The status of thematic roles such as Agent and Patient in cognitive science is highly controversial: To some they are universal components of core knowledge, to others they are scholarly fictions without psychological reality. We address this debate by posing two critical questions: to what extent do humans represent events in terms of abstract role categories, and to what extent are these categories shaped by universal cognitive biases? We review a range of literature that contributes answers to these questions: psycholinguistic and event cognition experiments with adults, children, and infants; typological studies grounded in cross-linguistic data; and studies of emerging sign languages. We pose these questions for a variety of roles and find that the answers depend on the role. For Agents and Patients, there is strong evidence for abstract role categories and a universal bias to distinguish the two roles. For Goals and Recipients, we find clear evidence for abstraction but mixed evidence as to whether there is a bias to encode Goals and Recipients as part of one or two distinct categories. Finally, we discuss the Instrumental role and do not find clear evidence for either abstraction or universal biases to structure instrumental categories. Thematic roles are routinely invoked in studies of the syntax~semantics interface, language production and comprehension, and child language learning. They are argued to be part of innate, core knowledge .Despite the difficulty of defining thematic roles, 50 years after the publication of Fillmore’s seminal 1968 paper “The case for case,” thematic roles are still common in scientific parlance and theory because of the possibility that they are fundamental to how human minds develop, how we represent the world, and how we express these representations in language. And although thematic roles are definitionally opaque, this makes them no different from other human concepts  in the truth-conditions of a sentence  = Jim, where e is a linguistic representation of an event. Across languages, diverse linguistic forms contribute agency to the meaning of a sentence . Nonetheless, if the nativist view of agency is correct, then the semantic content of Ag(e) is the same in every language. For children, if the nativist view of agency is correct, language learning would involve discovering which linguistic form(s) encode the role Agent, rather than constructing this category based on conceptual, linguistic, and cultural experience; and for adults perceiving events in the world, recognition and conceptualization of agents would proceed in the same way in every cultural context.Such a state of affairs would have wide-ranging implications for theories of linguistic representation, language development, and event representation. Many generative theories of syntax and semantics encode agency via the primitive predicate Kratzer, . The truA variety of evidence suggests that for the Agent role, the nativist view may in fact be correct. The strength of this evidence does not, however, imply that all thematic roles are innate universals. For the Recipient, Goal, and Instrument roles, evidence for the nativist view is more tenuous: the current literature on these roles is more consistent with theories in which conceptual and linguistic categories are constructed, and influence each other over the course of development. On closer examination, even for the Agent and Patient roles, the nativist view is not fully supported because we lack the detailed behavioral evidence required to fully understand the structure of these categories. Previous studies have focused more on elucidating the relationship between roles, rather than uncovering the structure of individual roles. Without a detailed understanding of how role categories are structured, we cannot address whether roles are truly cross-linguistically universal.a priori that event participants are represented in terms of categories. The existence of lexically-specific roles  is fairly uncontroversial. However, one can also ask whether there are abstract categories that range over lexically-specific roles, for example, a category that includes not only the thing that gets eaten, but also the thing that gets cleaned, broken, and so forth. Such abstractions would support novel verb learning, efficient sentence processing and rapid event apprehension, among other cognitive abilities.We support this argument in two steps. First, we ask whether thematic roles correspond to psychologically real categories. The human ability to create categories is ubiquitous, enabling us to interpret and learn from new experiences. As such, when humans encode events and the relationships between event participants, we expect bird. Thematic roles, however, often do not map cleanly onto words. For example, although agent, patient, and instrument are English words, there is only a loose connection between the commonly known meanings of these words and the event categories that researchers have labeled Agent, Patient, and Instrument. Instead, role categories have been thought to reveal themselves through a range of linguistic structures, both lexical  and syntactic . In addition, lexical markers of thematic roles are often closed-class and have wide semantic extension, seemingly encompassing multiple meanings and multiple thematic roles. The English preposition with, for example, marks instruments, as in (1a), but it also ranges over other roles, as in I want the room withtwo beds, Marnie delivered the talk withconfidence, and I walked to the store withmy brother.In the psychological study of concepts, categories are often probed through studying the meanings of words – researchers have asked, for example, about the structure of the category the journalist checked the spelling is processed more quickly than the mechanic checked the spelling , rather than incorporating abstract roles. In addition, Rissman and Rawlins  rather than negative evidence (findings contrary to the nativist view). We conclude this paper by discussing what some of these critical studies would be.Across the cognitive sciences, thematic roles are most often invoked within the language sciences, and within linguistics, thematic roles are typically understood to be linguistic representations whose theoretical function is to explain and predict syntactic behavior, for example, through syntactically-oriented theta-roles Baker, , event rMany theorists have argued that our action representations center around two maximally distinct participants  to communicate  emerged about 50 years ago: even the earliest cohort of NSL uses word order to distinguish animate agents from inanimate patients  and Goals . Studies of adult sentence processing have shown that adults activate information about recipients and goals upon hearing verbs that encode these participants   when primed by a sentence with the same thematic order  than a prime sentence where the goal was in the first position .Across proposed lists of thematic roles, frequently listed candidates are Recipients  to an animate participant, whereas Goals are typically characterized in terms of the endpoint of a spatial path. Are Goals and Recipients distinct categories that happen to overlap, or are they subtypes within a single overarching category? In many dominant theories of the language~cognition interface, spatial representations are considered fundamental, with non-spatial meanings extended metaphorically from spatial meanings . Minimally, these results indicate that in English, priming draws on distinct Goal and Recipient categories; but the results are also consistent with the stronger hypothesis that for adult English speakers, Goal and Recipient are representationally distinct. Along these lines, de Cuypere . Allative markers encode many senses beyond that of a spatial goal: in Japanese, for example, the allative marker ni is extended to 20 different senses (see Kabata Jane gave a bagel to her dog), concepts , purposes , and locations . Similarly, dative markers regularly extend beyond recipients to goals, beneficiaries , predicative possessors ’), experiencers , malefactive sources , and patients  have wide semantic extension cross-linguistically  to construct semantic maps, in which senses that tend to be marked in the same way across languages are plotted close to each other in a visualization of the overall data . As described above, Lakusta, Spinelli et al.  found thReba threw the ball toRonnie. If so, this super-category would have a vast extension, so as to capture the range of meanings commonly encoded by allative and dative markers cross-linguistically: from purposes and locations to experiencers, possessors, and patients. One problem with such an account is that it may be too inclusive to have any explanatory power.Considering the close relationship we observe between goals and recipients across a range of paradigms, a first possibility is that humans are biased to represent goals and recipients in terms of a single thematic role centered around an animate goal, as in Marnie taught JohnSpanish. In her discussion of dative extensions cross-linguistically, Næss  and the transfer domain   adults represent events in terms of Goal and Recipient categories that abstract beyond the verb-specific and event-specific level. These categories appear to be an important part of our conceptual and semantic repertoire: infants less than a year of age represent these (or similar) notions, and deaf children lacking exposure to a language model produce signs for these entities. In addition, humans robustly distinguish sources from goals, as shown through cross-linguistic research, adult psycholinguistic experiments, and studies with infants. Nonetheless, it is unclear how our concepts about recipients and goals are structured: are these subtypes of the same category, or are they distinct categories drawing on two distinct cognitive systems? Although the nativist view of thematic roles is not decisively falsified by the available evidence on recipients and goals, this evidence suggests that there is greater variability in how these event participants are categorized than in how agents are categorized.used by an agent to achieve something. Like other thematic roles, Instrument has been described as having prototype structure: Luraghi  are assumed to be less prototypical members of the category.We now turn to the final type of thematic role reviewed here – Instrument, introduced in (1) – and explore the evidence for an Instrument category. Instrument has a long-standing place in discussions of thematic roles, dating back at least to the Sanskrit grammarian Pāṇini. Fillmore  proposed Luraghi : 388 chawhich sword did the rebels behead the traitor king with? When the verb encoded the presence of an instrument , participants were faster at recognizing the wh-filler  was an instrument rather than a patient. This result indicates verb-specific encoding of instruments rather than an abstract Instrument category. The two words in English that most commonly introduce instruments are with and use. These words do not obviously encode Instrumental categories, however  was an Actor or an Instrument.The existence of an Instrument category is under-supported empirically. Nevertheless, there could be a universal bias to construct a participant category around the concept of a tool. As discussed above, instruments are often analyzed as extensions of agents, and this possibility is supported cross-linguistically: agent/instrument colexification is common outside of the Indo-European language family Stolz, . In the Coco went to the storewith Joelle)  and instruments (such as for cover and hit). In other words, the object being thrown  is often marked the same way as the object being used to cover . These ‘throwee’ and ‘cover’ microroles demonstrate a linkage between themes and instruments: both move through space from one location to another, and both can be used intentionally to affect another participant. Locative/instrumental colexification is also common: for example, in Troy cut the breadby hand and Troy went to Amsterdamby train, the train is both a means of travel and a container . Similarly, when people are asked to list members of a category, prototypical members are mentioned earlier, and more often (across people). Also, hedging language is more acceptable for non-prototypical members of a category than prototypical members .The behavioral phenomena supporting prototype representations are well-documented . As described in the introduction, role categories often do not map cleanly onto words. For example, neither English with nor use on their own point to the category Instrument, as discussed above. Only the intersection of these terms corresponds to intuitions about what a prototypical Instrument might be. Given this asymmetry between event participant categories and lexical meanings, the same methods that support prototype theories cannot be directly extended to the study of thematic roles. As a consequence, claims about thematic role prototypes are often put forth without extensive behavioral or cross-linguistic evidence, as pointed out by Rice . Nonetheless, many types of participants appear as Subject that are not particularly agentive, such as in Tasha believed the news. Dowty’s proposal is that for each English verb, the argument with the most Proto-Agent properties  is realized as Subject, and the argument with the most Proto-Patient properties  is realized as Object. An argument does not have to be a good example of an agent to appear in Subject position; it just has to have some Proto-Agent properties. Grimm : these have been argued to be related by meaning chains, where some senses involve a vertical arrangement and others involve physical covering, etc.  = Chloe. Nonetheless, use and with encode different instrumental features: use requires an intentional agent. This variability does not, however, falsify the hypothesis that the category Agent is universal. If we allow that Ag(e) has prototype structure, where an unintentional agent is still an Agent, then both use and with are compatible with this category. For Agent to truly be universal, however, it must first be the case that in English, the categories demonstrated by non-linguistic event cognition experiments are the same as the categories needed to account for natural language semantics . It must then be the case that this parallelism holds in all languages. If we find any language where this parallelism does not hold, this suggests domain-specific thematic role representations that may be structured in different ways. A category such as Ag(e), for example, may need to be relativized to a particular language or linguistic construction.Another crucial question for future research concerns the relationship between thematic roles as linguistic objects and thematic roles as conceptual categories. As mentioned previously, the syntax~semantics interface is variable across languages. This variability is also manifest within a single language. For example, in Rissman and Rawlins , both usdog, and categorization of furry, four-legged domestic animals at a conceptual level. As thematic roles are largely not labeled through open class lexical items, such conflation is not possible in the domain of event participant categories.One of the fundamental questions of cognitive science concerns the ways in which people categorize the world around them, and the extent to which humans form similar or different categories across languages and cultures. From a domain-general perspective, the study of thematic roles is the study of event participant categories, and studying these categories provides an opportunity to gain insight into the interface between conceptual and semantic knowledge. Many psychologists working on concept representation do not distinguish between the semantic category picked out by the particular English word At the outset of this review, we described two poles in theorizing about thematic roles – thematic roles are part of core knowledge or they are scholarly fictions. The evidence we have reviewed from adult psycholinguistics, development, typology, and emerging sign languages makes it untenable to maintain the view that thematic roles are fiction. At the same time, it is also premature to infer the contrary – there is simply insufficient evidence to conclude that thematic roles as a class constitute core knowledge. What the data do show is that for the best-studied roles, there is evidence for abstraction, scaffolded by universal cognitive biases. The exact nature of these abstractions – i.e., whether they have the same content and structure across languages – is not clear. In sum, despite the substantive literature reviewed herein, many foundational questions about thematic roles remain unanswered: what the structure of event participant categories is in individual languages, and whether, for lesser-studied roles such as Instrument, there are universal biases. Nonetheless, through an integration of diverse methods and sources of evidence, answers to these foundational questions are well within reach.


This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face‐to‐face meetings, telephone conferences, and e‐mail communications.A two‐step approach for the malnutrition diagnosis was selected, i.e., first screening to identify “at risk” status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria  and two etiologic criteria . To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology‐related diagnosis categories.A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re‐considered every 3–5 years. Historically, starvation and famine were prevalent causes of malnutrition and they remain so today. However, with improvements in agriculture, education, public health, healthcare, and living standards, nutrition disorders and related conditions now encompass the full scope of undernutrition, micronutrient abnormalities, obesity, cachexia, sarcopenia, and frailty.Malnutrition, e.g. undernutrition, may be caused by compromised intake or assimilation of nutrients but there is growing appreciation that malnutrition may also be caused by disease‐associated inflammatory or other mechanisms. The malnutrition that is associated with disease or injury invariably consists of a combination of reduced food intake or assimilation and varying degrees of acute or chronic inflammation, leading to altered body composition and diminished biological function.http://www.who.int/classifications/icd/en/) inconsistent with approaches or nomenclature that are currently used in clinical practice and research. Thus, there is an urgent need to establish a global consensus to be used in clinical care settings for adults.Although malnutrition is a global concern associated with incremental morbidity, mortality, and cost, there has been a fundamental lack of consensus on diagnostic criteria for application in clinical settings. No single existing approach has secured broad global acceptance.In order to respond to the needs of the clinical nutrition and medical communities the Global Leadership Initiative on Malnutrition (GLIM) was convened in January 2016. GLIM has engaged several of the clinical nutrition societies with global reach to focus on standardizing the clinical practice of malnutrition diagnosis. We also sought to clarify overlaps with related disease classifications including cachexia. The purpose of this specific initiative is to reach global consensus on the identification and endorsement of criteria for the diagnosis of malnutrition in clinical settings.22.1It was recognized that there was considerable consensus among stakeholders around many malnutrition diagnosis issuesThere was strong commitment for reaching broader global consensus in defining and characterizing malnutritionwww.nutritioncare.org), ESPEN (www.espen.org), FELANPE (www.felanpeweb.org) and PENSA (www.pensa‐online.org) was constituted to form GLIM. The core GLIM leadership committee then created a larger supporting working group comprised of invited members that brought additional global diversity and expertise to the consensus effort.A core leadership committee with representatives of several of the global clinical nutrition societies; ASPEN Reduced muscle massReduced food intake or assimilationDisease burden/inflammationIn order to establish consensus and endorsement of a minimum set of diagnostic criteria by the core leadership committee and the supporting working group a formal ballot was administered whereby participants ranked proposed diagnosis criteria. The top 5 ranked criteria by an overwhelming majority of GLIM participants were as follows:3.3There was strong GLIM consensus for the inclusion of weight loss as a phenotypic criterion. Validity is well established and there is a robust literature on which threshold selection could be based (Appendix). There must be priority to obtain repeated weight measures over time to identify trajectories of decline, maintenance, and improvement. GLIM participants felt that it is especially important to recognize the pace of weight loss early in the course of disease or injury and to highlight that many patients will have lost appreciable weight prior to presenting to the healthcare.3.4There is substantial regional variation in the use of low BMI as a phenotypic criterion for malnutrition diagnosis. North American GLIM representatives indicated that low BMI is seldom used as a clinical malnutrition marker in those regions. The experience from the current American population is that people are often overweight or obese and would need to lose substantial weight before low BMI designation would occur. Since other regions of the world currently make use of BMI as a criterion for recognition of malnutrition, the GLIM consensus includes low BMI. Further research is however needed to secure consensus reference BMI data for Asian populations in clinical settings.3.5Reduced muscle mass is a phenotypic criterion with strong evidence to support its inclusion in the GLIM consensus criteria. However, there is not consensus regarding how best to measure and define reduced muscle mass, particularly in clinical settings. Therefore, GLIM recommends measurement by dual‐energy absorptiometry or other validated body composition measures such as bioelectrical impedance, ultrasound, computed tomography or magnetic resonance imaging, but these methods are still not available in most settings for nutritional assessment throughout the globe. Physical examination or anthropometric measures of calf or arm muscle circumference are therefore included as alternative measures. Recommendations are likely to evolve as portable and less costly body composition technologies are developed and become widely available.For the purpose of recommended cut‐off values for muscle mass reductions, GLIM refers to recommendations from the European Working Group on Sarcopenia in Older People (EWGSOP)Assessment of muscle function using grip strength or other validated procedures is recommended as a supportive measure in the GLIM consensus Tables  and 4. D3.6Reduced food intake is a well‐established etiologic criterion for malnutrition that has strong validity. It can have multiple causes including poor oral health, medication side effects, depression, dysphagia, gastrointestinal complaints, anorexia and inadequate nutrition support. Thresholds for relevant impairment of food intake are widely reported (Appendix) and GLIM participants sought to empirically provide a practical synthesis. Reduced assimilation of food/nutrients is associated with malabsorptive disorders like short bowel syndrome, pancreatic insufficiency and after bariatric surgery. It is also associated with disorders like esophageal strictures, gastroparesis, and intestinal pseudo‐obstruction, as well as with gastrointestinal symptoms like dysphagia, nausea, vomiting, diarrhea, constipation, and abdominal pain. These symptoms have been incorporated as supportive indicators into this GLIM consensus criterion to help to identify poor food intake or assimilation.3.7GLIM members recognized that disease burden/inflammation has become a widely accepted etiologic criterion in existing screening and assessment tools Table . Clinica3.8Weight loss, reduced BMI, and reduced muscle mass were categorized as phenotypic criteria, and reduced food intake/assimilation and disease burden/inflammation as etiologic criteria Table . For the3.9It is clinically useful to categorize the severity of malnutrition depending on the degree of aberration from established thresholds. Suggested phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are shown in Table 3.10An etiology‐based diagnosis classification is endorsed by GLIM consistent with those suggested previously by the International Consensus Guideline Committee,4This GLIM initiative targets the priority to adopt global consensus criteria so that malnutrition prevalence, interventions, and outcomes may be compared throughout the world. A common malnutrition “language” is a paramount necessity in order to support the development of global standards of care that will promote improved outcomes. The proposed approach for diagnosing malnutrition is based upon a strong consensus endorsing core phenotypic and etiologic criteria that are already in widespread use throughout the world. The intent is to promote global use of these criteria that may in turn be readily used with other approaches and additional criteria of regional preference. The consensus criteria are intended to be simple and readily applied by clinicians and other health practitioners using tools and methods that are readily available. Only modest training should be required. The proposed approach encompasses risk screening and diagnosis but does not entail the robust detail of comprehensive nutrition assessment. It will provide a malnutrition diagnosis that may then be complemented by more comprehensive assessments to provide the basis for individualized care and treatment plans. Consultation of skilled nutrition practitioners like dietitians is recommended for comprehensive assessment based upon regional preferences and availability. Repeated criterion measures over time are recommended so that trajectories of decline, maintenance, and improvement may be identified.The recommended GLIM approach encompasses both phenotypic and etiologic criteria for the diagnosis of malnutrition but uses only phenotypic criteria cut‐points to provide for severity grading. While etiology has not generally been included in criteria supporting the diagnosis of medical conditions in the ICD construct, the inclusion of etiology has been widely adopted in the clinical nutrition community because it serves to guide appropriate interventions and expected outcomes.Impairment of muscle strength and function are core phenomena in conditions like sarcopenia,Similarly, patients with cachexia will meet GLIM consensus criteria for malnutrition related to chronic disease with inflammation. Since there is concern that inclusion of cachexia with other disease‐related malnutrition conditions may diminish appreciation for some distinctive features of cachexia, there has been understandable hesitation by some to equate cachexia with this GLIM diagnosis category. The GLIM consensus criteria for malnutrition are therefore intended to be used in parallel with established concepts and nomenclature, including for example, those of cachexia, sarcopenia and frailty.5A strong GLIM consensus endorsed the selected core phenotypic and etiologic criteria that are already in widespread use throughout the world. Many studies provide clear evidence that the agreed upon criteria for diagnosis of malnutrition are highly relevant and each of them alone is able to predict adverse clinical outcomes. Since these criteria may be readily used with other approaches and additional criteria of regional preference, their global adoption is more likely. As the initiative moves forward the creation of databases that use the selected criteria will facilitate the comparison of malnutrition prevalence, interventions, and outcomes throughout the world. Such observations can be used to support the development of global standards of care that will promote improved outcomes.After the launch of the GLIM consensus it is important that the nutrition community use the criteria both in prospective and retrospective cohort studies as well as clinical trials in order to validate its relevance for clinical practice. Next steps are to secure endorsements from leading nutrition professional societies and to promote dissemination, validation testing, and feedback. The GLIM consensus should be re‐evaluated based upon review of new studies and advances in screening and assessment every 3–5 years. We will also seek to share the GLIM consensus recommendations with the World Health Organization in the context of the International Classification of Diseases revision process (ICD‐11). This is a high priority since this classification scheme guides clinical diagnosis and reimbursement across much of the world. The proposed GLIM consensus criteria target adults in clinical settings but it will also be a priority to work with the World Health Organization and the United Nations to explore the potential for use in other global settings like famine.Gordon L Jensen: Conflicts of interest/ financial disclosures ‐none.Tommy Cederholm: Conflicts of interest/ financial disclosures ‐none.M. Isabel T.D. Correia: Conflicts of interest/ financial disclosures‐ none.M. Christina Gonzalez: Conflicts of interest/ financial disclosures‐ none.Ryoji Fukushima: Research grant from Taiho Pharmaceutical Factory, Inc.; Honoraria from Otsuka Pharmaceutical Factory, Inc., Terumo Corporation, and Abbotte Japan Co., Ltd.Takashi Higashiguchi: Conflicts of interest/ financial disclosures‐ none.Gertrudis Adrianza de Baptista: Conflicts of interest/ financial disclosures ‐ none.Rocco Barazzoni: Conflicts of interest/ financial disclosures ‐none.Renée Blaauw: Conflicts of interest/ financial disclosures ‐none.Andrew JS Coats: Conflicts of interest/ financial disclosures ‐none.Adriana Crivelli: Conflicts of interest/ financial disclosures ‐none.David C Evans: Paid for consulting by Coram / CVS Infusion  and Lyric; Abbott Nutrition and Lyric both paid Evan's institution for research grants; Paid by Abbott Nutrition for speaking honoraria.Leah Gramlich: Conflicts of interest/ financial disclosures ‐none.Vanessa Fuchs‐Tarlovsky: Hospital General de México, Mexico City (honoraria and travel expenses),Tata Memorial Hospital India (travel expenses), UPAEP (Puebla Autonomus University – travel expenses); professional societies including FELANPE, PENSA, the Academy of Nutrition and Dietetics, and the Colegio Mexicano de Nutriologos (travel expenses); and an industry sponsor Fresenius Kabi (travel expenses).Heather Keller: Paid by Nestle Health Sciences for Manuscript focused on dysphagia; Paid for development of educational presentations including service on speakers’ bureaus by Abbott Nutrition and Nestle Health Sciences; Travel/accommodations expenses covered or reimbursed by Abbott Nutrition.Luisito Llido: Conflicts of interest/ financial disclosures ‐ none.Ainsley Malone: Conflicts of interest/ financial disclosures ‐none.Kris M Mogensen: Board membership with ThriveRx; Consultancy from Pfizer, Employment with Brigham and Women's Hospital, Honoraria from Abbott Nutrition Health Institute and Baxter, Royalties from Wolf Rinke Associates.John E Morley: Conflicts of interest/ financial disclosures ‐none.Maurizio Muscaritoli: Conflicts of interest/ financial disclosures‐ none.Ibolya Nyulasi: Conflicts of interest/ financial disclosures ‐none.Matthias Pirlich: Consultancy from seca GmbH, Hamburg, Germany.Veeradej Pisprasert: Conflicts of interest/ financial disclosures‐ none.Marian de van der Schueren: Conflicts of interest/ financial disclosures ‐ none.Soranit Siltharm: Conflicts of interest/ financial disclosures ‐none.Pierre Singer: Grants from Baxter, B Braun, Abbott, and Fresenius Kabi; Honoraria from Baxter, B Braun, Fresenius Kabi, GE, and Cosmed.Kelly A. Tappenden: Conflicts of interest/ financial disclosures ‐none.Nicolas Velasco: Conflicts of interest/ financial disclosures ‐none.Preyanuj Yamwong: Conflicts of interest/ financial disclosures‐ none.Jianchun Yu: Conflicts of interest/ financial disclosures e none.Dan L. Waitzberg: Paid by Fresenius‐Kabi as a member of Member of the Felanpe Award; Paid by Danone for Overview of enteral nutrition in healing manuscript preparation; Travel expenses paid for by Fresenius‐Kabi and Nestle for Aspen and Espen conferences in 2018.Andre Van Gossum: Conflicts of interest/ financial disclosures ‐none.Charlene Compher: Conflicts of interest/ financial disclosures ‐none.Representing American Society for Parenteral and Enteral Nutrition (ASPEN): Gordon L. Jensen, Charlene CompherRepresenting European Society for Clinical Nutrition and Metabolism (ESPEN): Tommy Cederholm, Andre Van GossumRepresenting Federacion Latinoamericana de Terapia Nutricional, Nutricion Clinica Y Metabolismmo (FELANPE): Maria Isabel T.D. Correia, M. Cristina GonzalezRepresenting Parenteral and Enteral Nutrition Society of Asia (PENSA): Ryoji Fukushima, Takashi Higashiguchi.Baptista G, Barazzoni R, Blaauw R, Coats A, Crivelli A, Evans DC, Gramlich L, Fuchs V, Keller H, Llido L, Malone A, Mogensen KM, Morley JE, Muscaritoli M, Nyulasi I, Pirlich M, Pisprasert V, de van der Schueren MAE, Siltharm S, Singer P, Tappenden K, Velasco N, Waitzberg D, Yamwong P, Yu J.


Quantitative evidence about the burden of alcohol use disorders (AUDs) needs to be complemented with a nuanced qualitative understanding of explanatory models to help supplement public health strategies that are too often steeped uncritically in biomedical models. The aim of this study was to identify the role of various factors in the onset and persistence of AUD and recovery from AUD. This was a qualitative study nested in a population cohort from Goa, India. In-depth interviews of men with incident, recovered, and persistent AUD covered topics such as changes in drinking habits over time, perceptions and experiences about starting/stopping drinking, and so on. Data were analyzed using thematic analysis. Reasons to begin drinking included social drinking, functional use of alcohol, stress, and boredom. Progression to problematic drinking patterns was characterized by drinking alone, alternating between abstinent and heavy drinking periods, and drinking based on the availability of finances. Some enablers to reduce/stop drinking included consequences of drinking lifestyle and personal resolve; some barriers included availability of alcohol at social events and stress. Some reasons for persisting heavy use of alcohol included lack of family support, physical withdrawal symptoms, peer pressure, stress, and easy availability. This article offers a strong conceptualization and nuanced understanding of AUD across a spectrum of developmental courses. This adds to the limited literature on explanatory models of AUD in India and identifies potential targets for prevention and treatment strategies for AUD in low- and middle-income country settings. Alcohol use disorders (AUDs) are a growing cause for concern worldwide, accounting for 5% of the total global burden of disease  onset and persistence of AUD and (b) recovery from AUD.This was a qualitative study nested in a population cohort.The study was conducted in the state of Goa, one of India’s smallest states, with a population of just over 1.4 million people  was conducted in urban and rural areas of Northern Goa , a technique that allows for detailed in-depth probing of subject matter and provides information on context  within data . Written informed consent was taken individually from all participants, and permission to record the interview sessions on the digital audio recorder was sought from each participant prior to the interview.We interviewed 20 men with persistent AUD, 19 who had recovered from AUD, and 23 who had incident AUD. Social drinking or drinking for pleasure. The majority of users began drinking within social circles, with friends or coworkers, and did not view the drinking as problematic initially. Over time, the drinking became more frequent: “It was in 2007 that I started drinking. It happened for fun in the company of friends when I was working, and gradually increased” . Although it was generally believed that it was their personal choice to drink, peer pressure was sometimes reported. “My friends forced me to drink and I used to drink ½ peg just to satisfy my friends” .Functional use. Users cited alcohol as a means to overcome pain or fatigue or to help cope with a specific task . One cook described how work-related fatigue contributed to his drinking:I come home from work and then I work in our fast food restaurant … where I also help out as a cook … and then due to work load and fatigue I have a beer … this happens almost every day. Stress. Psychological stresses, often described as “tensions,” were instigators of problematic drinking patterns. Participants cited financial, familial, and work problems as sources of stress for which they self-medicated with alcohol.It was due to the tensions I was facing then, I started drinking and now it has continued. I was in debt due to failure in my business. My financial state was bad. It was difficult for me to face the lenders and with all this unbearable tensions I started drinking Boredom. In rural communities, being idle or staying at home all day were cited as justifications for drinking. The drinking was attributed to boredom, excessive free time, and the combined effect of idleness and unemployment. “I drink when I am not doing anything in particular. I don’t drink otherwise” .The progression of casual drinking to more problematic drinking patterns was characterized by drinking alone, alternating between abstinent and heavy drinking periods, and drinking based on the availability of finances.Lone drinking. While drinking started initially with friends, progression to lone drinking was a common occurrence in later stages of their drinking: “Initially I went (to drink) with my friends. As I got used to it I went alone” .On and off drinking pattern. A common drinking pattern was stretches of abstinence between long periods of heavy drinking. Such periods of abstinence were cited as proof of nonaddiction, and problematic drinking was equated to daily heavy drinking.I don’t drink every day. If I stop drinking I don’t drink for years. Like last time I had not drank for almost two years. So I can stay without drinking for one or two months. But if I drink, I drink continuously for four to eight days. Drinking based on availability of finances. The easy availability of funds was an enabler of more problematic drinking, while financial limitations in heavy drinkers tended to promote consumption of cheaper spirits. Rarely, participants reported drinking less rather than compromising on the quality of drinks when they were short on money. “We drink branded drinks like Scotch and whisky. If we have less money then we will reduce the quantity [of alcohol consumed], not the quality” .Consequences of drinking lifestyle. Those with AUD chose to stop drinking after they gained an understanding of the consequences of drinking on themselves, their peers, or their family.I used to get the urge to drink, but I controlled this urge as I was concerned about my health. I was also concerned about my family and the problems they would have to face if anything happened to me. These concerns about my health and family made me quit drinking and it is the same till date. In a few cases, individuals observed the negative behavior of their peers when drinking and were motivated to quit to avoid the same fate. “After seeing people suffer from drinking I decided to quit. A young man from my village and my brother-in-law expired due to excessive drinking” .A prominent theme that emerged was the decision to stop or reduce drinking following physical illness. People with AUD would experience either an alcohol-related or unrelated health problem and would stop drinking to avoid future health consequences. For example, after suffering an ophthalmological problem, one participant quit at the advice of his physician: “… since my doctor had informed me that if I drink, will have problem [eye would be affected] and because of that fear I stopped drinking” .Personal resolve. The majority of participants attributed their successful recovery to their personal strength and willpower to quit. Regardless of whether they received help from a family member or a doctor, many believed that the only means to a successful recovery was self-control.After quitting alcohol I was free from all the problems which I was suffering such as giddiness, trembling, urge to drink more. Many people asked me about the deity I prayed to for quitting. I don’t know much about God, but it was my own will which helped me quit my drinking habit. Support from family and friends. Family support, either indirectly or directly, was consistently cited as an enabler of recovery. In many cases, the wife of the drinker would disapprove of her spouse’s drinking and encourage him to quit. In other cases, a family member would take direct action, acquiring medicine for the drinker or taking him to see a doctor.Availability of alcohol at social events. Participants who drank following a period of recovery frequently cited they drank because of a social event. Others were encouraged to drink by their peers at social events, although all did not always succumb to the pressure by their peers:If I go out at night and meet someone [friends], they coax me to drink. That’s why I avoid going out at night. Last Narkasur [local festival], my friends were asking me to join them for drinks. I did not join them. I told them I have to go home and moved away from them. Functional use of alcohol. In many cases, people returned to drinking as a relief from tiring work and to induce sleep. Drinking following work was a way to cope with either physical pain or mental exhaustion.Stress. Family stress was considered a major barrier to recovery. Either family discord or stress to provide for their spouse caused participants to experience “tension,” which ultimately led to drinking as a coping mechanism.Self-help. Many recovered participants attributed their success to self-help strategies, regardless of whether they sought external help or not. Three main techniques emerged from the interviews: replacement of alcohol with nonalcoholic alternatives , resisting thoughts of alcohol, and gradually reducing their intake.Spiritual or religious help. An important source of support was informal help, most frequently from spiritual or religious sources. For example, one participant refrained from drinking alcohol one day a week in order to worship his god. More frequently, participants would stop drinking for an entire month during the Hindu holy month of Shravan.Formal help. Formal help from a physician was frequently sought but not necessarily accredited with successful recovery. In many cases, a physical health problem instigated a visit to the doctor, most frequently leading to the prescription of medicines such as tablets, intravenous fluids, or simply advice to quit drinking. In such consultations, it was very rare for anything but the physical health issue to be discussed.Lack of family support. In some cases, family members encouraged drinking behavior by simultaneously partaking, as in the case with one participant who drank with his brother:Yes … I had stopped drinking … but when I used to bring liquor for him [brother] … I started drinking heavily again. In many other cases, the families identified a problem but provided no support to the drinker to address it.Physical withdrawal symptoms. In many cases, the physical withdrawal symptoms deterred participants from beginning or sustaining their recovery. In many cases, the participants were motivated to quit but could not overcome the negative consequences of withdrawal:No, it [alcohol] does no good. I feel I should quit. But I cannot do so. Whenever I try to do it I cannot sleep and get hallucinations. Peer pressure. Peer pressure was consistently mentioned as a barrier to recovery, and many participants mentioned the difficulty associated with hanging out with drinking friends.Then all the men from my work place would go, there would be alcohol. I would say I have quit, they would force me to take a little beer. Once I drank then it would not stop. Stress. Similar to those who developed AUD, those with persistent AUD also cited psychological stress as a barrier to recovery. These included psychological stress from day-to-day activities and other stressors that were more acute and actionable:Not major tensions as such but the normal ups and downs of life sometimes make you drink. I have borrowed money which I have to repay, running of my business, also the minor issues in the family such as tensions between my mother and wife. All this gives you sleepless nights so to do away with it you tend to drink at times. Perception that drinking has not affected their life adversely/lack of understanding that health problems are affected by alcohol. In many cases, there was a lack of awareness of the drinking problem and the belief that sobriety didn’t have substantial benefits.Beliefs about medications. These included beliefs such as medications are the only solution, medications don’t work, or one cannot quit drinking without medications. In contrast to the recovered AUD participants who believed self-control was the solution to recovery, many persistent AUD participants believed that medicines were required to quit. They sought help from doctors and placed a heavy reliance on the ability of medicines to cure them.But you require something [medications] for it … means you should feel like not drinking [after taking the medication] … feel drained or feel bad about it. If there is some remedy or some medicine for it then it can be tried. Idleness and boredom. In a few cases, participants attributed their drinking to their boredom, similar to those who developed AUD. Many were at home due to an injury or unemployment and drank as a means to pass the time.Pain management. Similar to those who developed AUD, a main barrier to recovery was the functional use of alcohol. For example, one participant who worked as a laborer complained of body aches after work:I am a welder, so after the days hard work the body aches and it is difficult to get sleep. So I drink a little to do away with the pain. Acceptance of drinking as an inevitable habit. In many cases, participants recognized that they had drinking problems, but at the same time conceded that the habit was inevitable and they weren’t sure how to overcome it.There is nothing good that I feel about alcohol … . But once you get addicted you can’t quit … and then there is this tension about the health, the frustration about bad health. Easy availability. The availability, both financially and physically, was cited as a reason for continued drinking. Some had easy access because of work or neighborhood. One participant worked in a traditional alcohol manufacturing unit and therefore could drink for free, encouraging the behavior and reinforcing it later.Yes … I needed more and more to get intoxicated … and I had money … my salary was 700 rupees … apart from that I got a daily allowance, liquor was cheap then … today the allowance is 100 rupees, but living costs have gone up … all the bar and tavern owners know me well … so they do allow a little credit. Our study sought to examine the factors that contribute to the development and persistence of AUD and recovery from AUD. We found that the development of AUD was initially driven by social or functional reasons and progression was marked by drinking alone, drinking cheaper spirits to save money, and often drinking in binges. Recovery was impeded by lack of awareness about consequences of alcohol, unsupportive family environments, and the perceived need to drink alcohol to cope with stress. Conversely, those who recovered cited an awareness of the physical consequences and, less commonly, social consequences of drinking. Many cited poor physical health as an instigator to sobriety, and interestingly, despite consulting a doctor for their physical ailment, few attributed their reduction of drinking to any medical treatment. Instead, they attributed their success to personal resolve and self-control. Thus, strong self-will was the most poignant factor that was perceived to contribute to recovery. Notably, despite their success, participants still cited many barriers to recovery, such as presence of alcohol at social events and stress.Many of our findings are consistent with global evidence. Existing evidence has attributed peer influences (Kuntsche et al., Our findings have several implications. Notably, functional uses of alcohol such as inducing sleep or dealing with stress were cited by participants across all three categories that we examined. Whether as an instigator to begin drinking or a barrier to recovery, alcohol was frequently used as a coping mechanism. Thus, consistent with western societies, our results suggest that investment in interventions that emphasize healthier coping mechanisms would be useful for the prevention and treatment of AUD (Bowen et al., In contrast to many western societies (Wallhed Finn, Bakshi, & Andréasson, There were conflicting perspectives about the role of the doctor in treating AUD. In many with persistent AUD, the prevailing perspective was that the doctor can provide a quick recovery through medications. It appeared that by labeling AUD as an illness for which medical treatment is needed, many believed it would have a recovery process similar to other physical illnesses, with incremental progress and solutions external to the body, such as pills. Conversely, there were many recovered AUD participants who attributed their success to personal resolve, and many advised against a doctor. Thus, two perspectives emerged—that of the doctor as the only solution to an AUD and that of the doctor having no role. However, even in the former perspective, there was no psychosocial role for the doctor—an important component of AUD treatment (Huebner & Kantor, One of the limitations of our study is that the sample was entirely male. Although we interviewed only males to reflect the predominantly male sociodemographic of drinking and AUD in India, this limits the understanding of development and progression of AUD through a gendered lens. A second limitation is related to the method used to categorize the participants into the three groups. Participants were classified as persistent, recovered, or incident AUD according to the presence or absence of AUD at two timepoints, but this method is vulnerable to misclassification if the participant had relapsed and recovered frequently in between the two assessment points. This was evident in the interviews of some participants in both the recovered and persistent AUD group who described binge-drinking behavior. Nevertheless, the study’s limitations are offset by numerous strengths. Primarily, the detailed interviews of many participants allowed for a nuanced understanding of the natural history of AUD. Finally, this is one of the first community studies from India to assess long-term follow-up with detailed interviews examining the nature of development of and recovery from AUD.In conclusion, this article offers a strong conceptualization and nuanced understanding of AUD across a spectrum of developmental courses. In doing so, it allows for identification of intervention targets for prevention and treatment of AUD in LMIC settings. On a broader scale, our findings add to the limited literature examining contextually specific conceptualizations of AUD.


In this article, we present a dataset containing word embeddings and document topic distribution vectors generated from MOOCs video lecture transcripts. Transcripts of 12,032 video lectures from 200 courses were collected from Coursera learning platform. This large corpus of transcripts was used as input to two well-known NLP techniques, namely Word2Vec and Latent Dirichlet Allocation (LDA) to generate word embeddings and topic vectors, respectively. We used Word2Vec and LDA implementation in the Gensim package in Python. The data presented in this article are related to the research article entitled “Integrating word embeddings and document topics with deep learning in a video classification framework” [ Video transcripts length variation illustrated in box plot and the distribution of tokens among the entire video transcripts corpus represented by a density function are shown in In A visual representation of word embeddings generated from the MOOC video lectures corpora using principal component analysis (PCA) projected in a geometric space is illustrated in 2A new real-world dataset from the education domain is presented in this article. The dataset contains word embeddings and document topic distribution vectors generated by a corpus of 12,032 video lecture transcripts. The steps involved in collecting and creating the WET dataset are illustrated in As a first step, we downloaded video lecture transcripts from Coursera learning platform and annotated them. For annotation, we used a two-level hierarchical organizational structure of Coursera where each downloaded video transcript is associated with one fine-grained category and one general-level category of the structure. 8 general-level and 40 fine-grained categories constitute the dataset and the distribution of lecture transcripts among these categories is given in Prior to creating corpus and dictionary for generating word embeddings and topic distribution vectors, video lecture transcripts have undergone some preprocessing tasks including converting text to lowercase, removing stop words, punctuations, and removing words that are not purely comprised of alphabetical characters and those that are only one character. In addition, WordNetLemmatizer is used to lemmatize all words in transcripts. An open source Python Library for symbolic and statistical natural language processing called Natural Language Toolkit (NLTK) is used for performing preprocessing tasks.2.1To train and generate word embeddings, we used the Word2Vec  word embWe set various parameters for Word2Vec as shown in Each of four csv files contains 68176 lines comprising of a unique word followed by either 50, 100, 200, or 300 real numbers that correspond to 50, 100, 200, 300 respective dimensions.2.2We conducted unsupervised topic modeling on the MOOC lecture transcript corpus. A latent Dirichlet allocation (LDA)  conventiEach csv file contains 12,032 lines comprising of a unique word followed by either 50, 100, 200, or 300 real numbers that correspond to 50, 100, 200, 300 respective number of topics.Concatenation of document topics obtained from LDA model with either general-level or fine-grained categories produces the final csv file as shown in The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Waldenström macroglobulinemia (WM) is a rare, indolent B-cell lymphoma. Clinically, chromosome 6q deletion (6q del) including loss of the B lymphocyte-induced maturation protein 1 gene (BLIMP-1) is reported to be associated with poor prognosis. However, it remains unclear how the underlying biological mechanism contributes to the aggressiveness of WM with 6q del. Here, we conducted oligonucleotide microarray analysis to clarify the differences in gene expression between WM with and without 6q del. Gene ontology (GO) analysis was performed to identify the main pathways underlying differences in gene expression. Eight bone marrow formalin-fixed paraffin-embedded samples of WM were processed for interphase fluorescence in situ hybridization analysis, and three were shown to have 6q del. IL21R and JAK3 expression upregulation and activation of the B-cell receptor signaling (BCR) pathway including CD79a, SYK, BLNK, PLCγ2, and CARD11 were detected in WM with 6q del compared with WM without 6q del. GO analysis revealed significant terms including “lymphocyte activation” , which included 31 probes. Moreover, IL21R expression are activated in WM with 6q del. Moreover, FOXP1 and CBLB appear to act as positive regulators of the BCR signaling pathway. These findings might be attributed to the aggressiveness of the WM with 6q del expression signature. The present study suggested that the BCR signaling pathway and Waldenström macroglobulinemia (WM) is a rare, indolent type of B-cell lymphoma with monoclonal IgM gammopathy. B-cells, lymphoplasmacytic cells, and plasma cells (PCs) form neoplasms in WM, with the bone marrow (BM) being the main site of infiltration . The disBLIMP-1) and TNFAIP3/A20, in 40%–55% of WM patients in the US and European countries [Cytogenetic analysis previously detected chromosome 6q deletion (del), including loss of the B-lymphocyte-induced maturation protein 1 gene  classification of tumours of haematopoietic and lymphoid tissues [Newly diagnosed symptomatic WM patients attending the National Hospital Organization Disaster Medical Center from January 2010 to March 2014 were enrolled in this study. Samples of cases whose comprehensive agreement had been obtained were subject for the study. The WM diagnostic criteria used in the present study were according to the revised 4β2-microglobulin level, ISSWM [Patient clinical data were obtained from their medical charts and included age, sex, performance status (PS), hemoglobin level, platelet count, serum l, ISSWM , serum Ml, ISSWM .A pathological review confirmed that all cases were IgM-WM according to the revised 4th edition of WHO classification . MALT ly A20 and BLIMP-1 are located at 6q23 and 6q21, respectively, and the 6q deletion can be easily detected by comparing the signal intensity of this region with that of the chromosome 6 centromere [Cytogenetic aberrations were obtained by FISH analysis using the A20/BLIMP-1/SHGC-79576 Three Color Probe  to detect 6q del.ntromere . Interphntromere . The norμg of cDNA was fragmented at 37°C for 30 min and then biotinylated using the Encore cDNA . Biotin-labeled cDNA was hybridized to the Human Genome U133 Plus 2.0 Array . The array was incubated for 18 h at 45°C, then automatically washed, and stained using the GeneChip Hybridization, Wash, and Stain Kit (Affymetrix). The array was scanned using a GeneChip Scanner 3000 7G.cDNA microarray analysis was performed following the manufacture's instruction. Briefly, formalin-fixed paraffin-embedded BM biopsied samples were deparaffinized and total RNA was extracted using the RNeasy FFPE kit . Isolated total RNA was converted into cDNA, followed by cDNA amplification. After this, 4 Paraffin-embedded BM specimens underwent heat-induced antigen retrieval in pH 6.0 citrate buffer. Polyclonal antibodies against IL-21R  were used. After incubation with the primary antibody, slides were incubated with the secondary antibody, One-Step Polymer-HRP , for visualization. The IL-21R staining pattern was categorized into three groups: <30%, 30%–70%, and >70% of lymphoplasmacytic cells and PCs.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70511).Descriptive statistics of each clinical data were calculated by IBM SPSS Statistics for Windows 24.0J. Oligonucleotide microarray analyses were carried out using GeneSpring GX software version 13.0 . Briefly, described as follows, the expression values were calculated from the raw data using the MBEI algorithm [Eight patients were enrolled in the study, and characteristics are shown in  BLIMP-1 and A20 was 3%. Three of the eight cases had 6q del, in which both genes were deleted, and the other five cases did not have 6q del. Median serum M-protein levels were 3.14 g/dL in patients with 6q del, compared with 2.25 g/dL in those without 6q del. ISSWM low/int/high was 0/1/2 in patients with 6q del, compared with 0/3/2 in patients without 6q del. The median small lymphocyte %, lymphoplasmacytic cell %, PC %, and total neoplastic cell % were 41.6 %, 7.1%, 2.0%, and 46.4%, respectively, in those with 6q del, versus 36.4%, 3.0%, 1.8%, and 41.4%, respectively, in those without 6q del.To detect 6q del, fluorescent in situ hybridization (FISH) analysis was performed Figures . The cut BLIMP-1 and A20 were neither upregulated nor downregulated.All the eight cases' samples were subjected for oligonucleotide microarray analysis. To clarify the differences in gene expression between WM with and without 6q del, we performed oligonucleotide microarray analyses and detected that a total of 428 probes, corresponding to 324 annotated genes, were upregulated , and a total of 112 probes, corresponding to 96 annotated genes, were downregulated  in WM with 6q del .Consecutively, gene ontology (GO) analysis was performed, and GO terms including “lymphocyte activation”  and “B-cell activation”  were statistically significant in the upregulated gene lists relative to the all genes on the microarray . A netwoTo confirm the upregulation of the IL21R protein in WM with 6q del, we performed immunostaining analysis. Figures  MYD88 L265P mutation has been recognized in about 90% of WM cases in the US and in 70%–90% of cases worldwide [WM is a rare entity of low-grade B-cell lymphoma with IgM monoclonal gammopathy according to classification by the WHO . The mosorldwide . This muorldwide . It is korldwide . Furtherorldwide . BLIMP-1 [ A20 [In contrast, 6q del, including loss of BLIMP-1 –21 and A-1 [ A20 , 23, is -1 [ A20 –8, 14. H-1 [ A20 . 6q del  IL6, and the most significantly associated pathway for genes-set was MAPK signaling in WM compared to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). San Miguel and colleagues found deregulation of genes involved in plasma cell differentiation including PAX5, which was overexpressed, while BLIMP-1 and IRF4 were underexpressed in WM in comparison with CLL and MM. In addition, they hypothesized that lack of PAX5 repression contributed to the upregulation of 3 genes of BCR signaling pathway including CD79, BLNK, and SYK in WM [ CD79A (B cell activation), IRF3, MYD88, MEK1, P38 (TLR pathway), and WNK1 (MAPK pathway) were overexpressed in WM compared to IgM-MGUS, in which pathways might be responsible for WM cell growth and survival [Several studies regarding genes expression analyses in WM were performed, and these studies contributed to elucidate the biology and activated pathway in WM –26. ChngYK in WM . Jiménez CD79a, SYK, BLNK, PLCγ2, and CARD11 are upregulated in WM with 6q del patients compared with those without 6q del. Little is known about BCR pathway upregulation in WM [ BLIMP-1 suppresses B-cell proliferation and activation, including the BCR signaling pathway, and orchestrates mature PC differentiation by suppressing the expression of genes necessary for commitment and maintenance of the B-cell identity, including PAX5 and XBP-1 [One of the unique findings of the present study was that genes involved in the BCR signaling pathway , includion in WM , althougon in WM . Howeveron in WM . Moreovend XBP-1 , 30. BLIMP-1. However, no difference in the proportion of PCs in the BM was observed between WM with and without 6q deletion. Furthermore, BLIMP-1 was not among downregulated genes in the present study, suggesting that loss of BLIMP-1 does not affect PC differentiation. Considering these results, the loss of BLIMP-1 did not appear to act as a loss of heterozygosity regarding PC differentiation.During preparation for this manuscript, Staudt and colleague reported that MYD88, TLR9, and BCR complexes (My-T-BCR Complexes) exist in activated B-cell like diffuse large B-cell lymphoma and in WM, which might play a role in tumor growth and survival  Figure . In the  IL21R and JAK3 overexpression in WM with del 6q. Investigators from the Mayo Clinic previously reported that the IL21/21R pathway contributes to IgM secretion and WM cell proliferation via the JAK/STAT signaling pathway in a WM cell line and WM patient samples [We also observed samples . Conside FOXP1 overexpression is widely accepted to be a factor of poor prognosis in activated B-cell-like subtype diffuse large B-cell lymphoma and marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue type [κB pathway as well as BCR, CD40, and TLR signaling pathways [ CBLB encodes a protein involved in the ligand-induced clustering of BCR on the cell surface and delivery of BCR-captured ligands to TLR9 [ FOXP1 and CBLB might act as positive regulators for the BCR signaling pathway in WM with 6q del. patients .sue type , 34. Itspathways . CBLB en to TLR9 . Considepatients .Our present findings might represent an aggressive expression signature of WM with 6q del., although it should be noted that the study was rather exploratory and the sample size was very small. IL21R expression are activated in WM with 6q del., and FOXP1 and CBLB appear to act as positive regulators of the BCR signaling pathway. Thus, our present findings might represent an aggressive expression signature of WM with 6q del.The present study suggested that the BCR signaling pathway and


Malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences for health outcomes and quality of life. The aim of the present paper is to describe current approaches and evidence regarding malnutrition treatment and to highlight relevant knowledge gaps that need to be addressed. Recently published guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) provide a summary of the available evidence and highlight the wide range of different measures that can be taken—from the identification and elimination of potential causes to enteral and parenteral nutrition—depending on the patient’s abilities and needs. However, more than half of the recommendations therein are based on expert consensus because of a lack of evidence, and only three are concern patient-centred outcomes. Future research should further clarify the etiology of malnutrition and identify the most relevant causes in order to prevent malnutrition. Based on limited and partly conflicting evidence and the limitations of existing studies, it remains unclear which interventions are most effective in which patient groups, and if specific situations, diseases or etiologies of malnutrition require specific approaches. Patient-relevant outcomes such as functionality and quality of life need more attention, and research methodology should be harmonised to allow for the comparability of studies. Although geriatric patients are usually at an advanced age, a geriatric patient is not defined by a specific age, but rather by a high degree of frailty and the presence of chronic disease. Functional reserves are reduced and vulnerability to stress increased as a consequence of a cumulative decline in many physiological systems during ageing. Limitations are, however, not restricted to physical functions, but may also affect mental and/or social integrity, leading to the need of comprehensive treatment to maintain or restore independence in everyday life as far as possible.Among other typical geriatric syndromes, such as dementia, delirium, falls or incontinence, which are characterised by high prevalence, multifactorial origin and poor outcomes , malnutr®— the most widespread malnutrition screening tool for older people—has summarised the following estimates according to the setting of care: community, 3%; outpatients, 6%; home-care services, 9%; nursing homes, 17.5%; hospital, 22%; long-term care, 29%; rehabilitation/sub-acute care, 29%. In addition, a high proportion of older adults are at risk of malnutrition, with estimates ranging between 27% (community/outpatients) and 50%  [Malnutrition is reported in up to 50% of older adults, although prevalence estimates vary substantially depending on the population considered, the healthcare setting, and the tool used for its assessment ,3,4. A rSince low muscle mass is now included as one important phenotypic criterion in the new global definition of malnutrition ,9, and oDue to a variety of factors, older people and specifically in-patients are at increased risk of malnutrition. A decrease in food intake is common  and ofteThe decrease in food intake is often associated with a loss of the sensory abilities of taste and smell, that results in anorexia and is termed “anorexia of ageing” ,13, but Besides these individual aspects, external factors such as the quality of meals, meal ambience, and the quality of  care may affect dietary intake and contribute to malnutrition, in particular in hospitals and care homes.Many other factors may be involved ,15,16, wIt is well established that malnutrition is associated with increased morbidity and mortality both in acute and chronic disease and has serious implications for recovery from disease, trauma and surgery . Loss ofIn summary, malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences. In the following section, we aim to describe current approaches and evidence regarding malnutrition treatment, and to highlight relevant knowledge gaps that need to be addressed.Maintenance or improvement of nutritional status, which may replenish the protein and energy storage that is necessary to accommodate the needs induced by a metabolic stress;Maintenance or improvement of function and capacity for rehabilitation; this is mostly related to the muscle compartment including muscle mass. Activities of daily living but also community living may therefore be secondary aims;Maintenance or improvement of health-related quality of life, probably more important, compared to the reduction in mortality, than in younger adults; restoring food intake may play a direct role as being an important mediator of pleasure and well-being;Reduction of morbidity, including an improved outcome of underlying chronic diseases;Reduction of mortality as a consequence of morbidity reduction but also by increasing treatment tolerability of the underlying chronic disease ;Reduction of malnutrition-associated costs .Nutritional interventions in the older adult may have several complementary aims :MaintenaThus, the aims and approaches of malnutrition treatment in older patients do not generally differ from those in younger patients, but maintenance of function and quality of life gain in importance compared to reduction of mortality.Nutritional interventions for older people cover a broad range of different measures, which all may contribute to support adequate intake and go far beyond just providing adequate amounts of energy and nutrients. As with any geriatric syndrome, the identification and management of multiple causes constitutes the basis of appropriate nutritional care. Furthermore, adequate intake may be supported by various strategies—first of all but not only by help with eating if required. Regarding direct nutritional measures, oral strategies are always the first choice. These include various modifications of usual foods as well as offering oral nutritional supplements. Moreover, enteral and parenteral nutrition are important options also for older patients, although less often indicated.Current knowledge about the effectiveness of nutritional interventions is summarised in the updated ’ESPEN guidelines on clinical nutrition and hydration in geriatrics’, which were developed in a multidisciplinary group of 13 experienced experts from 9 European countries . In contCentral recommendations of the ESPEN guideline for the management of malnutrition and corresponding evidence are summarised in RC) for residential care and iv) both the Malnutrition Screening Tool (MST) and the Mini Nutritional Assessment Short Form Version 1 (MNA-SF-V1) for the hospital setting [It is common sense that, as a first step in the management of malnutrition, those affected and also those at risk need to be identified. Thus, routine-screening for (risk of) malnutrition is recommended in all older people in institutions and in the community  independent of their diagnosis and the presence of overweight or obesity . The use setting .In people with a positive screening result, a comprehensive nutritional assessment should follow as the basis for targeted interventions . The assRegarding interventions, due to the huge heterogeneity of older people and the multitude of potential causes of malnutrition ,15, indiIt is recognised that identifying and eliminating potential causes as far as possible is fundamental, although scientific evidence for this recommendation is unfortunately lacking. In older patients, adequate medical treatment is certainly of central importance, preferably avoiding medication with potentially harmful side effects on appetite, taste and smell perception, salivation or cognition.Comprehensive approaches and treatment focused on potential causes from all areas of life require the involvement of different professional disciplines namely dietitians, nurses, nurse-aids, kitchen staff, medical doctors including dentists, and all types of therapists . This team effort is regarded an important factor for successful nutrition interventions. Positive effects on body weight, functional and clinical outcome have been shown in several trials, although results are partly inconsistent .Several recommendations in the ESPEN guideline address supportive interventions, which were highlighted more than 15 years ago in the resolution of the Council of Europe on food and nutritional care in hospitals . BeneficIn addition, the ability to access the meal (in case of mobility limitations) and the food  may be relevant . Of courThe need for education regarding nutrition among all staff groups and the need for knowledge among patients about the importance of a good nutritional status are well recognised . SeveralNutritional counselling goes beyond information and education with the aim to develop a sound understanding of nutritional topics and to support sustainable health-promoting eating habits, and is regarded as the first line of nutrition therapy. Current guidelines recommend that older people with or at risk of malnutrition and/or their caregivers should be offered individualised nutritional counselling by a qualified dietician in several sessions to develop their understanding of the importance of nutrition and support healthy eating habits . IndividCounselling by a dietician or nutritionist is recommended, but in practice this may be impractical for all and reserved for those patients at highest risk. Many older people at risk of malnutrition live at home and will have initial contact with their primary healthcare team who could review their nutritional status and deliver appropriate advice, supported by local care pathways that include dietetic referral where appropriate . HoweverFood modifications include adjustments of macro- and/or micronutrient content, or the avoidance of specific allergens as well as modifications of food texture or of flavor, taste and/or visual appearance (organoleptic enhancement). Nutrients or additional ingredients can be added to regular foods in order to increase energy and/or nutrient density (fortified or enriched food) or to yield specific beneficial health effects  .It has been shown in several studies and summarised in two systematic reviews that food fortification—i.e., by means of natural foods  and/or specific nutrient preparations —can enable increased intake while eating similar amounts of food . Snacks Texture-modified foods are available in various qualities   and inteDue to little expense and no risk of harm, these recommendations were made despite presently very limited scientific evidence .In addition, it seems logical that increasing the variety of foods offered and considering individual food preferences could help to ensure adequate intake of older persons—this is however not studied up to now and not addressed in current guidelines.Several recommendations of the ESPEN guideline on clinical nutrition and hydration in geriatrics address whether older people with malnutrition or at risk of malnutrition should be offered ONS. Such supplements provide both macro- and micronutrients which are delivered as ready to drink liquids, or as semi-solids or powders that can be prepared as drinks or added to drinks or foods. According to a vast body of high-level evidence and strong consensus among experts, these supplements should provide at least 400 kcal and a minimum of 30 g of protein per day. They should be given to all older people with (risk of) malnutrition when nutritional goals cannot be met through dietary counselling for enhancing (fortified) food consumption, to improve dietary intake, body weight and to lower the risk of complications and readmission and to lower the risk of functional decline after discharge. Once offered, ONS should be given for at least one month with concurrent monthly assessment of presumed benefits and compliance evaluation, thereby tailoring ONS-type, flavour, texture and timing of supply to the older person’s characteristics .Enteral nutrition (EN)—mostly via nasogastric tubes or percutaneous endoscopic gastrostomy (PEG)—and parenteral nutrition (PN) via central or peripheral veins are important options also for old and very old patients. These invasive measures should however be reserved for those who are unable to meet their nutritional requirements by the oral or enteral route, respectively, but have a reasonable prospect of general recovery or at least stabilisation of health and well-being. Twelve recommendations in the ESPEN guideline refer to this topic, all based on available descriptive studies and expert consensus, since randomised trials would be unethical in this field. Application of these techniques always requires careful weighing of expected individual benefits and risks .Based on recent research activities, management of malnutrition in older persons cannot be described without pointing out the RFS, a serious metabolic complication after reinitiating nutrition in malnourished patients ,36. If pThe risk of developing RFS is suggested to be high especially among malnourished older patients, and is not restricted to enteral or parenteral nutrition. However, due to nonspecific initial symptoms  but alsoThe key to improved patient care in this context is to raise awareness of RFS among physicians involved in nutritional care in order to identify at-risk patients and to recognise the occurrence of the RFS. In the ESPEN guideline, it is recommended to pay special attention during the first three days of EN and PN therapy in malnourished individuals to serum levels of phosphate, magnesium potassium and thiamine, which decline in RFS and should be supplemented where appropriate . AccordiAfter the literature review for the ESPEN guideline was completed, a number of new systematic reviews and clinical trials addressing different nutritional interventions in different setting have been published.A systematic review and meta-analysis considered studies that only included older persons with malnutrition and found no beneficial effects of ONS in changing body weight, body mass index, MNA score, muscle strength, activities of daily living, Timed Up&Go test, quality of life and mortality. Results of other interventions  were inconsistent . AnotherThus, the number of systematic reviews is rapidly increasing with only few remarkable original studies. Among these, a pooled analysis of individual data from nine RCTs in older adults at risk of malnutrition merits attention. Positive intervention effects on energy intake and body weight were found, whereby the combination of nutritional counselling and ONS showed the strongest effects . Pooled Despite increasing numbers of systematic reviews on the topic, more than half of the recommendations in the ESPEN guideline are “good practice points”, meaning that they are based on the clinical experience of the guideline development group because of a lack of studies . The levRegarding outcome parameters, most studies testing the effects of supportive interventions or food modification focus on dietary intake but do not include functional or clinical outcomes.Most randomised clinical trials performed have examined the effects of ONS in  older adults. Given the large number of studies and the generally quite good compliance (78%) , this stA general lack of scientific evidence on the effects of nutritional interventions on functional or clinical outcomes in malnourished older adults is also concluded in multiple systematic reviews ,53,54,55The conflicting evidence regarding effects of nutritional interventions on functional and clinical outcomes of malnourished older adults may be explained by various limitations of previous studies. The limitations frequently addressed in the literature are summarised in With regard to sample selection, some previous studies have not only included malnourished persons but older adults without malnutrition as well, which likely dilutes the potential effect of treatment on outcomes . DiffereOverall, due to one or more of these limitations in most of the studies, the available evidence is mostly of only low or moderate quality. Moreover, due to large heterogeneity of inclusion criteria and study populations, intervention types and outcome assessments, the pooling of individual patient data and performing meta-analyses is currently seriously hampered ,57. ApplIn view of the recent global malnutrition definitions, which also consider muscle mass and inflammation as part of malnutrition , an updaValidity of available screening tools remains unclear due to multiple methodological problems . SettingBased on limited and partly conflicting evidence and limitations of existing studies outlined above, it remains unclear which interventions are most effective in which patient groups, and if specific situations , specific diseases  or specific etiologies of malnutrition require specific approaches. Interestingly and for example, an animal study with an infection-triggered model of acute malnutrition has recently demonstrated differential effects of parenteral glucose supplementation in addition to free oral intake on survival: Whereas in mice with an experimental viral infection a significant survival benefit was observed, mortality was significantly higher in mice with an experimental bacterial infection . Thus, iWith regard to a causative treatment, the complex etiology of malnutrition needs further research. The etiologic relevance of the many different potential causes and therefore the priority of distinct diagnostic measures remains unclear, and a treatment, based on individually identified causative factors is probably only rarely performed. More knowledge about the most relevant causes and their common pathophysiology would increase the potential for causation-oriented treatment and could in addition contribute to enhance malnutrition awareness and preventive approaches in patients with the respective problems.Regarding general intervention characteristics, individualised, multimodal and multi-disciplinary strategies seem to be promising and should be pursued further.In terms of specific interventions, food fortification, additional snacks and finger food are promising options but need high-quality reassessment through further studies that provide reliable evidence. Possible beneficial effects of all different types of food modifications including also organoleptic enhancement or texture modifications need to be tested in explorative trials as well as in subsequent sufficiently powered high-quality trials.Further research is also needed to determine which methods of delivering dietary counselling are appropriate and cost-effective for different participants and care settings. It is also unclear whether and if when the counselling should be repeated and followed up. Furthermore, the role of social care staff, such as domiciliary carers, in delivering nutritional advice and support should also be explored.Moreover, RFS must be highlighted as an area that needs further high-quality research to develop the best preventive strategies as effective treatments for malnutrition.Relevant outcomes for malnutrition intervention studies were recently agreed in a Delphi study among geriatric and nutrition experts , howeverAs studies were mainly conducted in the hospital setting, further research in other health-care settings is needed.Furthermore, the topic of dehydration urgently needs further research efforts. As one of the most frequent diagnoses of older patients, the issue of dehydration has been addressed in the current ESPEN guidelines , which hLast but not least, effective ways to implement current knowledge in clinical practice need to be explored.These and other topics considered important by the authors are listed in In conclusion, we are faced to a wide range of unresolved issues regarding the management of malnutrition in older persons which need to be addressed. Many of these questions cannot easily be answered, and it is an important next step to develop innovative strategies and well-conceived concepts for this purpose. Altogether, high-quality research is urgently required to develop effective strategies for the prevention and treatment of malnutrition in the increasing number of old and very old patients at risk.