Human adolescence is a period of development characterized by wide ranging emotions and behavioral risk taking, including binge drinking . These b Adolescence is defined as the transitional period between childhood and adulthood marked by biological, behavioral, and cognitive changes . Human aThe purpose of this review is to outline major neurological and behavioral changes which occur during adolescence and describe how exposure to stress or alcohol (or combined exposure) during adolescence can interfere with these developmental processes. We focus primarily on changes occurring in the PFC, as it is one of the final brain regions to fully mature and is known to be altered by alcohol consumption or exposure. In addition, the medial region of the PFC has been well connected to alcohol-seeking behaviors , although some argue that biological and social factors point toward a broader window spanning ages 10–24 . AdolescAnimal models can be used to study and characterize many of the neurobiological changes associated with adolescence which cannot be feasibly studied in humans. Rodent animal models show a transitional period between juvenile and adulthood stages marked by physical growth, final neurobiological maturation, and behavioral characteristics like those seen in humans . As withA major characteristic of adolescent brain development is the remodeling and growth of gray and white matter. Cortical gray matter volume changes according to an inverted U-shape over the lifespan, with increases throughout childhood, a peak in adolescence, and a steady decline throughout adulthood . SynaptiN-methyl-D-aspartate (NMDA) receptors are also necessary for development of this GABAergic system and for the proper excitatory/inhibitory balance in the PFC, indicating a role of glutamatergic input  system. Inhibitory inputs onto excitatory pyramidal neurons gradually increase throughout adolescence . The numic input . These rGlutamatergic connections in the PFC finish developing during adolescence. Glutamate binding to NMDA receptors in the frontal cortex increases until PND 28 and declines into adulthood, which could be indicative of changes in NMDA receptor expression or receptor sensitivity throughout the lifespan . Prior tIn addition to previously mentioned changes in dopamine-mediated input onto PFC GABA neurons, the dopaminergic system itself undergoes vast maturational changes in adolescence. Expression of dopaminergic receptors D1, D2, and D4 continues to increase until PND 60 . HoweverThe relatively late maturation of the PFC compared to other brain regions has been hypothesized to contribute to risk-taking and sensation-seeking characteristics of adolescents. In contrast to the PFC, other reward-associated structures including the dorsal striatum and nucleus accumbens mature earlier in adolescence . This mMonitoring the Future Study, 25% of 8th graders have used alcohol at least once, increasing to 46% of 10th graders and over 60% of 12th graders – all of which are under the legal drinking age in the United States  . AdolescAlong with these acute risks, adolescent binge drinking is hypothesized to lead to lifelong consequences, partially due to alterations in brain regions including the PFC . AlcoholNeuroimaging studies have found reductions in PFC volume in adolescents with AUD , especiaAlterations in white matter microstructure during early adolescence have been associated with familial history of alcohol use and future instances of binge drinking . AdolescRetrospective analyses conducted during adulthood may also provide clarity on cortical changes. An examination of cortical thickness and drinking patterns of United States veterans conducted after September 11, 2001, revealed that individuals with early onset binge drinking (defined as having first binge drinking episode before age 15) had thicker PFCs than post-9/11 veterans who started binge drinking in later adolescence (defined as first binge drinking episode at age 15 or later), and the early onset binge drinkers were at a higher risk for later development of AUD as well as other mental illnesses, as well as having poorer performance on attention and inhibition tests . Both grAs shown in Though the human literature provides clear evidence for the association between adolescent alcohol consumption, stress, changes in cortical development, and exacerbated problems in adulthood, it is thus far impossible to perturb precise neurotransmitters, cell types, and circuits in humans . Animal Animal models of adolescent alcohol consumption have allowed for greater control in alcohol administration while investigating the intersection between genetic background, biological sex, and the role of individual populations of neurons and circuits . Using aAlthough the previously discussed results indicate that adolescent alcohol exposure increases alcohol consumption in adulthood in rodents, other studies do not support this relationship. Rats which drank during adolescence did not show increased consumption compared to naïve rats when presented with alcohol in adulthood . ImportaAs seen in humans, adolescent rodents display different consumption patterns compared to adults. Studies continue to demonstrate the importance of including both males and females in alcohol studies, as alterations due to adolescent alcohol may be sex specific. Several studies have shown that female rodents consume more alcohol than males in both adolescence and adulthood e.g., , but occIn addition to changes in adulthood drinking levels, animal studies have reported long term effects of adolescent alcohol exposure on behaviors related to anxiety, risk taking, and memory. These effects may not present until adulthood and may be dependent on species of rodent, sex of the subjects, alcohol exposure paradigm, and timing of exposure. For example, male rats are vulnerable to developing social anxiety-like behaviors following adolescent alcohol exposure , 2020, aCorresponding with persistent changes in behaviors, adolescent alcohol induces alterations in maturing brain regions, including the PFC. Major changes to the PFC induced by adolescent alcohol are summarized in At the cell-type specific level, much work assessing changes in PFC neuronal function following adolescent alcohol has focused on excitatory glutamatergic pyramidal neurons, where several studies describe persistent electrophysiological and morphological changes in these output neurons after adolescent alcohol. It has been proposed that adolescent alcohol impairs the development of several neuronal properties, inducing these lasting deficits and possibly contributing to previously discussed behavioral changes in adults exposed to alcohol during adolescence. Pyramidal neurons in layer 5 of the prelimbic (PL) cortical region of the PFC show increased intrinsic excitability following adolescent alcohol exposure, with this effect persisting into adulthood, several weeks after alcohol exposure ended . This efA receptors. However, this work by A receptors without affecting expression of the delta-subunit  of male and female Sprague Dawley rats  and in tAnother critical developmental change during adolescence which is susceptible to alcohol use is the myelination of neurons within the PFC. Voluntary alcohol consumption reduced myelination density in the anterior cingulate cortex of male Wistar rats . AlthougNeuroactive steroids in the PFC are targets of alcohol and have been identified as potential treatment options to reduce excessive drinking. Male Wistar rats exposed to ethanol during adolescence showed increased mRNA and protein levels of 5 alpha-reductase in the PFC . The magTogether, the human and animal literature both demonstrate that adolescents are especially at risk of initiating alcohol use and that alcohol can interfere with PFC development during this critical stage. Studies using rodents have found major neurobiological changes following alcohol at the structural and cellular level, but factors including sex, species, alcohol exposure paradigm, and timing of exposure may influence results. Rates of alcohol use among adolescents remain high, making it prudent to understand persistent changes of adolescent alcohol consumption.While adolescence is a time of great physiological and psychological change, this change is often accompanied by varying levels of stress. Chronic exposure to stress in adolescence is associated with alterations in cortical structure, and an increased risk of neuropsychiatric illnesses, including AUD . Many neEngagement of the hypothalamic-pituitary-adrenal (HPA) axis is a classical response to stress, resulting in altered circulating cortisol levels as a response, although the directionality of a possible sex difference in response to more chronic stress is unclear as the literature reports conflicting findings  during adolescence (PND 25–59) significantly increased adulthood alcohol consumption in the DID model of binge drinking . An effePost-weaning social isolation has been used to model adolescent stress in rats and mice and to investigate the relationship between adolescent stress and alcohol intake. Social isolation beginning at weaning (PND 21) led to increased drinking in adult mice  and ratsMild foot shock and restraint stress have both been used to model mild physical stress in adolescence. A mild foot shock during adolescence but not adulthood led to higher levels of alcohol consumption in a strain of alcohol-preferring mice . ExposurAdolescent stress imposes neurobiological changes which underlie these behavioral consequences by impairing several critical maturational changes. These major changes within the PFC following adolescent stress are visualized in In the PFC, the impacts of adolescent stress on development of the GABAergic system have been characterized, with research investigating several subpopulations of GABAergic neurons. Development of the GABAergic system is necessary for proper cortical inhibitory/excitatory balance in adulthood, and impairments in this system have consequences for emotional development . This deAdolescent stress altered the expression of several neuropeptides in the PFC of male Wistar Han rats. After a stress paradigm of unpredictable exposures to fox odor or an elevated platform from PND 28–42, levels of SST-28 were reduced . SST hasNeurotransmitter systems such as the dopaminergic system and its alteration by adolescent social stress have undergone in-depth investigation. For example, During adolescence, inputs onto pyramidal neurons in regions including the PFC continue to mature; however, this maturation is disrupted by adolescent stress. Social stress during adolescence alters inhibitory transmission onto layer II/III pyramidal neurons in the adult medial PFC . GlutamaAdolescent stress impairs development of NMDA receptor expression in the PFC. Stressed male rodents show increased levels of NMDA receptor expression in the infralimbic region of the PFC . ExpressHuman and animal studies indicate that the adolescent period is particularly vulnerable to alcohol- and stress-induced changes in brain development because both alcohol and stress exposure interfere with necessary maturational processes naturally occurring in critical brain regions such as the PFC during this time. Stress and alcohol use are common among adolescents, and the ongoing COVID-19 pandemic is likely to exacerbate both of these phenomena. The American Psychological Association’s 2020 Stress in America survey found that over 40% of teenagers aged 13–17 report that their stress levels had increased over the previous year, due to the pandemic’s disruptions to their daily lives and uncertainty about their future . AdolescAlthough the literature discussed above indicates a variety of behavior and neurobiological characteristics which are sensitive to adolescent alcohol or stress exposure, it is paramount to note the vast variability in standard operating procedures for both preclinical stress and alcohol paradigms, which likely are a key driver in the discrepancies in effects seen in the literature. For example, though it has been argued that alcohol exposure during adolescence increases alcohol consumption in adulthood, not all studies have shown this relationship. Other factors which might mediate the effects of adolescent alcohol and stress include animal strain, timing of the experiment during adolescence, and duration of the stressor. In addition, new research indicates variables as seemingly innocuous as lab diet may influence alcohol consumption – making it particularly difficult to rectify differences in the literature . BecauseDespite the National Institute of Health 2016 mandate to include sex as a biological variable (SABV) , there rWhile the factor of sex in human studies of alcohol use and stress is important, considering gender identity is crucial to our understanding of alcohol use throughout the lifespan. Although newer studies are beginning to include gender identity as a factor in studies of stress and drinking, much of our understanding of adolescent stress and alcohol use only considers biological sex as a binary variable. Transgender and gender non-conforming adolescents are at increased risk for using alcohol and other drugs, and they are victims of disproportionate amounts of stress as a result of bullying and abuse from peers and family . UnderstAn additional factor for consideration in human studies of alcohol use is the pattern of alcohol consumption. Age of alcohol use onset or age of first intoxication are often primary outcomes of studies; however, this simplifies alcohol use to a binary variable. Monitoring frequency or amount of drinking, which are variables often included in animal studies, will strengthen future studies of human adolescent neurobiology. Importantly, assessment of some of these variables is likely limited due to the retrospective nature of human data science; ongoing studies will likely capture adolescent drinking in far greater detail along these variables. Adolescence is a critical developmental period characterized by behavioral, physical, and neurobiological maturation. Development of the PFC involves a variety of changes, such as myelination, synaptic pruning, and refinement of several key neurotransmitter systems. These maturational changes are susceptible to exposure to alcohol or stress during this period, with behavioral and structural changes often becoming permanent. Promising targets for future research may include populations of GABAergic neurons, as alcohol and stress both impact this system . FurtherThe original contribution spresented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.AS made the figures. All authors contributed to the literature review, writing, and editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


HIV implementation research evolves rapidly and is often complex and poorly characterized, which makes the synthesis of data on HIV implementation strategies inherently difficult. This is further compromised by prolonged data abstraction processes due to variable interventions, outcomes, and context, and delays in the publication of review findings; this can all result in outdated and irrelevant systematic reviews.The LIVE project (A Living Database of HIV Implementation Research) aims to overcome these challenges by applying an implementation science lens to the conduct of rapid living systematic reviews and meta-analyses to inform HIV service delivery priorities and guideline development.The LIVE project will generate a series of living systematic reviews exploring implementation strategies for improving HIV cascade outcomes . We will search Embase and MEDLINE as well databases specific to review questions for studies conducted after 2004 using predefined search terms to identify studies conducted in any age group or setting, and using implementation strategies that target policy makers, society, health organizations, health workers, and beneficiaries of care and their families. Both randomized controlled trials and observational studies will be included to ensure reviews include pragmatic data. In addition to assessments of methodological quality, features of the implementation strategies, relevance for implementation, and evidence quality will be determined using recognized frameworks. After initial publication, knowledge gaps will be identified, and review questions and search strategies revised to address ongoing critical areas of inquiry. Updated searches will be conducted every 6 months, with subsequent ongoing screening, data abstraction, and revision of meta-analyses.As of July 2022, five reviews are at various stages of development within the LIVE project. Three systematic reviews are underway and living review processes are in development for two reviews with estimated completion over the next 12 months.This project and resulting systematic reviews will provide critical insights for HIV service delivery to inform international guideline development.DERR1-10.2196/37070 Systematic reviews addressing HIV implementation research questions are challenged by difficulties in synthesizing heterogenous pragmatic research and can become outdated rapidly. As HIV prevention strategies, testing methods, and treatments become increasingly effective, current primary HIV research and evidence synthesis questions are refocusing on how best to implement effective interventions to ensure long-term sustained engagement in HIV care ,2. This Living and rapid review methods have been developed in recent years  to address these inefficiencies and increase the utility of review evidence; these methods have however been infrequently applied to HIV implementation research . The fieHeterogeneity, a frequent and desirable property of implementation research, further complicates evidence synthesis for HIV service delivery. The application of systematic review and meta-analytic methods—originally designed for homogenous efficacy data—to complex implementation research questions can result in systematic review findings that are of limited relevance to policy makers -19. EstaThe Living Database of HIV Implementation Research (LIVE) project aims to generate a series of methodologically robust rapid and living reviews characterizing and evaluating the effects of HIV implementation strategies on HIV cascade outcomes through an ongoing process of data abstraction and frequent review updates to produce valid and relevant synthesized evidence that contributes to a rapid public health response to HIV. In addition, this work will identify evidence gaps and put forward new approaches for reviewing and meta-analyzing complex implementation research specific to HIV but with relevance to evidence synthesis in the implementation science field more broadly.This project protocol was designed according to PRISMA-P  guidelines, living review guidelines, and World Health Organization (WHO) and Cochrane rapid review guidelines ,8,10,24.Relevant HIV implementation science questions will be developed in consultation with HIV guideline development groups. This will include questions regarding effectiveness of HIV implementation strategies. Individual review protocols will be published on PROSPERO, the international prospective register of systematic reviews.Studies eligible for inclusion in living rapid reviews include those conducted in any population group or age category from any setting. Randomized controlled trials (RCTs), cohort studies (with or without a comparison arm), cross-sectional studies, and natural experiments are eligible for inclusion. Incorporation of a broad range of study designs including both randomized controlled trials and observational studies will facilitate exploration of the broad spectrum of implementation research assessing the performance of implementation strategies under trial and real-world conditions.Studies must evaluate the implementation of evidence-based HIV interventions  and report on at least one HIV cascade outcome  . EligiblAn information specialist will conduct searches of a minimum of two databases—MEDLINE and Embase—and will include CINAHL and other databases depending on the considered added value for the specified review question as determined in consultation with an information specialist. Search outputs will be refined through an iterative process of cross-checking against known studies in the field. Once finalized, automated searches running at a predetermined frequency  will generate updated lists of studies for screening and eligibility assessment and abstraction. Searches will include studies published between 2004 to the day of the search, but may be restricted to more recent studies depending on the specified review question.At minimum, conference abstracts of the International AIDS Society and the Conference on Retroviruses and Opportunistic Infections will be searched for the previous two years. Additional conference searches will depend on their relevance to review questions. Clinical trial registries including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform registries will be searched routinely; depending on the specific review, further trial registries may be considered.Several team members may be involved in screening processes. Abstract and full-text screening will be conducted using Covidence software . For absStudy data will be abstracted into the LIVE database hosted on the Airtable platform . Pooled results and forest plots for random effects will be generated using Mantel-Hansel, Peto, generalized linear models, or generic inverse variance . Inconsicontexts . Where sIn addition, where multiple strategies are presented, network meta-analyses (NMA) may be conducted and will follow guidelines for conduct and reporting of NMA. The frequentist or Bayesian NMA approaches will be used to generate networks, evaluate inconsistency, and rank interventions. Although the inherent nature of implementation strategies may in some cases violate the assumption of transitivity due to variability in context and strategy heterogeneity—in terms of design and fidelity to intervention delivery—this analytic technique allows for the comparison of multiple interventions that have not been compared directly due to public health urgency and resource constraints .Where data are insufficient for meta-analysis, we will summarize data narratively. The overall confidence in the review findings will be evaluated using recognized methodologies for rating evidence certainty such as the Grading of Recommendations Assessment, Development, and Evaluation system .Once a review is completed and published, a continuous living process will be adopted to keep the review findings up to date as required ,35. FirsAs of July 2022, five reviews are at various stages of development within the LIVE project. Data extraction is underway for 3 systematic reviews with the aim of completion by the end of December 2022; living review processes are under development for 2 reviews.The LIVE project seeks to enhance the use of implementation research to inform guideline development and ultimately policy making. The project proposes to produce “living” systematic reviews by applying an ongoing updating and data extraction process to support guideline developers, including but not limited to questions on HIV service delivery at the WHO. In this project protocol, we outline a plan to support ongoing guideline development processes in HIV testing and use of antiretrovirals, but also identify how through the maintenance of living reviews this work can contribute to the future conceptualization and development of “living guideline” processes.The additional application of implementation research tools and taxonomies further position this work to contribute to guidelines that directly impact global implementation efforts, particularly for questions in HIV service delivery. By broadly exploring how, where, and for whom HIV implementation strategies are most effective, the LIVE project will advance the implementation science field by directly addressing inherent heterogeneity and intervention complexity in implementation science evidence synthesis and support future HIV service delivery guideline development.This work may be limited by difficulties in maintaining reviewers over the long term and ensuring continuous updates; the project will work to overcome this by involving a broad review team to ensure the ongoing longevity of individual systematic reviews. A further challenge may be decisions regarding when to publish an updated version of a review, retire a review, or alter review questions. To address this, decisions regarding review updates will be determined in close collaboration with experts and policy makers to ensure ongoing relevance.Synthesizing implementation research evidence is complex. This protocol and review portfolio propose new directions for implementation science evidence synthesis that also have relevance for other implementation questions beyond HIV service delivery.


Recent advances in digitalization and increasing integration of international markets are paving the way for a new generation of firms to use non-traditional entry modes that are largely marginalized in previous entry mode studies. While extant research revolves around the level of resource commitment and control in foreign activities, non-traditional modes are encapsulated by the extent of embeddedness required for exploring new and/or exploiting existing resources. In particular, we draw attention to four such categories of non-traditional entry modes the literature has touched on, i.e., capital access, innovation outposts, virtual presence, and the managed ecosystem. We explore the key attributes, antecedents, and strategic implications of these modes. Our paper highlights the need for enriching current entry mode research by considering a broader range of entry mode activities available to firms as well as employing new theoretical perspectives to understand the complex phenomena of internationalization. Journal of International Business Studies , with numerous classic articles claiming the Decade Award at the given firms’ strategic goals, they will choose the arrangement that economizes on transaction costs. A wide adoption of TCT unnecessarily restricts the conceptualization of entry modes to categories of organizational structures that serve to mitigate contractual concerns associated with specific cross-border transactions  of product offerings and business processes has drawn scholars’ attention to new ways of non-equity governance , seasoned equity offerings (SEO), cross-listings in foreign stock markets, bank loans, foreign bond issues, engagement with private equity firms, international investment syndicates, foreign venture capital (VCs), sovereign wealth funds (SWFs), as well as several informal equity capital channels  to embed in foreign business networks  or services (downloads) while actually avoiding the need to establish formal foreign-based subsidiary units or export channels , mobile app providers like Cheetah Mobile, or e-commerce retailers like BooHoo and SHEIN can be based in one country while providing their service/products to customers in other countries, through digital technologies, without having to embed in the local market.Finally, managed ecosystem entry modes tend to involve a higher level of embeddedness as these specific platforms rely on complementors in each country for value creation and often have to engage extensively with local stakeholders in overcoming legal and other governmental barriers  framework in Figure In summary, what seems to have remained underplayed in the IB literature is the fact that some value-adding activities in foreign markets are inherently oriented toward exploitation “to ensure its current viability” and others toward exploration “to ensure its future viability”  or by the actions of consumers (buyers/users) or network partners? Another critical question is related to the requirements for achieving and managing local embeddedness in foreign markets, which may determine firms’ decisions to pursue non-traditional entry modes. Once a firm decides on the right level of embeddedness in a foreign country, how is this task achieved in an efficient and effective manner? Do firms need large financial investments to enhance their embeddedness or can the cultivation of internal or external networks earn firms legitimacy and facilitate their embeddedness? What alternatives do firms have to establish, increase, or decrease the level of embeddedness in a foreign market?In addition to firm motivations that may drive non-traditional entry mode choices, it is equally imperative to consider the challenges that firms pursuing these entry modes may face. In particular, recognizing non-traditional entry modes employed by modern businesses extends our understanding of the challenge of overcoming LOO. Traditional entry modes usually focus on LOF, discussing how firms overcome institutional differences through mode choices . Another important research area is related to the roles of individual investors/brokers in the process. Researchers may explore implications of such entries for stakeholders – individual and/or institutional investors, entrepreneurs, policy makers, and overall communities – in both home countries of firms and host countries providing capital.It is also crucial to look at mode choices within this non-traditional entry mode , platform-as-a-service (PaaS), or infrastructure-as-a-service (IaaS), to name a few. While current research focuses on the exploitation of technology or capabilities for revenue generation across borders  require greater embeddedness in foreign markets as they rely on contributions by local complementors as well as customers/users who value the offerings of those complementors. However, local embeddedness may vary based on the location-boundedness of complementors; complementors on platforms like eBay are not always location bound, enabling the platform to penetrate some countries with fewer local complementors. On the other hand, complementors of sharing economy platforms like Uber have high location boundness, rendering local embeddedness critical for successful penetration. Other multi-sided platforms may require very high levels of foreign market embeddedness since all three legs of the business model  are embedded in the local market and are location-bound. Thus, future research needs to distinguish platforms based on their characteristics to better understand the deeper nuances within and between virtual presence and managed ecosystem entry modes. Indeed, even traditional MNEs are employing platforms like crowdsourcing or internet of things to access knowledge and resources in new and existing countries, which IB research should explore.While current research largely focuses on four major non-traditional entry mode categories that correspond to our theoretical framework, yet our framework is not confined to discrete mode types but builds on two continuums of exploration/exploitation and embeddedness. Hence, there really exist a much larger number of entry modes within these categories than we currently depict as firms can pursue several entry modes within the continuum between exploration and exploitation as well as between high and low embeddedness. With recognition of this variety of entry modes, we suggest that scholars can go beyond treating foreign entry as a discrete choice to explore deeper questions about how MNEs orchestrate their entries by choosing a combination of entry modes out of a large pool of traditional and non-traditional entry modes. Below, we discuss how we can cross-fertilize research on non-traditional and traditional entry modes to discuss not only mode choices but also configurations and constellations through which firms embed in foreign countries for resource exploration, exploitation, or a combination of both.One main objective of our paper is to acknowledge non-traditional ways for entering foreign countries, which could provide researchers with a more complete set of entry mode choices available to firms, in addition to traditional greenfield investment, acquisitions, joint ventures and wholly owned subsidiaries. This is a critical development in entry mode research as firms often make mode choices that are between traditional and non-traditional entry modes. For instance, digital platforms that are often considered non-location bound are pursuing more integrated modes by investing in physical infrastructure (Stallkamp & Schotter, We suggest that researchers go beyond conceptualizing entry modes as binary choices to acknowledge the processes and mechanisms of entering foreign markets, which require firms to make several strategic choices during their foreign entry into a country. Unlike traditional market entries where making physical investments or entering into a contractual arrangement can be genuinely considered the entry point, non-traditional entry modes may not entail such clear-cut events. Capital access may be an exception where success in obtaining foreign funds can mark an entry but other modes tend to unfold over a process of entry without discrete entry points. For example, digital firms or platforms may gain an initial foothold before penetration, which may enable them to iterate and improve their offerings to complete the penetration process (Chen, Wang, et al., Entry mode configuration refers to the sequence of entry modes adopted in a given country. A broader view of entry modes may unveil more nuances as to how firms evolve their entry mode choices and enhance or reduce their commitment in different countries. For instance, it is possible that firms may initially enter a foreign market by establishing innovation outposts and virtual presence and later choose the same or different markets for traditional entry. An important example is Dropbox, which entered many European markets through virtual presence channels, but later installed hardware infrastructure in some countries and established sales and technical support offices in others (Shaheer, Woo, Stallkamp, Li, & Chen, Researchers may explore if such relationships with external partners can influence subsequent entry mode choices in the same country through different processes such as mimetic, coercive, osmotic, and apprentice (see Borgatti & Halgin, A focus on entry mode configurations may also shed new light on why and how MNEs exit or reduce commitment from a given foreign market. In view of non-traditional entry modes, the closing or selling-off of physical facilities may not necessarily indicate an exit from a market as firms may maintain their presence through a digital platform or remote office. In this regard, an exit does not necessarily indicate a firm’s failure in a given market as it may simply reconfigure mode choices within the market to more efficiently serve its stakeholders. Future research needs to explore these ‘configurational dynamics’ and not assume firms exit and re-enter markets when in reality they are reconfiguring existing modes to better serve a market.Traditional entry mode research tends to emphasize control and commitment, seeking an ‘ideal’ or most efficient governance mode. But we acknowledge firms investing overseas can have multiple modes coexisting to better dovetail with the synergy and value in different foreign markets. By highlighting non-traditional modes, we hope future research will keep exploring how MNEs can manage the constellation of different modes in foreign markets to create value. An important example is Facebook which enters some countries via virtual presence modes while establishing local offices and digital infrastructure in others. Netflix, Zoom and Dropbox, which mainly focus on virtual presence modes of entry, either own or rent data storage hubs from third parties/platform providers like Amazon AWS to store complementors data locally, thus requiring more traditional modes. Investigating what factors drive the different combinations of entry modes in international markets provides important research opportunities.Similarly, many traditional firms are entering new countries or initiating new entry modes in current markets based on virtual presence or managed ecosystems, which allows these firms to conduct activities ranging from trading and marketing to crowdsourcing and user co-creation, all lying across different levels of exploration or exploitation and local embeddedness. Indeed, associating the primary entry modes with certain industries may substantially limit research potential of uncovering how MNEs enter and operate in foreign markets. There are numerous possible constellations of entry modes firms adopt as they choose across different levels of embeddedness, taking different positions in capability exploration and exploitation, or orchestrate different types of business operations in different countries based on their changing needs, motivations, institutional environments, and market characteristics. It might be fruitful for future research to further examine the factors leading to different constellations or combinations of entry modes, and their practical implications.Technological advancements and improved global connectivity are providing businesses novel ways to enter foreign countries. Instead of ownership and control, the non-traditional modes we highlight in our study largely focus on local embeddedness for exploration and exploitation of knowledge and resources. Recent IB and management research also acknowledges these non-traditional modes, though the literature on non-traditional entry modes remains largely fragmented and disconnected from the broader entry mode literature. Because of this, current research is missing the vital opportunity to inform entry mode research and create opportunities for the cross-fertilization between non-traditional and traditional entry mode literatures. We take an initial step toward incorporating non-traditional entry modes into the mainstream entry mode literature by consolidating developments in non-traditional mode research, highlighting areas for advancing this research, and integrating traditional and non-traditional entry mode research streams. While Hennart and Slangen  recogniz


Hyla arborea tadpole adaptation to background color, we followed oxidative stress parameters after rearing larvae on a constant background (black/white) and after changing the background color.Urban development results in habitat destruction, affecting populations of amphibians, the most fragile group of vertebrates. With changes in the environment, these animals become more exposed to light and predators. To enhance their chances of survival, they display plasticity of body coloration. Aside from adaptive benefits, animals exhibiting background matching meet the energetic costs and restrictions of changing body tones. To study the physiological consequences of Larvae cultivated for 20 days on constant substrate color exhibited differences in body coloration but without differences in lipid peroxidation (LPO) concentration between dark and pale individuals, suggesting that coloration investment during this period did not induce higher oxidative damage in darker tadpoles. Prolonged exposure of larvae (37 days) to a dark habitat increased antioxidative system defense and LPO concentrations, compared to animals reared permanently in the white surroundings. The positive correlation of oxidative damage with color intensity of individuals points to the physiological consequences of higher investment in the number of pigment cells necessary for dark pigmentation. In individuals faced with non-matching background and change in body coloration, defense system declined and LPO occurred relative to individuals cultivated in white habitat.Here, we have pointed to consequences related to background matching and stress that amphibians experienced during chromatic adaptations. Background color change causes a complex physiological response affecting the antioxidative defense parameters. This investigation elucidates the accompanying cost of amphibiansʼ adjustment to an altered environment. Natural habitats are greatly altered by anthropogenic activities, which lead to increased pollution and climate change. Urbanization and industrialization result in accelerated habitat loss. The outcome can be vegetation fragmentation or the development of gaps in a formerly contiguous habitat. Changes in forest cover near aquatic areas could be quite important for local amphibians. This process of vegetation loss increases the risk of animals being detected or recognized by natural predators . TherefoDepending on the species, alterations in body color can develop in different time ranges, from a couple of seconds to over a month , 7. PhysFor amphibians, cryptic coloration can be the initial defense line and a form of antipredator adaptation . By adapIntracellular transport of pigments is mediated by different hormones. Alpha-melanocyte stimulating hormone (α-MSH) induces the dispersion of melanin in melanophores that, then cover other color cells. In contrast, melanin-concentrating hormone (MCH) leads to the aggregation of pigment that causes lightening of the skin tone . Besidesde novo synthesis involves complex neuroendocrine control of the chromatophores and may be followed by high energetic costs and metabolic activities  as asH. arbH. arborea tadpoles is reversible as individuals respond to changes in substrate hue. Exposure to altered substrate color can activate neural-hormonal events that require energy for pigment translocations within chromatophores. A dark background can enhance the transcription of proopiomelanocortin (POMC) and the expression of α-melanocyte-stimulating hormone (α-MSH), which controls the production of melanin and dispersion of melanosome in darker individuals [Our investigation discloses that skin coloration of ividuals . These hividuals . The traIn this study, we report on major changes in antioxidant protection parameters followed by variations in skin pigmentation. In individuals that reverse body coloration (BW group), the defense system  failed and LPO occurred in comparison to individuals reared continuously in the white surroundings. We observed consequences related to background color matching. The presence of oxidative damage in tadpoles that developed on altered substrates and in ones that were continuously maintained on a dark background suggests that the change in body coloration carries an oxidative cost similar to the one imposed by maintaining prolonged dark pigmentation.Inverted body coloration as a response to a non-matching background can induce oxidative stress. However, color change from dark to lighter carries a higher oxidative cost. These individuals experienced both processes of melanin synthesis (aggregation) and destruction (dispersion), in contrast to only pigment production (aggregation) during the change from a pale to a darker coloration. Our results revealed that both processes involved in color change include oxidative stress as an associated cost.It has been shown that pigments involved in appearance modification are also significant for other body functions related to the immunologic response , 12 or aEven though body color modification is an effective tactic in many animals, its physiological repercussions have received limited attention. We deduce that alteration of background color induces very complex biological responses. These results indicate that amphibians encounter stress during chromatic adaptations, which eventually affects the components of their antioxidative defense.The influence of surrounding color tones on the behavior and physiology of animals is a field of science that is expanding and information concerning the effect of color on the development, fitness and survival of amphibians is of special concern. Examination of the ability of the amphibian population to cope with environmental variations, such as changes in substrate color, could help us understand how amphibians deal with background diversity and predict their susceptibility and resistance to these changes.


Untreated conductive and mixed hearing losses as a result of middle ear pathology or congenital ear malformations can lead to poor speech, language and academic outcomes in children. Lack of access to centralised hearing healthcare in resource-constrained environments limits opportunities for children with hearing loss. Red Cross War Memorial Children’s Hospital (RCWMCH) is one of only two dedicated paediatric hospitals in sub-Saharan Africa. Between 2016 and 2021, 29 children received implanted bone conduction hearing devices, and 104 children were fitted with bone conduction devices on softbands. The authors’ experience at RCWMCH suggests that bone-anchored hearing devices, either fitted on softbands or on implanted abutments, can provide solutions in settings where patients have limited access to hearing healthcare and optimal classroom environments. Hearing healthcare should be accessible and delivered at the appropriate level of care to mitigate the adverse effects of hearing loss in children.This article describes strategies employed at RCWMCH such as fitting bone conduction hearing devices on a softband immediately after hearing loss diagnosis and conducting follow-up via remote technology to make hearing healthcare more accessible to vulnerable populations. The World Health Organization WHO,  estimateThe adverse effects of hearing loss, irrespective of its aetiology, on childhood development manifest as delays in speech and language development  in the Western Cape province of South Africa over six years, followed by recommendations for accessible service delivery in resource-constrained settings.Red Cross War Memorial Children’s Hospital is one of only two dedicated paediatric tertiary-level academic hospital in sub-Saharan Africa and serves as a central referral hospital for patients across the entire Western Cape who require specialised healthcare services. The audiology department at RCWMCH provides diagnostic audiology and intervention services to children from birth to 13 years from the public healthcare sector.A retrospective review of clinical data, using an electronic departmental database, was conducted. Purposive sampling was used by the primary investigator to identify children between 0 and 13 years, who were fitted with bone conduction hearing devices, either on a softband or implantable abutment, between January 2016 and December 2021. The departmental database was established in 2016; therefore, data were reviewed from 2016 to 2021 to include a wide lens of records.Participants were identified retrospectively using an electronic departmental database from which their demographic and clinical information was recorded. Data were anonymised by assigning an alphanumeric code to each participant.All data were captured on an Excel spreadsheet, using Microsoft Excel 2022 . The data were analysed using SPSS 27, version 27.0 . Descriptive analysis was used to report on the findings.This article followed all ethical standards for research without direct contact with human or animal subjects.n = 104) and permanent implanted abutments (n = 29). The retrospective departmental database review indicated that a total of 9215 children were seen by the audiology department at RCWMCH during January 2016 and December 2021. Of these, 498 children were fitted with amplification devices, of which 133 were bone conduction hearing devices on softbands (n = 71). Nearly one-third of our sample  presented with single-sided hearing loss. It is notable that during 2020, when the COVID-19 pandemic was at a peak globally, the number of bone conduction implants and devices issued on softbands decreased. The decrease was likely because of audiology outpatient services de-escalating and patients having restricted access to nonemergency healthcare services.The majority of patients who received either implanted or softband bone conduction hearing devices during 2016 – 2021 presented with CHL  is documented via data logging software in the device. Patients who present with CHL caused by tympanic membrane perforations or chronically leaking ears, and who are too young for surgical intervention, are fitted with bone conduction devices on a softband until they are old enough for surgery. The bone conduction processor fitted to a softband means that the device can be issued on the day of diagnosis. This rapid response speaks to the principles of primary healthcare in terms of accessibility and acceptability.Functional hearing outcomes are measured by validated parent–teacher feedback questionnaires, such as the Parents’ Evaluation of Aural/Oral Performance of Children (PEACH) and the Teachers’ Evaluation of Aural/Oral Performance of Children (TEACH)  can be sent to the ear, nose and throat (ENT) surgeon, who can refer the patient directly to the appropriate level of care . Patients’ travelling distance to a centralised tertiary service can be reduced in this way, and infections that arise as a complication of the abutment surgery can be treated timeously. For patients who do not have access to a smartphone or mobile data, written information on wound care is given, and they are advised to come to the hospital immediately if any postoperative wound complications (such as skin redness or crusting) are observed.South African classrooms are often large and noisy, and resources such as FM systems and remedial support are not routinely available in many public schools. In order to facilitate inclusivity within the South African public education sector, bone conduction devices are offered to children with single-sided hearing loss, where the bone conduction device acts as a cross-router for better localisation. Bone conduction devices are often issued for children with single-sided hearing loss based on teacher feedback of poor scholastic performance. Functional listening progress  is measured by the TEACH questionnaire, as described earlier. Such a strategy manages the often-overlooked issue of unilateral hearing loss, which has a negative impact on children’s social and academic advancement.The above description of a system to manage hearing healthcare in a resource-constrained environment has implications for planning and policy in similar settings in South Africa and other sub-Saharan African facilities. A review of the guidelines for medical and audiological treatment of conductive, mixed or single-sided hearing loss in children is necessary, especially when delayed speech development and poor scholastic performance are reported.


It is unclear if state laws supporting breastfeeding are associated with exclusive breastfeeding (EBF) practice among low-income mothers participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). The main objectives of our study were to assess the relationship between such laws and EBF among WIC-participating mothers and to assess whether this association varied by employment status. We also assessed how mother’s exposure to WIC breastfeeding consultation was associated with EBF.A cross-sectional study was conducted across seven WIC program locations  between July–August 2020. Data were collected using convenient sampling from each program location and surveys were administered electronically or on paper to WIC-participating mothers. We restricted our analysis to data from 1161 WIC-participating mothers with infants aged zero to five months old. Multivariable mixed models were used to estimate the relationship between our exposures of interest  and EBF, while controlling for potential confounders and accounting for clustering by program location. Effect modification by employment status was assessed on the additive and multiplicative scales.Among WIC-participating mothers living in program locations with no employment-related breastfeeding laws, EBF was 26% less prevalent for employed mothers compared to unemployed mothers . Among all mothers, a one-unit increase in laws supporting breastfeeding was not associated with EBF . However, among employed mothers, living in areas with more employment-related laws was associated with a higher prevalence of EBF . Infants whose mothers received a WIC breastfeeding consultation had 33% higher prevalence of being exclusively breastfed compared to infants whose mothers did not receive a WIC breastfeeding consultation .Infants whose WIC-participating mothers were employed, were less likely to be exclusively breastfed, but our effect modification analyses showed that laws supporting breastfeeding at the workplace may promote EBF among employed women. EBF was more prevalent among mothers who received a WIC breastfeeding consultation compared to those who did not receive such a consultation.The online version contains supplementary material available at 10.1186/s13006-022-00490-9. Breastfeeding is an important practice that provides nutrients for the optimal growth and development of the newborn . BreastfThough breastfeeding initiation and duration has improved among mothers in the US over time, 60% of women do not breastfeed for as long as they intend to . While 8A number of US laws have been enacted at the state or federal levels supporting breastfeeding and potentially addressing some of the aforementioned barriers. The enactment of the federal law on Patient Protection and Affordable Care Act in 2010 requires employers to provide “reasonable break time” and space to support breastfeeding mothers . HoweverWIC is a nutrition assistance program that safeguards the health of low-income pregnant and post-partum women, breastfeeding women, infants, and children younger than five years by providing nutritious foods to supplement diets, information on healthy eating, and referrals to seek health care . The proOur goal in this study was to estimate the strength of association between WIC program locations’  breastfeeding laws and WIC mothers EBF prevalence, and to assess whether the relationship with employment-related laws was modified by employment status. We hypothesized that WIC mothers living in program locations that have laws supporting breastfeeding are more likely to report EBF compared to WIC mothers in locations with fewer breastfeeding laws. We also assessed how mothers’ exposure to WIC breastfeeding consultation is associated with EBF, and assessed whether this relationship is modified by employment status. We hypothesized that mothers who received a WIC breastfeeding consultation  are more likely to practice EBF compared to WIC mothers who did not receive this information, and that this relationship will be modified by employment status.This was a cross-sectional study conducted in seven WIC program locations in six states  and in one Indian Tribal Organization  between July 2020 and August 2020. In the overarching study, data were collected among WIC mothers of young children and expectant mothers in their third trimester aged 18 years old or above as part of a baseline survey of a one-year breastfeeding campaign in the six states and the ITO . The camParticipants for the study were recruited using a convenient sampling approach. The WIC staff in the six states and the ITO administered the surveys either electronically through an online survey application or on paper to WIC-participating mothers. Responses to both online and paper surveys were de-identified. WIC staff members in each program location kept the list of WIC participants numbers onsite and assigned a project ID to participants for use on the surveys. While responses to the online survey application went directly into a survey application, responses to the paper surveys were entered into the survey application by WIC staff. Data were collected on self-reported intention to breastfeed (but reported after birth), breastfeeding-related practices, obstetric characteristics, and socio-demographics. Data also were collected on breastfeeding services and resources available through the WIC program.The primary outcome of interest is EBF, which was defined as the mother feeding her infant only breastmilk up through 5 months of age.The predictors of interest in our study include laws supporting breastfeeding and WIC breastfeeding consultation. Employment status was assessed as an effect modifier.Laws related to the promotion of breastfeeding in each state or ITO were assessed by extracting data from the US National Conference of State Legislatures (NCSL) on breastfeeding laws, which provides a summary of breastfeeding laws from 50 states, the District of Columbia, Puerto Rico and the Virgin Islands, as of September 2020 . ProgramThere were both individual- and program-level covariates. Individual-level factors include mother’s age (years), education , marital status , has an adult support for baby at home , current smoker , and infant age . Other individual-level factors include the mother’s previous history of breastfeeding , parity , infant was delivered by cesarean section , and infant was born premature . Program-level factors include whether the mother received any breastfeeding promotional messages , and whether she received breastfeeding information from any breastfeeding support group .Descriptive statistics of the study population were stratified by program locations. The overall prevalence of categorical variables, and the means and standard deviations of continuous variables are presented separately for each of the program locations.We used four separate multivariable mixed models to conduct our analyses. Each of these models used modified Poisson regression with a robust variance estimator to estimate the prevalence ratio, and accounted for clustering by program location using a random intercept.The first model assessed the relationship between the number of laws supporting breastfeeding in each program location and EBF, while adjusting for potential confounders, which include WIC breastfeeding consultation, individual- and program-level factors. Biologically plausible potential confounders were specified a priori and were controlled for in the model  in the model and assessed effect modification by employment status on the additive and multiplicative scales, while adjusting for the number of laws supporting breastfeeding, WIC breastfeeding consultation, individual-and program-level factors.The third model assessed the association between WIC breastfeeding consultation and EBF practice, while adjusting for the number of laws supporting breastfeeding, employment status and individual- and program-level factors. The fourth model was similar to the third but included an interaction term between WIC breastfeeding consultation and employment status (WIC breastfeeding consultation*employment status). Effect modification was assessed on the additive and multiplicative scale, while adjusting for the same variables as in model 3.Effect modification on the additive scale was assessed using the relative excess risk due to interaction (RERI). The additive scale can reliably identify the correct group of individuals to intervene in order to achieve a significant public health impact , 23. TheWhile we did not assess the role of each of the specific breastfeeding laws on EBF, we did conduct sensitivity analyses to compare the prevalence of EBF among mothers in program locations with laws encouraging or requiring employers to provide break time and private space for breastfeeding employees to mothers in program locations without such laws. We also compared the prevalence of EBF among mothers in program locations with laws that prohibit employers from discriminating against breastfeeding employees to mothers in program locations that do not prohibit such discrimination. We conducted sensitivity analyses to see whether the relationship between the number of laws supporting breastfeeding and EBF remained the same across different infant age  groups. We also conducted sensitivity analysis to assess the relationship between a 10-unit increase in number of law-years in each program location and EBF. Number of law-years was defined as the number of total years of laws enacted in each state . There was also no association between mothers in program locations with laws prohibiting employers from discriminating against breastfeeding employees and EBF . Other sensitivity analyses focusing on infant age specific associations showed there was also no relationship between the number of breastfeeding laws and EBF among infants age ranges 0–1 month , or 2–3 months , and 4–5 months . Our sensitivity analysis on the number of law-years found no association between a 10-unit increase in law-years in a program location and EBF . We also conducted sensitivity analyses with mothers’ intention to exclusively breastfeed prior to delivery as a potential confounder and we got similar results.The objective of this study was to assess the role of breastfeeding laws and programs on EBF among WIC mothers. Our analysis found that the number of laws supporting breastfeeding in a program location was not associated with a WIC mother’s EBF practice. We found that WIC mothers who were employed were less likely to practice EBF compared to WIC mothers without employment in program locations without employment-related breastfeeding laws. However, EBF was more prevalent among employed WIC mothers in workplaces with laws supporting breastfeeding. EBF practice was also more prevalent among mothers who received a WIC breastfeeding consultation compared to mothers who did not receive such a consultation.Our finding of a higher EBF prevalence among employed mothers working in program locations with employment-related breastfeeding laws may lend support to the important role laws supporting breastfeeding at the workplace can have at promoting breastfeeding practice. The finding of no strong association between the number of laws supporting breastfeeding and EBF practice among all mothers could be due to several reasons. Most states’ laws supporting breastfeeding lacked enforcement provisions and few of these laws have penalties for violations . EnforciThe finding on EBF, which was more prevalent among mothers who received a WIC breastfeeding consultation compared to mothers who did not receive a WIC breastfeeding consultation, was not surprising. Mothers who received breastfeeding support from either WIC staff , lactatiOur study also showed that among WIC mothers in program locations without employment-related breastfeeding laws, those who were employed were less likely to practice EBF compared to those without employment. Being employed has been reported as a barrier to EBF in the US, but among the general population , 35. TheContrary to previous studies that were not restricted to WIC mothers , 41, ourThis study had strengths and limitations that should be acknowledged. Our study is unique as it is the first study to examine the role of breastfeeding laws and programs among WIC participants in the US. Our findings may not be generalizable to the general population as it was restricted to WIC participants in seven program locations. Nevertheless, our findings fill an important gap in the literature as it provides insight on the role of breastfeeding laws and programs among WIC mothers in the US. A major limitation of our study is that the design does not allow for our findings to infer causality. Another limitation is that we did not have individual-level data, particularly among employed mothers on whether their employers implemented laws supporting breastfeeding at their workplace. Additionally, some of our predictor variables were self-reported, but we have no reason to expect recall bias to be different between mothers who practiced EBF and those who did not. Another limitation was that we could not control for some potential confounders such as the maternity leave status of employed and medical conditions , active tuberculosis, brucellosis, or varicella), which are associated with breastfeeding , 50, butWe found that mothers who received a WIC breastfeeding consultation were more likely to practice EBF compared to mothers who did not receive such a consultation. While we also found that women who were employed were less likely to practice EBF, our study lends support to laws supporting breastfeeding at the workplace as these laws can promote EBF among employed mothers. We recommend for further research using large prospective studies to assess specific breastfeeding laws on EBF in all states.Additional file 1. Specific breastfeeding laws and the years of enactment in seven program locations.Additional file 2. List of potential confounders adjusted for in each model.Additional file 3. Effect modification of the association between employment-related breastfeeding laws and EBF by employment status (model II*).Additional file 4. The relationship between WIC breastfeeding consultation and EBF (Model III*).Additional file 5. Effect modification of the association between WIC breastfeeding consultation and EBF by employment status (Model IV*).


Glutathione (GSH) is the most abundant thiol antioxidant in the human body and serves many important biochemical functions, including the regulation of vitamins, such as vitamins D, E, and C, and detoxification of drugs and toxins. As a powerful antioxidant, GSH is particularly important as a regulator of mitochondrial metabolism and a free radical scavenger that limits oxidative damage to cellular components. Low GSH levels have been associated with many chronic pro-inflammatory conditions, such as metabolic syndrome, cardiovascular, renal, and hepatic disease, as well as neurodegenerative conditions and autoimmune diseases. Given GSH’s known direct protective role in mitochondrial metabolism and its association with chronic diseases of highly metabolically active tissues, this review aims to examine the literature for evidence that low GSH levels may be an important causative factor in the development of chronic illnesses. Because no large prospective human trials have been conducted using direct measurements of GSH, this review focused on the more common biomarker gamma-glutamyl transferase (GGT) which is directly correlated to low GSH levels. Several large prospective studies support this hypothesis by demonstrating that higher GGT levels are correlated with the risk of developing metabolic syndrome and cardiovascular disease in a dose-dependent fashion. Furthermore, as a corollary to this hypothesis, human and animal trials utilizing GSH augmentation using precursor supplementation in chronic conditions, including metabolic syndrome, cardiovascular disease, hepatic disease, renal disease, and neurodegenerative conditions, were also reviewed. While many of these trials were preliminary and small, there is strong evidence that GSH supplementation leads to improved outcomes in all of these chronic conditions. This review seeks to highlight these studies as preliminary evidence demonstrating the contributory role of GSH in chronic disease progression because a simple and cost-effective strategy can be created to screen for, track, and intervene in susceptible patients in the primary care setting at the earliest possible time in the disease process. Such a novel strategy would impact the majority of chronic diseases contributing to the bulk of morbidity and mortality in the Western world, and, thus, even minor benefits across many conditions may substantially impact population-wide health and longevity. Glutathione (GSH) is a tripeptide molecule consisting of the amino acids glutamate, cysteine, and glycine. It is the most abundant thiol-containing antioxidant in the human body and exists in both a reduced and oxidized state in cells, with over 95% of GSH existing in its reduced state . GSH wasSubsequent research on the biological role of GSH has shown that it serves a critical role in protecting cells from oxidative damage by neutralizing damaging reactive oxidative species (ROS) in cells by reducing them before they can damage critical cellular components such as DNA. This antioxidant function plays an especially important role in mitochondria which generate ROS through the natural function of the electron transport chain, particularly during periods of metabolic stress. Human studies support the clinical importance of this relationship by demonstrating that an increased ratio of oxidized to reduced GSH is closely correlated with global levels of oxidative stress and inflammation . SimilarGSH also plays an important role in the detoxification of toxins, xenobiotics, and drugs. Decreased levels of GSH have been noted in alcoholics, smokers, and patients with chronic liver disease . It is pThe biochemical role of glutathione as a driver of chronic illnessLow total GSH levels and elevated ratios of oxidized to reduced GSH are common in chronic illnesses as well as advanced age. While these relationships have been known for years, most literature has overlooked these findings as the predictable result of increased inflammation and oxidative stress similar to other biomarkers such as C-reactive protein (CRP). Few, if any, studies have explored the possibility of low GSH levels as a potentially important causative driver of disease pathology in itself . HoweverWithout adequate GSH to replenish NADPH, low NADPH levels result directly in increased ROS which can damage mitochondria, DNA, and other important cellular components ,25. ThisThe underlying biochemistry implicates low GSH as an important contributing factor in the development of several chronic illnesses that have been associated with increased oxidative stress such as metabolic syndrome, kidney disease, neurodegenerative diseases, liver disease, and cardiovascular diseases. Fundamentally, all of these conditions can be at least partially attributed to the dysfunction and failure of mitochondria in different highly metabolic tissues. This implies that GSH levels may be used as a useful predictive marker to identify patients who have an elevated risk of developing these chronic conditions and may also offer a novel way to delay or even outright arrest disease progression by replenishing endogenous GSH using simple dietary modifications and lifestyle changes at the earliest possible stage when such interventions are most beneficial. Interestingly, there is evidence in the literature that both of these hypotheses are true.Evidence that glutathione metabolism can predict chronic disease development and mortalityCurrently, there is very limited population-wide data on the potential predictive value of GSH levels because it is not a common clinical test and measuring the ratio of oxidized to reduced GSH in the body is time-consuming and expensive. The evidence for the possible predictive nature of GSH is seen in large studies utilizing the more common biomarker gamma-glutamyl transferase (GGT) and its correlation with increased all-cause mortality. GGT is a well-known biomarker typically associated with hepatocyte damage. Biochemically, GGT is associated directly with GSH regulation and maintenance of its normal redox status in cells by breaking down extracellular GSH which cannot cross the cellular membrane to release cysteine and glycine building blocks which can more easily cross into the cell for de-novo synthesis of GSH during periods of oxidative stress .2 of 0.6262 [Thus, elevations in GGT on the external cellular membrane are correlated directly to relative GSH deficiency in the cellular cytoplasm of the host cell. Furthermore, while this marker is traditionally associated with hepatocytes, studies have shown that this marker is elevated in cardiovascular disease and chronic kidney disease -29. Expef 0.6262 , supportExamining numerous liver function tests collected in the life insurance industry, Pinkham et al. showed that GGT levels had one of the best predictive dose-dependent negative correlations with all-cause mortality among a group of 560,000 life insurance applicants whose primary cause of death was cardiovascular disease . In anotEvidence that glutathione augmentation can delay or reverse chronic illness progressionWhereas population-wide studies tracking GGT illustrate the predictive potential for chronic diseases and mortality of decreased GSH levels, other studies utilizing NAC to increase cellular GSH stores have demonstrated that it is possible to intervene and have meaningful improvements in the same conditions. Oral GSH has extremely poor oral availability and is not lipophilic to easily cross the cell membrane and thus cannot be used to effectively increase systemic intracellular GSH levels. Instead, precursor supplementation with the rate-limiting precursor amino acid building block NAC is typically used in studies to increase endogenous GSH levels. NAC has been validated experimentally to increase GSH levels and redox homeostasis in patients with GSH deficiency  and is oIn liver disease, NAC administration was first utilized and proven efficacious in acute conditions. It was first suggested as a possible treatment for acetaminophen toxicity in 1974 , and itsThe benefits of NAC administration in heterogeneous causes of acute liver failure demonstrate that GSH augmentation can improve clinical outcomes in diverse conditions that lead to hepatic oxidative stress and not just acute acetaminophen toxicity. Analogously, improved outcomes should extend to more chronic inflammatory conditions as well. Indeed, using a rat model, Ozaras et al. demonstrated that supplementation with NAC in animals undergoing oxidative stress from ethanol infusions led to decreased inflammatory markers such as aspartate aminotransferase (AST), alanine transaminase (ALT), and GGT dramatically . In thisMetabolic syndrome is another chronic condition in which NAC administration has been shown to be beneficial. An open-label pilot study by Rani et al. utilized a six-month course of NAC supplementation in diabetic patients and showed beneficial effects, including improved glucose control via decreased HbA1C, decreased blood pressure, decreased CRP, decreased triglycerides, and increase in high-density lipoprotein compared to control group patients . AnotherAlthough no large human studies have been undertaken to examine the effects of NAC on the cardiovascular system long term, there are human randomized trials showing a decrease in ischemic damage by 60% after myocardial infarction in patients undergoing percutaneous coronary intervention for acute ST-elevation myocardial infarction in a randomized control trial by Pasupathy et al. . A smallIn renal disease, most trials utilizing NAC have typically focused on minimizing acute kidney injury due to contrast-induced nephropathy (CIN). Overall, these studies have reported mixed results, with a recent meta-analysis of 86 randomized controlled trials by Subramanian et al. showing that there may be a small benefit of low-dose NAC administration on CIN . In chroSirtuin 1 [Neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease are associated with neurofibrillary tangles and associated inflammatory oxidative stress. Small randomized controlled studies have shown benefits in both of these diseases. In patients with Parkinson’s disease, small randomized controlled trials of NAC and cysteine supplementation have shown an increase in dopamine binding in the caudate and putamen, as measured by ioflupane imaging . In patiirtuin 1 .Interestingly, the neuroprotective effects of NAC are also associated with notable benefits in some chronic psychiatric conditions which are known to be associated with low GSH levels such as schizophrenia and autism. In patients with schizophrenia, randomized trials of NAC administration have shown decreases in the Positive and Negative Syndrome Scale total score, negative symptom factor, and disorganized thought factor compared to the placebo group . In autiOverall, studies utilizing NAC supplementation for chronic illnesses are few and tend to be smaller pilot trials. Nevertheless, when taken together, this body of literature provides the strongest evidence that GSH plays a key role in many disparate conditions which may seem unrelated at first glance. More importantly, the evidence supports that augmenting GSH levels can lead to improved outcomes and presents a novel adjunct treatment modality that is currently not being utilized.Potential use of glutathione metabolism in patient careAlthough GSH metabolism is not directly monitored in primary care as a marker for health, the biochemical function of this molecule combined with supporting evidence from NAC trials suggests that it should. The best study supporting this assertion is by Kumar et al. . This smUltimately, additional studies would need to be undertaken to identify how to optimize screening and interventions for patients as well as to provide larger population-wide data on total GSH levels, reduced to oxidized GSH levels, as well as GGT. This would no doubt necessitate many longer-term, population-wide studies. However, by examining GSH metabolism in a new way, we may be able to identify chronic diseases at the earliest possible stage of development and intervene with low-cost strategies when there is the greatest potential impact to slow down their progression. Because the chronic diseases associated with GSH deficiency are also the leading causes of death today, it serves to reason that even small potential health benefits across many chronic illnesses would have a meaningful impact in decreasing population-wide morbidity and mortality.GSH is a key thiol antioxidant in the human body which, among its many functions, serves as a major mitochondrial protector, and through this function is linked to many chronic illnesses which make up the bulk of the healthcare burden in Western societies today. Studies presented in this review show that low GSH levels have a demonstrable correlation to the faster onset of these chronic diseases and increased mortality. Fortunately, other studies have reported that GSH levels can be easily augmented in patients with elevated metabolic stress states by supplementing with its precursor-building amino acids NAC and glycine. These studies have also shown measurable clinical benefits in the study participants across many different and unrelated conditions. This review aimed to present this literature because GSH metabolism can present a novel target to identify and treat high-risk patients at the very earliest stage of the disease development process with a simple, safe, and cheap intervention. If large future randomized controlled trials can confirm these findings and a population-wide algorithm could be created and applied, then the cumulative benefits across many conditions could be dramatic even if the measurable benefits of treatment are relatively small.


Uterine sarcomas are rare, aggressive tumors with poor prognosis that can be further negatively affected by inadequate surgical approaches such as morcellation. There are no clinical and radiologic criteria for differentiating leiomyoma from malignant uterine tumors. However, some ultrasonography and magnetic resonance imaging findings may be informative. We present a technique of ultrasound-guided trans-uterine cavity (UG-TUC) core needle biopsy for uterine lesions. As the procedure is an in-organ biopsy, there is no risk of needle canal contamination. The technique also enables the biopsy of lesions inaccessible by the transvaginal tru-cut biopsy. The core needle of the automatic biopsy system is inserted via the cervical canal into the uterine cavity and is directed and activated at the myometrial lesion under ultrasound control. The standard local treatment of localized uterine sarcomas is en bloc total hysterectomy; for fibroids, there are multiple options including conservative management or tumorectomy and tumor morcellation using minimally invasive techniques. Fragmentation of the sarcoma significantly worsens oncologic outcomes and should therefore be avoided. The UG-TUC core needle biopsy of uterine lesions can complement imaging to obtain sufficient material for histologic and molecular analyses of suspected or undetermined lesions, thus facilitating treatment planning and decreasing the risk of unsuspected sarcomas. Fibroids are common benign uterine tumors affecting approximately 70% of the female population. Treatment is required in 15–30% of female patients fluoro-17β-estradiol positron emission tomography (PET) to [18F]fluorodeoxyglucose PET [It has been suggested that the accuracy of uterine sarcoma detection may be improved by the simultaneous use of multiple diagnostic modalities. An example is the combined use of MRI (including dynamic MRI) and serum lactate dehydrogenase levels ; anothercose PET . Both apThe ESGO statement on fibroids and uterine morcellation recommends that ultrasound examination be performed by an experienced sonographer in patients for whom myomectomy or hysterectomy with morcellation is being considered. Additionally, when power morcellation is planned, a preoperative endometrial biopsy with hysteroscopy is mandatory . HoweverThe core needle biopsy of pelvic tumors is well established ,11,12,13In a meta-analysis of 32 studies comprising 7209 musculoskeletal lesions, the concordance between core needle biopsy and final histology results was 84% . For retThe open or laparoscopic biopsy of lesions suspected of being sarcomas must be avoided , as it cIt is unclear why the core needle biopsy is still not the standard of care or even recommended before treatment decisions are made for uterine tumors that are atypical or undetermined in imaging. Obtaining an adequate tissue sample is critical during a pretreatment workup, as it enables histologic evaluation of the specimen. When there is clinical suspicion of sarcoma, the biopsy specimen can be sent to a sarcoma reference center for detailed examination. In addition to immunochemistry, more sophisticated methods can be applied. In uterine tumors with uncertain malignant potential, the assessment of genomic index by comparative genomic hybridization array, that is, counting the genomic complexity of a tumor, allows leiomyosarcomas to be distinguished from benign tumors such as leiomyomas .The recurrence of sarcoma in the needle tract is rare but possible . Recent The previously described ultrasound-guided core needle biopsy of pelvic tumors was performed transvaginally ,11,12,13The transvaginal core needle biopsy procedure is generally safe; reported complications include vaginal bleeding 18–100%) and hematuria (4%), and none of these cases required any active management ,13. One 0% and heThe main advantage of the UG-TUC approach is that the needle tract is within the uterus only, which prevents any cell spillage (which would be harmful if sarcoma is diagnosed). Another is that the procedure is to some extent similar to curettage or hysteroscopy, and can therefore be performed by most gynecologists, the difference being that ultrasound is used to guide the needle. Additionally, after the UG-TUC core needle biopsy, endometrium and cervical canal mucosa biopsy specimens can be obtained.Gynecologists typically use 18-gauge core needles to perform a transvaginal biopsy of pelvic lesions ,11,12,13A limitation of the UG-TUC core needle biopsy method is that many different angles for the needle tract are not possible because the biopsy system is “fixed” by the cervical canal. A greater range of motion can be achieved by pressing on the uterine corpus from the anterior abdominal wall, even with the ultrasound probe, with simultaneous visualization of the needle. However, this maneuver would be impossible in patients who are obese or do not have an enlarged uterus. Additionally, there are lesions that cannot be targeted with the UG-TUC approach. Finally, a caveat of using the UG-TUC approach is that its accuracy and safety and the subsequent pathologic analysis have not been extensively validated because of the rarity of uterine sarcomas. However, a case series is provided in Preoperative core needle biopsy of uterine tumors that are atypical or undetermined by ultrasonography should be considered whenever possible as an adjunctive tool to imaging, as it allows the possibility of histologic differentiation between atypical uterine leiomyoma or sarcoma prior to management decisions; oncology patients can then be referred to a specialized center for surgery. It would also allow for the determination of benign lesions and the safe management of patients who opt for a minimally invasive or transvaginal approach or a nonsurgical treatment.Preoperative core needle biopsy of uterine tumors should be more widely used and available. Both transvaginal and UG-TUC approaches can be adopted, whichever is more applicable to the individual patient and tumor location, with greater consideration given to the latter because of its oncologic cleanness (in-organ biopsy). Future research should focus on further improving the accuracy of the preoperative workup, which could include the use of radiomics for imaging and the addition of core needle biopsy of uterine lesions including the UG-TUC approach. Multicenter, prospective studies with standardized imaging terms and definitions  and biop


Effectively managing Parkinson's disease (PD) symptoms is a formidable challenge for healthcare providers. PD patients exhibit considerable clinical heterogeneity in their symptoms, yet many patients struggle with receiving specialized care to personalize their treatment strategies. Advanced PD is associated with emergence of motor complications , axial symptoms including gait, postural and balance disorder as well as freezing of gait (FoG), and non-motor symptoms such as sleep disturbances and neurobehavioral disorders. Studies classifying Parkinson's clinical subtypes have predominantly relied on clinimetrics. Data driven approaches incorporating motor and non-motor symptoms associated with the disease have expanded the clinical spectrum with recent studies demonstrating overarching phenotypic clusters: mild motor predominant, non-motor predominant, intermediate, diffuse malignant  more precisely, enhance symptom monitoring, and gauge treatment response.Sensor technology, which represents a quickly growing consumer market in the U.S. and globally, has emerged as a tool capable of providing objective motor performance data on individuals afflicted with PD– expanding the horizon of clinical care for this neurodegenerative condition. This includes an array of electromechanical wearable sensors as well as motion sensing input devices such as cellphone cameras, among others. One in five U.S. adults currently uses a wearable health tracker or “smart watch.” Also, ~80–90% of all mobile devices used globally are designated a smart-phone. Given their widespread use, such sensors are increasingly being utilized to monitor patient health states and behaviors. The articles published in the Research Topic: Wu et al. utilized a motion capture device in 44 PD patients and 21 healthy controls to demonstrate that axial symptoms were indeed responsive, to a certain degree, to dopaminergic regimen. With more precise kinematic data, the researchers report improved time to rise from a chair, increased lower limb kinetics  and reduced truncal flexion in the PD cohort. In an article by Li et al., the authors proposed a novel multi-stage freezing of gait recognition model based on motion feature extraction of video using machine learning methods from a mobile phone video of timed up and go tests in 50 PD subjects. This model's recognition performance demonstrated good sensitivity and specificity–offering an opportunity to investigate its utility at a larger population level as FoG is one of the primary catalyst for falls and deterioration of quality of life in advanced Parkinson's patients. Recognizing FoG in a patient's native surroundings not only stands to enhance how it is managed but can influence future treatment trial design and execution.Axial symptoms have always been thought of and shown to be resistant to medications, thus, creating significant long-term disability for those afflicted. Two articles in this Research Topic sought to better delineate these symptoms. The first by Farzanehfar et al. used a wearable sensor [Parkinson's KinetiGraph (PKG®)] to identify patients experiencing “wearing off” periods, referred to as fluctuators, and showed that using objective and quantitative sensor data to guide treatment for these patients, as opposed to conventional non-sensor-based management strategies, provided better outcomes in terms of clinical scales. In another article by Pelosin et al., the authors used treadmill training with virtual reality (TT + VR) to examine the efficacy of various training plans in improving gait performance and cognitive function. The system included a camera (Kinect®) to collect quantitative measures of subjects' feet movement while walking on the treadmill and incorporated them into a computer-generated simulation along with virtual obstacles that are projected on a screen placed in front of the treadmill for subjects' view. The training included subjects walking on the treadmill while avoiding these virtual obstacles where they were assigned to either a 6- or a 12-week group (3 sessions/week). The results showed similar improvements of gait performance in both groups. However, the fall rate and fear of falling were decreased further in the 12-week group. Interestingly, improvements in cognitive functions were only seen in subjects after prolonged training (the 12-week group). Hence, objective, quantitative data has the potential to create new and improved treatment plans for PD patients while addressing a wide range of symptoms.Using objective, quantitative data to improve treatment planning for PD patients is another frontier that is currently being explored. Two articles in this Research Topic sought to leverage sensors and computing to characterize various aspects of the disease and symptoms in order to influence the treatment approach. Shokouhi et al., sought to examine the accuracy of step count in PD using wearable sensors. A total of 21 normal walkers (10 without PD) and 27 abnormal walkers were videoed while wearing a sensor (PKG) and the data were analyzed. The study revealed that the accuracy of step count was high in normal walkers but not in abnormal walkers and using a measure of the loss of rhythmicity in walking could assist in detecting the likelihood of error in step count. In particular, the study showed that care must be taken when evaluating the step count results for subjects with bradykinesia due to the potentially higher likelihood of step count errors.Finally, understanding the limitations of current sensor technology when it comes to PD and fine-tuning the methods to improve symptom monitoring is critical to move the field forward with respect to clinical diagnosis and management. One article in this Research Topic, by In summary, sensor technology is expanding our understanding of PD symptom burden, especially in motor and non-motor domains that have been challenging for providers to characterize and treat. Alongside this technological growth, the articles in this Research Topic demonstrate how leveraging objective data sets with machine learning and computing methods can impact symptom classification, symptom monitoring and treatment assessments, and treatment planning—creating a new multidisciplinary data-driven dimension of scientific inquiry and clinical care.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.