The onset, progression, and outcome of numerous pathological conditions, affecting different organs and systems, have been widely reported to be significantly impacted by the abuse of psychoactive compounds. In the last decades, preclinical and clinical reports have contributed to a lively scientific debate on the possible pathogenic role that redox imbalance, defined as a disequilibrium between reactive oxygen species (ROS) generating and degrading systems, plays in this scenario . MoreoveIn this special issue, a team of international experts presents their preclinical and clinical findings related to the impact of redox imbalance on pathological conditions associated with the abuse of psychoactive compounds, describing different underlying mechanisms and also highlighting the possibility of translating their results into the development of more targeted pharmacological interventions.The pathological consequences of ethanol (EtOH) consumption have been widely reported, also that it is considered one of the oldest and most intoxicating psychoactive compounds still being used and abused by humans. Among the different mechanisms proposed to explain the toxicity of this substance, its potential to induce the production of ROS in several body tissues and compartments has been confirmed and extended by several lines of preclinical and clinical evidence .In this context, D. Pamplona-Santos and coauthors performed a study on the effects of serious and episodic EtOH drinking patterns, comparable to weekend utilization. The acute consumption of EtOH promotes an imbalance in CNS metabolic functions, resulting in neurodegeneration and cerebral dysfunctions. In this study, the authors investigated the effects of physical training on a treadmill versus the deleterious effects of EtOH on hippocampal functions related to memory and learning. They demonstrate that physical exercise contributes to the reestablishment of the redox status by elevating GSH levels in the blood and hippocampus, and that exercise is a significant nonpharmacological intervention for the prevention of cognitive dysfunctions caused by EtOH exposure following a binge drinking pattern of consumption.Importantly, epidemiologic studies have highlighted enhanced EtOH consumption among specific subpopulations, such as women  and/or aPsychedelic substances have been the object of increasing interest with respect to the possible mental and physical pathological consequences related to their consumption. One of the most widely abused and addictive compound belonging to this class is methamphetamine (METH), which has been reported to induce episodic and/or permanent neuropsychiatric conditions. Moreover, prolonged abuse of this substance is associated with neurotoxicity as well as damages to other peripheral organs. Nevertheless, despite the significant efforts of the scientific community to better understand the complexity of the molecular mechanisms underpinning METH toxicity, several aspects of this process remain to be elucidated. In this context, the review by F. Limanaqi and coauthors discussed the epigenetic effects caused by METH. The manuscript reports the most important molecular events, starting at the presynaptic dopamine terminals to reach the nucleus of postsynaptic neurons. They describe how specific neurotransmitters and signaling cascades produce persistent genetic modifications that enable the shift of neuronal phenotypes to induce alterations in behavior. In the postsynaptic neurons, epigenetic effects induced persistent changes, including sensitization and desensitization, priming, and shift of neuronal phenotype.As noted earlier, METH induces the production of a number of ROS that leads to lipid peroxidation, protein misfolding, and nuclear damage in the CNS that are detrimental to axon terminals and cell bodies. The overproduction of oxidized proteins, lipids, and nucleic acids requires cellular clearing systems for detoxification and elimination. Cell clearing pathways such as ubiquitin proteasome (UP) and autophagy (ATG) are two such powerful defense mechanisms . HoweverThe pathological impact of ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on mental and physical health has been largely demonstrated by preclinical and clinical evidence. Ketamine is widely recognized in the treatment of resistant depression, although its penchant to induce psychedelic side effects and possible addiction limits its general use. This has prompted the search for alternative treatments or approaches that may abrogate ketamine's psychedelic effects. Among the different molecular mechanisms proposed to explain the detrimental effects of this psychedelic compound, oxidative stress has been reported to play a crucial role , which hIn recent years, opioid use has approached epidemic proportion, especially in some countries of Europe and North America. An increasing number of evidence has reported a pathological link between opioid addiction and redox dysregulation in both the CNS and periphery . With reIn conclusion, this special issue has confirmed and extended the pathological role of disordered redox systems in a variety of pathological conditions, including EtOH, METH, and opioid abuse, as well as the psychedelic substance, ketamine. These findings have been provocative to understanding how apparently different types of neuro- and psychopathology induced by a broad array of psychotropic substances ultimately impact cellular redox systems. Identifying the source of redox disturbance, e.g., ubiquitin proteasome (UP) and autophagy (ATG), as well as a putative pharmacological target, e.g., mTOR, may provide answers how to best treat a certain disorder presenting as a pro-oxidative state. While oxidative stress being prevalent in so many distinct illnesses questions the usefulness of redox parameters as a disease-specific biomarker , it does


Clinical guidelines produced in developed nations may not be appropriate in resource-constrained environments, due to differences in cultural, societal, economic and policy contexts. The purpose of this article is to describe an innovative and resource-efficient method to develop a clinical practice guideline (CPG), using the CPG contextualisation approach.The four phased contextualisation framework was applied to produce a contextualised, multidisciplinary CPG for the primary health care of adults with chronic musculoskeletal pain (CMSP) in the South African context. The four phases were: a contextual analysis, evidence synthesis, contextual integration and external evaluation. Qualitative methodology was used to investigate context factors influencing health care in this environment. A systematic review was conducted to identify current, high-quality CPGs on the topic, and to synthesise a core set of clinical recommendations from the CPGs. Consensus methods were used to integrate context information with recommendations. A multidisciplinary panel of local experts authenticated and contextualised recommendations. The resultant CPG was externally reviewed using a survey.The results from the contextual analysis phase indicated a wide range of contextual factors that could influence the applicability and implementability of the recommendations, including: the personal characteristics of the patient and clinician, social and environmental circumstances, healthcare interventions available, and healthcare system factors. During phase two, six existent high quality CPGs were identified and a core set of multidisciplinary recommendations were sourced from them. The contextual integration phase produced the validated recommendations, accompanied by its underpinning body of evidence and context specific information. The outcome of phase four  was that the recommendations were confirmed as relevant for the intended setting.CPG contextualisation was found to be a practical approach to develop a contextualised multidisciplinary CPG for the primary health care of adults with CMSP in a South African setting. The contextualisation approach enhanced the integration of multiple stakeholder perspectives and highlighted the importance of considering clinical, social and economic complexities during CPG development. Attention to contextual information is advocated to enhance the uptake of CPG recommendations, particularly in resource constrained settings.CRD42015022098).Health Research Ethics Committee of Stellenbosch University, South Africa (S14/01/018); the review protocol was registered on PROSPERO (registration number The online version of this article (10.1186/s12874-019-0771-3) contains supplementary material, which is available to authorized users. The implementation of clinical practice guidelines (CPGs) is advocated to optimise the quality, consistency, appropriateness and cost-effectiveness of health care . CPGs aradopted to another application or environment; or they can be adapted (modified) in accordance with varying needs or circumstances. In the literature these processes of adoption and adaptation have primarily been performed in comparable, developed-nation contexts [contextualisation was created [CPG contextualisation is a new and innovative approach to develop CPGs and to facilitate uptake in resource-constrained environments. Contextualisation is based on the premise that CPGs produced in developed nations may not be appropriate in resource-constrained environments, due to differences in the healthcare systems, socio-cultural, societal and policy contexts , 10. Thecontexts , 14. A hcontexts . To deep created . During This study adds to the body of knowledge for CPG contextualisation by proposing a feasible way to explore and integrate context-related factors into the guideline development process. Context factors represent the typical circumstances into which interventions will be implemented, such as the setting in which people receive healthcare services . AdditioCMSP, a global healthcare concern, is a major cause of disability and morbidity in sub-Saharan Africa. In SA, musculoskeletal conditions contribute significantly to the years lived with disability (YLD) . HoweverTo develop a framework of contextual factors that influence the primary health care of patients with CMSP in a SA context.To identify existing, current, high-quality CPGs for the primary health care of CMSP and to synthesise core recommendations from these guidelines;To endorse and contextualise clinical recommendations for inclusion in the CPG; andTo ascertain if the contextualised CPG is acceptable and feasible for the intended setting.Considering the need for the guideline and the array of context factors that may influence pain management in SA, the contextualising approach was proposed. A contextualised CPG was anticipated to offer a bridge between policy and best available evidence, whilst considering local circumstances, service provision factors, clinical expertise and patient choice , 23. TheWe performed a four phased CPG contextualisation process, each phase using different research methods see Fig. , drawingWe conducted two qualitative descriptive studies, one focusing on patients’ perspectives of CMSP and the primary health care they received; and the other focussing on healthcare practitioners’ perspectives on the management of CMSP in primary healthcare. The aim was to explore contextual factors that influence pain management in this setting. The study setting was the Western Cape, one of the nine provinces in SA. Three community health centres/clinics in the public healthcare sector were strategically chosen as study sites, based on their geographical location. The three clinics represented a rural, a semi-urban and a township setting, which allowed for diversity. This phase created a participatory opportunity for patients and clinicians in the contextualisation process .Phase 2 focused on the identification and synthesis of strategies for the management of CMSP , 10. A sClinical recommendations were extracted from the high-quality CPGs into a recommendations matrix for analysis. We extracted the recommendation, its assigned level of evidence, the strength of the recommendation and references supporting the recommendation , 10. RecConsensus methodology, consisting of a modified Delphi approach, was used for the contextual integration phase , 31–33. An external review via a small-scale survey was done to obtain the views of different stakeholders about the acceptability and applicability of the CPG for the intended setting , 39, 40.Twenty patients with CMSP and 21 clinicians participated in the interviews for the contextual analysis. The findings indicated that CMSP influenced patients in multiple ways. Participants largely agreed on the range of context factors that influence CMSP care. Components of the contextual framework which were reported to impact on the treatment delivery and adherence to care included: patients’ beliefs, goals, expectations, coping strategies, needs regarding empowerment and preparation for self-management, family support, occupational influences and financial considerations. Additionally, service provision and the application of best available evidence was influenced by practitioner beliefs, training, availability of resources, staff shortages and turnover, access to care and healthcare system load. These context factors presented important information that were utilised in the contextualisation process and they are potentially useful for designing an implementation plan for the CPG.Twelve clinical guidelines on the primary health care of CMSP were identified through the systematic review . Six of Seventeen panel members from a range of professions participated in round one of the Delphi process to evaluate the recommendations. Fourteen members participated in round two, while 13 participated in the consensus meeting. The panel of local experts comprised of clinicians, academics and researchers. The professions represented were physiotherapy, nursing, medicine , occupational therapy, psychology, and medical anthropology. The panel of experts, although from diverse backgrounds, professions and work sectors, reached consensus on 42 statements. The panel rated one statement as undecided. Two recommendations were not validated due to limited evidence for efficacy; unclear benefit vs harm relationship and context factors such as cost and availability of resources. The panel nominated an additional recommendation for inclusion, which was included in Delphi round 2, based on emerging evidence for that recommendation. It was noted that there is a need for additional recommendations, which were not included in the source guidelines, but were deemed applicable to the SA context. Examples of such recommendations include: socio-environmental strategies, management of multi-morbidities and team organisation.During the consensus meeting, the panel generated context and practice points for the implementation of each CPG recommendation in the intended setting. The context points represented the facilitators, barriers, requirements and possible solutions for implementation of the recommendations. These context criteria summarised how pain care can be optimised and were comprised of features of organisation of care, interdisciplinary referral and communication, processes of care skill and training required, access to care, local available resources, equipment required, patient and family involvement and policy factors Table . Work baThe 18 external reviewers, representing a variety of clinicians and four professional organisations, confirmed the content of the CPG to be largely applicable and acceptable for the intended context. The reviewers highlighted similar barriers to, and facilitators for implementation as identified in Phase 3. Training of primary care providers to use the CPG and to implement its recommendations was listed as a key prerequisite for ensuring successful implementation and achieving important outcomes.The study adds to the body of knowledge of CPG contextualisation as an innovative methodology in the field of CPG development . We inveA strength of the contextualisation process was the rigorous approach used to gain information about the context of the intended setting. Context plays a role in health behaviour change, knowledge translation, development of context-specific interventions, implementation of interventions and health outcomes , 12, 13.Stakeholder perspectives are a key consideration when developing contextually relevant CPGs . Recent Systematically reviewing existing CPGs to produce an evidence synthesis, is central feature of alternative CPG development –12. In oThis study highlights the strengths and the limitations of the contextualisation approach. Contextualisation has been advocated as a method to use available resources more efficiently, thereby permitting resources to be used for implementation , 10. TimWe outlined the steps we followed to contextualise CPG recommendations for the primary health care of patients with CMSP Fig. , Table 1The success of CPG contextualisation is dependent on the availability, quality, scope, and currency of the parent CPGs. If no up-to-date, high-quality, holistic CPG on the topic exists, the contextualisation process cannot take place, and de novo development is indicated. We took note of the authorisation information in some source guidelines, and contacted developers to request permission to use CPGs as part of the contextualisation process. However, few responded. Due to the relative novelty of CPG contextualisation, there is a need for communication with recognised CPG development bodies about the process and purpose of contextualisation. McGowan et al.  highlighThe distinctive features of our four phased CPG contextualisation process were the emphasis on identification, integration and explicit statement of contextual factors that could influence the phrasing, implementation and uptake of CPG recommendations. We advocate the systematic integration of context information and multiple stakeholder input during CPG development to enhance the acceptability and implementability of CPGs in resource-constrained environments.CPG contextualisation was found to be a practical, logical, and time- and resource-efficient approach towards developing a contextualised evidence-informed, multidisciplinary guideline for the primary health care of adults with CMSP in a SA setting. The approach provided the opportunity to blend clinical recommendations and multiple stakeholder perspectives within the SA context. The advantages of the contextualisation method are the explicit statements about contextual factors and the identification of indicators for the successful implementation of the guideline. An area for development for the process comprises the formalisation of the use of the strength of the recommendation.Additional file 1:A glossary to explain the concepts used in the study. (DOCX 19 kb)


Awake craniotomy allows for continuous monitoring of neurological functions during the surgery for brain tumors at or near the eloquent areas. It enables monitoring of language and motor functions by communicating with the patient and observing the patient during speech and motor tasks , 2. WithThus, the combination of the awake craniotomy and I-MRI has been used to optimize maximize safe resection taking advantage of each technique. The two techniques when used simultaneously seem to supplement each other by attaining maximal resection but minimizing neurological dysfunction. However, each of these techniques has specific concerns and challenges and using both together makes the procedure further demanding. This opinion based article presents anesthetic considerations based on current evidence from the analysis of secondary outcomes (anesthetic) in our systematic review  and is complementary to a recently published systematic review on the topic of awake craniotomy techniques during I-MRI .An I-MRI operating room posses a unique environment that produces several new concerns for the physicians which include restrictions on the use of ferromagnetic equipment because of the high magnetic field, the use of extra-long breathing circuits, long intravenous line tubing, and monitoring cables (required for movement of the patient in and out of MRI gantry). Moreover, there are other important concerns including hypothermia due to the low temperature in the MRI suites, loud acoustic noise with the potential to cause hearing problems, and other patient-specific concerns , which require proper patient screening and selection . There iSuccess of awake craniotomy procedures essentially depends on the patient's cooperation. A complaint and a motivated patient is required for continuous neurological testing during the awake craniotomy. A thorough evaluation before the surgery is important to explain the rationale, and technique to the patient in order to achieve better patient cooperation during the surgery. Also, a complete evaluation of an airway is essential to identify patients with a potentially difficult airway. Complexity of an awake craniotomy is increased in a patient with a difficult airway or history of severe obstructive sleep apnea. Such patients may not be appropriate candidates for this procedure. Moreover, the patient has to remain in one position for a considerable period of time, and this sometimes leads to fatigue.Thus, concerns about the patient's airway control, physical constraints, prolonged duration of surgeries, proper patient positioning, patient's comfort and safety, intraoperative thermoregulation, repeated intraoperative imaging with multiple transfers of the patient in and out of the MRI scanner, complex operative setup and equipment restrictions make the combination of these two techniques a potentially challenging task.We reviewed the available literature for anesthetic management during neurosurgical procedures, which were performed under awake craniotomy with I-MRI , 11–17. Based on current literature, it is unclear as to what percentage of patients undergoing craniotomy for tumors are eligible for awake craniotomy during I-MRI, as the selection of such patients is multi-factorial. Such decisions are based on tumor location, expected duration of procedure, patient's pre-operative clinical status, ability to cooperate, and experience of the operative team. It cannot be overemphasized the need for well-informed cooperative patients. Much of the success of such procedures rely heavily on the pre-operative discussion, ensuring that an accurate depiction of the procedure and operative timeline are portrayed. Little information is provided in the literature regarding these pre-operative discussions. At our institution, it is not uncommon to have multiple lengthy visits between the surgical team and the patient/family to discuss the details of such an operation prior to scheduling the procedure.In general, the following aspects of the patient selection should be considered. Patients harboring lesions near or within the eloquent areas  are subjected to awake craniotomies along with I-MRI. Patients are evaluated for their eligibility to undergo awake craniotomy with regards to their physical, mental (cognitive) and affective status. Patients with major neurological deficits that preclude testing of function (pronounced aphasia or motor), poor neuropsychological scores , significant deficits in concentration and sustained attention, patients suffering with severe anxiety or depression, claustrophobia, disinhibition, apathy and disorganized behavior are not candidates for awake craniotomy. Patients found eligible for awake craniotomy are informed about the intraoperative motor, sensory and language testing and are encouraged to rehearse this testing in the preoperative period. Moreover, patients are assessed for any contraindication to undergoing the procedure in a magnetic environment.At different centers awake craniotomy is performed either as an asleep-awake-asleep or awake-awake-awake technique with or without sedation under monitored anesthesia care (MAC). In the asleep-awake-asleep technique, the patient is anesthetized throughout the procedure except during monitoring of neurological function. The patient is awakened for neurological function monitoring during surgery and again anesthetized once the resection is complete and neurological monitoring is no longer required. In contrast to this, during the awake-awake-awake technique, the patient remains awake throughout the surgery. In most of these cases, conscious sedation is used to make the patient comfortable during these long procedures and the patient is monitored for their vital signs, neurological status, and level of sedation (MAC). Given the complex environment of the I-MRI suite, the duration of anesthesia is also prolonged substantially. This is attributed by many factors including performing anesthetic counts (depending upon scan frequencies), number of scans, further resection, setting up specialized infusion pumps, applying monitors, establishing invasive lines with extra-connections and length, positioning of the patient (both for the operation and scans), changing the anesthetic techniques , and managing intraoperative complications , if any.Before the start of the procedure, the standard MRI-compatible monitors are attached. Some authors use asleep-awake-asleep technique and patients are anesthetized using anesthetic and analgesic drugs, with the airway secured using LMA during the initial phase of surgery , 11. OthFor an awake craniotomy, a scalp block is performed by infiltrating with the local anesthetic. Sedation is usually administered prior to the scalp block to make the procedure comfortable for the patient. After an adequate level of sedation is achieved, the injection of local anesthetic drug  is given to block the nerves supplying the scalp. Various nerves supplying the scalp  are blocked on either side or a ring block is performed. The level of sedation is monitored using various monitors of sedation  to maintain an adequate level. Drugs commonly used for sedation are propofol, fentanyl, remifentanil, alfentanil, midazolam, and dexmedetomidine Table . In cont2 levels associated with awake craniotomy (non-intubated and sedated patients), a diuretic is given intravenously  at the start of surgery. Elevation of the head may further help reduce brain swelling.After the scalp block, patients are positioned for surgery with adequate padding . The pin sites are infiltrated with local anesthetic and the head is fixed to the table with a modified high-field MR imaging-compatible head holder. The surgical drapes are arranged in an “open tent fashion” such that the face is not covered under the drapes. It reduces anxiety and discomfort to the patient and allows direct eye contact and face-to-face conversation with the patient during the neurological testing. Oxygen is administered through nasal cannula or facemask during the surgery. Since the ambient temperature of the I-MRI operating room is low, hypothermia is prevented by covering the patient with drapes and use of warming devices placed outside the 5 Gauss line. To minimize brain swelling caused by higher COBefore incision, the site of skin incision and the base of skin flap are infiltrated with local anesthetic. The next potential pain sensitive structure encountered is the dura mater. Since manipulation of the dura mater and large vessels can elicit pain, after removing the bone flap, cottonoids immersed in the local anesthetic are placed over the dura mater . During Once the tumor resection, guided with clinical testing of neurological function in the awake patient, is complete and I-MRI is planned, preparation and transfer to the imaging unit is required. The added duration that the I-MRI component contributes to the procedure varies depending on the particular MRI system utilized and local safety protocols , with our recent systematic review on the topic suggesting upwards of 75 min for scan time alone . Our per2 levels and brain swelling. This may require securing of the airway with supraglottic airway devices or endotracheal tube. Other cardiovascular events, such as hypotension, hypertension, tachycardia, bradycardia or other arrhythmias need to be managed with appropriate drugs and/or fluids.Finally, any adverse event that may occur during the surgery needs prompt management. Focal seizures are usually managed by irrigating the cortex with ice-cold saline/ringer lactate, without the need for intravenous medication. However, generalized seizures may require the administration of an antiepileptic agent. Rarely, loss of airway due to oversedation or during the postictal phase may lead to desaturation and inadequate ventilation with a rise in COAs such, this article was designed to provide an opinion based overview of the anesthetic considerations involved in awake craniotomy techniques during I-MRI. It was not designed to be either completely comprehensive in its opinionated overview, nor present new and groundbreaking information, as such opinions should be based on the current evidence. Subsequently, the views presented are based on personal beliefs molded from both personal experience and the available body of literature till predefined date.Combining awake craniotomy and I-MRI offers the potential to improve the extent of safe resection for lesions located in close proximity to eloquent areas. Nonetheless, performing the surgical procedure under awake craniotomy with I-MRI is strenuous to the patients as well as the OR team. Patients should be carefully selected and extensively informed and counseled prior to the procedure. It requires a continuous motivation and cooperation of the patient while they are repetitively being asked to perform tiring tasks. Moreover, intraoperative imaging significantly adds to the total procedure time depending on the imaging sequences and number of times that imaging is performed. In spite of these multiple challenges faced by the anesthesiologists while providing anesthesia care to patients undergoing awake craniotomy combined with I-MRI imaging, anesthesia for these procedures can be safely performed.TC served as a guest associate editor for Frontiers in Neurosciences and is presently serving as an associate editor for Intensive Care Medicine and Anesthesiology section in Frontiers in Medicine. FZ has received salary support for dedicated research time, during which this manuscript was completed. Such salary support came from: the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada—Harry S. Morton Traveling Fellowship in Surgery and the University of Manitoba Clinician Investigator Program. FZ's research is also supported through the Thorlakson Chair in Surgical Research Establishment Grant. BS served as a guest associate editor for Frontiers in Neurosciences.TC has developed the hypothesis, assisted substantially in data collection, screening, reviewing, analyzing, contacting the authors, compiling and writing the manuscript. GS has collected and screened the data and helped writing the manuscript. FZ has reviewed and screened the data, and helped substantially in writing the manuscript. AH has assisted in collecting the data. HL has provided the initial data, abstracts, full-texts and formulated the search tables/prisma flow chart. BS has assisted in writing, reviewing and editing the manuscript. RC has assisted in developing the hypothesis, reviewing and editing the manuscript. MW has assisted in writing/editing 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.


Background: Neuropsychological assessment is central to identifying and determining the extent of Alcohol-Related Cognitive Impairment (ARCI). The present systematic review aimed to synthesize and discuss the evidence appraising the neuropsychological tests used to assess ARCI in order to support clinicians and researchers in selecting appropriate tests for use with this population.Methods: We searched for studies investigating the psychometric, diagnostic and practical values of tools used in the screening, diagnosis, and assessment of Korsakoff's Syndrome (KS), Alcohol-Related Dementia (ARD), and those with a specific diagnosis of Alcohol-Related Brain Damage (ARBD). The following databases were searched in March 2016 and again in August 2018: MEDLINE, EMBASE, Psych-INFO, ProQuest Psychology, and Science Direct. Study quality was assessed using a checklist designed by the authors to evaluate the specific factors contributing to robust and clearly reported studies in this area. A total of 43 studies were included following the screening of 3646 studies by title and abstract and 360 at full-text. Meta-analysis was not appropriate due to heterogeneity in the tests and ARCI samples investigated in the studies reviewed. Instead, review findings were narratively synthesized and divided according to five domains of assessment: cognitive screening, memory, executive function, intelligence and test batteries, and premorbid ability. Effect sizes (d) were calculated to supplement findings.Results: Overall, several measures demonstrated sensitivity to the cognitive deficits associated with chronic alcoholism and an ability to differentiate between gradations of impairment. However, findings relating to the other psychometric qualities of the tests, including those important for the accurate assessment and monitoring of ARCI , were entirely absent or limited. Additionally, the synthesis of neuropsychological outcomes presented here supports the recent impetus for a move away from discrete diagnoses  and the distinctions between them toward more broad and inclusive diagnostic conceptualizations of ARCI, thereby recognizing the heterogeneity in presentation.Conclusions: Based on the evidence reviewed, provisional recommendations for appropriate tests in each domain of assessment are presented, though further validation of most tests is warranted. Review findings can support efficient and evidenced-based test-selection and guide future research in this area. Chronic alcohol abuse has deleterious effects on both the function and structure of the brain . For the more impaired within this group, a diagnosis of Alcohol-Related Dementia (ARD) has been proposed  has been adopted in place of other diagnostic nomenclature to describe a spectrum of neurocognitive impairment encompassing both WKS and ARD , providing a wealth of information regarding the utility of various tests  and later published  and to differentiate these individuals from those with little or no impairment. We made two deviations from the initial aim of including only standardized, normatively defined neuropsychological tests. The first to include studies employing standardized observational measures of confabulation which are not normatively defined, enabling a more comprehensive review of ARCI assessment tools. The second to include a study evaluating the utility of the Brown-Peterson paradigm (a non-standardized test with normative data available) to allow a more detailed discussion of working memory assessment. We also deviated from our protocol by using the term ARCI over ARBD to frame this review as the former is more widely used outside of the UK.The following databases were searched on January 19th 2016 and again in August 2018: MEDLINE, EMBASE, Psych-INFO, ProQuest Psychology, and Science Direct. To achieve both aims of the review the process of study selection and subsequent data extraction was divided into two consecutive phases. In the first phase, we identified 105 studies meeting our original eligibility criteria . From these, we extracted only the type of ARCI sample assessed and the tool used, addressing aim 1 . In phase two, 43 studies were identified from within this selection which provided some evaluation of the psychometric, diagnostic or practical merits of the tools used. These studies were extracted in full using a table designed by the authors and presented in our protocol  was achieved from this process, indicating excellent consistency between reviewers  via Covidence online systematic review software. A pilot full-text screen of 20 texts was conducted to check inter-reviewer consistency. A Kappa statistic of .839 , medium (d = 0.5), or large (d ≥ 0.8). However, these cut-off points are somewhat arbitrary. All effect sizes should be considered in conjunction with the methodological quality of the study  before reaching conclusions regarding the size of the effect or the implications of this for the test used. Sensitivity and specificity values for tests were also calculated where relevant; though few studies provided the requisite information .As anticipated in our protocol, meta-analysis was not appropriate for the synthesis of findings due to heterogeneity in the tests used, the samples of focus, comparator groups, and the outcomes reported. Instead, findings are synthesized in the form of a narrative review, with tables used throughout to present key outcomes. Findings are divided into five sections covering cognitive screening instruments, memory, EF, intelligence and test batteries, and premorbid intelligence. Where relevant and possible, effect sizes were calculated for between-group comparisons  to supplement review findings , one of which was diagnosed according to the DSM-5's alcohol-related Mild Neurocognitive Disorder. The most commonly used tests are presented in Table n = 39), with few investigating ARD (n = 4), ALC (n = 4) or those with a diagnosis of ARBD (n = 2). Adding to the confusion surrounding the use of ARBD as a specific diagnosis that was highlighted in the introduction, neither of the two studies which assessed participants with this diagnosis , though four assessed only a single group, two assessed multiple clinical groups individually, and one was a case-study. Various outcomes of relevance to the review were reported, with the most common relating to the diagnostic value of tests, including sensitivity and specificity values (n = 23); the use of tests for discriminating between groups (n = 13); positive and negative predictive values (n = 1); and likelihood ratios (n = 1). Twelve studies commented on the practical values of tests, including ease or time of administration or the availability of parallel versions. Outcomes relating to validity were common, including convergent (n = 11), construct (n = 11), predictive (n = 2), concurrent (n = 1), and content validity (n = 1); while only four studies reported reliability values .Most studies employed a between groups design  in those with ARCI Table  was asseFurther support for the MoCA has come from Oudman et al. , who dirAlthough Oudman et al.'s  findingsIn total, 22 studies evaluated tests of memory, which are further divided into tests of episodic, autobiographical, procedural, and working memory and confabulation.Seventeen studies evaluated neuropsychological tools designed to assess episodic memory function  as impaired. However, poor specificity at this cut-off should not be viewed as a criticism of the measure, but rather highlights its sensitivity to all alcohol-related memory deficits and suggests a further reduction in the cut-off point is required to differentiate these groups. In relation to the FCSRT, Pitel et al. (d = 3.54) and—by some considerable margin—the largest between KS and controls of any test reviewed (5.93).Two tests which have demonstrated preliminary evidence of an ability to distinguish between the episodic memory deficits of those with ARCI and ALs are the Doors and People Test  bedside memory screening tool in those with KS. In its validation, Weintraub et al.  found thAutobiographical memory is a form of declarative memory for personal experiences (episodic) and facts (semantic) about oneself . Only one study was identified which evaluated tests of autobiographical memory , suggesting intrusions unrelated to the information learnt may be more closely associated with confabulations than those related.The NVCL-20 total score, unlike the DBCB and PCT, correlated significantly with RMBT-3 and CVLT scores in KS , approaching those observed on memory testing  was the largest of any observed in the review  participants, Van Den Berg et al. , Block Design, Picture Completion and Object Assembly  in those with ARCI . Overall, the reviewed studies present a clear picture of widespread cognitive impairment increasing in severity from AL through ALC and on to varying forms of more severe ARCI, highlighting the importance of neuropsychological evaluation. Compared with Horton et al.'s  previousCSIs are useful in providing a preliminary indication of the severity of cognitive impairment. Both the MoCA and MMSE have demonstrated some value in distinguishing those with ARCI from those without and between gradations of alcohol-related impairment, though the MoCA appears the superior of the two  between the two administration points. CSIs have also been criticized in the wider literature for their poor sensitivity to alcohol-related memory disorders  with ARBD performed within impaired ranges on a test of EF  may be warranted. However, the concept of a prolonged alcohol-related neurocognitive disorder with a distinct neuropathological basis from WKS or other disorders of vitamin depletion  remains tenuous. Given the similarities in cognitive profiles between groups with diagnoses of ARD, ARBD and KS seen here, the present review findings appear consistent with suggestions that common neuropathological processes, namely thiamine depletion, underpin most forms of ARCI Joyce, . This thSimilar cognitive profiles are also evident across gradations of alcohol-related impairment, suggesting less impaired groups sit earlier in the same underlying pathological process as those with KS. Indeed, AL & ALC groups appear to be impaired, to a lesser extent, on many of the same tests of memory  an individual best fits. Those adopting this view could acknowledge the central role of thiamine deficiency in producing ARCI , and the methods used for diagnosis . Second, further evaluations of the test re-test reliability of tests used with this population are necessary to ensure any variability in scores on repeat testing represent true differences, not practice effects. Third, to support clinicians in identifying those with or at risk of ARCI, it would be beneficial for studies to continue to identify test cut-off scores which delineate gradations of impairment , as has recently been done for the MoCA and MMSE , the systematic collation and comparison of studies conducted here makes it possible to proffer a number of provisional recommendations for tests in each domain of assessment.The MoCA is the most well-evidenced CSI of choice in this population, but the ACE, BEARNI, and TEDCA all require validation and comparison to determine the more effective measure. The CVLT and RBMT are recommended for more detailed memory assessment. The WMS is also likely to be of value, and the optional tests of orientation  should be included; although the most recent WMS-IV has not been evaluated in this population. The NVCL-20 should be the choice assessment of confabulation. Rule derivation tests  are sensitive measures of executive dysfunction in those with ARCI, with the BSPAT possessing greatest psychometric support. However, the BADS is recommended as a more comprehensive assessment of EF given the differential levels of impairment observed across EF tests in this group. The WAIS is the most commonly used and well-validated measure of intelligence in those with ARCI and its continued use appears justified; particularly if using its memory-focused analog (WMS) to permit direct comparison across functions using the same normative reference data. However, other test batteries  have received little evaluation of their utility to date. When determining premorbid function, the NART-R is the test of choice, though requires further evaluation in those with KS. Overall, while test selection will ultimately depend on a variety of factors, including the preferences and goals of the administrator, the present findings can assist clinicians and researchers assessing ARCI by supporting efficient, evidence-based decisions.All authors contributed to the conception and design of the review. RH was involved in all stages of the review process and wrote the original manuscript. GR-D contributed to the screening of studies, the interpretation and synthesis of findings, and the revision of the manuscript. BJ contributed to the extraction of data, the appraisal of study quality, the interpretation and synthesis of findings, and the revision of the manuscript. All authors approved the final manuscript before submission.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.


For some woody species and in particular for some coniferous trees, somatic embryogenesis induction has become a routine procedure. For the majority, the application of this technology presents yet many limitations especially due to the genotype, the induction conditions, the number of embryos produced, maturation, and conversion, among other factors that compromise the systematic use of somatic embryogenesis for commercial purposes especially of woody species and forest trees in particular. The advancements obtained on somatic embryogenesis in Arabidopsis and the development of OMIC technologies allowed the characterization of genes and the corresponding proteins that are conserved in woody species. This knowledge will help in understanding the molecular mechanisms underlying the complex regulatory networks that control somatic embryogenesis in woody plants. In this revision, we report on developments of OMICs  applied to somatic embryogenesis induction and its contribution for understanding the change of fate giving rise to the expression of somatic embryogenesis competence.Very early somatic embryogenesis has been recognized as a powerful method to propagate plants  Prediction of plant cell totipotency, the base concept of somatic embryogenesis, is due to Daucus carota  in the culture medium constitute routine procedures recognized as inducers of totipotency leading to somatic embryogenesis, whenever the appropriate culture conditions are found.Recognizing the great potential of somatic embryogenesis, a wide range of species have been studied ranging from monocots to dicots, and among them, herbaceous and woody/forestry species have been intensively studied .Attempting to succeed the production of somatic embryos from a wide range of species, factors such as age and type of explants, type of stress, auxin type and concentration and components of the induction medium have been tried  ; Pinus tus taeda ; coniferus taeda , Camellisinensis ; Coffea sinensis , Camellijaponica ;  have been assayed using different types and age of explants, different physiological conditions of the donor plant, different types and combinations of auxins, and different environmental culture conditions. For most species, the results achieved are far from being successful. However, E. dunnii, this method having been subject of property rights under the Patent No. PI 9801485-4 INPI). Eucalyptus globulus and E. saligna × Eucalyptus maidenii. For a review on somatic embryogenesis in woody plants, see In spite of the efforts to achieve adequate, highly reproducible protocols for somatic embryogenesis induction and embryo conversion, there is a very long way to go until this process can be used for commercial applications of important woody species. A good example is of Eucalyptus species, a forestry genus economically very important in the world industry. Since 1986, a number of Eucalyptus species  and jack pine (Pinus banksiana). However, these embryo-like structures were unable to produce entire plants.Attempts to produce somatic embryos from woody species started with the pioneer research of C. japonica, reported on fluctuations in the levels of inorganic elements namely Ca, K, Na, Mg, S, P, and Fe and considered that higher levels of these elements may be related to embryogenic/morphogenic competence. Considering the role of these elements in living cells, the results reported for C. japonica account for the involvement of Ca2+ in phosphorylation and dephosphorylation events, and modulation of enzyme actions especially of kinases. Ca2+ and phosphorylation are intimately connected with homeostasis, rapid recognition of signals and with changes in biosynthetic pathways. Recently, 2+ concentration in cytosol and mostly in vacuoles of rapeseed embryogenic microspores compared to the levels of non-embryogenic ones. The accumulation of Ca2+ in the vacuole may constitute a mechanism of control of calcium homeostasis in spores under somatic embryogenesis induction conditions. These authors also verify that the concentration of Ca2+ in the vacuoles is inverse to the presence of callose layer, which may account for the role of this layer in inhibiting the Ca2+ influx into the vacuole of the embryogenic cells. Ca2+ has been considered to function as a second messenger. Ca2+ signal results from signaling fluxes of Ca2+ across membranes, resulting in increase/decrease of cytosolic Ca2+ calcium concentrations  study during the induction of somatic embryogenesis from cell suspension cultures of Interestingly In spite of the very high input of data published until now, in woody species and in particular in conifers that represent a very high percentage of economically important forestry species, the molecular events underlying somatic embryogenesis induction and embryo development have been hindered by their large genome, slow growth, and long generation time.The capacity of an explant to produce somatic embryos depends on the genotype and on many other different factors including phytohormones, proteins, and transcription factors. Different chemical compounds also act in gene expression as signals. Cross-linking between phytohormones, proteins, and transcription factors is likely to play an important role in somatic embryogenesis induction.D. carota and A. thaliana but their application in improvement of woody species in general and of forest trees, in particular, are far from being achieved, especially when commercial purposes are concerned.Among the major bottlenecks still existing in reaching the high promises of somatic embryogenesis as a clonal propagation system of plant species in general and of woody species in particular, the recalcitrance to somatic embryogenesis induction, the low yield of somatic embryo production, and difficulties in the subsequent developmental steps of somatic embryos, in particular embryo conversion to plants, have to be mentioned. Studies have been performed in several species including model species such as A. thaliana, this species has soon become a model plant for cell biology and molecular studies aiming at understanding plant development, mechanisms of signaling, and resistance/tolerance to biotic/abiotic stresses, plant development, and gene regulatory networks. More recently, it provides an excellent system for studies of functional genomics, systems biology, synthetic biology, and embryogenesis in vitro among others. For a review, see Following the genome sequencing of A. thaliana,  was significantly enhanced by over-expression of csi-miR156a. Among the biological processes the authors suggested to occur in response to miR156 over-expression, hormone signaling pathways, stress responses, DNA methylation, and the cell cycle have to be mentioned. Citrus sinensis somatic embryogenesis system. By comparing the expression levels between embryogenic and non-embryogenic cells/tissues, the authors showed that the miRNA/siRNA-mediated differential regulation of specific biological processes and TFs may be associated with competence for somatic embryogenesis. Taking into account the great amount of miRNA/siRNA, and comparing its expression in non-embryogenic and embryogenic callus, the authors suggested the involvement of miRNAs and SiRNAs in somatic embryogenesis potential in citrus, by down-regulation of most of miRNAs and siRNAs accompanied by up-regulation of a few conserved miRNAs in the embryogenic tissues. The same authors have postulated that these conserved miRNAs should derepress important development-required and stress-response genes, at the same time that some TFs should be suppressed to finetune the embryogenic potential.Recently, the regulatory roles of miR156-SPL in citrus embryogenic callus have been postulated by The same authors reported on the identification of a set of candidate miRNAs that may play an important role in the regulatory network controlling the transition from vegetative to embryogenic state. The transcription factor miR393 may also play a role in the control of Arabidopsis somatic embryogenesis induction . These fThis knowledge will be helpful for identifying genes targeted by the candidate miRNAs in SE induction and its application to woody species.In fact, SE induction depends from hormone signaling, responses to different stresses, the genotype under study, and DNA methylation status in order for the competent cells to enter the cell cycle.These findings suggest the existance of an integrative regulation of somatic embryogenesis in woody species economically important in particular in Citrus species improvement.Combining the molecular and biochemical knowledge on transcriptional regulation under stress conditions will help in the generation of predictive network models that may regulate change of fate in somatic embryogenesis induction in plants.Pinus pinaster (three embryogenic culture types) reported that no significant differences in DNA methylation levels are observed when embryogenic and non-embryogenic lines are compared. The methylation values varied from hypomethylation in embryogenic lines to hyper-methylation in non-embryogenic ones. These results on DNA methylation values account for the need of more research on this subject in conifers as well as on its relationship with age of the donor material.A condition for somatic embryogenesis induction is the presence of an auxin in the induction medium. Later on, P. abies somatic embryogenesis .According to The results reported by different authors, in particular by Dedifferentiation, a requisite for somatic embryogenesis to occur, depends on the stress conditions applied.One of the conditions for induction of somatic embryogenesis either in woody or in herbaceous plants is the use of a stress . As a matter of fact, the same type of stress can induce SE in different species. This fact brings to mind the idea that a stress, whatever it is, may be responsible for switching on an initial reaction that may induce dedifferentiation of the embryogenically competent cells. The capacity to display competence for embryogenesis is very different among the plant species. The stress imposed for somatic embryogenesis induction triggers signals that play an important role in cell reprogramming.As a reaction to stress, plants may enter dedifferentiation, a step prior to acquiring a new cell fate. According to Proline is known as an important molecule used by plants to combat stress. Polyamines have been involved in plant abiotic stress responses . DiffereC. sinensis, following induction by osmotic stress.Polyamines have been suggested as crucial molecules that enhance cell proliferation and regeneration in plants . AccordiThe molecular mechanisms underlying the accumulation of polyamines (PA) following stresses, as well as the expression of PA biosynthetic genes and its transcriptional regulation network are far from being understood. PA biosynthesis and accumulation associated to gene expression, physiological, biochemical, molecular, and genetic approaches will certainly contribute to understanding the intricate regulation of PA synthesis under stress, as well as the crosstalk between TF-mediated signaling pathways.The resulting knowledge will surely contribute to better understand the role of polyamines in somatic embryogenesis induction.C. japonica leaves. The activity of these enzymes increased until the formation of globular structures and was higher for IBA-induced material. The authors also found a correlation between the expression of SODs and the values of Cu, Zn, Fe, and Mn at the embryogenic margin of the leaf. In fact, the results obtained account for a flux of these ions from the midrib to the leaf margin where the vegetative cells undergo a dedifferentiation process. The increase in the activity of oxidative stress enzymes may account for the protection of the embryogenic-responsive cells against the oxidative burst promoted by the stress induced with further dedifferentiation of competent cells to enter cell cycle.Results from Ananas comosus. These authors pointed out the role of this gene in somatic embryogenesis induction. Oryza sativa SE induction. In camphor, Transcription factors of LEC, BBM, AP2, ERF, DREB, WUSCHEL-RELATED HOMEO-BOX (WOX) families have also been suggested as playing critical roles in camphor somatic embryogenesis process. Q. suber microspores and immature zygotic embryos in vitro embryogenesis have demonstrated that phytohormones namely auxins play a role in signaling cell wall and chromatin remodeling activating specific morphogenic pathways interconnected in complex regulatory networks leading to reprogramming of competent cells for embryogenesis induction. According to these authors, DNA hypomethylation and cell wall remodeling by increasing pectin esterification are concomitant with increase in auxin levels at early stage of somatic embryo formation. B. napus pollen embryogenesis, the epigenetic reprogramming is related to a decrease in DNA methylation. It has also been suggested that the microspore reprogramming to embryogenesis entails a change in the expression pattern of BnMET1a-like (METHYLTRANSFERASE-LIKE) at the transcriptional level, which highly correlates with the DNA methylation dynamics (DNA hypo-methylation and BnMET1a-like expression)  .Coffea canephora , ENHANCER OF SHOOT REGENERATION 1 (ESR1) and HEAT SHOCK FACTOR B1 (HSFB1) may function as critical factors that potentially connect upstream stimuli to downstream developmental steps. The same authors pointed out that wound-inducible APETALA 2/ETHYLENE RESPONSE FACTORs (AP2/ERFs) may function as regulators of these key genes, which, in turn, undergo feed-forward cascades controlling downstream targets related to callus formation and organ regeneration. They also reported on other regulatory pathway, regulated by LATERAL ORGAN BOUNDARY/ASYMETRIC LEAVES 2 (LOB/AS2) transcription factors that may play a different but partially overlapping role with the AP2/ERFs in the putative gene regulatory cascades. In this very interesting paper, the authors not only provide a scheme of the global reprogramming network but also detail sub-networks highlighting cytokinin/auxin/wound-mediated pathways regulating plant cell reprogramming. To the best of our knowledge, this is the first report on a gene regulatory network governing plant cell reprogramming.Stress triggers cell reprogramming in plants . Woundinin vitro tissue culture. According to The list of genes mentioned above is far from being exhaustive. However, the data shown account for the intensive research and for the knowledge acquired on cellular events taking place under the conditions commonly used for plant somatic embryogenesis induction.D. carota and A. thaliana) aiming at understanding the complex network of regulatory mechanisms governing the expression of competence for somatic embryogenesis, many gaps still have to be fulfilled before considering the possibility of using the embryogenic process as generally applicable to woody species and of its possible contribution for the improvement of somatic embryogenesis protocols required for using this system in mass propagation of woody species, in particular in conifers, to satisfy forestry needs.In spite of the enormous amount of data gathered from transcriptomic research developed in woody species and in model plants . Studies have been performed in order to understand the complex process of somatic embryogenesis induction. P. abies somatic embryogenesis induction by, The role of chitinases and arabinogalactan proteins as signal molecules has also been reported in In spite of the huge amount of results produced to find adequate protocols for SE induction of important woody species and in particular of forest species, most improvements have resulted from empirical modifications of previously published protocols.Q. suber , HDA6 and HDA19, two histone mono-ubiquitinases (HUB1 and HUB2), a histone H3 kinase (AUR3), PICKLE and VP1/ABSCISIC ACID INSENSITIVE 3-LIKE 1 (VAL1). Inhibition of histone deacetylases interferes with somatic embryogenesis induction in conifers  and (CDC2A) play crucial roles in the early phase of embryogenesis. Cell-cycle genes have been correlated with cell competence and cell reprogramming during regeneration .A. thaliana roots. The same authors have pointed out that differentiated cells can also dedifferentiate and produce somatic embryos if AtPRC2 epigenetic repression is removed.At the same time that research is performed to unravel the factors underlying early events in somatic embryogenesis induction, efforts have been developed to understand the negative regulation of SE. C. canephora. These authors have provided evidence that those compounds released by somatic cells to the culture medium interfere with the embryogenic process by affecting directly or indirectly DNA methylation. According to the same authors, these compounds inhibit the activity of methyltransferases. This inhibitory effect has been previously demonstrated by C. canephora.Several proteins, namely B3 VP1/ABI3-LIKE (AtVAL) AtVAL1 and AtVAL2 have been reported as suppressors of somatic embryogenesis . They maB. napus. This assumption resulted from the use of trichostatin A (an inhibitor of HDACs) in the culture medium that resulted in a large increase of embryogenic mass production from the B. napus male gametophyte.Cell fate change is a key factor for success in plant somatic embryogenesis.In spite of the huge progress in the obtention of somatic embryos from a myriad of plant species, including woody species, a matter of fact is that for many of them, this is still a trial-and-error process.In woody species, in particular in forest ones, most of them recalcitrant or very difficult to produce somatic embryos, switching on the developmental program of adult cells to meristematic ones may be very time and money consuming.Several authors namely A general assumption is that the regeneration process does not comprise a single step. According to those authors, several steps may occur, in particular: (1) acquisition of embryogenic competence, (2) re-specification of cell fate, and (3) cell cycle re-entry.Much progress has been achieved in the understanding of basic processes of dedifferentiation, but a comprehensive knowledge of the epigenetic control of cell dedifferentiation is still far from being generalized and somatic embryogenesis in woody species continues to be strongly genotype dependent.Studies on reprogramming adult cells in terms of definition of facts responsible for changes in regulation of genes will be of most interest to unveil basic mechanisms regulating cellular plasticity.Characterization of reprogramming-related genes and proteins will provide a deeper insight into the mechanisms and networks involved in the expression of competence for embryogenesis. The control of the crucial step of fate change from differentiated to undifferentiated stage combined with the control of further steps in the somatic embryogenesis process will constitute a real opportunity to apply this technology for the improvement of forest tree species and potentially for the applicability of somatic embryogenesis in the production of synthetic seeds and its use for the benefit of reforestation programs.Combining the information gathered on SE induction in model plants, one can expect to improve the expression of competence in woody species, making use of the molecular means available.The capacity of deciphering the genome of woody species is growing at an incredible speed. The data generated by transcriptomics, combined with those of proteomics and metabolomics will have a tremendous impact on the knowledge of the molecular mechanisms underlying somatic embryogenesis induction. Knowledge on transcripts associated with the expression of competence for SE will allow its use as markers of competence for embryogenesis which is of most importance for achieving more accurate selection of donor explants and higher reliability of the embryogenic process in woody plants.Deciphering genes related to signal transduction pathways like SERK (SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE) is of crucial importance to determine the specific conditions needed to switch on of different signal cascades during somatic embryogenesis induction.Also, knowledge on genes encoding transcription factors such as BBM, LEC1, and LEC2 brings insights into the regulation of somatic embryogenesis induction and may have a potential to be used in somatic embryogenesis control, in particular in the expression of competence for embryogenesis.Proteome data can also reveal markers that may constitute useful tools in the definition of conditions for induction of embryogenesis competence.Combining data from genome, transcriptome, proteome, and metabolome may help in the identification of regulatory mechanisms and networks responsible for orchestrating the reprogramming of gene expression and may undoubtedly give insights into the dedifferentiation process giving rise to SE induction.The roles of elements, auxins, stress, proteins, and polyamines together with their putative interaction may contribute to understand the complex interplay of signals resulting in the switch of the somatic embryogenesis process.Data obtained from metabolome studies may help in the definition of metabolites controlling cell fate change from differentiated cells to dedifferentiated ones, a condition essential for somatic embryogenesis induction. It will also help in defining the metabolites that may function as inhibitors of somatic embryogenesis induction.The definition of efficient embryogenic systems capable of generating high yields of somatic embryos will facilitate the use of these embryos for the obtention of large numbers of plants and its use in crop improvement (in particular woody species) making use of new breeding techniques and obtention of different lines for further screening of the desired trait(s).The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The 13 research articles/communications, six reviews, and one perspective that comprise this Special Issue on Lignans, highlight the most recent research and investigations into this diverse and important class of bioactive natural products. Lignans are traditionally defined as a class of secondary metabolites that are derived from the oxidative dimerization of two or more phenylpropanoid units. Despite their common biosynthetic origins, they boast a vast structural diversity. It is also well-established that this class of compounds exhibit a range of potent biological activities. Owing to these factors, lignans have proven to be a challenging and desirable synthetic target that has instigated the development of a number of different synthetic methods, advancing our collective knowledge towards the synthesis of complex and unique structures. New lignans are constantly being found and this Special Issue details some of the most recently discovered novel lignans—Liu et al. isolated three new dibenzocyclooctadiene lignans, heilaohulignans A–C from Heilaohu, the roots of Kadsura coccinea, which have a long history of use in Tujia ethnomedicine for the treatment of rheumatoid arthritis and gastroenteric disorders . HeilaohA subclass of lignans, norlignans lack a carbon present in the parent lignan structure, with 9-norlignans lacking a terminal carbon (C-9). An overview of the occurrence and biological activity of all the 9-norlignans reported to date are given in the article by Eklund and Raitanen, which also reports the semisynthetic preparation of a number of 9-norlignans using the natural lignan hydroxymatairesinol, obtained from spruce knots, as the starting material . As stated above, owing to their potent biological activities, lignans are a popular synthetic target. A summary of the advances in lignan natural product synthesis over the last decade is outlined in the review by Fang and Hu . Davidson et al. have presented their work on their novel, efficient, convergent, and modular synthesis of the well-known dibenzyl butyrolactone lignans through the use of the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate . Not onlAdvances in the synthesis of aryldihydronaphthalene and arylnapthalene lignans are also detailed in this Special Issue through the concise synthesis of (+)-β- and γ-apopicropodophyllins and dehydrodesoxypodophyllotoxin . This waAs stated, lignans are formed from the oxidative dimerization of two or more phenyl propanoid units. However, numerous oxidative transformations of lignans themselves have been reported in the literature. Runeberg et al. provide an overview on the current findings in this field, focusing on transformations targeting a specific structure, reaction, or an interconversion of the lignan skeleton . Bursera fagaroides [The extensive analysis of the potent biological activities of lignans remains a popular avenue of investigation. Antunez-Mojica et al. used a zebrafish embryo model to guide the chromatographic fractionation of antimitotic secondary metabolites, ultimately leading to the isolation of several podophyllotoxin-type lignans from the steam bark of garoides . SubsequDiphylleia cymosa and Podophyllum hexandrum with in vitro bioassays testing the antibacterial, anticholinesterasic, antioxidant, and cytotoxic activities of these lignans [Pereira Rocha et al. combined the in silico prediction of biological activities of lignans from  lignans . In thisSchisandra rubriflora and Schisandra chinesis (wuweizi), Szopa et al. used UHPLC-MS/MS [S. rubriflora extracts, while individual lignans showed significant inhibitory activity against 15-LOX, COX-1 and COX-2 enzymes. Closely related, Chen et al. evaluated the quality and effect of cultivated and wild growing methods on the lignan composition of Schisandra chinesis through the use of UFLC-QTRAP-MS/MS in combination with multivariate statistical analysis, demonstrating that the composition differs between plants grown in these conditions and the quality of cultivated wuweizi was not as good as wild wuweizi [To explore the differences in lignan composition profiles between various parts and genders of LC-MS/MS . Additio wuweizi .While lignans have been shown to exhibit extensive potent biological activities, other factors need to be considered for them to be potential drugs. The physicochemical properties of various lignans subclasses were analyzed by Dr Lisa Pilkington to assess their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) profiles and establish if these compounds are lead-like/drug-like and thus have potential to be or act as leads in the development of future therapeutics . OverallTraditionally, health benefits attributed to lignans have included a lowered risk of heart disease, menopausal symptoms, osteoporosis, and breast cancer. Rodriguez-Garcia et al. present a review that focuses on the potential health benefits attributable to the consumption of different diets containing naturally lignan-rich foods . Currentp-coumaric acid glucoside are the main contributors to the antioxidant capacity. A review of the use and effect of flaxseed as a food source for dairy cows has also been presented [Lignan composition profiles of flaxseed, the richest grain source of lignans, was also studied, assessing the relative impact of genetic and geographic parameters on the phytochemical yield and composition . It was resented , coverinWith the rise in exploration of dietary lignans and their various effects, exemplified by the aforementioned studies, the study by Durazzo et al. provides assessment and analysis of the development and management of databases on dietary lignans, which includes a description of the occurrence of lignans in food groups, the initial construction of the first lignan databases, and their inclusion in harmonized databases at national and/or European level . In addition to work into their notable biological activities, there has been a recent increase in investigations exploring lignans in other roles. This includes gaining insight into the effects of barrel-aging on spirits, whereby lignans present in the wooden barrels are released into the aging spirit. To evaluate the impact of lignans in spirits, screening of a number of lignans was set up and served to validate their presence in the spirit and release by oak wood during aging . The mosIn summary, it can be seen in this Special Issue that research in natural lignans and lignin-derived compounds continues to be a fruitful area of research. Scientists working across a large number of disciplines continue to be attracted to work on lignans due to their relatively high natural abundance, coupled with their highly potent and diverse range of biological activities.


A joint effort of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) aims at clinical guidance for the use of FDG-PET in neurodegenerative diseases. This paper addresses the diagnostic utility of FDG-PET over clinical/neuropsychological assessment in the differentiation of the three forms of primary progressive aphasia (PPA).Seven panelists were appointed by the EANM and EAN and a literature search was performed by using harmonized PICO  question keywords. The studies were screened for eligibility, and data extracted to assess their methodological quality. Critical outcomes were accuracy indices in differentiating different PPA clinical forms. Subsequently Delphi rounds were held with the extracted data and quality assessment to reach a consensus based on both literature and expert opinion.Critical outcomes for this PICO were available in four of the examined papers. The level of formal evidence supporting clinical utility of FDG-PET in differentiating among PPA variants was considered as poor. However, the consensual recommendation was defined on Delphi round I, with six out of seven panelists supporting clinical use.Quantitative evidence demonstrating utility or lack thereof is still missing. Panelists decided consistently to provide interim support for clinical use based on the fact that a typical atrophy or metabolic pattern is needed for PPA according to the diagnostic criteria, and the synaptic failure detected by FDG-PET is an earlier phenomenon than atrophy. Also, a normal FDG-PET points to a non-neurodegenerative cause. In the lack of clinical guidelines for the use of FDG-PET to diagnose dementing neurodegenerative conditions, the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) launched a joint effort aimed at providing clinicians with clinical guidance for using the exam. To this avail, a set of 21 clinical questions was defined to perform literature searches and assessment of the evidence supporting FDG-PET clinical use, and feeding a group of experts defining consensual [In this paper, we report the availability of evidence supporting the use of FDG-PET for the differential diagnosis between different forms of primary progressive aphasia (PPA). PPA is divided into clinical variants based on specific speech and language features characteristic of each subtype. Clinical criteria for the three variants of PPA—nonfluent/agrammatic, semantic, and logopenic—were developed by an international group of PPA investigators . This clIn this study, we thus assessed the quality of available evidence supporting the utility of FDG-PET in the differential diagnosis of PPA variants, which is relevant for indicating a diagnosis and prognosis in individual patients.EANM and EAN appointed respectively four and three panelists to produce recommendations based on the incremental value of FDG-PET, as added on clinical-neuropsychological examination, to differentiate among clinical presentations . Consensus recommendations were developed through a Delphi procedure , where pBriefly, we performed literature searches using harmonized PICO  question keywords edited by panelists; we screened the studies for eligibility, extracted the data to assessed their methodological quality, and provided an evidence assessment consistent with the EFNS guidance  in the sFDG-PET should be performed, as adding diagnostic value , as compared to standard clinical/neuropsychological assessment alone, to differentiate among clinical presentations  and to obtain indirect information on the molecular pathologies in patients with primary aphasias. Note that, within the whole initiative, the incremental diagnostic value of FDG-PET versus clinical diagnosis was meant in terms of increased accuracy of the nosological diagnosis. Other exams, and particularly amyloid PET or CSF biomarkers in this case, were expressively not included in the PICO question, nor in the Delphi sessions, not being the focus of the project.For this paper, the PICO question was whether Only original full papers published in English on international impacted journals were considered, excluding reviews, management guidelines, abstracts, and gray literature. Any sample size was allowed if pathology was the gold standard for diagnosis. Otherwise, the minimum sample sizes for including papers was five.Electronic search strategy, developed and tested with panelists, was performed through predefined strings, specific to the PICO question, and including a selection of terms taken from a largely inclusive literature selection, in order to pick all variants for the same keyword .Literature searches were performed using the Medline and Embase databases, and included literature published by April 2016. In reporting the findings of this review, we adhered to the standards of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . A firstrelative availability of evidence was formulated, keeping into account the evidence availability among all of the 21 PICOs. This ranking was summarized as very poor/lacking, poor, fair, or good.We extracted data to evaluate the quality of evidence in support to the clinical use of FDG-PET for PPA as described by Boccardi and colleagues . Data exhttps://drive.google.com/drive/u/0/folders/0B0_JB3wzTvbpVFYtUGxHdGZWYmc).Among the 156 papers identified and screened by the referent panelist (FB), 16 reported the comparison of interest  a pattern of atrophy already clearly suggestive for a subtype of PPA. A systematic investigation of the potential added value of FDG-PET in patients with pattern of atrophy already supporting the diagnosis of PPA is outside the aim of the present study and should be addressed when discussing a complete diagnostic algorithm for PPA. With respect to perfusion SPECT, due to the worse resolution, SPECT should not be performed when FDG-PET is available .Considering the recent advances in molecular imaging and currently available neuropathological biomarkers for Alzheimer’s disease (AD), i.e., CSF abeta, tau, ptau, and amyloid PET, the focus of this paper covers only a part of the comparative analyses that should be performed to outline a complete and cost-effective diagnostic algorithm. Indeed, the added value of FDG-PET over both clinical/neuropsychological evaluation and specific AD biomarkers needs to be addressed. Especially since a negative amyloid marker firmly rules out AD, although co-pathology of AD may occur in sv-PPA and av-PPA, yielding positive amyloid biomarkers, while the causative underlying pathology may be non-AD . The hypometabolic pattern on FDG-PET is supportive in these cases providing information on the extent and localization of neuronal dysfunction, and thus the endophenotype of neuronal injury. In this way, FDG-PET may give indirect information on a supposedly underlying molecular pathology, such as TDP43 pathology in semantic dementia. Actual and direct information on the underlying neuropathology naturally requires more specific biomarker and/or genetic analysis. All in all, though, the aim of the EANM-EAN initiative, and of this paper, was limited to assessing the incremental value of FDG-PET over clinical assessment, to give a guideline specific to the use of FDG-PET in a clinical setting. We should also consider that both CSF analysis as well as amyloid PET are not widely available in all memory clinics yet, whereas FDG-PET is a widely used technique also in other specialties such as oncology, and therefore widely available in most memory clinics. In the future, when CSF analysis, amyloid PET, and possibly other neurodegenerative biomarkers and/or tracers  become widely available for clinical purposes, a formal comparison with FDG-PET will be needed to define a cost-effective algorithm for diagnosis in PPA and dementia in general , 16.Panelists also mentioned that solving standardization issues  may overcome some of the current heterogeneity in FDG-PET diagnostic performance , 17, as The main limitation of the present study consisted in the fact that the evidence assessment had to be performed, to the best of our methodological resources, on literature characterized by important methodological limitations. In order to evaluate and compare quantitatively the incremental value of diagnostic tests, only papers reporting validated measures of test performance could be included for analysis. Thereby, as many as 12 out of the 16 papers found in the literature had to be excluded, although they performed investigations potentially relevant to the PICO question. Information on sensitivity and specificity, and, even more, measures of test performance that be independent on the prevalence of the disease in the population  are mandatory to allow assessment of incremental diagnostic value, and thus the definition of evidence-based diagnostic guidelines. To allow comparison of diagnostic methods such as FDG-PET, we encourage research groups to compute and report these critical outcome measures in future publications, since this can usually be easily done with the data normally collected in this kind of study.On the other hand, the lack of direct quantification of patient outcomes  following FDG-PET-based diagnosis is a main limitation not solvable in the short term. However, even accepting accuracy studies as proxies for more appropriate patient management , 25, manAlso for this set of reasons, these recommendations are defined late compared to other diagnostic appropriate use criteria, e.g., those for amyloid-PET , which aNotwithstanding the heterogeneity of results and poor evidence in the literature, consensus was achieved on Delphi Round I, when six out of seven panelists (being experienced clinicians in neurodegeneration of both neurology (EAN) and nuclear medicine (EANM)) supported clinical use of FDG PET in PPA. With synaptic failure being an earlier phenomenon than atrophy, FDG-PET is particularly valuable for the differential diagnosis between different forms of primary progressive aphasia. This recommendation may be weighted based on the availability of other kinds of examination more directly investigating underlying pathophysiology, which comparison was not the focus of the present paper.


Preeclampsia is a hypertensive disorder affecting 3–5% of all pregnancies. The only curative treatment is delivery of the placenta and the pathophysiology is poorly understood. Studies have demonstrated altered levels of antiangiogenic factors in patients with preeclampsia. One such factor is the antiangiogenic and antivasodilatatory peptide hormone vasoinhibin, which is higher in the circulation, urine, and amniotic fluid of women with preeclampsia. Normal pregnancy is characterized by elevated circulating prolactin and placental lactogen levels, both of which can serve as vasoinhibin precursors when they are enzymatically cleaved. A dysregulation of vasoinhibin generation during preeclampsia is indicated by higher vasoinhibin, prolactin, placental lactogen, and vasoinhibin-generating enzymes levels and activity. The present article integrates known vasoinhibin levels, effects, and signaling mechanisms to the clinical characteristics of preeclampsia to substantiate the notion that vasoinhibin dysregulation can be causally linked to the development of preeclampsia. If this view is demonstrated, assessment of vasoinhibin levels and regulation of its activity could help estimate the risk of preeclampsia and improve its treatment. Preeclampsia (PE) is a severe complication of pregnancy, defined by gestational hypertension and proteinuria after the 20th week of pregnancy . HyperteA role of PRL in preeclampsia has first suggested around 1975 by Redman, Horrobin , 12, andDue to the rise of vasoinhibin precursor levels, the state of pregnancy as such is a predisposition for a dysregulation of the prolactin/vasoinhibin axis. Vasoinhibin-generating enzymes may utilize a manifold higher supply of substrates, and their activity and regulators in the tissue microenvironment would control both, their normal pregnancy-adapted vasoinhibin levels, as well as the pathological (suppressed or excessive) vasoinhibin levels. Circulating PRL levels start to rise in pregnant women at week 10 and reach up to ≅ 200 ng/ml at week 40 of pregnancy . At 1 wein utero placental tissue through the action of various cleaving enzymes such as cathepsin-D. The incubation of PRL with lysates from placental trophoblasts results in its conversion to vasoinhibin, and addition of pepstatin A, a cathepsin D inhibitor, abolishes such conversion. The generation of vasoinhibin is significantly higher when lysates from women with PE are used, compared to lysates from normal pregnant women, indicating a higher activity of cathepsin D in the placenta during PE . Decreased levels of VEGF and NO occur in PE and inhibition of placental VEGF action and NO production causes reduced perfusion of the fetoplacental unit, hypertension, proteinuria, and fetal growth restriction, indicating that blockage of VEGF-induced NO production is causal in preeclampsia . VasoinhAltogether, a sequence of events throughout pregnancy, from the rise of vasoinhibin-precursors, an upregulation of vasoinhibin-generating enzymes, an excessive vasoinhibin generation in the placenta or elsewhere, high vasoinhibin levels in the maternal circulation and other compartments, and the consequence of PE manifestation, points toward a dysregulation of the prolactin/vasoinhibin axis in PE . A causaSeveral publications reported a possible involvement of vasoinhibin to the pathophysiology of preeclampsia . The majThe present analysis reinforces the recommendation that a detection of vasoinhibin levels in blood, urine and amniotic fluid can be useful for screening of PE onset, and as a prognostic marker when PE is manifested . Also, pFurther consolidation and clinical evaluation will demonstrate whether the assessment of vasoinhibin levels, its precursors and regulatory enzymes can contribute to estimate the risk of preeclampsia or to improve its treatment.LL and JT wrote the draft of the manuscript. GM, CC, and TB contributed critical revisions and intellectual content. All authors approved the final version 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.


This Frontiers Research Topic provides an inter- and multi-disciplinary platform for reviews and researches dedicated to microbial biotechnology providing bio-based components for the food industry. The findings presented in this special issue give a foundation for enlarging the current exploitation of the metabolic diversity in fungi, yeasts, bacteria, and microalgae for improved production of food and other industrial products. Thus, this topic did appeal not just to those interested in the screening and metabolic investigation of microorganisms but also to the industrial biotechnology, the process optimization, the fermentation technology, and the bio-products research community.Ingredients derived from microbial fermentation or extracted from microalgae are steadily gaining ground in the food industries Dufossé, . ThickenThe special issue emphasizes the crucial role that microorganisms and microalgae are currently playing and are likely to continue to play in future as microbial cell factories for the production of food grade components and bio-based ingredients in general. This is due to the versatility in their metabolic pathways and biochemical profiles, amenability for easy large-scale cultivation, and a long history of production by well-investigated production strains. Topics broadly cover studies in Screening and selection, Molecular traits, Metabolic investigation and regulation, Analytical chemistry, Physiology and biochemistry, Process optimization, Fermentation, Extraction techniques, Biomass and bio-products, Cultivation technology, Formulation and applications.Joseph et al. have reviewed the current state and the perspectives of bioproduction of the recombinant sweet protein thaumatin, which is one of the most promising alternatives for sugar and artificial sweeteners. Recombinant DNA technology is used in the most favorable host known today, the methylotrophic yeast, Pichia pastoris.Sen et al. have provided comprehensive information about challenges and the way forward for application of microbial pigments in the food industry.Liu et al. have examined the diversity of chemical structures from Monascus, including chemical modification of orange Monascus pigments and fine analyses of commercial red and yellow Monascus pigments present in Chinese market.In the same pigments and colorants scientific field, Kallscheuer wrote a systematic study about engineered microorganisms for the production of food additives approved by the European Union. Currently, the list of substances authorized by the European Food Safety Authority (EFSA) (referred to as “E numbers”) comprises 316 natural or artificial substances including small organic molecules, metals, salts, but also more complex compounds such as plant extracts and polymers. It is impressive that a broad range of different compounds ranging from small organic acids to more complex secondary metabolites or polymers such as oligopeptides can now be accessed by tailor-made microbial cell factories.As a global approach Ali et al.), (ii) wheat, rice, corn, and amaranth flour proteins treated with microbial transglutaminase, followed by immunoreactivity testing of gluten-sensitized sera toward modified flours , (iii) bioconversion of beet molasses to alpha-galactosidase and ethanol , (iv) production of fructooligosaccharides from aguamiel, the sap from agave plants , or (v) degradation of toxic steroidal glycoalkaloids from potato juice, a by-product of the potato industry, of the starch processing .Many articles of this special issue emphasize the power of microorganisms which are able to modify, to improve the properties of many food products or by-products: (i) production from whey of peptides with bacterial antivirulence effects  and the second one on the induction of malolactic fermentation of Patagonian Malbec wine with blend cultures of native Lactobacillus plantarum and Oenococcus oeni strains .Two papers focused on beneficial effects of microorganisms and microbial metabolites on food preservation. First one on the biopreservative efficacy of Liu et al. with small GTPases involved in Monascus ruber, a filamentous fungi used for more than a thousand years in Asia for the production food ingredients or as demonstrated by Sgobba et al. who genetically modified Corynebacterium glutamicum for utilization of alternative feedstocks such as pentose sugars or hexosamines, to produce the amino acids L-glutamate, L-lysine, and the carotenoid lycopene.Fine tuning of primary and secondary microbial metabolisms is also of crucial importance, as shown by Taken all together, all the papers gathered in this Research Topic illustrate how microbial cell factories  are able to provide at an industrial scale biobased components for the food industry.Last but not least, we, as Frontiers Guest Editors would like to deeply thanks all the referees for their huge input in handling the manuscripts, and the Frontiers Editorial team.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.