Loss of control eating is a core, transdiagnostic eating disorder symptom associated with psychological distress, functional impairment, and reduced quality of life. However, the factors that contribute to persistent loss of control eating despite negative consequences are not fully understood. Understanding the mechanisms that maintain loss of control eating is crucial to advance treatments that interrupt these processes. Affect regulation models of loss of control eating hypothesize that negative emotions trigger loss of control eating, and that loss of control eating is negatively reinforced because it temporarily decreases negative affect. Several variations on this basic affect regulation model have been proposed, including theories suggesting that negative affect decreases during loss of control eating rather than afterwards (escape theory), and that loss of control eating replaces one negative emotion with another that is less aversive (trade-off theory). Experience sampling designs that measure negative affect and eating behavior multiple times per day are optimally suited to examining the nuanced predictions of these affect regulation models in people's everyday lives. This paper critically reviews experience sampling studies examining associations between negative affect and loss of control eating, and discusses the implications for different affect regulation models of loss of control eating. The review concludes by proposing an expanded affect-focused model of loss of control eating that incorporates trait-level individual differences and momentary biological and environmental variables to guide future research. Clinical implications and recommendations are discussed. Loss of control eating  is a transdiagnostic eating disorder (ED) symptom associated with considerable psychological distress , functioThough current DSM-5 diagnostic criteria focus on objective binge eating , other forms of LOC and dysregulated eating that do not meet the formal definition of an “objective binge” in DSM-5  may be even more prevalent  and assoUnderstanding the etiology and maintaining factors underlying LOC is crucial for advancing research and treatment. Several prominent etiologic theories highlight the role of negative affect  and emotion regulation difficulties in promoting LOC. These theories are consistent with evidence of elevated LOC among individuals with internalizing disorders  , and incSeveral affect regulation models have been developed, each of which proposes a somewhat different mechanism underlying the association between NA and LOC see . In its increase following LOC. Alternatively, trade-off theory posits that LOC may replace a highly aversive negative emotion  with one that is more easily tolerated   . The ove improve .While all affect regulation theories predict that elevated NA may trigger LOC, they diverge in their predictions regarding trajectories of NA during and after LOC. The affective consequences of LOC are difficult to measure with the granularity necessary to distinguish between affect regulation theories using questionnaires administered once or at a limited number of timepoints, and may be distorted by the artificial and unfamiliar laboratory context in experimental research. Instead, changes in affect during and after LOC are optimally examined using experience sampling designs, which ask participants about their emotions and eating behavior in the context of their everyday lives. During experience sampling, questionnaires are administered once per day for several days (in daily diary studies) or multiple times per day [in ecological momentary assessment (EMA) studies], providing information about changes in emotions over relatively short timespans. Experience sampling designs have been used to study dynamic affective processes across EDs and other forms of psychopathology , and proThis paper will comprehensively review evidence from experience sampling studies (including both daily diary and EMA designs) that have examined NA-LOC relationships to determine which affect regulation theory or theories are best supported by current research. The review will address three primary questions. First, what do the data say regarding changes in NA before and after LOC in naturalistic settings ? Second, are certain negative emotions  particularly likely to precede LOC, and do these differ from the negative emotions that are most likely to follow LOC (as predicted by trade-off theory)? Third, are there individual differences in momentary NA-LOC associations, and, if so, do they align with existing affect regulation theories ?Studies published prior to January 1, 2021 were considered for inclusion. Relevant studies were identified by searching PubMed and PsycINFO using the terms  and . Additional studies were identified through manual search of the reference lists of prior meta-analyses . StudieThree primary experience sampling designs have been used to examine changes in affect surrounding LOC in daily life. Daily diary designs, in which participants report on their affect and eating behavior once at the end of the day, are the least intensive. While daily diary designs represent the lowest burden to participants, they also provide less fine-grained data than more intensive designs. Conversely, daily diary designs are better suited to detecting longer-term associations between NA and LOC  than briefer, more intensive studies. Intermediate in intensity are EMA designs that collect information on a participant's affect at several semi-randomly distributed times throughout the day, signaled by an alert on a participant's cellphone or a similar device . Some EMA studies also ask participants to immediately report when they experience LOC . Similar to daily diary designs, these kinds of EMA studies can be used to examine whether NA is elevated near LOC episodes, but provide greater temporal precision . The most intensive experience sampling designs ask participants to report on NA at multiple timepoints during LOC itself. These are the only designs that provide information about a participant's emotions while LOC is in progress. However, this method risks altering the natural consequences of LOC by directing participants to focus on their emotions during the behavior.Results from each of these study designs will be discussed, then synthesized with respect to their implications for affect regulation models of LOC. Study details  and key findings for each study are summarized in Two studies have examined prospective  associations between NA and LOC , 31. ThoFive additional studies examined whether NA was greater on days with LOC, but did not include prospective analyses. NA was elevated on days with LOC in all five studies –36 acrosTogether, daily diary studies indicate that NA may be a proximal trigger for LOC on a given day, but not across longer time spans . These studies also suggest that dysregulated eating may result in increased NA in the medium-term. Results are not necessarily inconsistent with the standard affect regulation model that posits an immediate decrease in NA following LOC, but suggest that any emotional relief obtained through LOC is likely short-lived.In total, 60 studies were identified that examined changes in NA in the hours surrounding LOC through moderate intensity EMA methods.Three studies examined whether certain patterns of NA across the day  were particularly likely to predict LOC on that day. While these studies sample affect at a higher rate than the daily diary studies discussed above, they are conceptually similar in seeking to understand how LOC may be related to NA across an entire day, rather than just immediately before or after LOC. All three studies –39 were per se. However, disambiguation of LOC and overeating may have been challenging in Berg et al. . These studies all showed greater NA at the time of perceived binge eating , 41 or eAn additional 20 studies examined whether NA prospectively predicted LOC within a given day, but did not examine changes in NA following LOC. Nearly all studies found that greater NA predicted greater likelihood of LOC at the next assessment, at least under certain conditions. Positive associations between NA and subsequent LOC or binge eating urges have been found for individuals with BN or BED –50, womeIn addition to suggesting that NA tends to be elevated over a person's average before LOC, most research also indicates that NA is greater prior to LOC than prior to meals and snacks not characterized by LOC. For example, Davis et al.  found thOne exception to this general pattern is Sanftner and Crowther , which fTwo studies examined whether NA was elevated after LOC, but did not include an analysis of pre-LOC affect , 62. TheNineteen studies used a pre/post design to examine absolute changes in NA from EMA assessments completed before LOC to EMA assessments completed after LOC. These studies used one of two sampling approaches. In the first approach (used by 12 studies), NA was assessed at multiple times throughout the day, and NA at the last signal prior to a reported LOC episode was compared to NA at the next signal following LOC. One benefit of this approach is that affect is captured around eating episodes even if the participant did not know LOC would occur when they started eating. This approach may also be less susceptible to reactivity , as LOCResults from studies using this approach were relatively consistent in showing that NA was greater after LOC than before LOC. This result was replicated in eight out of 12 studies, including studies of women with AN , 65, womnegative association between LOC and later NA in women with BN. However, once methodological differences are accounted for, results of Lavender et al. .The three studies that yielded different results have interesting potential implications for our understanding of NA-LOC associations. Of all 12 studies, only Lavender et al.  found anr et al.  are moreSimilar to Lavender et al. , Wegner Svaldi et al.  also fouA second approach to examining absolute changes in affect across LOC (used by seven studies) is to ask participants to rate their affect immediately before and immediately after LOC. This approach has the advantage of capturing the most proximal affective antecedents and consequences of LOC. However, it is possible that drawing a person's attention to their emotional state right before or after LOC could alter the effects of eating on their emotions .All studies in this category showed increases in NA following LOC, but with some nuances with respect to who experienced these increases, and when. Alpers and Tuschen-Caffier  and SherGoldschmidt et al.  dismantlIn summary, studies that measured NA shortly before and after LOC consistently suggest that NA is greater immediately following LOC. NA may then decrease in the hours following LOC, but appears to remain elevated over NA on days without LOC. As observed by Haedt-Matt and Keel  in an eadecreasing trajectory following LOC. Decreasing NA in the hours following LOC has been found in women with threshold or subthreshold BN (Seventeen studies examined trajectories of NA before and after LOC. Rather than focusing primarily on whether the absolute level of NA was higher or lower pre- to post-LOC (as in the studies discussed above), these studies investigated whether NA was increasing or decreasing  before and after LOC. In contrast to research examining absolute levels of NA before and after LOC, 15 out of 17 studies found that NA was on an increasing trajectory prior to LOC, but a shold BN , 80–87, shold BN , women wshold BN , 81, 89,shold BN , 91, andshold BN .N = 48). Effects may have also been more subtle in Stevenson et al.  may be less effective at shaping behavior than immediate reinforcement , and couAdditionally, studies examining the trajectory of NA after LOC have not typically investigated whether LOC is associated with a steeper decrease in NA than would be observed over a similar timespan if a person did not engage in LOC. One exception is Stevenson et al. , which fAltogether, the data suggest that NA decreases in the hours following LOC, but whether this decrease is caused by LOC remains unclear. Research across analytic methods also indicates that NA remains higher post-LOC than pre-LOC. Nevertheless, it is possible that individuals who experience LOC may come to believe that this behavior is responsible for the eventual decline in NA that follows a peak in uncomfortable emotions, and eat in response to their emotions to achieve this desired consequence. It is also possible that other perceived benefits of LOC may outweigh the consequences of a temporary increase in NA. For example, LOC is often proceeded by food restriction in daily life . TemporaFive studies assessed affect over the course of LOC episodes themselves. These studies can provide unique insight into an individual's affective experience as they are engaging in LOC. However, the intensive monitoring that is the inherent strength of these studies may also risk altering the experience and consequences of LOC.Results of studies examining NA across LOC episodes are mixed, with some suggesting a decrease in NA during LOC (consistent with escape theory) , 101, anReasons for discrepant findings regarding NA during LOC are not immediately evident. The two studies , 101 thaA second possible explanation is differences in the methods used to measure affect across studies. Most of the studies that did not find a decrease in NA during LOC asked participants to rate the extent to which they felt various emotions  on a Likert scale. In contrast, Deaver et al.  requiredWhile most studies have considered NA as a composite construct , some have attempted to tease apart whether patterns of change for specific negative emotions differ across LOC . One caveat to these analyses is that NA scales tend to show high internal consistency , suggestFive studies examined changes in specific negative emotions from immediately before to immediately after LOC , 107. AsTwo additional studies that used intensive EMA designs to sample affect during LOC itself suggest there may be subtle differences between different negative emotions during LOC. Stickney and colleagues  found thStudies examining the trajectories of individual negative emotions surrounding LOC also suggest that guilt may be uniquely important. Two studies found that guilt was increasing prior to LOC and decreasing following LOC (similar to the trajectories of composite NA scores described above), but that the slopes of fear, hostility, and sadness were not significantly different from zero before or after LOC , 92. In Rather than examining discrete negative emotions, Becker et al.  took a sSome people may be more generally prone to LOC after an increase in NA due to individual differences in personality , beliefs , or diagnostic status. Additionally, how a person feels at a given moment may affect the association between NA and LOC. Three potential moderators of NA-LOC associations are discussed below: diagnostic categories, eating expectancies , and negative urgency/impulsivity. These factors were chosen for their relevance to affect regulation models and because they have been examined in multiple studies, and thus have the greatest body of evidence from which to draw conclusions.stronger when LOC is experienced over larger amounts of food ].within-person changes in eating expectancies show a different pattern of effects. In the two studies that examined within-person changes in eating expectancies among individuals with recurrent OBEs . In making sense of these findings, it is important to note that behavioral and questionnaire measures of impulsivity are only modestly correlated . It is triction . Most sttriction , 70, 74,triction , who fouThree additional limitations of existing experience sampling research on associations between NA and LOC should be acknowledged. A first key limitation is inherent to the methodology—namely, that intensive monitoring of NA surrounding LOC may itself alter NA-LOC associations. If one function of LOC is to escape awareness of NA, drawing attention to emotions may negate this effect. This is particularly true for more intensive EMA designs that sample affect at multiple timepoints during LOC itself. One potential solution is to incorporate affect measures into future EMA research that do not require active reporting by participants. While physiological sensations do not correlate perfectly with verbal reports of emotion , non-invA second limitation relates to who has been included in experience sampling research on LOC. The vast majority of studies, particularly studies with clinical populations, have only included women. Among studies that have included men, none have examined whether associations between NA and LOC differ across gender. Relatedly, most studies have used participant samples that are predominantly (often over 95%) white. This is despite the fact that LOC is equally or more common among people of color than among white individuals . AdditioA third limitation is that experience sampling research on NA-LOC relationships has thus far paid little attention to biological and environmental contextual factors that might impact NA, LOC, or their association at a given moment in time. Emotions, and adaptive responses to emotions, are intimately tied to the context in which they occur . Both enA proposed, revised affect-focused model of LOC is depicted in Of note, the proposed affect-focused model in Conceptual similarities between the proposed affect-focused model of LOC and NSSI suggest that similar treatment approaches may be appropriate. In particular, DBT has shown promise for both NSSI and disorders characterized by LOC by targeting underlying difficulties with distress tolerance , problem solving, and emotion regulation . HoweverWhile additional work remains to be done, research to date nevertheless offers some practical clinical implications. Evidence that elevated NA increases risk for subsequent LOC supports key aspects of existing CBT-based treatments, such as working with clients to identify the situations that are most likely to trigger NA and develop strategies to help regulate their emotions at these times . Adding Though the standard affect regulation model may require some revision, experience sampling research has affirmed the importance of NA as a driver of LOC in daily life. Future research that incorporates individual differences and momentary biological and environmental factors will help us continue to expand our understanding of when, why, and for whom negative feelings may trigger dysregulated eating.The author confirms being the sole contributor of this work and has approved it for publication.This work was supported by a grant from the National Institute of Mental Health (R01 MH111715-03S1). The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institute of Mental Health.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We have the great pleasure of editing a special issue concerning the sensory integration of visible light across different exposure durations by the non-image forming photobiological system including the central circadian system. Throughout the past several decades, the circadian field has seen extraordinary progress. Sixty years have passed since the seminal Cold Spring Harbor Symposium on Biological Clocks. Forty have passed since the finding that light gates melatonin secretion in humans, while only 20 years separates us from the discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) and their expression of the short-wavelength photopigment, melanopsin. The field is once again at an exciting watershed, this time created by advances in semiconductor light emission technologies that offer the ability to “tune” multiple characteristics of photic stimulation , thereby enabling us to engineer human-centric lighting that is designed for not just optimal vision but also mental and physical health. In observance of this watershed (which is still unfolding), we have drawn together an issue of 16 articles covering a wide range of model organisms and considerations for what constitutes “biologically active” light, how to quantify, measure, and report it, as well as applications of biologically-active exposure patterns that might improve health outcomes. The issue is thus comprised around the following topics.Spitschan introduces the concept of time-varying light (from milliseconds to hours), its properties, and how to describe its ambient/environmental and exposure characteristics during laboratory investigations assessing the impacts of light on sleep and circadian function. Important issues are raised in the specification of these domains, including: (1) the challenges with calibrating the temporal output of light generators operating on the sub-second timescale, and (2) the possibility of non-linear distortions occurring in light emission across the exposure duration based on input variability . The mini-review ends with a call for more consistency in scientific communication to assure that current reports are “future-proofed” as changes in lighting technology increasingly fuel investigations of non-image forming responses to new and enhanced human centric lighting devices.Kicking off the volume with a didactic tutorial, Schlangen and Price introduce fundamental concepts related to the measurement and characterization of emission sources and of the lighting environment in general, with reference to the recent International Standard CIE S 026/E:2018. This standard recommends grounding predictions about the wake or sleep-promoting effects of light exposure on its activation of each of the five photoreceptor types. The authors close their article by contributing new data illustrating how the melanopic content of light can be derived from everyday light sources, including daylight, and how such assessments, if standardized, can be used to better understand and improve the impact of lighting on human well-being.Understanding the biological potency of light exposure requires accurate metrology. bench-to-bedside extension of laboratory findings on the biological effects of light exposure into everyday application. First, Stefani and Cajochen review current advisories on ambient lighting that are intercalated across various societal frameworks, from academic recommendations to formal “best-practices” guidelines and workplace-industry ordinances. They conclude that in many cases existing standards are based on visual lighting needs for a given occupational setting  and have yet to fully integrate an understanding of the influence of light exposure on non-visual physiological responses . Rounding out their perspective, the authors discuss several laboratory experiments suggesting that dynamic lighting mimicking changes in natural daylight can improve circadian and sleep health while maintaining adequate illumination for work-related visual tasks. As such, regulations looking to integrate visual and non-visual lighting considerations can be credibly developed, as embodied in several design guidelines for the built environment already emerging in North America and Europe.Three author teams examine the Houser and Esposito outline a five-step process for imbuing current scientific knowledge on the non-visual effects of light exposure into  human-centric lighting design. These steps include characterizing the lighting application, determining the habitual or desired sleep-wake schedule of the occupants and their sleep needs, and staying informed of building specifications that optimize functional balance between the visual, arousal, and circadian systems. Like Stefani and Cajochen, the authors conclude that architecture lighting (with the proper control systems) can be engineered to deliver biologically potent light during the day and low-potency light at night, all while balancing traditional factors such as color quality, flicker, and visibility.Next, targeting practitioners, Soler and Voss discuss principles for the application of emergent lighting technology including LED lighting from an industry perspective. They summarize the influence of important variables such as spectral power distribution and spatial geometry of the built environment that require careful consideration when designing indoor lighting solutions. Incorporating such principles at the design stage has the potential to maximize the ability to create “biologically” brighter days and darker nights. Their piece complements the reviews from Stefani and Cajochen, and from Houser and Esposito providing insights relevant for industry practitioners.Walbeek et al. review evidence that naturalistic intensities of light at night (nLAN) provide important information that orients mammalian circadian and neuroendocrine physiology. The authors note that the terminology used in the field to date has been wildly inconsistent, with the term “dim light” being used to describe light levels ranging seven orders of magnitude (0.0001 to 500 lux). When properly defined and calibrated to intensities approximating the moon and stars, extant data suggest that nLAN can influence common parameters measured within circadian oscillations , function as a zeitgeber, and produce direct non-visual effects on melatonin secretion and pupil constriction. While the properties of nLAN have been documented exclusively in rodents, there is a reasonable expectation that they will have translational potential for humans—imparting either analogous effects to those in animal models or more subtle effects on the plasticity of light responses. The authors close their discussion with a consideration of some of the challenges involved with measuring nLAN and the need to possibly rethink the current human-centric lighting recommendation that nights should be completely dark.Taking a broad comparative-translational perspective, from rodents to humans, Tabuchi et al. review the signaling biology that connects oscillations of the molecular clock with daily changes in membrane excitability in Drosophila timekeeping neurons. At the cross-roads of each is cryptochrome (CRY), a photosensitive molecule in flies that is embedded within the circadian transcriptional–translational machinery and an effector of the potassium ion channel β-subunit redox sensor. In addition to CRY, several other molecular clock constituents have been shown to modulate the neural activity of fly timekeeping neurons via interactions with ligand-gated and voltage-dependent/independent channels, channel-binding proteins, and subunits of the electrogenic ion pump. The authors suggest that the generalization of this crosstalk motif—between clock gene oscillations and daily changes in neuronal excitability—offers a new paradigm by which to study the effects of light exposure on sleep-wake rhythms, cognition, and neurological disorder.Understanding the effects of light exposure on the circadian pacemaker requires understanding the molecular and cellular mechanisms underlying the encoding of stimulus strength and the circuitry that integrates the signal from the retina to the pacemaker. In this issue, four contributions provide unique insights into these mechanisms and pathways, each using a different model system. First, Hannibal provides an intriguing and in-depth review of the comparative neuroanatomy of the retinohypothalamic tract and its role in mediating non-image forming (NIF) responses to light exposure in mammals. Drawing insights from studies on various genetic models and unique neuroanatomic features , Hannibal elucidates the molecular and neuronal pathways underlying NIF responses to light exposure. A spotlight is placed on neurotransmitter systems connecting the front-end of circadian photoreception to the hypothalamus, including those using the neuropeptide PACAP. A perspective is also provided on the harmful effects of light exposure at night on humans and other animals.Wong and Fernandez zoom out of the picture to discuss how intermittent light exposure through a sequence of millisecond light flashes is encoded as a coherent stimulus by the circadian system. They place the signaling of time at twilight within a theoretical framework that suggests the pivotal role of cones in this process, tying together different ideas from Gestalt theory and bringing them into a non-image forming context, thus generalizing principles of efficient sensory coding from one to the other. To support their “Cone Sentinel” model, the authors provide the first experimental data showing that ipRGC responses to short light flashes are dependent on extrinsic synaptic relays from classic photoreceptor cells and not intrinsic melanopsin expression. These data offer the unique perspective that flash protocols optimizing the stimulus-response characteristics of cone photoreception have the potential to be used clinically to treat sleep/circadian disorders and other medical conditions with an underlying circadian impairment.Next, Ruby introduces the disruptive phase shift (DPS) protocol, a simple manipulation of ambient lighting that renders animals (Siberian hamsters) arrhythmic without altering their genome, or the tissue and developmental integrity of the brain's clock, the suprachiasmatic nucleus (SCN). The DPS model has the advantage of studying arrhythmia in a “natural” state within the brain. In this model, the SCN circuitry remains normally intact  and thus can influence other structures to which it projects and receive input from networks returning from those structures. In that regard, Ruby offers an inroad to studying the neurophysiology of circadian dysrhythmia in an animal the way it is most likely to present in a human. DPS hamsters show severe impairments in declarative memory that are associated with fragmentation of electroencephalographic theta oscillations, as well as altered GABAergic and cholinergic signaling in the hippocampus. These phenotypes may point the way toward developing pharmacological treatments for circadian disturbances related to jetlag and those incurred with chronic disease.While light exposure can be modulated to examine how the circadian system responds to it, it can also be used to disrupt the system—or eliminate it entirely. To do so, Mure provides a state-of-the-art review on what is currently known about the functional properties of human ipRGCs, an extremely difficult system in which to conduct electrophysiological recordings. The article takes an integrative stance, reviewing transcriptomic and morphological phenotypes that may distinguish various subtypes  and brain connectivity maps generated via PACAP (pituitary adenylate-cyclase-activating polypeptide) immunohistochemistry. By and large, the light-response characteristics of human ipRGCs are similar to their variants in rodents and primates. In each case, the spectral sensitivity of the cells peaks around ~460 nm, with kinetic properties of intrinsic responses exhibiting a slow, sustained period of activity during stimulation that continues after light exposure. The author concludes the article by reviewing how altered ipRGC response kinetics or cell loss might provide insight into pathological mechanisms underlying aging-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease.Finally, Kawasaki et al. investigate the extent to which morning bright light  influences metrics related to sleep and non-visual physiological function in patients with glaucoma, an optic neuropathy that results in ipRGC loss. Post-intervention, those exposed to light therapy reported better subjective sleep quality on a Likert scale. The treatment group also demonstrated increased melanopsin-dependent, post-illumination pupil responses that correlated with common measures employed to quantify the robustness of daily ~24-h oscillations in physical activity assessed using actigraphy. The authors concluded that scheduled bright light exposure may be a cost-effective strategy to improve sleep, circadian entrainment, and general sense of well-being in patients with glaucoma.Current lighting technology allows tuning of various stimulus characteristics, including timing, intensity, spectrum, and pattern. Grant et al. examined whether daytime exposure to LED task lighting with different spectra conferring different melanopic illuminance (melEDI) can affect neurobehavioral performance. Their key finding was that long duration (8 h) light exposure with higher melanopic content was associated with significant improvements in working memory and processing speed (as assessed using a 2-min addition task) and improved procedural learning in a motor sequence task. These data provide preliminary evidence indicating that the incorporation of lighting with higher melEDI in the built environment  may improve neurobehavioral performance in the classroom in college-aged young adults with a naturally restricted sleep schedule.Using an overnight (2-day) in-laboratory randomized trial in healthy college-aged young adults, Raikes et al. examined the extent to which daily morning short-wavelength (blue) light therapy over 6 weeks, compared to therapy with longer wavelength (amber) light exposure, changes regional functional connectivity in the brain and ratings of subjective sleepiness in patients recovering from a mild traumatic brain injury (mTBI). At the conclusion of the 6-week treatment, improvements were observed in gray matter volume in the right thalamus and functional connectivity between regions of interest related to attention, somatomotor, and visual networks as well as the default mode network  in patients receiving blue light exposure as compared to amber light exposure. Furthermore, these morphological and functional connectivity improvements were associated with less daytime sleepiness reported with the Epworth Sleepiness Scale. The authors concluded that blue light therapy might be a non-invasive way of improving sleep and thereby improving functional outcomes after mTBI.An additional two primary reports from randomized trials elucidate how spectrally tuned light exposure affects the brain and behaviors associated with underlying mood, cognition, and arousal. First, Alkozei et al. examined changes in indices of functional and directed connectivity between the amygdala and the left dorsolateral prefrontal cortex, and the association of these outcomes with affect. The authors report that individuals receiving blue light exposure had greater bidirectional information flow between these two regions about an hour after the light exposure had stopped. This enhanced connectivity was associated with decreased negative affect. These results suggest that short-interval blue-light therapy can facilitate the engagement of cognitive control strategies needed to regulate arousal/mood and provide some mechanistic insight into why conventional bright light therapy during the winter months might improve depressive symptoms in people with seasonal affective disorder.Using a shorter duration (30 min) single-exposure administration of blue and amber light, Figueiro and Leggett review the evidence for the beneficial effects of intermittent light exposure in Alzheimer's disease (AD). Two strategies are discussed relating to (1) the delivery of 40-Hz flickering light to promote gamma oscillations and gamma-related clearance of the amyloid beta (Aβ) peptides contributing to plaque formation in the AD brain and (2) the delivery of timed millisecond flashes during sleep to induce phase-resetting responses that may help reinforce entrainment of sleep-wake schedules, thereby also facilitating Aβ clearance . Overall, the authors point out that these two strategies are not mutually exclusive when considering how intermittent light stimulation can be parlayed for the treatment of AD-related phenotypes and envision the development of personalized light therapy devices that might one day achieve both.Finally, zeitgeist.This volume touches on only a sliver of the developments that are currently permeating the field of circadian photobiology. Nevertheless, we hope that we have been able to capture some of the current “frontier” thinking in editing this issue, thus inching a little beyond the All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.SAR holds patents for Prevention of Circadian Rhythm Disruption by Using Optical Filters and Improving sleep performance in subject exposed to light at night; SAR owns equity in Melcort Inc.; has provided paid consulting services to Sultan & Knight Limited, Bambu Vault LLC, Lucidity Lighting Inc.; and has received honoraria as an invited speaker and travel funds from Starry Skies Lake Superior, University of Minnesota Medical School, PennWell Corp., and Seoul Semiconductor Co. Ltd. These interests were reviewed and managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques  in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed. Chronic musculoskeletal pain is defined as a persisting or reoccurring pain that originates in musculoskeletal structure . In the Living with chronic musculoskeletal pain is a great burden to an individual experiencing pain, along with large-scale implications for society including enormous medical annual costs worldwide, the occurrence of sick leave, and work disability . DespiteResearch has revealed that the brain in chronic and acute pain stage differs . HoweverMultiple emotional and cognitive factors impact on the experience of pain, thus brain circuits involved in the processing of emotion might play an important role in the development of chronic pain , 17. EviAlthough neuroimaging studies allowed to further advance our knowledge about plastic changes related to pain chronicity, they cannot provide causal relationships between them. In this context, non-invasive brain stimulation (NIBS) methods have been used to modulate cortical excitability in specific brain areas, in order to show a direct relationship between brain and behavior. NIBS allows a step further into the understanding on the mechanisms of pain, acute and chronic, and can be applied on both healthy participants and chronic pain patients .In this review, we will present an overview of the available NIBS studies with respect to pain development and discuss these studies in the context of a mechanistic understanding of pain chronicity. We further review to what extent NIBS studies offer additional targets on brain circuits see  involvedNeuroimaging studies in chronic pain patients have revealed altered structure and function of the brain in chronic pain. Studies in fibromyalgia, chronic tension-type headache, and chronic back pain patients have reported structural and functional changes in regions not typically involved in nociceptive processing, such as limbic and prefrontal cortices , 20, 21.In addition, the brain of chronic pain patients might differentially process acute and chronic pain, with the prefrontal cortex being a key region for this dissociation . MoreoveFrom the few available longitudinal data, it seems that similar networks are involved in the acute to chronic transition process, and that particularly corticostriatal circuits play an important role in pain chronicity. In a sample of subacute back pain patients followed over 1 year, increased functional connectivity between the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc) , and decTwo methods of non-invasive transcranial brain stimulation have dominated recent decades: transcranial magnetic stimulation (TMS), which activates axons through short-pulsed stimulation and leads thereby to new action potentials; and transcranial electric stimulation (tES), most used transcranial direct current stimulation (tDCS), which can be used to manipulate the membrane potential of neurons and modulate spontaneous firing rates, but which by itself is not sufficient to discharge resting neurons or axons .TMS operates on the electromagnetic induction principle . The devrepetitive transcranial magnetic stimulation with low repetition rates under or at about 1 Hz decreasing excitation, whereas high frequencies of ≥5 Hz are generally believed to increase excitability of stimulated region  occupies intermediate positions, in the physical sense, between pulsed rTMS and continuous tDCS. In tACS, the electrical current alternates between electrodes, usually in a sinusoidal form . The exaThere is a substantial variability of responses to NIBS techniques across subjects on an individual level . Beside The two most explored NIBS targets in pain are the primary motor cortex (M1) , which hTo uncover the mechanisms behind pain chronicity, the NIBS studies that are helpful are the ones that (1) focus on an experimental induction of prolonged pain in healthy individuals and follow the course of pain progression and pain resolution, thus providing a time course of pain development in relation to extended painful stimulation, or (2) focus on stimulation effects on clinical and induced pain in chronic pain patients to disentangle brain alterations from non-clinical compared to functionally and structurally altered clinical brain states, in relation to findings from (1).Through the experimental application and manipulation of pain in healthy individuals, we can monitor the time course when pain develops and gradually resolves and relate these changes with other clinical or neural measures. Prolonged pain in healthy humans can mimic symptoms seen in chronic conditions such as increased pain sensitivity , increased sensitivity to sensory stimuli , or muscle soreness , 78.Among the available NIBS studies of long-term pain induced in healthy subjects, NIBS has been used in the context of central sensitization, which has been proposed to underlie pain chronicity , and canMotor cortex was often targeted with NIBS due to analgesic effects that stimulation of this region has exhibited, most successfully when the target within M1 was the somatotopic representation of the painful body area .Meeker et al.  delivereIn contrast to previous findings,  reportedrTMS also reduced muscle soreness, narrowed the painful area, and increased pressure pain thresholds, and by day 14, the last experimental session, almost completely resolved muscle soreness and pain. Interestingly, rTMS did not exhibit significant effects on corticomotor excitability . Since the CPM task and motor excitability remained unaltered, the authors concluded that the observed effects are neither likely to be the result of M1 stimulation affecting descending pain inhibition networks, nor that they might emerge from local changes in M1. They rather discussed that the beneficial effects might have arose from changed activity of areas connected to M1 that are involved in pain processing or in affective processing of pain. Since these results were not confirmed by imaging, the mechanisms remained unclear. Nevertheless, it is plausible that M1 can indeed affect the activity of ACC, thalamus, insula, or DLPFC, as shown by imaging studies and by studies using electric field modeling to determine the current spread after M1 stimulation , 90.Schabrun et al.  examinedGiven that rapidly occurring neuroplastic changes often relate to pain duration in chronic pain conditions, it has been suggested that these changes could be preceding the chronic stage and therefore represent a risk factor for chronicity , 93. MorAmong the studies that have addressed the DLPFC, Fierro et al.  showed hStudies that applied brain stimulation shortly after induced pain onset showed how a specific region can foster recovery from pain, but since stimulation was usually initiated when pain already developed, these studies cannot tell if such a targeted stimulation would also prevent the development of pain. To investigate whether stimulation applied before pain onset can induce early recovery, Seminowicz et al.  applied NIBS studies underline the importance of the DLPFC in pain chronicity, since it seems that DLPFC affects not only the affective but also sensory component of the pain, independently of motor cortex activation. This is in accordance with a study in fibromyalgia patients where tDCS over DLPFC modulated heat pain thresholds . In furtNotably, structural and functional differences that may be “prewired” could make individuals more prone to the development of chronic pain. Lin et al.  found thThe processing of acute pain can be profoundly altered in chronic pain conditions, such that distinct patterns of alterations emerge across several brain regions including somatosensory cortex, thalamus, insula, motor and cingulate cortices , 106–108To date, only one study employed non-invasive stimulation methods to study changes in the acute stage of clinical musculoskeletal pain. Chang et al.  recruiteOccipital nerve field stimulation with subcutaneously implanted electrodes was shown to have positive effects in treating fibromyalgia . De RiddrTMS and tDCS are the most prominent non-invasive techniques used in chronic pain studies. Oscillatory protocols such as tACS are largely unexplored and underrepresented in pain research . To dateWith respect to the non-invasive stimulation targets, only very recently additional targets such as the medial prefrontal cortex were investigated in chronic pain patients. In a study that attempted to modulate clinical pain manifestations via affective and attentional manipulations, chronic low back patients underwent active and sham HD-tDCS over the medial prefrontal cortex . ConditiStudies that would be suited to mechanistically investigate the role of specific brain circuits in the development of chronic pain would have to consider several factors. Firstly, we could target neural activity previously found to be associated with and/or predictive for the development of musculoskeletal pain to investigate immediate effects of such a manipulation on pain regulation and demonstrate causal relation to chronicity. Studies thus far used either excitatory or inhibitory stimulation protocols depending on the method in question to potentiate analgesic effects, but rarely focused on up and downregulation with the aim to investigate a causal involvement of targeted area in pain processing. For instance, since it has been shown that activity in prefrontal brain regions in relation to spontaneous pain is increased in CBP patients , neuromoHowever, there are inherent challenges related to NIBS studies in chronic pain aiming to arrive to mechanistic explanations. A common non-invasive stimulation approach to investigate the causal role of a brain region in a specific behavioral or cognitive domain follows the “virtual lesion” principle. Hereby brief disruption of normal brain activity leads to immediate effects on the behavioral and/or cognitive level reflected by a changed response to the experimental task . Given tNext, careful consideration of the control conditions is a prerequisite toward more conclusive mechanistic interference. Sham procedures ensure the control of non-specific effects of TMS such as placebo effect, auditory noise, or sensory percepts of pulse discharge. To evaluate specificity of the brain region, TMS can be applied over another area presumably not involved in pain processing . To confImportantly, our recent tACS studies emphasize the need for an active control condition to explicitly test frequency specificity, which is usually ignored in most NIBS studies to date , 132. NIPrecise targeting is necessary to restrict stimulation effects to the desired region. Due to intrasubject variability, MRI-based TMS neuronavigation should be preferred instead of the traditional 10–20 EEG system positioning that is less accurate and has been found to induce different electrical field distributions compared to imaging-based localization , 135.Next, to track which changes are pre-existing in the chronic stage and at the same time putative causes of chronicity, NIBS interventions might be introduced in the acute and then to and in the subacute stage. In this manner, any brain activity-pain relation found before the chronic stage would be marked as a potential risk factor for pain chronicity. In contrast to brain imaging studies which enable mainly correlational evidence between brain activity and pain, NIBS would provide controlled manipulation cause-effect relationships.The mapping of NIBS-related effects could be performed by combining NIBS and imaging or NIBS and electrophysiological methods. Non-invasive stimulation is primarily confined to the superficial cortical layers , but viaSince it is conceivable that complex perception such as the pain experience depends on several key factors, the neuronal network on a whole, rather than an isolated brain region, is highly likely to be affected as pain progresses to the chronic state. One specific characteristic of the neural network is its oscillatory activity , thus itTo date, only one study in chronic musculoskeletal pain patients at our knowledge, combined tACS and EEG to successfully demonstrate an impact on chronic low back pain via an influence on somatosensory alpha frequencies . NetworkOverall, there is a great need to employ the NIBS interference framework to elucidate changes in brain circuits as potential causal factors of the development of chronic musculoskeletal pain. This research should be built upon previously demonstrated significant predictors of chronicity in imaging studies that provide potential targets of non-invasive stimulation. Non-invasive stimulation applied in models of prolonged pain or in chronic musculoskeletal pain patients thus far seems to confirm the importance of prefrontal regions in the transition to chronic pain. Importantly, NIBS showed that interventions applied preceding or in an early time windows of long-lasting pain can revert maladaptive responses. Moreover, NIBS findings point to the relevance of the connectivity patterns and deeper areas, justifying their targeting by methods such as neurofeedback . AdditioFurthermore, an intact descending inhibitory pathway seems necessary to counteract early maladaptive changes associated with central sensitization, although this could be related to the predominance of central sensitization in the mechanism behind symptoms, since not all chronic pain patients exhibit CS symptoms . It has Employment of novel variants of non-invasive stimulation, such as theta burst stimulation that has a potential for more reliable excitatory and inhibitory effects on brain regions , should Last, spinal cord stimulation (SCS), as another well-established therapeutic option for the treatment of chronic pain, has also been examined for patients with chronic back pain, specifically those with failed back syndrome . A functA mechanistic understanding of the transition from acute to chronic musculoskeletal pain is needed to permit targeted early intervention . HoweverMK, HF, and FN conceived the design. MK drafted the manuscript. MK, VM, JA, HF, and FN edited the manuscript, provided the content, and contributed to the organization. All authors approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Successful and durable treatment of cancer requires the stimulation of adaptive immunity as well as the re-establishment of anticancer immunosurveillance. Certain antineoplastic agents, the so called immunogenic cells death (ICD) inducers, are endowed with the ability to stimulate cellular stress responses such as autophagy, transcription inhibition and endoplasmic reticulum stress, altogether leading to the liberation of danger associated molecular patterns (DAMPs) from the cancer cells. Such DAMPs include adenine nucleotide triphosphate (ATP), which serves as chemoattractant for antigen presenting cells, annexin A1 (ANXA1), which acts as a homing signal for dendritic cells, calreticulin, which functions as an phagocytosis-inducing signal and high mobility group box 1 (HMGB1), which stimulates the maturation of dendritic cells (DCs) and the presentation of tumor antigens to T cells. ICD induction is stimulated by a minority of anticancer agents such as mitoxantrone, doxorubicin and oxaliplatin that have the ability stimulate such defined patterns of immunogenic signals. However, ICD is not induced when these drugs are used at suboptimal concentrations or when drugs that are intrinsically unable to induce ICD are employed. In this latter case, ICD can be reinstated by complementing antineoplastic treatments with the pharmacological induction of cellular stress pathways such as endoplasmic reticulum (ER)-stress and autophagy , 3. MoreEncouraged by these findings, we decided to use a system biology approach for the discovery of additional pro-autophagic agents within the chemical group of chalcones. In an unbiased screen, we identified isobacachalcone (ISO) as a non-toxic inducer of autophagic flux in vitro and in vivo in mice . ISO wasIn summary, our results support the notion that pharmacological induction of specific cell stress pathways has the ability to stimulate anticancer immune responses in the context of immunogenic chemotherapy. We anticipate that future investigations will yield optimized regimens for combination treatments consisting in improved ICD inducers together with additional immunotherapies such as immune checkpoint blockade. It is tempting to speculate, yet remains to be formally proven, that such combination therapies may improve the clinical efficacy of antineoplastic treatments and minimize the probability of relapse through the induction of long-lasting anticancer immune responses.


Increasingly more studies are showing that daily activities can be beneficial to wellbeing and cognitive abilities of older adults, but discussions about through which psychological mechanisms daily activities are associated with wellbeing and cognitive health have been scarce. This symposium, including three ambulatory assessment studies and one cross-sectional study, presents emerging theoretical hypotheses and recent empirical findings on this matter. Specifically, with 5-6 days of observations from 313 older adults, Brown and colleagues show that greater daily activity diversity is related to older adults’ higher overall cognitive functioning . Hueluer and colleagues examine the moderating role of interaction modality on the relation of daily social interactions with wellbeing using data from 116 older adults over 21 days. Their results show that more face-to-face interactions — but not telephone or digital interactions — are associated with higher positive affect and lower loneliness. With data from 153 older adults over 15 days, Luo and colleagues show the mediating effect of positive affect in the association between momentary working memory performance and subsequent social activity engagement. Sharifian and colleagues show the mediating effects of solitary-cognitive activities in the association between depressive symptoms and global cognition, using cross-sectional data from 453 older adults, and also examine the moderating role of race. Finally, Tom Hess will serve as a discussant and provide an integrative discussion of the papers, informed by his extensive work on daily activities, motivation, and aging.


The heterogeneous group of myelodysplastic syndromes (MDS) needs an individualized and patient-tailored therapeutic approach. Consensus-based guidelines for diagnosis and treatment provide a basis for clinical decision making. MDS guidelines are issued by expert panels. Our main objective was to examine how guidelines influence patients’ adherence to expert recommendations and how they ensure healthcare quality. To approach this question, we reviewed the most common guidelines for diagnosing and treating MDS in adult patients. Furthermore, we critically looked at quality indicators for everyday practice and studied adherence in an everyday outpatient setting. Finally, we also paid close attention to patient-reported outcome measures and studied how they are used as endpoints in clinical trials. We can conclude that the combination of evidence-based diagnostic tools, standardized treatment recommendations, and patient-centered shared decision making will eventually lead to a healthcare standard that will significantly improve outcomes in adult patients with MDS. Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem and progenitor cells mainly affecting the elderly population . The cliWhen analyzing adherence to guidelines, the critical question arises as to how the guidelines were conceived. Methodology is often non-transparent and varies greatly depending on the disease and the institution that organizes the authoring. In addition, the status of approval of pharmaceutical products in different countries must be taken into account when guidelines are established and also when adherence to guidelines is assessed. While there is an abundance of practice guidelines for solid tumors, often based on extensive multicenter phase III clinical trials, MDS guidelines are commonly issued by international expert panels drawing on their clinical expertise. For patients with lower-risk MDS and those who cannot tolerate intensive treatment, therapeutic guidelines generally concentrate on improving the QoL, whereas guideline recommendations for patients with higher-risk MDS are primarily concerned with extending OS, particularly emphasizing the importance of identifying patients who may be eligible for allogeneic stem cell transplantation .Although the results of clinical trials serve as cornerstones in guideline development, clinical trials designed to prove the efficacy and safety of drugs are not well suited to assess how well patients are going to adhere to a particular treatment once it has been incorporated into the guidelines.As guideline adherence becomes more widely used for healthcare quality assessment, it is important for clinicians not only to be familiar with guidelines, but also to understand how patients perceive guideline recommendations and why recommended actions may fail despite good intentions. To raise awareness of this topic, we have reviewed the work of experts in the field of guideline adherence and healthcare quality in MDS.Heins et al.  studied The national cancer registry of the Netherlands provided information on individual adult patients with cancer, regarding patient-specific features like age and comorbidities, as well as disease-related features like cancer type, initial stage at diagnosis, and treatment given. Patients matching the defined profiles were retrospectively identified among those older than 18 years and diagnosed between 2007 and 2012. The group managed to compile sizeable profile-fitting cohorts ranging from 1,160 patients with lung cancer to about 15,000 patients with breast cancer. The cases identified in the registry were then checked for guideline adherence.p < 0.001). Adherence was also dependent on the type of therapy, ranging from a mean adherence of 44% for recommendations involving chemoradiation to 92% in those focusing on hormonal therapy.The mean adherence to therapeutic guideline recommendations varied from 40 to 99%, strongly depending on the tumor entity. A high level of adherence was found in melanoma and breast cancer patients (99% each), whereas adherence was much lower in lung cancer patients (53%). Interestingly, recommendations that advised against a treatment had considerably higher rates of adherence than recommendations that recommended a specific treatment , which cover solid tumors and hematological malignancies, including MDS , are comThe diagnosis of MDS may be suggested by a patients’ medical history and a thorough physical examination, confirmed by the microscopic examination of blood and bone marrow specimens, and corroborated by cytogenetics, flow cytometry, and mutation analysis. The complete array of diagnostic techniques may be required to rule out the most important differential diagnoses, i.e., AML and aplastic anemia (AA). Following standardized procedures improves the accuracy and swiftness of diagnosis and allows for the identification of possible therapeutic targets .The diagnosis of MDS consists of several elements, which together define a standardized diagnostic approach that enables physicians to make an accurate diagnosis and plan adequate treatment. The first element is taking a detailed medical history, paying attention to (1) previous exposure to mutagenic agents like cytotoxic drugs used for chemotherapy, as well as radiotherapy or radioiodine treatment. This information is important to make or to exclude a diagnosis of treatment-related MDS, and also helps to assess the patient’s prognosis. (2) Occupational hazards such as long-term exposure to benzene must be considered, too, as they may justify the recognition of MDS as an occupational disease. (3) Comorbidities must certainly be recorded because they may influence therapeutic decision making. For instance, a history of frequent falls or easy bruising or gastrointestinal bleeding suggests that serious bleeding complications may occur during treatment regimens that induce or aggravate thrombocytopenia. A history of frequent infections may point to an increased risk of septic complications during treatment. Furthermore, the medical history should consider the nutritional status, current medication, prior or concurrent neoplasms, and risk factors for hepatitis and HIV infection.The second diagnostic element is a thorough physical examination, which can yield more information about cytopenia-related signs and symptoms: dyspnea, tachycardia, petechial bleedings, pleural or pericardial effusion, inflammatory changes, constitutional symptoms, organomegaly, and lymphadenopathy . Patients should also be screened for vascular events, again especially in MDS/MPN (myeloproliferative neoplasms) overlap syndromes such as CMML and RARS-T (refractory anemia with ring sideroblasts and thrombocytosis).The third pillar of MDS diagnosis is the morphological assessment of blood and bone marrow. A complete blood count and a peripheral blood smear to detect dysplasia or other abnormalities are mandatory. It may be useful to assess peripheral blood smears repeatedly at the time of first diagnosis.A well-performed bone marrow biopsy is the core element of MDS diagnosis. The aspirate should provide enough material for a series of bone marrow smears, including specimens for special cytochemical staining, as well as flow cytometric analysis. Cytomorphological examination of the bone marrow smears should always be guided by a clear clinical question and knowledge of the blood cell counts, in order to enable a meaningful interpretation. If only subtle signs of dysplasia are present in the bone marrow, cytomorphological assessment of peripheral blood cells is important to differentiate between MDS and idiopathic cytopenia of unknown significance (ICUS). As cytomorphological evaluation strongly depends on the experience of the hematologist or pathologist, diagnosis accuracy may be augmented by flow cytometry. In addition, histopathologic examination of a trephine biopsy should be performed in order to achieve a more reliable estimate of bone marrow cellularity and detect the presence of fibrosis.The fourth element of MDS diagnostics is karyotype and mutation analysis of blood and bone marrow cells. This part is essential, because the results are critical for determining the correct MDS subtype and assessing the patient’s prognosis. The results may also identify anomalies that can be targeted by specific drugs. Chromosomal aberrations are detectable by conventional cytogenetic analysis and fluorescence in-situ hybridization (FISH), while somatic mutations can be detected by polymerase chain reaction (PCR) and next-generation sequencing using targeted gene panels or whole exome analysis.Cytogenetic and mutation analyses are also relevant for separating MDS from clonal hematopoiesis of indeterminate potential (CHIP) and possibly clonal hematopoiesis of oncogenic potential (CHOP) . IncreasA recent study on the same topic showed that diagnostic procedures in the non-academic setting have improved, perhaps because of the availability of licensed medications that can only be used for patients with a narrowly defined MDS subtype . NeverthAs our overview illustrates , the mosThe first step in treating MDS is defining a treatment goal. Treatment goals in patients with MDS are twofold. Improving cytopenias and reducing complications like falls or bleedings is the goal for patients with lower risk MDS. In those patients with higher risk disease, the goal, however, is to alter the natural course of the disease.Treatment strategies in lower risk patients include regular transfusions, iron chelation to prevent secondary hemochromatosis, antibiotic and antifungal therapy during potential infectious complications, and granulocyte-colony-stimulating factor (G-CSF) administration. This treatment course is called best supportive care, and ought to be the cornerstone in treating MDS patients so as to reduce the burden of disease.Furthermore, erythropoiesis-stimulating agents (ESA), such as high dose erythropoietin (EPO), play a key role in patients with symptomatic anemia needing regular transfusions. Patients with a low transfusion burden of less than two units per months and an EPO level of less than 500 U/l are expected to have a superior response rate than those with a higher endogenous EPO level .Patients with hypocellular bone marrow are eligible for immunosuppressive approaches with antithymocyte globulin or cyclosporine. Both treatments are used to treat AA and have also been proven to be effective in this subgroup of MDS patients.Another special subgroup is represented by patients with del(5q). Bone marrow analyses often reveal ring sideroblasts paired with a SF3B1 and/or JAK2-mutation. Responses to ESA were often lower than in non-del(5q) patients, and hence they are eligible for treatment with Lenalidomide . LenalidHigher risk patients are eligible for therapy with hypomethylating agents (HMAs). Azacytidine is approved for higher risk patients in Europe and for patients of all risk groups in the United States. MDS patients exhibit genome-wide hypomethylation and CpG island hypermethylation, which results in genetic instability typical of cancer and tumor suppressor gene silencing. Hypomethylating agents help to erase the aberrant methylation, resulting in the activation of tumor suppressor genes.As alloSCT is the only curative treatment eligible, high-risk patients should be offered a consultation to discuss alloSCT close to the time of their initial diagnosis.What are the core values of an MDS guideline? Which components are important enough to be considered useful indicators of the quality of care?Stojkov et al.  from theThe diagnostic domain includes aspects related to diagnostic procedures, risk stratification using risk scores like the IPSS-R, and patient-reported outcomes. The therapeutic domain emphasizes supportive care as a basic concept for all patients. Further treatment options are divided into those most relevant for lower-risk MDS, i.e., erythropoiesis stimulating agents and Lenalidomide, and those more relevant for higher-risk MDS, i.e., hypomethylating agents and alloSCT. Infrastructural features include a multidisciplinary care team and access to clinical trials.The selected quality indicators are measurable and can be used to establish improved process quality in MDS patient care. GBIs should be representative of the cornerstones of clinical decision making. Nevertheless, there is a potential pitfall: although it is important to consider GBIs during the diagnosis and treatment of MDS, we should keep in mind that clinical decision making is a process shared between the physician and patient. Patient-related factors and patient preferences play a key role. Thus, we further examined adherence to MDS guidelines in a real-world setting.Our MDS working group in Düsseldorf studied adherence to treatment recommendations based on ELN guidelines. We conducted a prospective study including 381 adult patients with MDS who received an ELN-based treatment recommendation in our outpatient clinic . During Considering the limited number of therapeutic options available, an overall adherence of 67% appeared rather low. Is this detrimental to the outcome? We were curious to know whether guideline adherence really has an impact on the prognosis of MDS patients. Therefore, we performed a retrospective analysis of 1681 patients, comparing those who were eligible for a certain treatment and accepted it, and those who chose not to adhere to the treatment recommendation. The results were disappointing: only patients who adhered to a recommendation for alloSCT or iron chelation gained a significant survival benefit over those who did not follow such recommendations. Adherence to other treatment recommendations did not result in a survival advantage.Our findings do not invalidate the ELN guideline that we looked at nor any other guideline presented in Several factors influence adherence in everyday practice. In general, professionals are more likely to follow recommendations if they are part of a set of guidelines they are familiar with . FurtherStudies on the treatment outcome in MDS patients usually focus on OS and transformation into AML as endpoints, because measuring them is easy. However, patient-reported outcome measures (PROMs) should be included as well. PROMs include information about patients’ general health condition, burden of disease, and other aspects influencing health-related quality of life . ImpairmStauder et al.  conducteIn clinical trials, PROMs were mainly used as secondary end points, and more frequently employed in phase 3 than phase 1 or 2 studies. The focus was mainly on health-related quality of life, assessing symptom burden, and physical and psychological features. Only 3% of the trials used PROMs as a primary endpoint.Stauder et al. also studied whether PROMs were included in labelling claims. They searched the PROLABELS database to identify EMA- and FDA-approved drugs for the treatment of MDS and AML. In total, 13 drugs were identified, of which only two, namely lenalidomide and azacytidine, included PROMs in their labelling claims for MDS treatment submitted to the EMA. PROMs are only used as secondary endpoints. In contrast with the EMA, the FDA does not include PROMs in their MDS drug approvals. Among all of the FDA- or EMA-approved drugs approved for the treatment of AML, none report PROM data in their labels.We must be aware that, despite guideline recommendations and physician expertise, it is the patient who, consciously or unconsciously, makes the really important decisions. The patient seeks advice from a trusted physician, gives consent to certain diagnostic procedures, and decides which therapeutic recommendations to follow. It cannot be the intention of guidelines to put pressure on patients. Instead, guidelines should facilitate clinical decision making by offering and ranking therapeutic options that are corroborated by evidence from clinical trials or, at least, expert consensus. We should like to emphasize that there is no obligation to use a certain drug simply because it is formally approved for the patient’s medical condition. Guideline-adherent treatment must be aligned with the moral principle of primum non nocere. In other words, rather than simply following guidelines, physicians must take into consideration that a guideline recommendation may actually harm the patient. Guideline adherence is not an end in itself.Guidelines for the diagnosis and treatment of MDS try to augment healthcare quality for MDS patients. We considered the physicians’ perspective by looking at guideline-based core indicators reflecting diagnostic workup and therapeutic options . FurtherWe can show  that varFrom the sparse literature, we conclude that more needs to be done. Research and scientific evidence in MDS are evolving rapidly, especially in the field of molecular and immunological findings. Guidelines are thus frequently adapted. However, in our view, more emphasis should be placed on PROMs in order to be better improve the quality of care.In closing, we would like to mention a project that is designed to merge all important diagnostic and therapeutic aspects under the slogan “providing the right care to the right patient with MDS at the right time”. The MDS-RIGHT project is designed for patients with lower-risk MDS and symptomatic anemia. Fifteen European partner organizations joined forces to implement standardized diagnostic and therapeutic interventions in order to promote more effective use of healthcare resources and boost treatment compliance . The proOur work emphasizes that proper patient management should go beyond guidelines and should involve shared decision-making. Guidelines should be considered a useful framework rather than a dogma.


A knowledgeable and motivated workforce is critical for health systems to provide high-quality services. Many low- and middle-income countries face shortages in human resources and low health worker motivation but are also home to a burgeoning number of quality improvement (QI) programmes. This study evaluates whether and how motivation and clinical knowledge in three cadres of health workers changed in the context of a QI programme for maternal and newborn health in Ethiopia. This mixed-methods study used a pre–post comparison group design with matched comparison areas. We interviewed 395 health workers at baseline in April 2018 and 404 at endline in June 2019 from seven districts (woredas) with QI and seven comparison woredas. Three cadres were interviewed: health extension workers, facility-based skilled midlevel maternal and newborn care providers, and non-patient-facing staff. A qualitative component sought to triangulate and further elucidate quantitative findings using in-depth interviews with 22 health workers. Motivation was assessed quantitatively, exploratory factor analysis was used to categorize motivation dimensions, and regression-based difference-in-difference analyses were conducted. Knowledge was assessed through a clinical vignette. Qualitative data were analysed in a deductive process based on a framework derived from quantitative results. Although knowledge of the QI programme was high (79%) among participants from QI woreda at endline, participation in QI teams was lower (56%). There was strong evidence that health worker knowledge increased more in areas with QI than comparison areas. Three motivation dimensions emerged from the data: (1) ‘helping others’, (2) ‘pride and satisfaction’ and (3) ‘external recognition and support’. We found strong evidence that motivation across these factors improved in both QI and comparison areas, with weak evidence of greater increases in comparison areas. Qualitative data suggested the QI programme may have improved motivation by allowing staff to provide better care. This study suggests that although QI programmes can increase health worker knowledge, there may be little effect on motivation. Programme evaluations should measure a wide range of outcomes to fully understand their impact. A knowledgeable and motivated health workforce is important for health systems to provide high-quality care. QI programmes seek to improve healthcare quality through a variety of mechanisms.We find that a QI programme was associated with an increase in health worker knowledge, but not associated with an increase in health worker motivation. Qualitative data suggest that motivation can be improved through increasing health worker skills.It is critical that programme evaluations measure a range of outcomes to understand their impact on patients and health workers.Present, productive, and skilled health workers are key to a well-functioning health system , and equIn the Millennium Development Goals era between 1990 and 2015, Ethiopia reduced maternal and under-5 mortality by 70% , yet matThe focus of this study is a quality improvement (QI) programme implemented in Ethiopia. The ‘Ethiopia Health Care Quality Initiative’ was implemented by the Ethiopian Federal Ministry of Health with support from the Institute for Healthcare Improvement between 2017 and 2020. Although there is no unambiguous definition of what constitutes a QI programme  and the Ethiopian Federal Ministry of Health, and implementation was accompanied by an impact and process evaluation, of which this study is one element . We used mixed methods, combining a repeated quantitative survey with supporting in-depth qualitative interviews—the purpose of the quantitative work was to measure motivation over time in QI and non-QI areas, whilst the purpose of the qualitative work was to validate quantitative measures and help understand the mechanisms of any impact observed in quantitative work. The quantitative component comprised a survey conducted with a cadre-stratified sample of randomly chosen HEWs, midlevel care providers and non-patient-facing staff. The survey sought to quantify motivation through a range of indicators and motivation domains, and the same tool was used at baseline and endline. We attempted to contact all baseline respondents to participate at endline. Because the QI programme sought to foster a culture of quality improvement in programme areas, we analysed data from all participants in QI programme and comparison areas, regardless of their participation in QI collaboratives or other QI activities. The qualitative component was conducted in between baseline and endline quantitative data collection, after a descriptive analysis of baseline data. We conducted semi-structured interviews with healthcare workers who were interviewed at baseline to triangulate and further expand quantitative findings and to capture other dynamics or factors which were not included in quantitative tools.In seeking to measure the overall level of motivation that drives health worker behaviour, we take a ‘motivation intensity’ approach. Pinder defines motivation as a ‘set of energetic forces that originate both within as well as beyond an individual’s being, to initiate work-related behaviour and to determine its form, direction, intensity, and duration’ p. 11 . The ‘moTo measure health worker knowledge we used a clinical vignette. The vignette presented patient-facing respondents with a hypothetical scenario of a pregnant woman seeking antenatal care for the first time, and asked (1) what history questions they would ask, (2) what examinations and investigations they would perform, and (3) what drugs or supplies they would provide. The tool was taken from the World Bank Impact Evaluation Toolkit  reviewedWe adapted a quantitative tool to measure motivation which was developed and validated among community health workers in Uganda (16), making minor changes to wording to suit the Ethiopian context. This initial tool consisted of 17 questions, and we added eight questions based on the World Bank Impact Evaluation Toolkit to explore extrinsic motivating factors in more depth. Finally, with input from senior staff implementing the QI programme we added five further questions around activities which were part of the programme, relating to training and recognition for doing a good job. In addition, we simply asked participants how they would rate their motivation at present. The motivation questions from the final tool are shown in Qualitative in-depth interview guides were initially developed using key themes reported by other health worker motivation studies in Ethiopia  where other evaluative work was also taking place, to triangulate findings in other evaluation components.For each of the seven QI programme woredas chosen for data collection, we chose one matched woreda from the same region which was not subject to QI activities. Repeated cross-sectional data were available, however, on maternal health care utilization from DHS data sets. DHS data report at the regional level, so we used GPS co-ordinates from the DHS data to identify woreda and estimate the woreda-level health service utilization levels. Using the three most recent DHS surveys , we estimated woreda-level means of the three DHS variables relating to a woman’s most recent birth: the proportion of women delivering in a health facility, the proportion who received no prenatal care and the proportion who received no postnatal care. We used a simple and transparent approach to this, selecting the comparison woreda in each region with the closest utilization compared to QI woreda across three equally weighted indicators.In a cadre-stratified sample, we sought to interview 50 participants per woreda. We interviewed around four maternal and child health care providers from the hospitals and two from each health centre, around five HEWs from each health centre and one HEW from each health post. We also interviewed non-patient-facing staff: the heads or clinical directors of the woreda, each hospital and each health centre. We did not specifically include or exclude participants who were part of QI collaboratives or who had attended learning sessions.We obtained permission letters from woreda health offices and sampled providers from all health facilities in the woreda. Woreda health offices were also asked to report any other QI programmes or initiatives in the area, and no major activities were identified outside of the programme under evaluation. In each health facility we obtained a list of all maternal and newborn health (MNH) providers and randomly selected participants for interview. Their names were written in alphabetical order next to a column of randomly generated numbers and interviewers sequentially chose participants from the smallest random number upwards until the requisite number of participants was reached. If participants were not available, we sought to arrange interviews via phone and returned to the facility up to three times before classifying them as unreachable and selecting the next worker from the list.www.opendatakit.org) and analysed in STATA.Quantitative data collection was conducted by seven research assistants who received one-week training at the start of the data collection process. Each worked in regions they were familiar with to assist with community entry and mitigate language issues. In both survey rounds, tools were translated to Amharic and Oromiffa languages and data were entered on tablet computers using Open Data Kit software  more than 10% missing data, (2) being given the same score by over 80% of participants and (3) with factor loadings less than 0.4 . We ran In quantitative motivation analyses, we used individual variables and the factors identified in baseline data to explore variation in motivation over time and across geographic areas. We take an intention-to-treat approach, analysing data from all respondents regardless of their participation in QI activities. First, for each cadre we report the mean scores on each variable and for each factor at baseline and endline, and in QI and comparison areas. Second, we ran linear ordinary least squares difference-in-difference regression models to explore if there were differences in individual variables and mean factor scores for each motivation dimension between QI and comparison areas.As the purpose of the qualitative work was to triangulate facets of motivation and understand mechanisms of change, we first developed a coding framework based on emergent patterns in the exploratory factor analysis. We added one additional code to capture perspectives on the impact of the QI programme on motivation. Although we were prepared to adapt this coding framework in light of emergent themes from the data which did not fit into it, no changes were deemed necessary to the initial coding framework developed from baseline quantitative data. After the coding frame was developed, the lead author wrote narrative summaries of relevant themes and subthemes and identified relevant quotes.The research protocol and tools were reviewed and approved by the Observational/Interventions Research Ethics Committee and the Ethical Review Committee of the authors’ institutes.P = 0.05). On average compared to other cadres, HEWs had worked in their current facility the longest (40 months) and non-patient-facing staff had worked in the health system the longest (45 months). Reported annual salaries varied across cadres with the managerial cadre of non-patient-facing staff earning the most , followed by midlevel care providers (ETB 4191) and HEWs (ETB 3290). The non-patient-facing cadre was the most likely to report unauthorized absenteeism in the previous 3 months where 33% reported any absenteeism, although we cannot rule out equality in absenteeism across cadres.n = 164), just 37% of HEWs were members of a QI team, compared with 70% of midlevel care providers and 88% of non-patient-facing staff. Of those in a QI team (n = 136), midlevel care providers and non-patient-facing staff attended 10 QI meetings and learning sessions on average, HEWs attended nine.Finally, 79% of the sample in QI areas were aware of the QI programme at endline, and there was no evidence of differences in awareness of the QI programme across cadres. Of those aware of the QI programme  helping others and reaching personal goals; (2) pride and self-efficacy in job and (3) external recognition and support . Qualitative data triangulated this definition of motivation construction, highlighting specific motivators and demotivators within each.Because we measured motivation and knowledge in many woredas in Ethiopia and included three cadres of health workers—including HEWs whose motivation has not previously been comprehensively assessed—this study may provide a comprehensive picture of motivation across cadres in Ethiopia. In addition, no previous work has sought to measure how QI programmes affect health worker motivation in any setting, nor explore concurrent knowledge changes. In particular, findings of increased knowledge are consistent across patient-facing cadres of midlevel care providers and HEWs; similarly, the lack of evidence for changes in motivation is also consistent. We note that the main demotivating factors identified in qualitative data were things which the QI programme did not address, such as health worker salaries or a lack of equipment. Although the QI programme had the intention to fill the equipment gap of the health facilities, the plan was not fully successful and a subset of facilities received the equipment at or after the completion of the programme and others received only minor supplies during the programme.The inconsistency between motivation and knowledge findings in this study can perhaps be attributed to the fact that the QI intervention we evaluate is complex and multifaceted, whilst motivation and knowledge—although both are positively related to quality of care—may act in different directions in response to a QI intervention, or over different periods of time. For example, an increase in workload needed to increase knowledge may temporarily demotivate health workers before motivation may be later increased through self-efficacy—the latter was more salient in our qualitative data than the former. A priori, we were not able to identify a clear hypothesis of whether motivation and knowledge would move in the same direction—represented by a dashed two-way arrow in the hypothesized theory of change. This relationship remains difficult to conceptualize and would merit greater exploration in the future to understand how QI programmes can maximize impact.This study is consistent with findings in the literature that motivation is generally high among health workers in Ethiopia, but that the determinants of motivation are difficult to elicit . The conHowever, this study has important limitations. The quantitative motivation tool was adapted from studies conducted in other countries, and although these were sub-Saharan African settings, Ethiopia has a distinct cultural, political and health system which may have affected the sensitivity and internal or external validity of the quantitative tool. In addition, the qualitative tool was adapted from a community health worker study in Uganda, and although adaptations were made to make it relevant across cadres, some important areas may have been omitted. Motivation scores were generally high at baseline, which potentially led to ceiling effects whereby we are not able to detect small changes to already-high reported motivation. Although none were reported when study staff asked woreda leadership, other programmes in QI or comparison areas may have sought to improve motivation or knowledge. Qualitative interview guides were based on the analysis of baseline quantitative data, which may have led to the omission of important topics from interviews. In addition, qualitative data were collected at one time point in the last month of the QI programme and this may have been after demotivating pressures had reduced. There may not have been sufficient power at the cadre level to detect changes in motivation, particularly in the presence of heterogeneity in QI areas arising from some participants not being involved in the QI programme or being part of QI teams Comparison woreda were selected based on maternal healthcare utilization data because these were widely available from DHS surveys, however, may not have produced a reliable comparison group for health worker motivation. Although a criticism of all health worker motivation studies, quantitative data were self-reported and may be subject to acceptability biases. QI data have been found previously to be influenced by whether questions were framed positively or negatively , yet altWe used a mixed-methods approach to investigate whether health worker knowledge and motivation changed as a result of the ‘Ethiopia Health Care Quality Initiative’. We found some evidence that clinical knowledge improved more among patient-facing staff in QI areas than comparison areas, but little evidence that the programme impacted motivation, with some divergent findings between qualitative and quantitative data. Although motivation and knowledge are not necessarily primary goals of QI programmes, they can be important antecedents to good quality care, and it is critical that QI programmes measure possible intended and unintended consequences among health workers.czab094_SuppClick here for additional data file.