has since been described in human neuroimaging studies which capture neurobiological and behavioral overlap between FA and SUDs. A biopsychosocial perspective on FA considers biomarkers such as inflammatory markers and other measures of AL, the HPA axis including the output of cortisol, epigenetic mechanisms including those that influence the HPA axis, and various structural, functional, and morphological brain changes, following exposure to ELA and STA. In order to contextualize risk, a biopsychosocial model considers the upstream drivers and fundamental causes of health disparities, such as SES and environmental  factors that impact food access and food choices. Furthermore, obesity frameworks should incorporate weight stigma as an important cause and consequence of the epidemic, suggested herein as a form of STA that can also become biological embedded. Finally, the role of dietary restraint has been included as an important psychological factor that should be accounted for when conceptualizing FA and obesity, particularly given the strong relationship between ELA and EDs, as recently reviewed elsewhere . Stress proliferates over the life course and across generations, widening health disparities between advantaged and disadvantaged groups . This miBased on the biological plausibility of FA as a consequence of psychosocial STA, potential solutions to the obesity epidemic may include: (1) improve social conditions in order to reduce exposure to ELA, as well develop community-based programs for early intervention (2) decrease weight stigma based on FA data implying that body weight is not simply a “choice” (3) mind-body approaches  designed to improve the human stress response and (4) policy proposals aimed at the food industry to reduce exposure to highly palatable foods. More information is needed about the role of nutrition in the reversibility of unfavorable gene expression. More research is needed to investigate whether long-term dietary changes such as abstaining from highly palatable foods is even feasible. If so, will this improve the microbiome and stimulate/reverse epigenetic change and/or lead to altered reward pathways in the brain? At a minimum, it is reasonable to predict that reducing exposure to addiction-like eating can improve executive functioning. Since dietary restraint is a known risk factor for the development of EDs, drastic individual nutrition changes should be implemented in consultation with a qualified professional such as a registered dietitian nutritionist, particularly when there is underlying trauma and/or SUD. Treatment models should be trauma-informed and include staff trainings. FA and SUD share multiple predisposing factors including ELA which can become biologically embedded. These findings may link social determinants to specific health outcomes and elucidate pathway effects of risk across the life course. Epigenetic processes may be a key mediator between social environments during childhood and disease risk in adulthood. Mediating mechanisms such as AL, the HPA axis, DNA methylation, and altered reward sensitivity  have scientific merit, however the fundamental causes of health inequalities present in society should not be overlooked. Low SES and neighborhood disadvantage remain important drivers of ELA, particularly within the context of the obesity epidemic. The cumulative effects of STA that impact neural function and heighten threat vigilance have significant implications for substance-seeking behaviors, including eating. The FA construct has gained credibility from animal and human studies reviewed herein, which may help reduce stigma associated with addiction-like behaviors, including obesity. More research is needed to understand the differential impact of inflammatory signaling markers on the brain, including assessment of blood brain barrier integrity. The study of neuroinflammation is likely to add explanatory power to our conceptual model and guide future research questions.If the DSM accepts FA, it will lead to better treatment and eventually public health efforts to improve the national food environment and global nutrition landscape. More resources should be allocated for nutrition education during pregnancy and lactation, particularly in underserved communities where stress and adversity are high, and the food environment is suboptimal. Applying the FA framework has the potential to influence the way people view food, and to ultimately decrease addiction in future generations. FA treatment does not always require specific “food abstinence” but it does warrant reduced exposure and harm reduction strategies. Given the strong evidence that neurobiological responses to food differ among people, personalized precision nutrition interventions are warranted. In order for these strategies to be successful, cultural shifts around food norms will be necessary. Furthermore, FA is both an individual and collective health problem, and should be addressed at the societal level with broad policy interventions. We propose that unregulated promotion of addictive foods by the food industry are major contributors of obesity, particularly in the face of disadvantage and distress. Government interdiction may be required to reduce the epidemic of obesity and the growing problem of food addiction. Multidisciplinary efforts using trauma-informed integrated biopsychosocial frameworks will be necessary to reverse obesity trends.


Consumers’ environmental awareness have appeared on the scene and are bringing nature-based tourism demands to the rise. Related practices have led to camels being used as an income generator for tour companies and locals in exotic appealing destinations. The long-term viability of the respective breeds markedly depends on the fact that the principal income sources for camel breeders in some regions are tourist activities. The present research was intended to outline what are the social and cultural factors that can act as tourism attractions and satisfaction conditioning elements within this particular tourism enterprise. Staff performance, sociospatial motivating factors, diverse and humane close interaction, camel behavior and performance, sociotemporal context, and positive previous experience, are the principal dimensions affecting experiential consumption in camelback riding tours. The understanding of such experiential consumption enables tour operators to customize its camel saddlery offers based on the diverse patterns influencing the buying behavior and general satisfaction of the customers. In its broadest sense, responsible and sustainable camel-based tourism will create positive impacts for destination economies and provide long-term conservation opportunities both at a natural and cultural level.Camels are exotic elements, which can be comprised within adventure travel companies promoting ecotourism activities. Such recreations contribute to sustainable livelihoods for local communities and educational empowerment towards nature and its conservation. At present, some local camel breeds’ survival reduces to this animal-based leisure industry and its reliability to perform and promote customized services accurately. By conducting an on-site questionnaire to customers participating in camelback riding tours, we assessed the motivational factors affecting participation, satisfaction, and loyalty in this tourism segment that may have made it socially differentiated. The sixfold combination of staff performance, culture geography, diverse and humane close interaction, camel behavior and performance, sociotemporal context, and positive previous experience involves the elemental dimensions that explain customer satisfaction and return intention probability within this entertainment business. Customer knowledge is essential for stakeholders to build personalized riding experiences and align profits with environmental sustainability and biodiversity mainstream concerns into their everyday operations. In turn, domestic camel tourist rides could be managed as a viable path to nature conservation by helping endangered local breeds to avoid their functional devaluation and potential extinction. Animal-based tourism is an emerging business around the world, which lets holidaymakers closely view or interact with animals. The interaction between animals and tourists may be the basis on which to support conservation and/or an educational purpose ,2. The aTourists engage with a country or region’s culture not only for its past heritage but for its practices in a living context . The recIncreasing social awareness on animal welfare issues has made animal-human touristic encounters face harsh constant criticism and global concerns over the years about the wider impacts on animals’ freedom violation . For thiFor camel-based tourism, research briefings on the social side and economic impact of this subsector worldwide are noticeably scarce. Donlon et al.  and SeifCamelus dromedarius) arrived in the Canary Islands around 1405 accompanying the first human expeditions of the European colonization of the islands . Our. Our1]. Although some breeders might abuse or neglect camels for their conception as trade tools for their own benefit, most of the animal owners fortunately realize that well-reared and healthy animals are the best working ones . Here, cIn the same frame-analytic scenario, the variables integrating the fourth dimension PC4,  might reThese undesired behavior traits not only could be derived from poor habit training and idiosyncratic components but also affect camel performance by overstraining practices and improper-fitting saddles. Given that these activities are concentrated in a short period of time and the number of animals involved is limited, since it is an endangered species and, in the particular case of Doñana, in process of functional reintroduction, the animals may be susceptible to cumulative fatigue and tiredness as the business takes advantage of this high season as much as it can because it is the most economically fruitful time for their self-financing and maintenance for the rest of the year. Besides, due to the fact that is an activity preferable to experience accompanied, it is most common for camels to support two riders on its back PC5, . HoweverIn this sense, considering that Andalusia continues to be a tourist preference and the Doñana National Park receives visitors during the rest of the year, this overburdening fatigue can be avoided by proper fairly constant training and physical stimulation as long as camel rides and camel-close interactions could become an alternative for other recreational experiences with transversal education purposes and serve as a therapeutic resource for social groups with special needs . AccordiLast, the combination or co-occurrence of all considered sociocultural dimensions of camel rides in this pioneer research approach would not only affect satisfaction but also return intention probability. With large added value, positive previous experiences seemed to be a conditioning and predicting factor for tourists when seeking for further involvement in this emerging exotic tourism attraction PC6, .Despite this study offers an all-round and overall view of camelback riding as emerging tourist experiences with a large potential to contribute to sustainable socioeconomic development and natural resources conservation, we discuss possibilities for future research within this academic field. First, despite of the fact that pricing is not presumably influencing customer satisfaction and return intention probability, the categorical inclusion of users’ profession would help to improve the knowledge of the socioeconomic level of camel riding consumers. In addition, we will be able to test whether a new experiential dimension, including variables already considered  and the new one proposed, appears on the scene. Income levels could be a potential factor conditioning users’ expenditure in destinations where camel rides are offered, in such a manner that tourists cannot spend more money than which they have already spent in secondary activities, as camelback tourist rides actually are. Further guidance would be provided for stakeholders when aiming to implement strategic actions .Within the same framework, it would also be interesting to investigate the different sources of information from which consumers had learned about the places where camel rides were available as tourism attractions and whether prior to booking they had knowledge about the welfare and general care of the animals in a specific location. Findings will enable us to identify weak points in the value chain of this touristic alternative and propose multivariate sources to meet its specific needs and goals as well as distribute the latest product information.A third consideration is the potential utility of an ethological and biomechanical characterization of the camel breed. The first one is a useful tool to empirically evaluate the real impact of tourist rides in camel welfare and general health status by comparing behavioral features that camels show during rides and natural behavioral patterns. In this regard, investigate if ridden camel behavior whether is sexually dimorphic could also provide valuable information. Regarding kinetics assessment, it allows to correlate camel physical performance and constitution with customer satisfaction, as camels with greater lightness and agility are expected to put up with a strict sports practice and reach the desired performance during riding walks. This functional appraisal ,26,27 anDifferent types of camel saddles would also be a good opportunity to inference consumer perception on the easiness and comfortability of camel riding and managerial implications on camel well-being.Last, the replication of this research proposal in other geographical locations where Canarian camels are present, such as the Canary Islands, may give greater validity to our findings and make results more likely to be generally applied to the whole endangered population.This paper presents a pioneer systematic approach of the sociocultural dimensions that surround camel tourism, particularly camelback riding tours. This exotic leisure activity attracts flocks of tourists seeking for traversing sandy environments on the back of these animals in caravans while supporting their positive welfare at the time of encountering. Essentially, the diverse social and cultural determinants that potentially contribute to creating this experience can be summarized as follows: staff performance, culture geography, diverse and humane close interaction, camel behavior and performance, sociotemporal context, and positive previous experience. The resultant specific-consumer knowledge assessment not only supplies the dire need for further practical research of animal-based tourist experiences but also capacitates involved stakeholders to refine their abilities to successfully meet and satisfy customer’s expectations according to the current social concerns, travel decision-making criteria, demands, and sustainability issues within this adventure enterprise. Tourism companies will, in turn, gain customer loyalty and fortify revenue opportunities. Contextually, this empirical marketing segmentation sheds light on the potential functional reintroduction of Canarian camels in national-protected areas out-of-the-archipelago that reunite geological and orographic conditions for these species’ survival, thus contributing to the long-term viability of this autochthonous endangered breed and avoid its extinction.