Nutritional support continues to receive much attention as a possible intervention to prevent loss of lean tissue mass, promote recovery and re-establish proper immune function in critical care patients. Yet there remains much controversy regarding the clinical efficacy of such interventions. In addition to the direct effect of nutrition in terms of micro- and macronutrient content, nutritional formulations may exert an effect via the physiological response to feeding. Here, we highlight the key role of postprandial reabsorbed bile acids in attenuating both the inflammatory response and autophagy. These observations suggest that not all patients would benefit from aggressive nutritional support. Three observations strongly suggest that sickness-associated anorexia (SAA) serves an important function during an infection. First, the fact that inflammatory mediators such as interleukin-1 beta (IL-1β), IL-6 and tumour necrosis factor (TNF) induce SAA ). Also, Notwithstanding these considerations, nutritional support is administered in various contexts. The implementation of aggressive nutritional support is motivated by two considerations. First, it is often argued that a decrease in appetite removes the incentive for foraging behaviour, thereby conserving energy for other critical functions such as the mobilisation of the immune response. However, nutritional support can be administered to patients without the associated metabolic cost of gathering food. Second, activation of an inflammatory response is associated with a remarkable increase in metabolic rate, leading to a severe nitrogen deficit and the loss of lean tissue mass. In addition, critically ill patients are most often immobile which likely aggravates the catabolism of lean tissue. Since the loss of lean mass is associated with an increase in mortality and morbidity, nutritional support not only may halt the extensive catabolism in critically ill patients but also may avert malnutrition. These considerations then provide a rational justification for implementing nutritional support in critically ill patients.Despite these considerations, there is currently no single study providing “unequivocal evidence that feeding protocols targeting full-replacement nutrition early in the course of critical illness result in clinical benefits” . A numbeHere, we argue that a major mechanism by which nutritional support mediates its therapeutic effects relates to the hormonal effect of postprandial reabsorbed bile acids (BAs). In particular, BAs may attenuate the inflammatory response transcriptionally but also could compromise lipopolysaccharide (LPS) clearance by attenuating the expression of scavenger receptors as well as autophagy, a cell survival response. Emerging evidence has also implicated BAs as transcriptional inhibitors of autophagy. Furthermore, evidence has demonstrated that BAs alter the vascular system, suggesting that postprandial reabsorption of BAs may have an impact on the development of shock. Finally, we briefly point out that nutritional support may exert other clinically relevant effects such as altering the microbiome. Taken together, these observations strongly suggest that, during an infection, nutritional support may curtail immunological functions and compromise autophagy but conversely may also prove beneficial in averting an excessive inflammatory response to sterile injury.Following a meal, fatty acids in the lumen of the gut induce the release of cholecystokinin, which in turn causes the sphincter of Oddi to relax and bile to flow into the small intestine. Of note, the fatty acid chain length plays a vital role in regulating the release of cholecystokinin, and long-chain fatty acids provide a much more pronounced release of cholecystokinin , 7. MechAlthough BAs are typically associated with digestion, BAs have long been known to mediate an anti-inflammatory effect. As an example, BAs induced a 50% suppression of IL-6, IL-1 and TNF-α in monocytes at a concentration of between 60 and 80 μmol/L . SimilarMechanistically, it is now well established that the reabsorbed secondary BAs act as hormones targeting cell surface G protein–coupled BA receptors  and the nuclear receptor, farnesoid-X-receptor (FXR) , which aBAs may also indirectly alter the inflammatory response by compromising LPS clearance. The scavenger receptor class B type I (SR-BI) plays an important role in transporting cholesterol associated with high-density lipoprotein (HDL) into a range of cells, including macrophages and hepatocytes . LPS alsTaken together, these observations demonstrate that nutritional support may exert clinically relevant effects through the subsequent reabsorption of BAs. The effect of BAs may be particularly relevant in the context of bacterial infection: given the observation that hepatic clearance of LPS is important in preventing excessive inflammation , it is pet al. [Another important consequence of feeding is the suppression of autophagy. Here again, the postprandial reabsorption of BAs has been shown to attenuate autophagy transcriptionally via the activation of FXR. FXR activation suppresses the expression of various proteins involved in autophagy by antagonising the function of other transcription factors such as cAMP response element-binding protein (CREB) . Similaret al.  recentlyet al.  and posset al. .Indirect evidence also suggests that the inhibition of autophagic/lysosomal function may result in a compromised ability to clear LPS during an infection. Earlier studies have documented the localisation of LPS within lysosomal vesicles . In thisIt is thus evident that increased BA reabsorption as a result of nutritional support may alter the immune response and impact on the inflammatory status of a patient. However, BAs have also been implicated in a range of other clinically relevant contexts. As an nutritional support may also complicate haemodynamics, not only by directly increasing blood flow towards intestines but also indirectly through the effect of BAs on the liver. It has long been noted that BAs cause an increase in blood flow through the splanchnic circulation . In hepaThere is also a need to evaluate the role of BAs in other peripheral systems beyond the liver. BAs have been shown to alter haemodynamic parameters outside of the enterohepatic circulation, which collectively result in decreased blood pressure (reviewed in ). This iOther evidence suggests that BAs may have a protective role in liver regeneration. Cholic acid has been shown to promote liver regeneration in mice in an FXR-dependent manner . SimilarConversely, in both rats  and humaTaken together, these observations highlight a number of mechanisms by which BAs mediate clinically relevant physiological response Fig. . It is tFinally, although we have focused on postprandial BAs, it is also worth noting that other elements of nutrition may have adverse effects on critically ill patients. As an example, iron is the rate-limiting element in bacterial growth, and it is now well established that iron withdrawal plays an adaptive immunological function directed at starving bacteria of this critical element . Yet it It is thus clear that elevation of BAs resulting from nutritional support may alter autophagy and inflammation and possibly impact the development of shock. Collectively, these observations suggest that nutritional support may be more beneficial in patients where an immediate threat of infection is not present or where an anti-inflammatory effect is pursued. However, it is not clear how elevated BAs after a meal and the elevation of BAs in other disease states  are functionally related. There is also a need for more targeted studies aimed at elucidating the direct effect of BAs and the possible therapeutic application of BA supplementation in critically ill patients. Finally, the potential impact of postprandial reabsorbed BAs highlights an important consideration: nutritional support may exert effects that extend beyond the nutrient needs of the patient.


Successful aging is a construct regularly addressed in the gerontological literature, most typically referred to as living in the best physical and cognitive health possible, experiencing the least amount of disease, and engaging actively within one’s social environment. There are, however, conceptually distinct aspects of aging for older adults who identify as transgender, particularly given lifelong experiences of marginalization and stigma. In order to identify factors transgender older adults consider most relevant to successful aging, a Theory-Generating Qualitative Meta-synthesis was conducted. The study utilized systematic methods and thematic analysis with qualitative data from empirical studies focusing on transgender aging experiences, particularly drawing upon data that amplified the transgender older adult point of view. Findings of this study indicate that although trans older adults do not minimize unique challenges inherent to aging as a gender minority, successful aging rests on the relief and resilience offered by authentic gender expression. As such, data from this study informed the development of a model of successful aging that centralizes the importance of gender expression. Understanding the central role of gender expression in later life can be especially impactful for social and health service providers, as it emphasizes gender affirming experiences as highly salient to one’s own assessment of quality aging. Furthermore, conceptualizing aging for transgender elders in a way that prioritizes the importance of identity can aid in preventing an unnecessarily deficits-based perspective for service providers, and supports the necessity of amplifying a culturally specific understanding of successful aging.


Cytokines are key cell signalling proteins in a number of immune and homeostatic pathways of the human body. In particular, they mediate intracellular mechanisms of allergy on the ocular surface by triggering cellular responses that result in typical physiological ocular allergy symptoms, such as itchiness, watery eyes, irritation, and swelling. Given the recent research focus in optometry on the aetiology of corneal ectasia subtypes like keratoconus, there is an increasing need for the development of new clinical diagnostic methods. An increasing trend is evident among recent publications in cytokine studies, whereby the concentrations of cytokines in healthy and disease states are compared to derive a specific cytokine profile for that disease referred to as ‘biosignatures’. Biosignatures have diagnostic applications in ocular allergy as a cheap, non-invasive alternative to current techniques like IgE antibody testing and skin prick tests. Cytokine detection from tear samples collected via microcapillary flow can be analysed either by enzyme-linked immunosorbent assays (ELISA), multiplex magnetic bead assays, or immunoblot assays. Characterising patient hypersensitivities through diagnostic tests is the first step to managing exposure to triggers. Investigating cytokine biosignatures in ocular allergy and their links to physiology are imperative and will be the focus of this systematic review article. The global impact of allergy is on the rise, with over 40% of the population currently suffering from some level of hypersensitivity . AllergyCurrent diagnostic methods for allergy rely heavily on patient history, subjective physical assessment, and grading of ocular symptoms. Alternative objective tests are invasive, requiring blood samples or multiple pricks with small volumes of allergens in a skin prick test (SPT) . Blood sTo diagnose ocular allergy conditions with tear cytokines, preliminary research into ocular allergy and regulatory tear cytokines is imperative. Ocular allergy is a localised allergy occurring in 40–60% of allergic populations . Key feaOcular allergy is divided into four clinical subtypes: seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are most common, followed by vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) . SAC andThere are a number of cellular changes that occur among ocular allergy patients during an episode ,20. MostPhysical symptoms of ocular allergy on the surface of the eye are controlled by interactions between cells and cytokines on a subclinical level . CytokinThis review focuses on deviant levels of regulatory cytokines in ocular allergy and their theoretical clinical applications in diagnosis and in the rationalisation of ocular allergy symptoms. A vast majority of cytokine concentration increases are linked to one another due to not-yet clearly defined biochemical mechanisms of ocular allergy. What is known about cytokines in allergy, however, is that they play a major role in the upregulation of IgE and may thus have a direct link to the magnitude of allergic responses . IncreasThere are a number of techniques available for analysing cytokine levels in the tears of ocular allergy sufferers. In 2000, Schultz and Kunert used polyacrylamide gel electrophoresis (PAGE) followed by immunoblotting to determine the concentration of IL-6 in the tears of contact lens wearers . This prMultiple studies of inflammatory mediators in allergy rely on ELISA for quantitative analysis, due to the high sensitivity and reproducibility of results . The priGiven the important regulatory role of the tear film, most cytokines detected in healthy subjects are inflammatory. A summary of these regulators is shown in During cellular proliferation, IL-1, IL-2, and IL-3 have primary roles in maintaining the ocular surface and replacing damaged cells, as well as acting as a sort of alarm system that triggers allergic pathways once they reach a certain concentration . SimilarThe current research in ocular allergy focuses on using cytokines as biomarkers by quantifying their concentrations to diagnose immune and genetic disorders ,43,44. TN < 100) datasets, leading to high variations in cytokine biosignatures [Most cytokines shown in gnatures . ConductA study by Willcox et al. from 2015 states that degree of ocular irritation is not directly related to cytokine concentration variations . HoweverFuture prospects for this field are plentiful. Full cytokine biosignature characterisation for ocular allergy will allow research to progress to flow cytometry as a means of investigating intracellular cytokine roles in the allergic pathway on the surface of the eye . LinkingImprovement of current treatment options is a potentially important future field of research. Typical treatment options for ocular allergy include anti-histamines and mast cell stabilizers, taken orally either before or during a reaction to reduce degranulation of immune cells . IntranaUtilising cytokine-centric ocular allergy research, development of a drug that directly inhibits cytokine signalling on the ocular surface, in the form of eye-drops or oral tablets, could be a universally beneficial alternative that is not subject to individual sensitivities. Similar technologies are currently being developed, with a study by Chassin et al. in 2017 reporting the development of a lab-synthesised dual Th2 cytokine sensor (DCS) device modelled on mammalian cells . This DCDrugs like tralokinumab are currently being used in treatment of allergic disorders such as atopic dermatitis . TralokiA paper by Bahn in 1998 suggests that the lack of current anticytokine therapies is due to the unpredictable and potentially devastating impact of inhibiting singular cytokine production as a result of their highly pluripotent nature . As suchIn addition, this proposed meeting of optometry and biomedical science could spark the future development of hypoallergenic contact lenses to reduce the impact of allergens on the eye while functioning regularly to correct vision. Such a product would be revolutionary in optometry, and could drastically alter the impact of eye rubbing-induced vision loss and corneal degradation that is currently on the rise. It would also contribute to the not-yet consolidated, although thoroughly hypothesised link between ocular allergy, contact lens wear, and corneal degradation that may progress further to corneal ectasia . More reLaying the groundwork for cytokine biosignature studies in ocular allergy is imperative for ensuring bigger-picture disease research is based on factual and robust data. Compiling an ocular allergy biosignature does not only impact this subsection of the global population but provides a framework for investigating cytokine pathways in ocular degeneration which could change the future of keratoconus sufferers by shedding light on the cellular basis of gradual thinning and sagging of the cornea they experience, and may contribute to prevention or treatment . Beginni


Is being bilingual/multilingual an advantage? The answer, invariably, is yes. The reasons provided are intuitively sensible and leave little room for disagreement. Multilingual speakers can communicate with different people, they understand different cultures, they have more job opportunities, they can travel the world with more confidence, and so forth.When we ask our students or members of the general public the question Is being bilingual/multilingual an advantage for cognitive development? Answers are not as straightforward. Some are concerned that second language learning may delay language acquisition in early stages of life, others think that children should focus more on one language to avoid mental confusion. In some cases, and this is probably the most disturbing situation, education professionals advise parents from different cultures to raise their children as monolinguals, advocating that this is more likely to lead to good academic achievement , indicating that second language learning may have modest implications for the development of social competence, although well-grounded explanations for this association are currently lacking.Mercure et al. explored attention to still faces in monolingual infants, unimodal bilingual infants  and bimodal bilingual infants of Deaf mothers (learning British Sign Language and spoken English). Equivalent attention capture and maintenance by face stimuli was observed in monolinguals and bimodal bilinguals, but unimodal bilinguals showed comparatively faster attention capture and maintenance, raising implications of multilanguage learning for social communication during infancy. Poarch provides a replication study with findings partly consistent with the central claim of the bilingual advantage theory, that controlling multiple languages in daily life confers genuine benefits in domain-general cognitive control. Specifically, equivalent performance among monolingual and bilingual children was observed on the Simon task, but the bilinguals demonstrated a significant advantage on the flanker task, indicating that these tasks may recruit partly distinct mechanisms of cognitive control that are differentially sensitive to language environment and may also follow different developmental trajectories. Struys et al. also employed the Simon and flanker tasks in a comparison of performance among younger and older monolingual and bilingual Dutch-French children. They report equivalent performance across language groups but, crucially, there was marked variation in the actual strategies employed to resolve conflict in the tasks. This finding is consistent with recent (currently unpublished) work from our lab which indicates significant differences in the neural networks recruited among bilingual and monolingual participants when resolving conflict despite the absence of any group effects at the behavioral level.Five studies address the impact of multi-language experience on cognitive control in infants or children. Janus and Bialystok consider the reported association between executive function and emotion regulation, arguing that bilingual advantages in executive control may, intuitively, also underpin performance benefits in emotional contexts. However, in their study of emotional face N-back task performance in monolingual and bilingual children, there were no group differences in the overall effect of emotional valence on reaction time . Czapka et al. present a novel and intriguing study of real word and non-word spelling in monolingual and bilingual third grade (~9 year-old) primary school children in Germany, providing compelling evidence that monolinguals at this age are better able to deploy higher level cognitive control during spelling, most likely due to superior knowledge of the German language. For bilinguals, German lexicon size was a better predictor of spelling ability than executive function. These findings reinforce the importance of adopting a fine-grained, developmentally informed approach to charting interactions between multi-language learning and cognitive development, without which we are unlikely to resolve the contradictory claims and entrenched positions so prevalent in the recent literature.Naeem et al. address the potential importance of an alternative explanatory variable: socioeconomic status (SES). Employing demonstrably low and high SES monolingual and bilingual participants, these authors found evidence (from Simon task performance) that bilingualism may promote a speed of processing advantage, but only in those with low SES. Furthermore, there was no evidence for a bilingual advantage in executive planning ability (based on Tower of London performance), with monolinguals showing a disproportionate advantage. Van der Linden et al. explore interference suppression, response inhibition, and short-term memory performance in professional simultaneous interpreters. To the extent that bilingual cognitive advantages are associated with the requirement to manage and control simultaneously active languages in daily life, the authors argue that a comparison of such highly skilled bilinguals against monolinguals should increase the likelihood of detecting a bilingual advantage, if it exists. In fact, the two groups performed similarly on all measures , a finding reinforced in a second experiment which incorporated an additional group of second language teachers. Despite anecdotal evidence for an STM advantage over monolinguals among interpreters, this evidence is clearly difficult to reconcile with bilingual advantage theory. In their study on the effect of language similarity on the association between linguistic performance and executive function, Oschwald et al. found very limited evidence for benefits in executive function associated with the increased demands of managing more dissimilar languages. These results, therefore, also offer evidence against the claim that managing cross-language interference promotes or enhances executive function. Evidence presented by Borragan et al. provides a possible explanation for lack of transfer from control of language interference to non-verbal executive function. These authors examine performance in highly proficient but unbalanced bilinguals on a multilingual rapid picture naming task incorporating multiple inhibitory demands. Findings are most consistent with the existence of functionally independent inhibitory mechanisms associated with language processing which may not be recruited in non-verbal tasks.Seven studies examine bilingual processing in adults, each of which focuses on a key issue in current debate. Paap et al. In this study, no effects attributable to bilingualism were observed on the tasks whether (i) participants were separated into monolingual or bilingual groups or (ii) degree of bilingualism was treated as a continuous variable, and Bayes factor analyses robustly supported the null hypothesis. The study by Goldsmith and Morton tests recent evidence by Grundy et al. (Frontiers (available here), outlining that the study is not a direct replication but differs in several ways. Perhaps, most importantly, they point out that Goldsmith and Morton employ long rather than short response-to-stimulus intervals, and it is at short intervals that language group differences in the disengagement of attention can most readily be observed.Further evidence against the existence of a genuine bilingual advantage, either in attentional control or response inhibition is presented by y et al.  that bilSundaray et al. take the novel approach of addressing non-literal language (pragmatic inference making) in young and older monolingual and bilingual participants. With the exception of conventional metaphors  no differences between language groups in processing pragmatic inferences were observed. Thus, the evidence here suggests a possible protective effect of bilingualism in comprehension of non-literal language, restricted to conventional metaphors.The possibility that bilingualism may offer protection against age-related cognitive deterioration and/or neural degeneration is an important issue in the literature. Rather than addressing vocabulary, syntax, or comprehension, There are many challenges in this line of research, but when there is challenge there should also be opportunity to advance knowledge. In collecting these articles within a single volume, we hope readers will take the opportunity to digest the full range of empirically supported inferences, and further develop a well-informed understanding of how (and the extent to which) the process of acquiring a second language confers domain general cognitive benefits.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.


Early recognition and pre-notification by emergency medical services (EMS) improves the timeliness of emergency department (ED) stroke care; however, little is known regarding the effects on care should EMS providers fail to pre-notify. We sought to determine if potential stroke patients transported by EMS, but for whom EMS did not provide pre-notification, suffer delays in ED door-to-stroke-team activation (DTA) as compared to the other available cohort of patients for whom the ED is not pre-notified–those arriving by private vehicle.We queried our prospective stroke registry to identify consecutive stroke team activation patients over 12 months and retrospectively reviewed the electronic health record for each patient to validate registry data and abstract other clinical and operational data. We compared patients arriving by private vehicle to those arriving by EMS without pre-notification, and we employed a multivariable, penalized regression model to assess the probability of meeting the national DTA goal of ≤15 minutes, controlling for a variety of clinical factors.Our inclusion criteria were met by 200 patients. Overall performance of the regression model was excellent (area under the curve 0.929). Arrival via EMS without pre-notification, compared to arrival by private vehicle, was associated with an adjusted risk ratio of 0.55  for achieving DTA ≤ 15 minutes.Our single-center data demonstrate that potential stroke patients arriving via EMS without pre-notification are less likely to meet the national DTA goal than patients arriving via other means. These data suggest a negative, unintended consequence of otherwise highly successful EMS efforts to improve stroke care, the root of which may be ED staff over-reliance on EMS for stroke recognition. Optimizing the management of acute ischemic stroke is a priority for emergency departments (ED).13Multiple studies have demonstrated that pre-notification for acute stroke has improved timeliness of care including time to imaging,We postulated that EMS recognition and notification of acute stroke may be so effective that failure to pre-notify by EMS may influence timeliness of recognition of stroke symptoms by ED staff after ED arrival. We theorized that among patients for whom EMS did not recognize stroke symptoms, arrival by EMS may be associated with delays in subsequent stroke team activation by ED staff, compared to patients for whom only ED staff were responsible for recognizing stroke .Get With The Guidelines recommendations have been implemented,This was a cohort study in which we employed a previously developed methodology to retrospectively query the prospective stroke registry of our urban, regional referral stroke center hospital to identify all consecutive patients who presented to the adult ED and met criteria for stroke team activation between June 15, 2014, and June 15, 2015.What do we already know about this issue?Stroke patients for whom emergency medical services (EMS) provides prenotification to the receiving hospital experience improved timeliness of care including time to imaging and stroke activation.What was the research question?Do stroke patients arriving by EMS without prenotification experience the same timeliness of care as those presenting in a similarly undifferentiated state to triage?What was the major finding of the study?Stroke patients arriving by EMS without prenotification experience poorer timeliness of care than those who arrive to triage.How does this improve population health?This finding suggests the need for improved Emergency Department provider awareness of EMS patients with potential stroke as well as the need for increased awareness for EMS providers as well.Given our geographic location and tertiary care status, the catchment area for potential stroke patients is large. Approximately 25 unique EMS agencies bring patients to our facility each year, almost all advanced life support services. EMS providers provide pre-arrival notification via radio for all inbound patients and give in-person handoff directly to ED nursing staff. EMS providers are encouraged to independently activate the stroke team from the field for patients who have a positive prehospital stroke screen. For patients without prehospital activation, ED nurses receiving in-person handoff are empowered to activate stroke resources independently, prior to physician involvement. For potential stroke patients not recognized by either EMS or ED nurses, stroke resources may be activated by a physician.EMS providers undergo stroke recognition education as part of their biannual continuing education. In Massachusetts, EMS providers operate under standardized prehospital statewide treatment protocols, and stroke assessment is performed under the guidance of these protocols using, at the time this data were gathered, the Massachusetts Stroke Scale (MASS) or “or equivalent nationally recognized stroke scale.”16Our investigation was approved by the University of Massachusetts Medical School Institutional Review Board.By protocol, the stroke team was activated when any patient presented to the ED with symptoms or findings consistent with an acute stroke within 12 hours of symptom onset. Our multidisciplinary stroke committee previously established the 12-hour window, accounting for three key considerations: prioritizing sensitivity over specificity for the mobilization of the stroke team and resources, availability of resources enabling possible treatment beyond 4.5 hours of symptoms in select cases, and institutional research protocols. The committee felt that the potential patient benefit to be gained from this expanded window outweighed the potential inefficiencies it may have caused. Because the key criteria for stroke team activation were symptoms or findings consistent with stroke at the time of activation, some patients within the registry may have had an ultimate diagnosis other than stroke, such as transient ischemic attack.The institution maintains a prospective registry of all patients for whom the stroke team is activated, which includes patient demographics and time stamps for care events, including ED arrival, stroke team activation, computed tomography completion, and thrombolytic administration time. A stroke nurse coordinator maintains the registry and verifies its accuracy based upon established institutional guidelines. Numerous automated and manual processes exist to ensure 100% registry capture of all patients for whom stroke resources are activated.Research assistants (RA), blinded to the study aims, were trained in data abstraction from the electronic health record (EHR). One study author independently abstracted at least the first 10 encounters reviewed by each RA to test for rater reliability, and there were no discrepancies. A formal analysis of inter-rater reliability was not performed. The RAs retrospectively reviewed the EHR  for each patient in the registry to validate the registry data and abstract the following fields (determined a priori) using standardized abstraction forms: mode of arrival (EMS vs non-EMS); prehospital stroke activation (yes or no); initial vital signs ; supplemental oxygen use and delivery method ; Glasgow Coma Scale score (GCS); level of orientation ; National Institutes of Health Stroke Scale (NIHSS) score; initial blood glucose value; elapsed time since the patient was last known to be at his or her baseline neurologic condition; previous history of stroke or transient ischemic attack; previous history of diabetes mellitus; and previous history of hypertension.In order to identify cases in which staff inadvertently omitted documentation of prehospital activation, in the case of patients for whom there was not specific documentation regarding prehospital activation, we also compared the stroke team activation timestamp and the ED arrival timestamp. If the activation time occurred prior to the patient’s arrival, we considered prehospital activation to have occurred. Abstractors also reviewed the EHR to determine whether the ED team documented treatment of another emergent, life-threatening condition that may have delayed stroke recognition or care, such as airway/breathing intervention required, hypertension, hypotension, hypoglycemia, emergent electrolyte abnormality, or more than one of the above conditions. Rare missing values in the registry were obtained from the EHR by the abstractor.A second investigator independently searched the EHR for missing values after the initial abstraction and also independently validated all abstracted data for a subset of cases primarily abstracted by each RA. Missing values not available in either the registry or the EHR  were replaced with the corresponding median value for the remaining data set, except for GCS, which was replaced with the value 15, after verifying that the remaining registry fields and NIHSS supported such as value. One entry in the registry was an exact duplicate, so the affected patient was analyzed only once. For 12 patients, there were conflicting entries between the EHR and the stroke registry as to the mode of arrival. Two senior investigators, not involved in initial abstraction (Martin Reznek and Sean Michael), reviewed each of these cases independently and blindly and had agreement upon the mode of arrival for 10 of the 12 patients (Cohen’s kappa=0.81). The two patients for whom consensus was not reached were excluded from analysis. We have previously validated and employed a similar abstraction and data verification methodology for another registry-based study.17Based on the electronic timestamps for ED arrival and stroke team activation, we calculated the door-to-activation (DTA) time for each patient in the stroke registry. We chose DTA to isolate any subsequent variation in stroke care processes from the process we wished to study–that of time to stroke recognition and the effect of EMS pre-notification. All subsequent stroke care processes are dependent on timely recognition of stroke syndromes and activation of stroke resources, the most appropriate measure of which is DTA. National guidelines stipulate a goal of stroke team activation within 15 minutes of patient arrival. We selected this dichotomous variable of DTA ≤ 15 minutes as our primary outcome given its prevalence in the literature as a key step in ED stoke care.Secondary clinical outcomes were admission to a neurology service, final ED diagnosis of stroke or intracranial hemorrhage, and administration of IV thrombolytics or neurointerventional procedure, which were recorded directly in the registry and verified in the EHR.Our routine quality monitoring data suggested that approximately 72% of patients achieved DTA ≤ 15 minutes, so we estimated that the sample size required to demonstrate a two-sided difference in proportions of 10 percentage points with 80% power was 179, which was achievable using one year of registry data. We filtered the dataset to include all patients who either did not arrive via EMS or who arrived via EMS but did not have stroke team activation initiated from the prehospital setting or immediately upon arrival. Patients transferred from other facilities for stroke care were excluded, as their symptoms were, presumably, already recognized. We excluded patients with documentation of another emergent, life-threatening condition that may have delayed stroke team activation and occurred prior to activation or initial neuroimaging. Patients for whom the documented duration of symptoms was shorter than the DTA time  were reviewed for potential exclusion by full-text review of the EHR documentation by a senior investigator, but no cases of documented symptom onset while in the ED were identified in the included population.Our primary predictor of interest was mode of arrival . We chose our comparison groups because they represent a population presenting to the ED without prior knowledge that a stroke is suspected, which allows for assessment of the time to recognition of stroke symptoms. In contrast, comparing EMS arrivals with prehospital activation to either other category risks an unbalanced comparison. We identified 17 additional candidate predictors by investigator consensus, which are listed in Specifics of our statistical data analysis are available in There were 490 consecutive stroke activation patients in the registry during the study period. Of these, 383 arrived via EMS, with 277 (72.3%) presenting with EMS stroke pre-notification. Of the 213 patients who arrived either by EMS without pre-notification or arrived by other means, 11 were documented to have delays in stroke care due to a more emergent management consideration  and were excluded. NIHSS was captured on 100% of patients. Clinical outcomes of included and excluded patients are shown in the study flow diagram . Tables Of the 200 included patients, 83 (41.5%) achieved DTA ≤ 15 minutes, and DTA ranged from < 1 minute to 3 hours 37 minutes . Among patients who arrived via EMS without prehospital activation, 32.1% achieved DTA ≤ 15 minutes , compared to 52.1% among patients who did not arrive via EMS .Overall performance of the multivariable regression model was excellent, with area under the curve 0.929. Parameter estimates for all terms are listed in Our investigation found that potential stroke patients arriving without EMS pre-notification were only 55% as likely to meet the national 15-minute goal for DTA time as those arriving via means other than EMS. This striking finding is important and likely reflects an unintended, negative consequence of the ongoing emphasis on prehospital recognition of stroke and activation of in-hospital resources by EMS. While it is well known that pre-notification hastens ED stroke care processes, this is the first study to show that failure to pre-notify actually results in erosion of timeliness of care.Even when controlling for demographics, patient factors , stroke severity (including NIHSS and duration of symptoms), and propensity to arrive via EMS, stroke patients arriving via the “front door” enjoyed more timely recognition and resource activation by ED staff than those arriving via the ambulance entrance if EMS had not already recognized the stroke symptoms in the field. Our investigation was not designed to investigate causality; however, we believe the underlying mechanism is likely to be multifactorial, including triage process, ED operations , nursing assessments, or physician evaluations. Most importantly, however, we postulate that our observed results also may have been due to the success of EMS early identification and pre-notification efforts in our region, potentially creating a false sense of security and causing ED staff to become over-reliant on EMS decision making. Like our region, pre-notification success has occurred in many regions across the United States, leading us to believe that our findings may be relevant and significant for ED stroke care processes nationwide.During the study period of our investigation, 106 patients arrived by EMS without pre-notification, while 277 (72%) did enjoy pre-notification by EMS, prompting reflection of why over a quarter of patients did not experience pre-notification by EMS. In Massachusetts, EMS providers operate under the Massachusetts Statewide Treatment Protocols, which contain and mandate the use of the MASS, or an “equivalent nationally recognized stroke scale.”The initial validation study of the Cincinnati scale listed presenting complaints of the 13 patients missed by the scale and eventually diagnosed with stroke.Because chief complaints in our center were recorded as unstructured free-text, and total NIHSS scores do not differentiate between posterior circulation symptoms and other stroke patterns, our data provide little ability to objectively determine whether delays in recognition in our study stemmed from the same limitations. We did, however, visualize terms and phrases entered as the free-text chief complaint in our EHR among patients without pre-notification and DTA > 15 minutes using a word cloud . This poIn addition to improving prehospital identification and notification as a potential counter-measure to the primary findings of this investigation, ED provider-focused intervention may also be prudent. As EMS providers have become increasingly aware and astute at identifying strokes and providing pre-notification, it is possible that ED staff have become too reliant upon EMS identification of the patients. Additional education for ED nursing and provider staff regarding the findings of this investigation and the potential limitations of the screening tool in use by EMS may help boost index of suspicion as cases come through the door by ambulance. Further education and empowerment of triage staff may also reduce DTA times in this subpopulation.The primary limitation of our investigation was the single-center design, which naturally prompts consideration of the generalizability of our results. It may be the case that our EMS and ED triage processes related to acute stroke were unique to our center and region. However, as the regional stroke center, significant efforts had been made to follow nationally accepted guidelines and recommendations in standardizing our EMS and ED stroke care, so we believe that our processes were likely to be similar to other regions and centers. As in any single-center investigation, we also could not rule out other unmeasured, locally-unique factors beyond our stroke specific processes having influenced our results. While our investigation was not multicenter, we feel that the findings remain important in that they are novel and reveal an opportunity for improvement that likely exists at centers outside of ours.Our study intentionally did not focus on clinical endpoints, instead favoring process metrics known to affect the timeliness of stroke care. The study was not powered to evaluate door-to-thrombolytic time, given the rare nature of this outcome. Thus, it is possible that patients who experienced DTA delays fared no worse than those who met the goals; however, we feel that our primary process endpoint of DTA remains important and relevant given the accepted national emphasis on timely stroke recognition. Our results also do not precisely identify which subprocesses made the largest contributions to delays . Our EHR did not differentiate between arrival via basic life support (BLS) vs advanced life support (ALS). While the majority of 911-originated calls in our system arrive ALS, and both ALS and BLS providers uniformly used the MASS, it is impossible to assess for differences in prehospital stroke recognition between ALS vs BLS EMS providers.Ambulatory patients and those arriving via EMS were initially triaged in different areas in our ED. While the triage systems were identical, there were potential differences in workflows at each of the triage areas, and it would be difficult to account for some of these factors systematically. For example, the triage nurse at our ambulance entrance had the additional responsibility of bed assignment of all incoming ED patients. While this nurse was responsible for relatively fewer patients requiring triage, it remains possible that the additional job demands may have eroded the effectiveness of stroke identification by the ambulance-entrance triage nurse. Additionally, ED patients arriving to our institution via EMS vs private vehicle, while fewer in number, were of higher acuity in general. This may have created an unmeasured demand-capacity disparity between the triage areas. However, it remains unclear in which direction this potential unmeasured effect would have biased the results, if at all. While our ED employs “pull to full” practices, and triage nurses prioritize patients using standardized scoring methods at both triage locations,Prehospital activation documentation was unstructured in our EHR. While it was commonly documented by providers and nurses, this left the potential that it was inadvertently omitted. We employed a secondary capture mechanism of comparing the stroke team activation time and the patient’s ED arrival time to determine whether activation had occurred for patients if prehospital activation was not specifically documented. As with any surrogate marker, there was potential that some patients may have been misclassified to either the prehospital activation or no prehospital activation group. However, we believe this to be unlikely given our objective secondary capture method. Finally, a limitation of any observational study is the possibility that unmeasured variables may play a role in confounding  and/or may directly affect the outcome of interest. Our use of a prospectively-collected stroke registry with robust data-cleaning and validation somewhat mitigated this risk, as the design of the registry by multiple stakeholders and the influence of national data collection standards for accreditation were more likely to have identified important variables than the authors alone. However, our methods could not have entirely accounted for the possibility that important predictors may have gone unidentified.Our final model’s strong area under the curve suggested against there being a large number of unmeasured predictors, but it was difficult to identify unmeasured confounders in the propensity score creation. The associated tradeoff of potential model overfitting due to the inclusion of many variables and interaction terms was also mitigated by our use of penalized regression and model validation techniques. Our final model had intuitive appeal and face validity based on theory, which also suggested against overfitting.In summary, our single-center data demonstrate that potential stroke patients arriving via EMS without prehospital notification (and presumably without EMS recognition of their stroke symptoms) are less likely to meet door-to-activation goals than patients arriving via other means. These results suggest the existence of a deleterious, unintended consequence of otherwise highly successful programs to improve prehospital identification and notification. The root of this unintended consequence may lie in over-reliance on EMS pre-notification and a resultant decreased index of suspicion for stroke among ED staff for patients not identified as such by EMS. Future efforts may be directed toward both increasing the sensitivity of prehospital stroke screening tools and developing improved processes for secondary screening on arrival for this cohort of patients.


Organisms seldom exist in isolation and are usually involved in interactions with several hosts and these interactions in conjunction with the physicochemical parameters of the soil affect plant growth and development. Researches into below and aboveground microbial community are unveiling a myriad of intriguing interactions within the rhizosphere, and many of the interactions are facilitated by exudates that are secreted by plants roots. These interactions can be harnessed for beneficial use in agriculture to enhance crop productivity especially in semi-arid and arid environments.The rhizosphere is the region of soil close to plants roots that contain large number of diverse organisms. Examples of microbial candidates that are found in the rhizosphere include the Arbuscular Mycorrhizal Fungi (AMF) and rhizobacteria. These rhizosphere microorganisms use plant root secretions such as mucilage and flavonoids which are able to influence their diversity and function and also enhance their potential to colonize plants root. In the natural environments, plants live in interactions with different microorganisms, which thrive belowground in the rhizosphere and aboveground in the phyllosphere. Some of the plant-microbial interactions  protect the host plants against detrimental microbial and non-microbial invaders and provide nutrients for plants while others negatively affect plants. These interactions can influence below-ground-above-ground plants’ biomass development thereby playing significant role in sustaining plants. Therefore, understanding microbial interactions within the rhizosphere and phyllosphere is urgent towards farming practices that are less dependent on conventional chemical fertilizers, which have known negative impacts on the environments.Drought stress is one of the major factors militating against agricultural productivity globally and is likely to further increase. Belowground rhizobacteria interactions could play important role in alleviating drought stress in plants. These beneficial rhizobacterial colonize the rhizosphere of plants and impart drought tolerance by up regulation or down regulation of drought responsive genes such as ascorbate peroxidase, S-adenosyl-methionine synthetase, and heat shock protein.Investigating complex microbial community in the environment is a big challenge. Therefore, omic studies of microorganisms that inhabit the rhizosphere are important since this is where most plant-microbial interactions occur. One of the aims of this review is not to give detailed account of all the present omic techniques, but instead to highlight the current omic techniques that can possibly lead to detection of novel genes and their respective proteins within the rhizosphere which may be of significance in enhancing crop plants (such as soybean) productivity especially in semi-arid and arid environments.Plant-microbial interactions are not totally understood, and there is, therefore, the need for further studies on these interactions in order to get more insights that may be useful in sustainable agricultural development. With the emergence of omic techniques, it is now possible to effectively monitor transformations in rhizosphere microbial community together with their effects on plant development. This may pave way for scientists to discover new microbial species that will interact effectively with plants. Such microbial species can be used as biofertilizers and/or bio-pesticides to increase crop yield and enhance global food security. The recruitment of a foreign species into a new ecosystem is dependent on the type of host and indigenous microbial community. Generally, an ecosystem with lost species diversity has a high tendency to accept new species or invaders and the invaders have to interact with species in the new ecosystem in order to occupy the niche  and on some enzyme activities involved in enhancing drought stress of wheat leaves [Gluconacetobacter diazotrophicus PAL5. Enhanced plant acclimatization to arid environment through AMF interaction is connected to the fungal ability to enhance plant nutrient and water uptakes resulting in an increase in the plant tissue water content. Thus, AMF interactions enable plants to acclimatize to drought conditions through different mechanisms which comprise nutritional, morphological, and physiological mechanisms [One of the ways to understand the impacts of abiotic stresses on plants is through omic studies which help to elucidate plant microbial processes that can be harnessed for biotechnological purposes. At the transcriptomic level, it was observed that the bacterium d plants . With thondition . Also, qt leaves . Illuminchanisms . AlthougPhaseolus vulgaris L.) with P. polymyxa-DSM36, P. polymyxa-Loutit strain and Rhizobium tropici-CIAT 899 resulted in greater growth compared to single inoculation with Rhizobium species. Moreover, combined inoculation increased the number and weight of nodules of the plant under drought stress environment compared to inoculation with Rhizobium alone [Pseudomonas mendocina significantly improved root phosphatase activity and proline accumulation in lettuce leaves [Pseudomonas species and Azotobacter chrocoocum reduced drought stress in wheat through increased modifications of the anatomical structures such as mesophyll and phloem tissues, thickness of epidermis and diameter of xylem vessel whereas water deficiency had negative effects on the anatomical tissues of the control [Bacillus cereus AR156, Serratia species and B. subtilis SM21 enhanced drought resistance in cucumber plants. After exposing the plant to drought for 13 days, the plants treated with the bacterial isolates showed darker green leaves with mild symptoms, increased chlorophyll and proline content and decreased relative electrical conductivity. The bacterial consortium treated cucumber plants also enhanced the superoxide dismutase activity and alleviated the drought-activated down-regulation of genes coding for ribulose-1, 5-bisphosphate carboxyl/oxygenase (Rubisco) large and small subunits and ascorbate peroxidase in the leaves of cucumber plants [In addition to single inoculation of rhizobacterial species, a further inoculation with AMF enhances plant drought tolerance. Inoculation of common bean  seed germination [Arabidopsis changed the microbial communities in the root and rhizosphere. Alkaloids, terpenoids and phenolics are commonly produced by plants. As an illustration, the order Brassicales and Arabidopsis produce glucosinolates, but Avena strigosa commonly known as oat produces avenacins which are effective against a wide range of fungi. Mutant oat deficient in avenacins exhibits different rhizosphere culturable fungal species which are more vulnerable to pathogenic fungi than the wild type [The production of plant hormones such as indole-3-acetic acid and gibberellins are common among rhizobacteria species and they are known to enhance plant growth.  opening  while stmination . Glucosiild type . Upon anild type . This su8Plants establish interactions with several different microorganisms and a large proportion of these exceedingly complex microbial groups have not been characterized. In particular, it was recently reported that only 7% of all terrestrial fungi have been characterized  and a sivia modeling. This strategy was recently utilized to gain insights into interaction involving ectomycorrhizal Laccaria bicolor and Populus tremuloides roots. Transcriptomic profiling of matured ectomycorrhizal via next generation sequencing technique resulted in the detection of transcripts which were matched to definite metabolic channels and used to establish the fungal metabolome model. The model was used to project that other metabolites such as glycine and glutamate produced by L. bicolor might be utilized by P. tremuloides which in return, supplies carbon substrates such as glucose and fructose to the AMF [Real-time application of metagenomic, metatranscriptomic and transcriptomic to rhizosphere microorganisms may possibly provide more insights into complex microbial interactions , 110. A  the AMF .Arabidopsis and some bacterial spp.Furthermore, omic will be useful in detecting the roles of different genes, RNA, proteins and metabolites involved in plant-microbial interactions which would eventually unveil important processes that strengthen these interactions. This approach could simply be accomplished by establishing ‘genome-scale models’ that are appropriate for metabolic flux analyses in which microbial groups might be seen as a single interacting super-organisms while interacting plant’s ‘genomic-scale models’ integrate a certain level of division and differentiate metabolic processes , 112. Th9According to Babalola , interacStudies have also depicted that plant-microbial interactions could also play a role in sustainable agriculture by helping to control a wide range of pathogens thereby enhancing crop health, productivity, yield and consequently boosting global food security . Howeverin vitro and in vivo techniques or models is paramount [Researches into microbial ecological interactions have resulted in significant outcomes biotechnologically . Thus, taramount .Plant roots are extremely important for mineral nutrient uptake and productivity, and there is therefore the need to continue study on plant interactions with soil microorganisms. Similarly, more attention should be paid to field application of these microorganisms as biofertilizers and/or bio-pesticides so as to abate the negative effects of conventional chemical fertilizers and pesticides, increase crop yield and enhance global food security. With the emergence of advanced omic technologies, it is now possible to effectively monitor transformations in rhizosphere microbial community together with their effects on plant development. This may pave way for scientists to develop discover microbial species that will interact effectively with plants.


Much attention has recently been devoted to finding ways to strengthen global governance mechanisms of AMR. The call for implementing binding global commitments and strengthening global institutions has figured prominently in this debate. Less attention has been paid to the tensions between global and local solutions. These tensions are particularly prominent in AMR stewardship, i.e., in the processes of formulating policies and strategies to deal with AMR. This commentary argues for an increased focus on glocal governance to strengthen AMR stewardship.Infectious Diseases that legally binding governance mechanisms are necessary for strong, swift, and coordinated action to curb AMR [Lancet emphasized the need for binding legal agreements and establishing a novel supranational entity to facilitate such agreements [Calls for increased global antimicrobial stewardship to curb antimicrobial resistance (AMR) have been heeded in recent years. Many have pushed for legally binding international agreements and the establishment of a supranational entity dedicated to curbing AMR. The director of the WHO’s AMR Secretariat argued in a co-authored article in curb AMR . A multireements . Severalreements . Most rereements .Interestingly, all these calls included comparisons to climate change. Indeed, the similarities between AMR and climate change are striking: both have adverse consequences today that might potentially turn catastrophic in the future; both risk tragedies of the commons where the benefits from antibiotics and emissions are local but the costs of resistance and climate change are global; both contain clear ethical dilemmas where some overuse a common resource  while others lack access to the resource; and responding to both threats includes high complexity and multiple constituencies.However, one key lesson to take away from the international efforts to curtail climate change is that binding commitments are not necessarily effective. Several key states opted out of these climate treaties. Even the most prominent global governance effort, the 1997 Kyoto protocol, had only 37 industrialized countries committed to legally binding reductions in emissions, and they have mixed results to show for it . Legallyglocalization can provide insights on how to establish such more complex global governance regime.The global challenge of AMR, more so than with climate change, requires solutions that are compatible with local needs and contexts. The equivalent to universal emissions targets is hard to find in the realm of AMR. In some countries, the most effective solution may be to provide incentives for patients, doctors, and farmers to reduce their use of antibiotics. In other countries, access to clean drinking water or fast diagnostics matter more than adjustments in antibiotic consumers’ behavior. This marked variability in both the state of public health and type of health challenge necessitates a broader pallet of solutions than the binary climate change option of either restricting the consumption of energy or lowering emission intensity. Hence, a combination of non-binding and binding agreements at multiple levels and across different sectors are more likely to be effective than the more comprehensive, wide-scoped treaties that we know from climate change. The analytical lens of Glocal governance, therefore, suggests that global challenges should be addressed by the effective reconciliation of the local and the global. Three concrete strategies can help facilitate a strong glocal governance regime of AMR.Examining AMR stewardship through the prism of glocalization places an emphasis on tensions between the universal  and the particular  . GlocaliFirst, from the perspective of glocal governance, effective AMR stewardship might be achieved by policy diffusion where ‘frontrunner’ countries or institutions set best practices/ideas that spread across nations and are adapted to local contexts . While apolycentric governance in the form of horizontal collaboration on a subnational level [Second, an effective glocal governance strategy of AMR might rely on al level . A globaProblem-Driven Iterative Adaptation (PDIA) is a glocalization strategy that focuses on solving specific problems in particular local contexts rather than transplanting “best practice” solutions [Lastly, olutions . It reliThe WHO has produced several useful scenarios for stronger global governance of AMR . Glocal The global challenge of AMR requires solutions that are compatible with local needs and contexts. Glocal governance might constitute an effective international regime of antimicrobial stewardship. Three concrete strategies can help facilitate a strong glocal governance regime of AMR: (i) policy diffusion where agenda-setting at the global level stimulates (but does not dictate) local policy innovation and practices; (ii) polycentric governance where subnational agencies form horizontal networks to solve particular problems; and (iii) problem-driven iterative adaptation practices that activate multiple levels of governance and sectors in addressing country-specific problems related to AMR.


Meiosis is a specialized cell-division process in germ cells that ensures proper segregation of a single haploid genome into each gamete from a diploid precursor cell. This process ensures that the embryo receives the correct number of chromosomes upon fertilization. To accomplish this, meiotic germ cells duplicate their genome one time followed by two rounds of cell division (meiosis I and II) to produce haploid gametes. Therefore, there are major modifications that occur compared to mitotic cell divisions to ensure that the two successive meiotic cell divisions faithfully segregate one copy of every chromosome into each gamete . In contHow homologous chromosomes find each other and pair during meiosis I is somewhat of a mystery but seems to involve the telomeres. In many organisms, including vertebrate animals, the telomeres attach to the nuclear envelope at the beginning of meiosis. This attachment is mediated through binding of telomere-associated proteins to a protein complex that spans the nuclear envelope and interacts with the cytoskeleton . The telThe mechanisms underlying meiotic chromosome segregation have been elucidated through studies on several model organisms, including yeast, fruit flies, nematodes, and mice. The zebrafish has more recently become an additional favorite model system as an intermediate between invertebrates and mammals. Zebrafish research has contributed extensively to many aspects of germ cell biology, including how primordial germ cells are guided to the developing gonad as well as the role of germ cell-specific small RNAs (pi-RNAs) in the germ line, to name a few –7. The zIn this issue, Blokhina and colleagues  detail pSpo11 function, but pairing and synapsis are severely impaired [Spo11 function. Male Spo11 mutants display meiotic arrest and apoptosis at the zygotene to mid-pachytene stage. In females, some oocytes persist beyond this stage and a few oocytes mature. However, both sexes are infertile. The ability of female oocytes to continue through oogenesis despite the meiotic defects points to a commonly observed feature of female meiosis in which oocytes seem to have more relaxed checkpoint control relative to males [To ask how recombination between homologous chromosomes fits into this picture, Blokhina and colleagues generated and characterized zebrafish mutants that were unable to make meiotic DSBs. The SPO11 topoisomerase is a conserved protein that initiates meiotic DSBs . In miceimpaired ,11. In mto males .spo11 mutants exhibit similar meiotic defects as those observed in mice. In both male and female mutants, the bouquet forms normally and the assembly of axial elements commences; however, pairing and synapsis are severely impaired. As in mammals, zebrafish mutant males exhibit meiotic arrest, spermatozoa are not present, and males are sterile. By contrast, female mutants produced normal numbers of eggs, yet embryos were generally not viable and died before feeding stages (prior to 5 days post fertilization). This suggests that female meiosis may have even more relaxed checkpoint regulation in zebrafish than in mammals, because egg production is not compromised. Analysis of mutL homolog 1 (mlh1) mutant zebrafish, encoding a protein involved in recombination, demonstrates that females with meiotic defects produce a small number of triploid offspring that are viable and develop as sterile males [spo11 mutants, because rare viable offspring were produced from mutant females, all of which were male. Overall, the similarities in meiotic processes observed between mammals and zebrafish further validate the zebrafish model as a key resource from which we can gain new insights into the mechanisms underlying meiosis.Bolkhina and colleagues demonstrate that zebrafish le males . A similThe analysis of zebrafish meiotic chromosomes at high resolution is a key advance in our ability to utilize the attributes of this model for studying defects in spermatogenesis and oogenesis. The many similarities to mammalian meiosis reported by Bolkhina and colleagues sets the stage for in-depth analysis of meiotic chromosome interactions and utilization of other mutant resources to tease apart mechanistic gaps in our knowledge of this process. This experimental system is primed to address unanswered questions, such as how homologous chromosome find each other and pair in a homology-directed fashion, as well as the role that telomere-directed bouquet formation plays in this process.


It has been suggested that individual differences in interoception  can be divided into three distinct dimensions: interoceptive accuracy (performance on objective tests of interoceptive accuracy), interoceptive sensibility (self-reported beliefs concerning one’s own interoception) and interoceptive awareness (a metacognitive measure indexed by the correspondence between interoceptive accuracy and interoceptive sensibility). Research conducted under this model underscores the importance of interoceptive awareness for a variety of disorder-specific and transdiagnostic symptoms. However, the clinical importance of interoceptive awareness means that this aspect of interoception warrants further scrutiny, and such scrutiny suggests that revision of the three-dimensional model of interoception is necessary. In this theoretical paper, we outline such a revision, highlighting a need to distinguish not only how interoception is measured (objective measures vs. self-report), but also what is measured (accuracy vs. attention). The model refines how individual differences in interoception are categorised, with important consequences for the measurement of interoceptive awareness. Such a revision may help researchers to identify the strengths and weaknesses in interoception observed across clinical conditions, and to isolate clinically relevant individual differences. Theories linking individual differences in interoception  but also incorporates what is being measured (e.g. attention or accuracy) in order to distinguish possible individual differences in interoception. Crucially, such a distinction holds important consequences for measurement of interoceptive awareness. In the existing three-dimensional model interoceptive awareness refers to the correspondence between measures of interoceptive accuracy and interoceptive sensibility – regardless of whether the measure of interoceptive sensibility relates to one’s perception of the accuracy of interoceptive perception (e.g. confidence ratings) or one’s beliefs regarding one’s degree of attention to interoceptive signals (e.g. the BPQ). However, as noted, existing data suggest that these two ‘interoceptive awareness’ measures appear to quantify distinct aspects of interoception; for example, they often show differential associations with symptomology and differential patterning across disorders  are not usually correlated with self-report measures of interoceptive accuracy  may benefit from different treatment than an individual with atypical awareness of interoceptive accuracy (confidence-accuracy relationship). Whilst the exact patterning of interoceptive processing across disorders remains a question for future research, this framework may help to conceptualise potential differences across disorders and, in the future, may be useful for translating these findings to clinical practice.It is important to acknowledge, of course, that other aspects of interoception that are not captured by existing models may hold clinical relevance. For example, individuals may differ with respect to the extent that they use interoceptive signals in their everyday lives, in addition to the extent to which they can accurately perceive interoceptive signals and the extent to which interoceptive signals are the object of attention. Likewise, individuals may also differ in terms of how unified their interoceptive attention and/or accuracy is across different interoceptive signals . Moreover, it is indeed possible that the relationships between the facets of interoception outlined in our 2 × 2 model may differ depending on the interoceptive signal of interest (e.g. cardiac vs. gastric). At present, our understanding of the clinical relevance of these additional aspects of interoception, and the relationship between facets of interoception across interoceptive signals, is limited by the paucity of tests designed to assess these possible individual differences. However, further work may highlight a need to include additional aspects of interoception within this 2 × 2 model.In summary, with growing interest in interoception, there is a need for a framework that adequately distinguishes between the various individual differences in interoception. The 2 × 2 factorial model provides a refinement of the existing model of interoceptive abilities, separating both whether interoceptive accuracy or attention is the target of measurement and how interoception is measured. It highlights the existence of two distinct interoception-related metacognitive measures, and explains mixed results in the literature. It is hoped that use of this model will allow researchers to identify the strengths and weaknesses in interoception observed across clinical conditions, and to isolate the clinically-relevant individual differences in interoception.


However, how these different brain states work in concert to create long-lasting changes in brain circuitry is unclear. Considering that wakefulness and sleep are profoundly different brain states on multiple levels , it is unlikely that they operate exactly the same way. Rather it is probable that they engage different, but coordinated, mechanisms. In this article we discuss how plasticity may be divided across the sleep–wake cycle, and how synaptic changes in each brain state are linked. Our working model proposes that waking experience triggers short-lived synaptic events that are necessary for transient plastic changes and mark  circuits and synapses for further processing in sleep. During sleep, synaptic protein synthesis at primed synapses leads to structural changes necessary for long-term information storage.It is commonly accepted that brain plasticity occurs in wakefulness  Experience-dependent plasticity, including memory, is divided temporally into an induction (encoding) and consolidation phase. A general consensus in the field is that while encoding of new information occurs during wakefulness, sleep integrates and stabilizes the resulting plastic changes  . This woWhile existing theories on sleep function posit different roles for wake and sleep in experience-dependent plasticity, they do not systematically distinguish between mechanisms known to participate in plasticity induction and consolidation. For example, synaptic potentiation, which has been proposed to occur during either wake  or sleepIn this paper, we discuss new ideas about how plasticity mechanisms are divided across the sleep–wake cycle and how plastic events in one brain state set in motion plastic changes in another. More specifically we propose that waking experience promotes two parallel events that recruit shared mechanisms: transient plastic changes and the priming of neurons for further modification in sleep. Priming refers to experience-dependent mechanisms that mark neurons in a synapse- and circuit-specific manner for further modifications. During sleep, reactivation of primed circuits leads to more permanent changes in synaptic weights via stabilization of structural plasticity. Structural plasticity stabilization involves a set of localized molecular mechanisms that transforms the transient priming instructions into lasting morphological changes at synapses. We conclude with predictions, open questions and future directions.When considering experience-dependent plasticity, it is important to understand the nature and timeline of processes that underlie plasticity induction and stabilization. New experience activates a cascade of events in neurons whereby each step triggers specific molecular mechanisms necessary for the full expression of long-term synaptic plasticity. The lasting nature of plasticity-related changes in neurons is traditionally viewed to depend on activation of new gene transcription and translation . Severalin vivo and in vitro indicate that the plasticity induction process triggers short-lived changes that mainly depend on post-translational modifications of existing proteins and rapid morphological alterations of dendritic spines (N-methyl-D-aspartate receptors (NMDARs) activation leading to intracellular calcium (Ca2+) influx and rapid activation of various protein kinases  and phosphatases   impairs hippocampal LTP dependent on cAMP/PKA/CREB signaling, but not LTP that requires new translation  has no effect on waking plasticity  and thus allow delayed consolidation while maintaining cell- and input-specificity, as well as bidirectionality of plastic changes. Although current metaplasticity mechanisms do not consider sleep and wakefulness and have been mainly integrated into models of memory allocation . Among sticity”  and chansticity”  provide location , it is elocation .Long-term synaptic plasticity does not appear to involve a change in the total number of synapses but is instead accompanied by the formation and loss of synapses . This isWhile their identity is still under investigation, tags are thought to be localized molecular processes that render synapses temporally permissive for PRPs capture . Tags caThe complete identity of PRPs is also unknown Figure . An impoarc, homer1a, bdnf, narp) and thus rapidly transcribed in an experience-dependent manner. Second, a majority of genome-wide studies report that the transcription of these mRNAs is maximal during waking and drops during sleep  activated by experience . Changesin vivo electrophysiological recordings in rodents have shown that both spontaneous neuronal firing  correlate positively with changes in Caendrites  and CaMKendrites  during Rendrites .in general can promote synaptic capture of PRPs because they all involve a reactivation of a network and they increase in number or intensity in a use-dependent fashion.According to current ideas about the STC, the first and necessary step toward stabilization of functional and structural plasticity is the capture of PRPs during the lifetime of the tag (minutes to hours) . We propThis idea is supported by several observations. Three main NREM sleep oscillations have been implicated in experience-dependent plasticity and memory consolidation: slow-wave activity  and spindles (sigma: 10–16 Hz) in the cortex, and sharp wave ripples  in the hippocampus . AlthougWaking experience has also been shown to increase synchronization and coherence in the activity of task-related neurons in the hippocampus and cortex during sleep . This inin vivo only in neurons that were not engaged in a previous novel experience  range  range . Intereslidation . Furtherlidation .Immediate activation of consolidation upon learning is not optimal at the cellular and system levels. As discussed in An advantage of the STC model is that cellular consolidation mechanisms are triggered within successive check points in time by binding significant experiences within shared circuits and neurons using shared cellular pathways. We propose in our model that these check points occur in sleep, when the brain is partially disengaged from incoming information and experience. This is consistent with the idea that memories are not just consolidated during sleep but are also actively reorganized to help cognitive processes such as generalization  or creatand negative tagging, subsequent increases in NREM SWA lead to synaptic weakening and strengthening, depending on the synaptic tag. If this is true, one would predict that changes in priming  parallel changes in sleep need. There is evidence to support this idea. Increased synaptic phosphorylation, which is involved in synaptic tagging according to our model (see the section “Tags”), parallels increases in sleep need and decreases during sleep . In contrast to other ideas positing different roles for REM and NREM sleep in plasticity , our ideOur model also differs from the ‘Synaptic Homeostasis Hypothesis (SHY)’ which proposes that sleep weakens synapses while sparing others (a process referred to as ‘down-selection’), resulting in a ‘net’ weakening of synapses after sleep. This type of plasticity has also been termed ‘downscaling’  and descThis does not make our model incompatible with synaptic homeostatic adjustments during sleep. Some evidence cited in support of SHY may be explained by circadian rhythms rather than sleep . Other fAccording to our model, labile forms of plasticity are induced when we are awake and are consolidated into more permanent forms while we sleep. Waking plasticity involves transient plastic changes and priming mechanisms (changes in excitability and synaptic tagging). Waking plasticity also includes transcription and dendritic targeting of PRPs  for synaptic capture during sleep. Plasticity during sleep promotes capture and translation of PRPs at synapses for stabilization of structural plasticity. Our model, informed by the STC model and new discoveries regarding priming, provides a molecular bridge between plastic changes induced in one state (wakefulness) and the other (sleep). Although speculative, this model explains a number of disparate findings in the field and leads to falsifiable predictions.in vitro to in vivo experiments, and studies in many different animal species often in different brain regions. It is important to consider some general caveats in how one interprets these data. Many experiments use SD as a model of the natural waking brain state. SD, however, can increase stress levels and stress hormones can influence metaplasticity  and molecular  correlates of priming.• If NREM oscillations are necessary for the synaptic capture of PRPs, manipulating these oscillations should alter the synaptic mRNA content. In other words, NREM oscillation disruption should result in more PRPs in the cytoplasm (soma and dendrites) compared to synapses. Conversely, enhancing these oscillations should increase synaptic PRPs content while decreasing their presence in the cytoplasm.• If REM sleep increases synaptic mRNA translation, then manipulating REM sleep amounts should modify the synaptic proteomic content. In addition, given the high amount of REM sleep during early life , it is eand REM sleep following exposure to an enriched experience  also increase during REM sleep in the hippocampus and cortex (Figure perience , 2007. Zperience  and has perience . One intin vivo hippocampal LTP induction (in vivo (reviewed in It is also not clear if all or most synaptic translation occurs during REM sleep. Studies using the uptake of radio-labeled amino-acids show positive correlations with NREM sleep and cortical protein synthesis . It is pnduction  and has nduction . FurtherJS wrote the manuscript and prepared the figures. MF helped to write 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.