Drought escape (DE) is a classical adaptive mechanism which involves rapid plant development to enable the completion of the full life-cycle prior to a coming drought event. This strategy is widely used in populations of native plants, and is also applicable to cereal crops such as wheat. Early flowering time and a shorter vegetative phase can be very important for wheat production in conditions of terminal drought since this can minimize exposure to dehydration during the sensitive flowering and post-anthesis grain filling periods. A gradual shift toward early flowering has been observed over the last century of wheat breeding in countries with a Mediterranean-type climate and frequent terminal drought. This trend is predicted to continue for wheat production in the coming years in response to global climate warming. The advantage of early flowering wheat is apparent under conditions of impending terminal drought, and modern varieties are significantly more productive due to minimization of the risk associated with drought stress. Under favorable conditions, a short vegetative phase can result in reduced plant biomass due to the reduction in time available for photosynthetic production and seed nutrient accumulation. However, high yield potential has been reported for the development of both shallow and deep roots, representing plasticity in response to drought in combination with the early flowering trait. Wheat productivity can be high both in well-watered and drought-affected field trials, where an efficient strategy of DE was associated with quick growth, yield potential and water use efficiency. Therefore, early flowering provides a promising strategy for the production of advanced drought-adapted wheat cultivars. The topic of early flowering as a DE mechanism is extremely important and has very long history of discussion amongst a wide range of plant biologists. This Mini-review is not designed to be comprehensive but instead is focused on a conceptual vision of the advantages and limitations of the topic based on published data. We discuss the topic of early flowering and DE from different angles, with high wheat production as a final target. We hope our paper can initiate further research and fruitful discussions.Drought escape is one of many strategies employed by plants under conditions where water limitation late in the growing season is likely, and it ensures that the plants can complete their life-cycle quickly during the brief period of favorable conditions. Initially DE was described as a classical mechanism for ephemeral native plants, developed over a long period of evolution, mostly in perennial species such as bulbs and shrubs , but alsIn contrast, DA can be defined as a mechanism of slow plant growth, associated with small or closed stomata with reduced photosynthesis as well as low cell metabolism in general. High WUE minimizes water loss and prepares the plants for the changing environment and coming drought. This is also commonly referred to as the ‘succulent strategy’ .In reality, the classification of plants into the discrete categories of DE or DA is not entirely accurate since they take place at different times: prior to and after the occurrence of a drought event, respectively. This means that theoretically plants can use a combination of DE and DA or other strategies for drought tolerance.Drought is a complex abiotic stress which can act at any stage of plant growth to varying degrees of severity. For the purposes of this mini-review we will identify three major periods of cereal plant development that can be affected by drought: (1) Vegetative (before transition to the reproductive stage); (2) Pre-anthesis (from tillering and booting until full flowering); and (3) Post-anthesis or terminal (after flowering and until maturity). The severity of drought can be determined by the actual water deficit experienced by plants, whereas the general categories of light, mild and severe levels of drought stress are usually used in publications.Arabidopsis thaliana, where selection under drought conditions can favor early flowering , photoperiod (Ppd) and earliness per se (Eps). Due to the very high importance of this trait for cereal production, the genetics of FT is well studied, with a long history of documented research  and seven mutant mungbean lines (Vigna radiata (L.) Wilczek) flowered 2–4 weeks earlier than traditional cultivars and parental forms, respectively, displaying enhanced seed yield , and Chile . There aCurrent observations for wheat grown in Mediterranean-type climates have confirmed that wheat genotypes with a DE strategy show higher yield under terminal drought stress. In Cyprus, new successful durum wheat varieties (with higher yield) produced spikes 5–10 days earlier than the current standard, while a screen of barley lines showed a curvilinear correlation, where very early and very late flowering genotypes failed to match the yield of a local standard . At ICARIn other regions with different climatic conditions involving heat and drought events, EF wheat genotypes with a DE strategy can also produce significantly higher yield. For example, five years of field trials in four South Asian countries  showed a strong positive trend in high-yielding wheat breeding lines produced by CIMMYT and a negative correlation between yield and FT of tested wheat germplasms compared to local controls/checks , 2016. IAnthesis and grain filling in wheat are the stages most sensitive to drought, when assimilates are mobilized from stem and leaves to seeds . InsteadEarly flowering and maturity is an effective DE mechanism, but it can limit grain yield potential  due to tHowever, this is not always the case. Incidences where wheat with EFT/EM and SVP traits showed a HYP and produced more grain than wheat with traditional FT under non-stressed conditions have been described in both computer simulations and experimental approaches in field trails . For exaVrn-B1 alleles into breeding material with different genetic backgrounds showed a change to EFT by an average of 2.6 days and a significantly increased HYP in non-stressed conditions in field trials, by the main yield components of both grain per spike and spike weight (There are published reports describing EFT/EM wheat germplasms producing significantly improved HYP in the absence of drought. A study involving the introgression of e weight .In Western Australia, two commercial EM wheat cultivars and five early/very early-maturing breeding lines produced significantly higher grain yield compared to commercial later-maturating wheat controls in two sites over four seasons . The anaCommercial cultivars of wheat with EFT/EM traits must have an exceptional HYP. This depends on the combination of strong and vigorous early growth, high nutrient and WUE, balanced photosynthesis and respiration, and the production of more biomass prior to anthesis for fast and effective uptake of metabolites into seeds, all culminating in high yield and good quality wheat grain . WithoutDrought escape is an important strategy that can improve crop yields. It is beneficial for yield stability of crops such as wheat under conditions of an approaching terminal drought. In this scenario, EFT and SVP are beneficial relative to plants with a later FT and longer vegetative period. In favorable conditions, if no drought event occurs, the advantages of EFT/EM can be detrimental to yield. However, there are several cases indicating that the boost seen in the growth of EFT/EM wheat plants can produce significantly higher grain yield potential even under non-stressed conditions.Ideally, wheat farmers should be able to choose which varieties to plant based on the relative probability of a future terminal drought and balance their risk by using cultivars with the FT and vegetative phase that best suits their conditions. Mismatches in the prognosis and choice of wheat genotypes can, of course, result in losses at harvest.Biologically, a DE growth habit does not mean that wheat plants with EFT/EM traits are more or less sensitive to drought. Indeed, the DE strategy assumes active growth and metabolism for the rapid completion of the life-cycle before drought events occur. However, if drought stress occurs earlier DE plants can gradually switch to DA with the succulent strategy or a more advanced drought tolerance strategy such as osmolyte production and high WUE . This caA breeding program has been established based on similar wheat genotypes, with the potential to support grain yield both in the absence and presence of early drought at vegetative and pre-anthesis stages  but greaYS generated an idea and wrote first draft of the manuscript. LZ and AK collected data for section 1 and edited all sections after completing. SJ and VS collected data, wrote, and revised the Sections “EFT and EM in Wheat Represents Successful Strategies Against Terminal Drought in a Mediterranean-Type Climate” and “EFT and EM Wheat Can Have Comparatively HYP”. FK and SdG collected data and completed the Sections “Mechanism of DE in Plants: Early Flowering” and “DE and EFT/EM Can Provide Benefits to Plants Under Drought Stress”. KS edited the Section “Comparison of DE and DA”. PL coordinated the all parts of the review and made final corrections and revisions.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.


Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, “toxins” released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy. Traumatic brain injury (TBI) is a leading cause of death and disability, affecting approximately 1.7 million Americans annually . The proIn direct contrast to other tissues in the mammalian body, the brain is unable to properly regenerate and reconnect the injured areas to the uninjured areas of the brain . The detAfter brain injury, there are blood-brain barrier breakdown and neurodegeneration in areas including the injured cortex, hippocampus, and a portion of the diencephalon. Microglia, monocytes, macrophages, and neutrophils invade areas exhibiting blood-brain barrier damage  8], whi, whi8], α and IFNγ promote differentiation into M1, which is capable of producing oxidative metabolites and proinflammatory cytokines. This response is essential for host defense but can lead to secondary damage in healthy cells and tissue . Sh. Shα)  peptides. These results are very important since Aβ is a hallmark in pathology of Alzheimer's disease, and many studies have linked brain trauma with an increased risk of developing Alzheimer's disease [β peptides following TBI is unclear, long-term formation of Aβ peptides may play a role in the link between a history of brain trauma and increased risk of developing Alzheimer's dementia.In addition to ongoing inflammation following TBI, a study of the porcine brain injury model by Chen and colleagues revealed that axonal degeneration continues up to 6 months following initial brain trauma, which causes continued impaired axonal transport and, in effect, accumulation of amyloid precursor proteins (APP) and amyloid-B  to the olfactory bulb and the subgranular zone (SGZ) of the hippocampal DG, which integrate within the DG and become fully mature within a few weeks in a process called adult hippocampal neurogenesis . It remaThere has been some evidence to support self-renewal of progenitor cells in the DG occurring throughout life suggesting that some newly regenerated cells are morphologically and phenotypically similar to hippocampal neurons . Just hoIncreasing evidence suggests that TBI induces neurogenesis in animal models via ipsilateral NSC maturation and integration into functionally active brain cells of peridamaged regions of the hippocampus . InteresThe regenerative capacity of NSCs found in the adult brain is important for responding to TBI-related injuries. Recently, manipulation of various growth factors has shown significant efficacy in promotion of neurogenesis. In adult animal studies, it has been shown that intraventricular infusion of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) enhances cell proliferation in the hippocampus and SVZ leading to improved cognitive function , 62. In Compared to animal brain models, simply promoting neurogenesis is significantly more complex in humans. Concerns over possible treatment-related injuries from stimulation of endogenous neurogenesis following TBI are still under investigation and are associated with worrisome results. It has been suggested that post-TBI–induced neurogenesis has contributed to the onset of post-TBI epilepsy . SpecifiThe use of embryonic stem cells (ESCs) in the treatment of traumatic brain injury remains a growing field of research. Three notable clinical trials have used embryonic stem cells in TBI rodent models with promising results. Across the board, using ESCs is associated with better outcomes, such as recovery of motor function , improveIkeda and colleagues were one of the first investigators to use nonhuman primate stem cells, which they used to study embryonic stem cells' capacity to restore function to damaged neural tissue. In this experiment, Cynomolgus monkey embryonic stem cells were first treated with retinoic acid before being transplanted into the periventricular area of mice brains. Some of the treated cells later developed into Islet1+ motoneurons. These cells were then transplanted into mice that had undergone an experimental stroke model of brain injury. Approximately one month after the transplant, mice in the experimental arm had greater recovery of motor function than that in the control mice .The team of Peruzzaro and colleagues aimed to determine if an enriched postsurgical environment will have a beneficial effect on three key factors of embryonic stem cell transplants in terms of their integration, migration, and survival. In a rodent TBI model, the medial frontal cortex was injured via cortical impact. One group of rats was placed into an enriched environment, while the other was placed in a standard environment. In each group, two arms of the study emerged; the rats were treated with either murine cortical embryonic stem cells or did not receive such treatment. The enriched environment animals performed statistically as well as the sham group, compared to groups with just embryonic stem cells or only an enriched environment . This trA preclinical trial performed by Haus and colleagues aimed to study the long-term benefits of treating TBI with neural stem cells. Rats underwent an impact immunodeficient model of TBI and were found to demonstrate hippocampal-dependent spatial memory impairment for at least two months. The experimental group, treated with transplanted human neural stem cells, had better long-term consequences, including an increased survival in the host hippocampal cells, improved cognitive function, and no change in scar tissue. The investigators concluded that although no change was observed in the volume of scar tissue, beneficial effects were still seen, suggesting that measure of recovery should focus more on percentage of surviving cells rather than a decrease in lesion volume. This study also observed a small number of improved behavioral components correlating with a 9–25% survival rate of the transplanted cells . This coMAPCs are a population of bone marrow-derived adherent progenitor cells . First iNeural stem cells (NSCs) are multipotent cells that can differentiate into neural cells; however, their differentiation into other tissue types is limited . NSCs arIn a TBI rat model, adult NSCs were transplanted into injured areas of the brain. They survived the transplantation process and migrated to injured sites while expressing markers for mature astrocytes and oligodendrocytes . In otheThe optimal time window for transplantation is 7–14 days , and beyTo observe functional aspects of transplanted induced pluripotent stem cells (iPSCs) compared to those of ESCs, Wang and colleagues used a rodent model of ischemia and three different treatment options, which were comprised of pluripotent stem cells, embryonic stem cells, and phosphate-buffered saline for the control. The animals received injections into the left lateral ventricle stereotactically. At the two-week period, it was found that the embryonic stem cell treatment group animals exhibited a marked recovery in their glucose metabolism, which was then followed by a decrease. Imaging tests were performed approximately one month after treatment. Both stem cell treatment groups had better neurologic scores than the control group, signifying that the experimental groups experienced greater recovery of their cognitive function. Further analysis revealed that the transplanted cells survived and migrated to the region of ischemia. However, in the conclusion of their study, the investigators endorsed that iPSCs may be a preferable option to ESCs .In a similar study conducted by Perruzzano, the team of Dunkerson and colleagues explored the impact of an enriched environment in stem cell transplants. Since treatment with iPSC therapy had previously produced promising results, it was time to evaluate the efficacy of the two therapies combined. An animal TBI model of impact to the medial frontal cortex was used. As in previously mentioned experiments, two groups were formed: one in an enhanced environment and the other in a standard environment. Approximately one week following injury, the rats underwent either an iPSC transplant or media control. Notably, the rats that were exposed to both an enriched environment and iPSCs performed as well as the sham and enriched environment group. Across the board, the combined therapy group demonstrated the best cognitive recovery in comparison to that of other groups. Investigators concluded that combined therapy must be strongly considered in future studies that attempt to explore treatment options for TBI .2 using plastic culture dishes to improve the differentiation into MSCs. The modified protocol achieved enrichment of iPSCs-MSCs, as they expanded more rapidly and to a greater extent, but eventually underwent senescence. This method did not result in teratomas in murine models [Although iPSC therapy is promising, like many treatments, it is not free of potential side effects. Early animal model studies of iPSCs showed a tendency for embryonic-derived cells to form benign tumors from the embryonic germ layers. Some of the cells transplanted into animal models have led the animals to alternatively develop conditions such as neurodegenerative disease. However, assays have been developed to target problem cells and decrease these events . One of e models . Anothere models . An in ve models . Since uMSCs are multipotent stromal cells derived from a variety of tissues  and haveThe ability of MSCs to differentiate into neural cells was evidenced by Sanchez-Ramos and colleagues. They demonstrated that when human and mouse MSCs are exposed to specific experimental culture conditions, human and mouse MSCs have the ability to differentiate into neuron and glia-like cells . In addiBesides their ability to differentiate, MSCs selectively migrate to injured tissues in TBI rat models, with subsequent differentiation in neurons and astrocytes and subsequent improvement in motor function . The proAnother noteworthy fact regarding MSCs is their ability to suppress lymphocytes. This characteristic was observed in vitro and in vivo models. A study conducted by Bartholomew and colleagues made it evident that MSCs reduced the proliferative response of lymphocytes , which cOne appeal for use of MSCs as a TBI treatment method is their ability to cross the BBB through paracellular pathways . Given tMSCs provide an opportunity for clinical translation, as evidenced by recent clinical trials. A significant challenge with use of MSCs for TBI treatment remains to be the long-term possibility of brain tumor development due to the MSC's capacity of antitumor response suppression . Two cliFrom 2012-2013, 10 patients with severe TBI were recruited for a phase I clinical trial. MSCs were administered intravenously or intrathecally. Individuals had improvement in neurological function as measured by the NIHSS , GCS , and GOS . No mortality or adverse events occurred, bringing support for the safety and feasibility of this treatment. Similar to the previous study mentioned, limitations include a small sample size as well as no control group . AlthougHuman bone marrow contains hematopoietic and nonhematopoietic stem cells with multipotent characteristics. Bone marrow stromal cells (BMSCs) differentiate into mesenchymal stem cells and, which when exposed to appropriate conditions, possess capacity to differentiate into numerous cell types , such asShen et al. investigated outcomes in TBI rat models that were transplanted with BMSCs. The cultured BMSCs were implanted into the injured area of the brain followed by evaluation of neurologic function. Data analysis revealed an increase in expression of glial cell line-derived neurotrophic factor (GDNF), which is thought to be a potent promoter of neuronal survival, as well as genes of other neurotrophic factors. The investigators also noted that a great number of BMSCs that survived and migrated around the site of injury had done so 14 days following transplantation. Furthermore, the TBI rats with transplanted BMSCs presented with less apoptotic cells when compared to those of the control group and had improved neurologic outcomes .In 2016, Cox et al. conducted an investigation utilizing BMSC treatment in human adults with TBI. This trial enrolled patients that were admitted to trauma or neurotrauma ICU and were assigned to one of the dosage treatment arms. The investigators were able to demonstrate the safety of this treatment modality and downregulation of inflammatory cytokines, as well as its ability to preserve critical regions of the brain, which correlate with an increase in functional outcomes .Local and intravenous administration of BMSCs has been investigated for treatment of neurological injury and other neurological diseases . A studyMSCs have an important role in improving functional outcome after experimentally induced traumatic brain injury (TBI). Exosomes, which are of endosomal origin, are secreted by all cells, including MSCs . These mIn 2015, Zhang and colleagues administered MSC-derived exosomes to TBI rats via tail vein injections. Compared to saline-treated controls, exosome-treated TBI rats exhibited significant functional recovery as well as an increase in newly formed endothelial cells in both the lesion boundary zone and the dentate gyrus. The mechanisms involved may be related to an increase in brain vascular density and angiogenesis in those that received MSC exosome administration. Additionally, exosome treatment significantly reduced brain inflammation by reducing the number of CD68+ microglia/macrophages and GFAP+ astrocytes . As a foβ [Important areas to consider when working towards clinical translation of stem cell therapy are choosing which type of stem cells to use and the systemic effects of stem cell therapy. MSCs have been found to reduce the persistent inflammatory response following TBI by decreasing lymphocytes . A studyβ . Kim andβ . Additioβ , but in β , 122. UnAs mentioned previously, Zhao and colleagues found that iPSC-MSCs were less tumorigenic than BM-MSCs, readily expandable, and homogenous, thereby offering more uniform biological activities . In respThe proinflammatory environment leads to BBB breakdown and worsens neurological deficits following injury. MAPCs have been shown to bypass the pulmonary capillary bed compared to larger MSCs after intravenous injection, leading to more cells contacting splenocytes . InvestiDirect implantation of stem cells promotes neuronal regeneration, improved neurological scores, and anti-inflammatory effects in animal models studying responses after controlled cortical impact injury. However, diffuse axonal injury has not been as thoroughly studied in animal models and present in humans from blast injuries  and evenClinical trials have shown that MSC transplantation may decrease TBI patients' sequela and has the potential to become an effective treatment modality . MSC safStem cells used as a marker for TBI recovery and improved Glasgow Coma Scale are the focus of another ongoing investigation. Endothelial progenitor cells, which play an active role in vascular repair and revascularization, have been shown to increase 48 hours after TBI and were correlated to clinical outcomes. In the same study, patients with low circulatory levels of endothelial progenitor cells were more likely to present with poor clinical outcomes . Even thAlthough significant research has been conducted in the area of traumatic brain injury, both in terms of complexity underlying the pathophysiology and utilization of stem cell therapy in its treatment, a lot remains to be understood in order to determine the best method to promote recovery of functional brain tissue. Unfortunately, compared to other mammalian tissues, the brain does not have sufficient capacity to regenerate itself and theoretically requires assistance to do so after TBI. Use of neural stem cell therapy, whether through manipulation of endogenous or transplantation of exogenous NSCs, is an approach that numerous studies revealed to have significant potential to promote recovery of brain function in individuals suffering from TBI-associated disability. However, significant amount of research remains to be done in use of stem cells for treatment of TBI due to our limited understanding of potential complications, unexplored ethical implications, routes of administration, and use of combination/cotransplantation therapy. Combination and cotransplantation therapy that utilize NSCs and other cells, such as astrocytes and endothelial cells, which make the central nervous system's microenvironment more optimal for NSC grafting, likely hold the key to the best approach for treatment of aftermath of TBI, especially when considering the multifaceted nature of its underlying pathophysiology. In summary, all studies and future interventions that may impact treatment of TBI require multicenter and randomized prospective trials with long-term follow-up; this will allow future investigators to define the role and impact that each treatment may have on a given patient population.


Doctors are exposed to high levels of stress in the course of their profession and are particularly susceptible to experiencing burnout. Burnout has far-reaching implications on doctors; patients and the healthcare system. Doctors experiencing burnout are reported to be at a higher risk of making poor decisions; display hostile attitude toward patients; make more medical errors; and have difficult relationships with co-workers. Burnout among doctors also increases risk of depression; anxiety; sleep disturbances; fatigue; alcohol and drug misuse; marital dysfunction; premature retirement and perhaps most seriously suicide. Sources of stress in medical practice may range from the emotions arising in the context of patient care to the environment in which doctors practice. The extent of burnout may vary depending on the practice setting; speciality and changing work environment. Understanding dynamic risk factors associated with burnout may help us develop strategies for preventing and treating burnout. Some of these strategies will be reviewed in this paper. Doctors are often exposed to high levels of stress in their day-to-day work and are at greater risk of experiencing mental disorders, substance abuse, suicide, and impairment in functioning. By virtue of their work they are exposed to a plethora of emotions, including a need to rescue the patient, a sense of failure and frustration when the patient's illness progresses, feelings of powerlessness against illness and its associated losses, grief, fear of becoming ill oneself or dying, facing uncertainty in clinical practice, dealing with sexuality, or a desire to separate from and avoid patients to escape these feelings ,2. These“Physicians in many countries are experiencing great frustration in practising their profession, whether because of limited resources, government and/or corporate micro-management of health care delivery, sensationalist media reports of medical errors and unethical physician conduct, or challenges to their authority and skills by patients and other health care providers”5, p. 114). [, p. 114.Doctors are exposed to stressors from emotions and situations that arise outside the doctor–patient relationship too. They have to work in an increasingly litigious and unforgiving environment . BureaucFurthermore, doctors are finding themselves working in an environment or in roles for which they were not trained. Service delivery is changing from an office-based model to a population-based health model. Doctors have to fulfil administrative duties, such as dealing effectively with workforce issues, often in addition to their significant clinical commitments . FulfillExperience of high levels of stress for protracted periods may have wide-ranging effects on doctors. Those who work with traumatised patients may experience compassion fatigue. Doctors experiencing compassion fatigue may experience intrusion, avoidance, and arousal that may occur even after exposure to one incident . Two copAnother consequence of chronic exposure to stressors is burnout. Burnout, a term in common usage, was first coined by Freudenberger  in 1974 Exposure to severe and chronic stressors may also predispose doctors to a variety of mental morbidities and dysfunction including depression, anxiety, sleep disturbances and fatigue, broken relationships, alcohol and drug addictions, marital dysfunction, premature retirement and perhaps most seriously suicide ,11. As ap < 0.001) among family physicians [It is also possible that compassion fatigue, burnout and various other forms of mental morbidities in the face of chronic exposure to stress may be part of a spectrum and the manifestations may be related to each other. A recent study did find strong correlation between compassion fatigue and burnout ; individual satisfaction, ; family-work balance, ; opportunities for professional development for staff; and competent leadership . DoctorsWhile most people working in poorly functioning organisations may be exposed to high levels of stress putting them at greater risk of experiencing burnout, certain demographic factors may accentuate the risk for burnout. These include young age, female gender, negative marital status, long working hours and low levels of job satisfaction . Being mSeveral dynamic or modifiable contributors to doctor burnout have been identified. Interference with family life is often cited as a significant contributor toward burnout among doctors. A study of medical specialists reported that interference of work on home life  and not being able to live up to one’s professional standards  were most related to stress. The study also found that feeling poorly managed and resourced  diminished job satisfaction . Job satMany of the risk factors for burnout among doctors are static in nature or are difficult to address through intervention strategies. In general, three levels of change are recommended in order to reduce the risk of burnout: (1) modifying the organisational structure and work processes; (2) improving the fit between the organisation and the individual doctor through professional development programmes so that better adaption to the work environment occurs; and (3) individual-level actions to reduce stress and poor health symptoms through effective coping and promoting healthy behaviours . Some ofWork engagement is being increasingly identified in occupational health psychology literature as preventative against burnout  as it haBuilding resilience is often suggested as a preventative strategy against burnout among doctors ,39. At athat attracts individuals into the health profession, encourages them to remain in the health workforce and enables them to perform effectively including professional development programmes to facilitate better adaptation to the work environment” [Deploying resilience-building strategies at an individual level in the effort to prevent burnout among doctors may be akin to building “herd immunity” through individual vaccination and yield greater reductions in stress levels among doctors. It is important to recognise focusing on resilience training of the individual doctor may distract attention from the work environment and organisational culture that causes burnout itself. No measures to prevent burnout will be effective unless attention is paid to enhancing a positive work environment. Isolated strategies directed at individual doctors may prove of limited benefit. A recent systematic review that examined correlates of physician burnout across regions and specialities identified that while it was important to reduce stress and poor health symptoms at the individual level through effective coping and promoting healthy behaviours that ultimately modify the organisational structure, work processes and improving the fit between the organisation and the individual physician were also crucial for preventing burnout . A positronment” . Key feaOnce burnout has set in, one has to look at therapeutic strategies. There is a shortage of well-designed studies on interventions for established burnout among doctors. There are anecdotal reports of a wide range of strategies being effective against burnout once it has set in. Such strategies include participation in panel and group discussions, conferences, and retreats without having to take time off; providing a list of resources to doctors including books, websites, and contact information for experts and workshop leaders who are trained in combating burnout; having professional body policy acknowledging the specific occupational stressors faced by physicians and encouraging physician self-care through proper rest and exercise, spending time with family and having a personal physician to assess well-being objectively; setting limits on hours and choosing a certain type of medical practice, being positive and maintaining a balance in life .Stress management programmes are often recommended for managing burnout. A systematic review  found noFindings from a systematic review  may shedThere is some evidence to suggest participation in a mindful communication programme may be associated with short-term and sustained improvements in burnout among doctors. An American study examining the effect of an intensive educational programme consisting of an eight-week intensive phase  followed by a ten-month maintenance phase (2.5 h per month) teaching in mindfulness, communication, and self-awareness found improvements in mindfulness to be associated with significant improvements in all three dimensions of burnout  .Based on the evidence reviewed, one could speculate an intense stress management programme with booster sessions delivered over a longer period may yield longer-lasting results among those experiencing burnout. Alternatively, mindfulness-based strategies may be promising. Intervention studies comparing the efficacy of long- and short-term programmes of varying intensities against burnout among doctors are needed.Burnout among doctors is a global phenomenon. By virtue of their profession, doctors are a vulnerable group for experiencing burnout. Burnout among doctors can lead to poor quality of care delivered to patients, increased medical errors and poor retention, in addition to poorer health outcome. Enhancing resilience and work engagement at an individual doctor level while also creating a positive work environment that helps doctors achieve work−life balance and enjoy job security, and provides a family-friendly work environment may help prevent burnout among doctors. Once burnout has set in, there is limited evidence to support the usefulness of modalities such as cognitive behavioural therapy, relaxation, music, or creating a positive work environment. Prevention appears to be, once again, far more beneficial than treatment when it comes to burnout.


Transcranial magnetic stimulation (TMS)-induced virtual lesions in healthy subjects can be used to test neurofunctional models of disease. The interhemispheric rivalry model of heminglect is well suited for such investigations, as simple predictions derived from clinical data can be tested without the caveats normally associated with lesion studies. One of these predictions is that release from contralateral inhibition should lead to increased parietal responsiveness, which, in turn, would enhance spatial attention. Here, we detail studies showing TMS-induced paradoxical functional facilitation of attention in healthy individuals and highlight their contribution to the understanding and treatment of neglect syndromes.


Cooperative breeding, in which more than a pair of conspecifics cooperate to raise young at a single nest or brood, is widespread among vertebrates but highly variable in its geographic distribution. Particularly vexing has been identifying the ecological correlates of this phenomenon, which has been suggested to be favored in populations inhabiting both relatively stable, productive environments and in populations living under highly variable and unpredictable conditions. Griesser et al. provide a novel approach to this problem, performing a phylogenetic analysis indicating that family living is an intermediate step between nonsocial and cooperative breeding birds. They then examine the ecological and climatic conditions associated with these different social systems, concluding that cooperative breeding emerges when family living is favored in highly productive environments, followed secondarily by selection for cooperative breeding when environmental conditions deteriorate and within-year variability increases. Combined with recent work addressing the fitness consequences of cooperative breeding, Griesser et al.’s contribution stands to move the field forward by demonstrating that the evolution of complex adaptations such as cooperative breeding may only be understood when each of the steps leading to it are identified and carefully integrated. Soon after W. D. Hamilton revolutionized behavioral ecology with his ground-breaking papers formalizing the theory of inclusive fitness , field bWhat drives the evolution of cooperative breeding? One clearly important factor is Hamiltonian kin selection, although the precise role that genetic relatedness plays is to some extent controversial. In support of the hypothesis that kin selection plays a key role in providing fitness benefits to helpers, the majority of cooperative breeders are indeed composed of family groups. An intuitively pleasing extension of this hypothesis is the idea that monogamy, because of its presumed role in enhancing genetic relatedness within family groups, has been foundational to the evolution of cooperative breeding and eusociality . AlthougCampylohynchus wrens [Aphelocoma coerulescens) [Melanerpes formicivorus) [Picoides borealis) [Beyond the importance, both real and potential, of kinship and inclusive fitness, the one thing that almost all workers agree on is that ecological factors play a key role in driving cooperative breeding. The earliest and most widespread ecological hypothesis for cooperative breeding focuses on what are now generally known as “ecological constraints” or “habitat saturation.” Based originally on a proposal by Robert Selander to explain cooperative breeding in us wrens , the idelescens) , acorn wcivorus) , and redorealis) —all 3 ofBut, alas, such optimism was short-lived. Not only were flaws in the logic of habitat saturation pointed out—including the fact that many or even most species are ecologically constrained in some way but do not delay dispersal or breed cooperatively ,20—but sThe field of cooperative breeding has progressed in many ways since these early studies , but 2 aOne relevant observation is that both these concepts, despite being virtual opposites, involve constraints—the first on obtaining a reproductive position and the second on successful breeding once a position is obtained . But thiPerisoreus infaustus), a species in which young typically remain in their natal territory for up to 3 years—that is, delay dispersal well into adulthood—but do not help feed at subsequent nests [Although early papers distinguished delayed dispersal from helping behavior, particularly when considering their fitness consequences ,3, few tnt nests . SiberiaGriesser et al. , howeverThey find that the best-fitting model includes transitions between all pairs of the 3 categories, but that the transition rate from nonfamily living directly to cooperative breeding is rare compared to the transition rate from nonfamily living to cooperative breeding via the intermediate stage of family living without cooperative breeding. In other words, cooperative breeders almost always evolve from family-living but noncooperative-breeding ancestors. This insight sets the stage for a multinomial analysis investigating the ecological and climatic correlates of the 3 major categories of species, thus focusing on the potential drivers of family living separate from that of cooperative breeding.And here’s where it gets exciting. Griesser et al. find that the apparent ecological factors distinguishing nonfamily-living species from both family-living and cooperative-breeding species are generally similar, with both of the latter species tending to occur in habitats in which rainfall is greater and growing seasons are longer. Cooperative breeders, however, are more likely to be found in environments with higher within-year variability in environmental productivity compared to family-living species that are not cooperative breeders.These results suggest a novel resolution to the conundrum of how 2 apparently contradictory environmental conditions appear to drive cooperative breeding. Relatively stable, productive conditions favor the transition from nonfamily living to the intermediate stage of family living, whereas subsequent evolution of cooperative breeding is favored when conditions subsequently deteriorate, becoming less productive and more variable. Such a scenario fits in well with the current geographic distribution of cooperative breeding, which occurs disproportionately in Australia, southern Africa, and northern South America—places that have undergone dramatic climatic changes from past geological epochs, resulting in less productive and more variable conditions that may have favored the evolution of cooperative breeding from family-living ancestors.Although Griesser et al.’s paper is focused primarily at the level of evolutionary origins, their hypothesis also has implications for the fitness benefits associated with family living and cooperative breeding. As such, it dovetails with recent work by Shen et al. , which iThus, both papers are interested in the ultimate drivers of cooperative breeding and attempt to explain how very different environmental conditions appear to drive cooperative breeding but at complementary time scales and levels of analysis. It is the longer temporal scale combined with the 2-step evolutionary progression leading to cooperative breeding envisioned by Griesser et al. that allow their analysis to potentially explain the ecological and climatic factors leading to the highly heterogeneous incidence of cooperative breeding observed on a continental scale that has until now gone largely unexplained.The ultimate goal of these, as well as other recent broad-scale investigations of social behavior , is to b


The role of sex as an effect modifier of developmental lead (Pb) exposure has until recently received little attention. Lead exposure in early life can affect brain development with persisting influences on cognitive and behavioral functioning, as well as, elevated risks for developing a variety of diseases and disorders in later life. Although both sexes are affected by Pb exposure, the incidence, manifestation, and severity of outcomes appears to differ in males and females. Results from epidemiologic and animal studies indicate significant effect modification by sex, however, the results are not consistent across studies. Unfortunately, only a limited number of human epidemiological studies have included both sexes in independent outcome analyses limiting our ability to draw definitive conclusions regarding sex-differentiated outcomes. Additionally, due to various methodological differences across studies, there is still not a good mechanistic understanding of the molecular effects of lead on the brain and the factors that influence differential responses to Pb based on sex. In this review, focused on prenatal and postnatal Pb exposures in humans and animal models, we discuss current literature supporting sex differences in outcomes in response to Pb exposure and explore some of the ideas regarding potential molecular mechanisms that may contribute to sex-related differences in outcomes from developmental Pb exposure. The sex-dependent variability in outcomes from developmental Pb exposure may arise from a combination of complex factors, including, but not limited to, intrinsic sex-specific molecular/genetic mechanisms and external risk factors including sex-specific responses to environmental stressors which may act through shared epigenetic pathways to influence the genome and behavioral output. Low level exposures to a variety of potential neurotoxicants can result in serious and sometimes fatal health conditions, that can appear either acutely or delayed. The incidence, manifestation, and severity of such health problems may differ between males and females  as a resLead (Pb) is a potent neurotoxicant, exposure to which alters normal brain developmental trajectories resulting in an increased risk for a variety of cognitive/behavioral problems. While recent studies have documented sex-dependent effects of Pb on a variety of physiological and functional outcome measures ex., , the bas1. Thus, early life exposure to Pb remains a serious public health concern in the United States and elsewhere in the world. Children are more sensitive to, and more frequently exposed to, Pb than adults because of their behavior  and physiology   . In 2012orption) . Low incorption)  that estorption) . No obviorption) . NumerouNumerous epidemiological studies have been performed in an effort to understand the effects of Pb on the developing brain, however, a focus on sex-specific analyses of outcomes have only recently been incorporated into many of these studies. In many early epidemiological studies, sex was either not taken into account in the analysis  or sex was included as a confounding variable along with statistical measures to eliminate the confounding effects of sex rather than examining the potential influence of sex on outcomes. In those studies where sex was taken into account in the analyses, more often than not, the neurotoxic effects appeared to be more pronounced in males than females. However, this conclusion may be misleading, as the influence of sex on outcomes may depend on the type and the age when outcomes are measured. Various statistical approaches to estimate the role of sex in modulating toxicity  has recently been highlighted as a key aspect in the interpretation of potential sex-specific effects across studies .While detrimental neurological effects of low-level postnatal Pb exposure are well-known, effects of prenatal exposure on intellectual development have also been described. Early life deficits in sensory-motor and cognitive development have been reported based on umbilical cord blood lead levels, even at exposures below 10 μg/dL , 1986 bup < 0.001) higher than in females. However, a recent study by N = 13), these results need to be viewed with caution and further work is needed to identify any potential sex-related differences in the risk of developing a neurodegenerative disorder in adulthood as a result of prenatal exposure to Pb.In addition to adverse effects of prenatal Pb exposure on childhood cognitive development, prenatal Pb exposure has also been reported to be associated with adverse behavioral outcomes including aggression, antisocial behavior, and criminal activity . Wright Thus, while the few studies that have specifically looked at differential effects of maternal Pb exposure on male and female offspring more often than not suggest that males may be more vulnerable to the effects of Pb than females, the small number of studies and the use of different outcome measures in different studies make it difficult to draw firm conclusions regarding the modifying effects of sex on cognitive/behavioral outcomes following prenatal Pb exposures. The influence of sex on outcomes from developmental Pb exposure may very well be outcome and age dependent.In human epidemiological studies of prenatal Pb exposure, factors such as maternal stress and diet can modify the potential outcomes from Pb exposure in unpredictable ways. However, in animal studies, these and other variables can be explicitly controlled. Although numerous animal studies have examined sex as an effect modifier of prenatal Pb exposure, there is not a clear and consistent picture of sex-specific effects of prenatal Pb exposure. In adult mice exposed to Pb from gestational day 8 to postnatal day 21 (blood Pb level not reported), male but not female mice showed severe aggressive behavior toward their littermates as evidenced by a larger number of injured littermates in cages housing male Pb-exposed mice than in cages housing female Pb-exposed mice . The samper se to childhood Pb poisoning, even low level exposures in children can result in a spectrum of neurodevelopmental problems that include cognitive impairments  and behavioral problems    that mayression) . In anotression) . A signiression)  was alsoression) . Howeverression)  suggest ression) , whereasression) . Howeverression) . These eRelatively few studies of the effects of postnatal Pb exposures on the brain and behavior have incorporated both sexes into the study design. Chronic postnatal Pb exposure at a high concentrations (500 ppm) (blood Pb level∼70 μg/dL measured after 70 days of exposure) starting at weaning (21 days age) and lasting into adulthood  resulted in an anxiogenic effect observed in male but not female Swiss mice . An anxiData from human and animal studies unequivocally demonstrate that early life Pb exposures significantly impair cognitive, neurobehavioral, and motor functioning suggesting that these exposures alter brain structure and/or function. Both sexes are vulnerable to Pb toxicity and suffer adverse outcomes, however, evidence suggests that depending on the circumstances, one sex may be more vulnerable than the other. The underlying cause of sex differences in outcomes from Pb exposure could be linked to naturally occurring structural, neurochemical, and neuroendocrinological sex differences in the brain . As discUnderstanding the pathways that influence the sexually dimorphic brain development under normal circumstances is prerequisite to understanding how disruption of these mechanisms may result in differential vulnerability/resiliency to various adverse outcomes associated with developmental Pb toxicity. The traditional model of sex differentiation in the brain, referred to as the linear serial model of sex differences, asserts that the structural/functional differences in the brain between the sexes arise due to interactions between genetic assignment of sex (XX or XY) and gonadal hormones secreted by the sexually differentiated gonads . Until rSry gene, an important primary sex-determining gene, leads to differentiation of the testis in males and has been characterized as a crucial sexually dimorphic gene directly affecting brain structure/functioning . A subset of these genes, associated with depression  showed pression  and plaspression .Npas4, cFos, JunB, Egr1, Egr2, and Arc were differentially affected in males and females. Sex-specific Pb-induced alterations in transcription factor expression can have far reaching effects on brain plasticity, since TFs are involved in regulating genes involved in diverse functional pathways  has been identified as candidate gene for Pb toxicity and is involved in Pb toxicokinetics) and down-regulation in its transcription ], and these effects varied by sex, amount of Pb exposure, developmental window of exposure, and duration of Pb exposure. Perinatal exposure to Pb has also been reported to result in sex-specific hypermethylation in the hippocampus of female mice but not in males . We identified methylation changes in genes involved in neurobehavioral functions and neurodevelopment [for example, in males . Sen et in males  from thein males . Umbilicexposure . The autThe information briefly reviewed above suggests that the response to Pb exposure at the level of DNA methylation may occur in a sex-specific manner and that sex-specific Pb-induced alterations in the expression of DNA methylation regulators could be important factors influencing sex-related differences in gene specific methylation levels. DNA methylation profiles in brain are sexually dimorphic  and hormMEG3 imprinted gene, as measured in genomic DNA from umbilical cord blood. The same group also reported that while childhood exposure to Pb (mean blood Pb level between 8 and 14 μg/dL) was associated with significant DNA hypomethylation at the DMR  of the PEG3 imprinted gene in blood of adult males and not females, neonatal Pb exposure (mean blood Pb level between 3 and 15 μg/dL) resulted in a moderate decrease in methylation at IGF2/H19 DMR in females (PLAG1/HYMAI (ZAC) DMR with neonatal Pb exposure occurred in both sexes. These data are interesting in that PEG3 is important for brain development as it regulates network of genes concerned with neural development  is an environmental factor that has been shown to modify the effects of Pb on the brain in numerous animal studies ex., . A recenKdm5c, a histone demethylase which removes di and tri methylation of H3K4me2/3, located on X chromosome escapes X-inactivation and is expressed at a higher level in XX cells compared to XY cells. Although Kdm5c has a Y-paralog-Kdm5d, its expression level has been found not to be able to compensate for lower levels of transcripts in XY cells  that are altered by Pb ± PS exposures. A whole genome wide approach is crucial for identifying global regulators and downstream target genes affected by Pb, PS and behavioral experience, since studies to date suggest that multiple pathways and targets rather than specific single genes contribute to Pb neurotoxicity. Currently available analytic methods combined with proper bioinformatic and statistical approaches should provide important new information regarding the nature of adaptive vs. maladaptive responses to environmental exposures at the molecular level.ALAD and VDR (vitamin D receptor) involved in Pb toxicokinetics) and Pb toxicity, but a clear protective or vulnerable role could not be linked at least through studies performed till now  and Pb exposure interactions in a study cohort where low Pb exposure (<10 μg/dL) in children has been shown to be inversely associated with IQ scores  polymorphisms and sex on birth outcomes in participants in Mothers and Children’s Environmental Health  analysis of the candidate genes and their human homologs were enriched for categories related to neurodevelopmental processes in both sexes. In addition, distinct GO categories were also identified in males and females. The study also identified Drosophila homologs of some previously characterized susceptibility genes from human studies, such as VDR and GST. Interestingly, childhood blood lead level was shown to be associated with anomalous DNA methylation at the human PEG3 as well as IGF2 loci  showed that genetic variation can influence outcomes from developmental Pb exposure . The higDnmts. In fact polymorphisms in DNMTs have been implicated in governing epigenetic susceptibility to schizophrenia in human population .The term exposome was proposed to complement the genome and was described as the sum of all environmental exposures an individual experiences throughout life . Later tBox 1). The molecular networks involved in defining the sexome, genome and epigenome are integrated with each other and the need now is to identify those factors that interact with these biological entities and integrate them into a mechanistic framework to understand the ways in which sex is an effect modifier for Pb neurotoxicity.This review has highlighted some of the known sex-related outcomes associated with early life exposure to Pb and some of the potentially different mechanisms involved in males and females. The review has also highlighted that it is becoming increasingly clear that multiple factors can further influence an individual’s response to Pb and that epigenetic factors, as targets of Pb toxicity, may play key role in programming the long-term effects from early life Pb exposure. While much remains unclear regarding the sex-specific responses of the brain to Pb, one thing that is very clear is that much more study is necessary in order to further identify and understand the complex mechanisms contributing to different outcomes from Pb exposure in males and females ((1) Are there global regulators/factors at the molecular level that play a critical role in determining adaptive/maladaptive responses to Pb?(2) If such factors exist, how are they modulated by sex, genetic background, and other environmental exposures?(3) Can such factors occupy important nodes in gene networks to integrate multifactorial influences so that even small magnitude changes, in aggregate, may result in significant functional effects?(4) Integration of current unbiased genome wide technologies with appropriate bioinformatic approaches and statistical designs are needed in order to unravel these complex multifactorial mechanisms of biological responses to toxic exposures.GS wrote the initial draft of the manuscript and worked on subsequent revisions. All the other authors worked on revising 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.


The focus of the very few existing studies that included obese patients was on metabolic and body composition changes and not on walking or biomechanical improvement  in obese patients, with walking speeds that also appear inversely related to body mass index  physiological stimulus for weight management. In healthy older community dwellers, changes of time-based gait parameters  from the beginning to the end of a 40-min treadmill walk occurred, but these fatigue-related effects were similar to a 2,600-m simulated altitude or those near sea-level  in overweight subjects (body mass index >27 kg/m2) leads to larger (+1.14 vs. 0.03 kg) weight loss than similar training in normoxic environments  weight loss (yet of undefined composition) and improve metabolic and cardiorespiratory health  that would influence the load applied to the weight-bearing joints of obese individuals. Surface electromyography (EMG) recording during various locomotive tasks would elucidate muscle activation strategies used by obese patients to cope with these situations, including whether hypoxia exposure modifies neuromuscular responses. While the surface EMG may be feasible in severely obese individuals  that can be conducted in normobaric or hypobaric  conditions with the use of artificial devices or by ascending to elevated terrestrial environments , while ensuring an adequate exercise stimulus for weight management. Alternatively, hypoxic conditioning may be an appropriate form of exercise training for obese patients as it can lead to effective weight loss due to a negative energy balance. These acute and chronic hypoxic-related interventions would contribute to the support of an appropriate and individualized prescription for obese patients to reduce the biomechanical load involved in walking and eventually improve training adherence Figure .All authors listed, have made 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.


Understanding the ways in which individuals cope with threats, respond to challenges, make use of opportunities and mediate the harmful effects of their surroundings is important for predicting their ability to function in a rapidly changing world. Perhaps one of the most essential drivers of coping behaviour of adults is the environment experienced during their early-life development. Although the study of coping, defined as behaviours displayed in response to environmental challenges, has a long and rich research history in biology, recent literature has repeatedly pointed out that the processes through which coping behaviours develop in individuals are still largely unknown. In this review, we make a move towards integrating ultimate and proximate lines of coping behaviour research. After broadly defining coping behaviours (1), we review why, from an evolutionary perspective, the development of coping has become tightly linked to the early-life environment (2), which relevant developmental processes are most important in creating coping behaviours adjusted to the early-life environment (3), which influences have been shown to impact those developmental processes (4) and what the adaptive significance of intergenerational transmission of coping behaviours is, in the context of behavioural adaptations to a fast changing world (5). Important concepts such as effects of parents, habitat, nutrition, social group and stress are discussed using examples from empirical studies on mammals, fish, birds and other animals. In the discussion, we address important problems that arise when studying the development of coping behaviours and suggest solutions.The online version of this article (10.1007/s00265-018-2452-3) contains supplementary material, which is available to authorized users. The behaviours that animals display to respond to challenges in their environment—whether to avoid a threat or to utilise an opportunity—relate directly to their ability to survive and reproduce. This is especially the case in a quickly changing world , there is an important unexplored niche in the ways through which the environment during early-life development shapes coping behaviours used later in life  to adapt to ever changing environments, it is essential to study coping behaviour and its causal factors, as coping behaviour directly relates to animals’ ability to adapt to novel and changing environments Taborsky . While oIn this review, we offer an environmental perspective on the development of coping and simultaneously consider the process from an evolutionary angle—a novel synthetic approach that has been lacking so far. Without going too deeply into neurobiological details, we highlight the importance of the early-life environment on the development of coping behaviours and extensively review relevant literature to further an understanding of both ultimate (why) and proximate (how) causes of this essential role of the early-life environment in the way animals respond to challenges in their surroundings. The early-life environment is defined here as the non-genetic biotic or abiotic external factors that affect an animal in the period from conception to the time it can survive independently.The review includes 1) a working definition of coping behaviours and a brief overview of components that are precursors to successful coping, (2) evolutionary reasons for the development of coping to be strongly affected by the early-life environment, (3) developmental processes through which the early-life environment affects later-life coping behaviours, (4) environmental influences shown to affect these developmental processes and (5) non-genetic intergenerational transmission of coping behaviours, an overarching topic that concerns both why and how coping behaviours are affected by the early-life environment, which we discuss in the context of behavioural adaptation to a rapidly changing world , evaluating an effective response (2), ability to give that response (3) and paying the cost for that response (4). As a thought experiment: in order to successfully cope with a larger animal encroaching into its habitat, a potential prey has to have a sensory awareness of the larger animal, followed by the perception (1) that this animal is either harmless or dangerous. If the latter is the case, the prey has to evaluate (2) whether hiding or running away is the most effective way to respond in this situation and to this type of predator, and (3) whether it is physically capable of running fast enough to get away. If it does hide or run, it can lose foraging time and valuable resources or encounter other dangers. These state- and condition-dependent costs need to be factored into the decision in favour of a particular coping behaviour.When coping behaviours are considered as the decision an animal makes with regards to the behaviour it will use to mediate a challenge presented by its environment, as follows from our definition, it becomes relevant to consider precursors to that decision. For all animals, it can be hypothesised that successful adaptation to environmental conditions depends on (at least) four pillars: There is strong selection on traits making up each of these four pillars, as each directly factors into an individual’s coping behaviour, and there are immediate and possibly life-threatening consequences to responding with ineffective behaviours  early in life. As a result, the situations they perceive as a threat or a danger later in life is closely linked to early-life conditions. An adult responding aggressively in certain situations may be doing so because their early-life environment has induced a heightened threat perception, or may respond impulsively because their experiences did not prepare them for the possibility of a predator , who had never experienced a predator before, were challenged to respond to predator cues, to which they responded less appropriately than wild-bred fish with past experience of a predator  phenotype, and as a source of information in predicting the phenotype Schoener . It has A key concept in this context is phenotypic plasticity, sometimes defined as the flexibility of developmental processes to generate a variety of different phenotypes from the same genotype, through sensitivity to early-life environmental input  raised in larger social context developed greater social competence . In this species, juveniles generally learn foraging skills from their parents. When juveniles were exposed to developmental stress, however, they switched to learning foraging skills exclusively from biologically unrelated adults. Stress has been suggested as an environmental cue , and at the same time minimally sensitive to those that are caused by short-term stochastic processes . One way to navigate this trade-off is through sensitivity to maternal stress, which is increasingly argued as potentially beneficial to offspring  experienced an unstable social environment, her male offspring developed a behavioural camouflage strategy, hypothesised to be beneficial at the time of social challenge , pre-natal stress experienced by the mother resulted in inheritance of the same stress-coping traits in offspring across neuroendocrine, physiological and behavioural traits. These responses have been suggested as adaptations to preparing offspring for a future environment in which the same stressors are experienced , so as to increase the fitness of both parents and offspring. When wild cavy mothers  exposed to a predator spider during gestation showed greater anti-predator immobility in response to spider cues than offspring of non-exposed females. “Warned” offspring then survived better when faced with spiders (Storm and Lima Zootoca vivipara), maternal exposure to snake cues during gestation affected juvenile behaviour and dispersal towards increased risk avoidance strategies  stable and unchanging environments, close and individualised adaptation to the environment is relevant. There are two main reasons for this: differential experience or impact and differential susceptibility or biological sensitivity to context. Although these are not new ideas  showed that offspring consistently differed in postnatal body temperature and early growth. These individual differences in life history corresponded to consistent differences in coping behaviours: pups with lower body mass struggled more when handled and explored more in an open field test, while pups with higher body mass jumped sooner from a platform , a cooperatively breeding species of fish, rearing group size and the time juveniles spent in these groups affected the development of later-life social behaviours , the deMaternal effects, defined as the direct effect of a mother’s phenotype on that of her offspring Bernardo , have beT. guttata) showed that offspring exploratory type was predicted by exploratory type of the foster, but not the genetic parents , parental activity during parental care was negatively correlated with the freezing versus activity factor in female offspring  increase androgen concentrations in their eggs as competition from their sister species increases, resulting in more aggressive male offspring that are more likely to disperse and create new colonies  were exposed to imprinting on similar or dissimilar items and through visual or acoustic modes or both, males showed more positive response to novel stimuli when they had been imprinted on dissimilar items. This response was even stronger when they had been imprinted across both modes. Females, on the other hand, were more attracted by familiar patterns  to a predator cue was most rapid with the least realistic models (Magurran and Girling Perca fluviatilis) were found to lead to differences in risk-taking behaviour even after being kept in a predator-free environment for 9 months  habituated faster to urban disturbance than their rural conspecifics: while rural and urban birds were initially equally likely to hide, the urban birds came out of hiding faster over repeat trials  that were conditioned to recognise chemical predator cues as dangerous, significantly increased anti-predator behaviours , unlike trout from a control group. This response was still exhibited up to 21 days after conditioning , conditioning with a song as reward influenced the effectiveness of song learning during development but not song preferences in adulthood (Adret O. cuniculus) could be habituated to human handling, but not outside this window (Pongrácz and Altbäcker Rana lessonae and R. esculenta) were conditioned for 30 days to a variety of predators, after which species differences were found in the ways general activity levels and use of refuge changed, as well as differences in the type of predator they responded to  where adults were shown to teach pups prey-handling skills , through active parenting by means of example and correction, and through conditional parenting based on offspring performance. What all such mechanisms have in common is that they involve learning from observation of a conspecific or from interaction with them Heyes . A speciMalurus cyaneus) learned to recognise unfamiliar sounds as alarm calls through social “eavesdropping”  become conditioned to being illegally fed by recreational fishers depended on both the degree to which the dolphins would frequent areas with a lot of tourism, and the degree to which they associated with previously conditioned dolphins , effects of early-life habitat conditions were studied by means of natural habitat , where they were shown to affect coping behaviours: barren housed pigs were less active, less explorative and less playful and showed more social aggression than pigs raised in enriched housing  displayed increased courtship, aggression and curiosity towards a novel predator compared to pond-reared fish and commenced foraging on novel food more rapidly , exposure to enriched conditions improved learning and ability to navigate a maze without errors  behaviour: exploratory behaviour, predation and anti-predation response were higher in fish reared in enriched or semi-natural environments than in barren environments  never exhibited a behavioural syndrome between boldness and foraging aggressiveness, while field-reared penultimates (but not juveniles) did  were found to base habitat choice, an important life-history decision that affects coping success in many aspects of life, on the habitat type in which they had been reared—an adaptive effect as they were also found to be more effective in locomotion in these habitats than in others  separated from their mothers early in life displayed reduced activity and risk taking, and increases in orienting time  reared by mothers showed more escape and vigilance behaviour than automat-reared cows when faced with an isolation test, and displayed overall more social behaviours towards conspecifics  separated from their mothers and/or social group as juveniles showed decreased activity and increased abnormal behaviours, with stronger effects in younger individuals (Martin C. japonica), mothers of large broods emitted more maternal vocalisations at the start of mothering but covered the young less towards the end. Chicks in turn huddled more and had higher social motivation than chicks in small broods  from friendly fathers were quicker to approach, touch and rub an unfamiliar person and remain in close contact with novel objects than those from unfriendly fathers (McCune T. guttata), offspring exploratory type was predicted by the exploratory behaviour of the foster, but not the genetic parents , offspring of mothers exposed to predator cues dispersed three times more in an unfamiliar semi-natural environment than offspring from unexposed mothers , females exposed to predator cues produced offspring with altered behaviour, and males  exposed to predator cues produced offspring that were less active , an unstable social environment experienced by mothers during pregnancy and lactation led to camouflage behaviours in male offspring, whereas a stable social environment led to earlier reproductive behaviour , exploratory behaviour and anxiety levels were correlated with body mass in early life, but not with body mass and age at the time of testing (Rödel and Monclús Phaedon cochlaeriae), low-quality food induced boldness, and by extension, potential foraging success, while animals raised on high-quality food were more active  with larger yolks showed more aggressive personality traits than siblings with smaller yolks and, subsequently, were more aggressive in territory establishment and more socially dominant (Andersson and Hoglund Kryptolebias marmoratus), low food conditions reduced exploration but not boldness or aggression (Edenbrow and Croft Parus major) selected for fast exploration, food rationing was linked to increased aggression  raised on rich diets developed an aggressive phenotype, whereas those raised on poor nutrition became non-aggressive “scramblers” , for example, was related to a higher number of social interactions in males (Bölting and von Engelhardt N. pulcher), fry raised with adults showed more aggressive and submissive behaviour to each other than fish raised with siblings only (Arnold and Taborsky .) showed that being raised in a social environment affected the degree of behavioural plasticity males exhibited later in life, i.e. the flexibility they had to choose a coping behaviour depending on the situation at hand, something that can significantly affect a male’s fitness (Han and Brooks Marpissa muscosa) reared in groups are better at exploration of a maze and at sociality than those reared in isolation, which is especially relevant since isolated rearing adds no known additional stress in this species , which was not reversed after birds were re-housed in larger groups  together as juveniles showed that the type of social experience during early life affected social behaviours: all mixed-group fish were more inclined to biting, while mixed-group fish of one strain were also more exploratory. No effects were found on activity, predator response or stress recovery , young males reared in the presence of conspecific acoustic sexual signals were less aggressive and less likely to become dominant relative to those reared in the absence of acoustic signals  reared alone and without predatory cues showed no personality and no behavioural syndrome between activity and risk-taking behaviours, while those raised with predator cues displayed activity and risk-taking personality traits, and those raised with predators and conspecifics both displayed an activity—risk-taking behavioural syndrome  born and raised in high predation localities showed more boldness than those from low predation localities , non-pathogenic immune challenges, administered at different stages of development, were found to affect both activity and exploratory behaviour, as well as colour-dependent novel object exploration. Specifically, individuals immune-challenged during mid and late developmental stages were more active in novel environments , early pathogen exposure did not influence mean boldness behaviour directly, but it did affect the presence of a personality construct  altered later-life personality traits of vigilance and escape attempts  social behaviour , it is described how brief intermittent exposure to early life stress  actually promoted the development of arousal regulation and resilience, rather than leading to vulnerability  from a population in urban areas were more tolerant of humans, less aggressive and bolder after a simulated predator attack and spent more time exploring new environment than lizards from a population in a nearby forest. These changes in behaviour were suggested to be due to adaptive behavioural adaptations to novel selective regimes  were less reactive and had poorer locomotive performance when exposed to elevated CO2 levels, but parental exposure to high CO2 reduced these effects in some—but not all—traits  whose mothers had been exposed to early-life stress, even when those mothers no longer displayed hypo-responsiveness themselves , where prenatal stress experienced by mothers resulted in the same stress-coping traits in the offspring across all phenotypic levels studied, including behavioural traits  showed that the amount of contact mothers had with their offspring was related to the amount of contact they themselves had with their mothers. In this, a female’s experience in infancy was a better predictor of adult mothering than variables such as social learning as a juvenile, shared circumstances and average similarity between mothers and daughters  environmental cues across multiple generations have been studied almost exclusively in rodents and are often targeted to understanding depression, anxiety and effects of stress in humans. This one-sided approach makes it more difficult to place empirical findings in an ecologically relevant context, although it does provide advantages in testing the limits of the developmental system in ways ecological studies in the wild would not. It might be argued, given the positive effects on coping behaviours consistently shown by cage enrichment and communal housing, that laboratory conditions in themselves represent multigenerational environmental stress on the level of habitat, parents, social group and possibly other influences.Important concepts when discussing the adaptive advantages and disadvantages that come with sensitivity of developmental processes to early-life conditions are resilience and reversibility. Resilience, the capacity to recover from difficulties, is important in estimating the strength with which negative experiences continue to influence animal health and fitness


LEP (leptin), LEPR (leptin receptor), and LEPROT (endospanin) genes has allowed protein structure modeling, stoichiometry predictions, and even functional predictions of leptin function for most vertebrate classes. Here, we apply functional genomics to model hundreds of LEP, LEPR, and LEPROT proteins from both vertebrates and invertebrates. We identify conserved structural motifs in each of the three leptin signaling proteins and demonstrate Drosophila Dome protein’s conservation with vertebrate leptin receptors. We model endospanin structure for the first time and identify endospanin paralogs in invertebrate genomes. Finally, we argue that leptin is not an adipostat in fishes and discuss emerging knockout models in fishes.Over a decade passed between Friedman’s discovery of the mammalian leptin gene  and its  In 1994, Friedman’s laboratory described leptin as a peptide hormone that is synthesized by adipose tissue . In mammLEPs and LEPRs in all classes of vertebrates  leptins vs. leptins from bony fish. In other words, bony fish leptins diverged along their own lineage independent of leptins in higher mammals  express a single ortholog of leptin  (acc# XP 018609810 and KPP63040). This duplication event appears to be ancient, but it is unresolved if the duplication of lepr was present in the ancestor of teleost fishes and then lost, or if loss of lepr predates teleosts  are subtypes of A and B  or do nknockout ]. It mayknockout , 126, arHow does the status of the adipostat model in fishes affect leptin as an adipostat in other vertebrates? We now know that human obesity is influenced by changes in food perception and metabolism after weight loss , and theob/ob) mouse, a long-standing model of human obesity (LEP gene (db/db) mouse, a LEPR-deficient model, leptin administration effects have been demonstrated repeatedly. Intraperitoneal leptin injections in ob/ob mice causes 30% decrease in body mass, and db/db mice are similar to controls (ob/ob mouse . In doiAll procedures performed by the authors that used animals were approved by the institution’s IACUC.All authors contributed to drafting and editing of the manuscript. JWP completed all molecular modeling.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. The reviewer RD and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.


People with chronic obstructive pulmonary disease (COPD) have a higher incidence of and mortality from cardiovascular disease, and reducing cardiovascular mortality is an important target area for reducing overall mortality in people with COPD. Huge strides have been made in recent decades in reducing mortality after myocardial infarction (MI) in the general population, however, these improvements may not have been mirrored in all patient groups, such as those with COPD.Recently, much attention has been paid to investigating how COPD patients present with acute MI and how their management and outcomes compare to people without COPD. The evidence seems to point to an increased risk of death after MI in people with COPD, however it is unclear if this difference is due to COPD itself or if it is due to potentially modifiable factors, such as less aggressive treatment after MI. In a recent review we studied the evidence for differences between COPD and non-COPD patients after MI in terms of presentation, recognition of MI, in-hospital care, secondary prevention and outcomes both in-hospital and in the longer term.People with COPD have both a higher risk of MI and poorer long term outcomes following MI. Previous studies have also shown that COPD patients are less likely to receive beta-blockers on discharge after an MI and are less likely to receive PCI after a STEMI. Findings for differences in in-hospital mortality have been mixed, with some studies finding higher mortality for COPD patients and some studies finding no difference. The heterogeneity in findings may be due to differences in treatment practices. The extent to which differences in treatment can explain differences in mortality at the population level, the “mortality gap”, is unclear.Delayed diagnosis, timing and use of reperfusion of a STEMI, use of angiography after a non-STEMI, and use of secondary prevention medicines are all potential explanations for the mortality gap after MI in people with COPD. In a recent study, we have found that differences in potentially modifiable in-hospital processes may explain some of the mortality gap between COPD and non-COPD patients after an MI. Clinicians need to be aware that it may be easier to miss MIs in people with COPD and may need to be aware of more unusual presentations of MI in people with COPD. In addition, our results suggest that COPD patients may benefit from more aggressive treatment after an MI.Troponin is presently used as a prognostic indicator in the context of predicting COPD morbidity and mortality. Acute exacerbations of COPD (AECOPD) are associated with a rise in troponin. Patients with higher troponin have longer hospital stays and worse survival outcome at 1-year. Cardiac Troponin T ≥ 0.04 during AECOPD hospital admission conferred approximately a twice as likely risk of mortality at 1-year than those with non-detectable Cardiac Troponin T. Cardiac Troponin T appears a better prognostic indicator for long-term outcome amongst COPD patients following an MI compared to Troponin I. Clinicians should not be reassured by relative lower troponin levels in COPD patients at the time of an MI.Despite being at higher risk of death following admission for acute coronary syndromes, people with COPD are less likely to receive investigation and treatment than people without COPD and this difference may explain some of the difference in mortality. It is recommended that those at moderate (3–6%) or high (>6%) Global Registry of Acute Coronary Events (GRACE) score predicted risk of death at 6 months after admission to hospital for non-ST-segment elevation myocardial infarction or unstable angina receive earlier aggressive investigation and treatment. We undertook a nationwide multicentre study involving 481,849 hospital admissions and demonstrated that GRACE scores underestimate risk of death after acute coronary syndromes for those with COPD. This study also found that multiplying the predicted risk of death for those with COPD by 1.3 provides a better approximation for their risk of death. Using a more accurate estimate of risk of death for those with COPD after admission for acute coronary syndromes one third of COPD patients previously categorised as low risk would be reclassified as moderate risk, and therefore would be eligible for earlier, more aggressive investigation and treatment.


Deformational plagiocephaly and craniosynostosis are two of the most common neonatal cranial head shape anomalies. Traditionally, both entities were thought to cause aesthetic concerns solely. Recently, many groups have demonstrated that both conditions are strongly associated with developmental delays. The relationship between the abnormal neonatal cranial shape and early developmental delays manifested in both conditions remains poorly understood. Neonatal cranial head shape anomalies are common and have been attributed to a multitude of factors. Interestingly, despite recent advances in global health care, the incidence of some cranial anomalies has been increasing, making awareness and access to care ever more important. Typically, cranial head shape anomalies are identified in the 1st months of life by primary care providers, who refer these infants to a multi-disciplinary team that specializes in craniofacial disorders. While craniofacial clinics have always been well-suited to manage the aesthetics concerns of cranial head shape anomalies, only recently have concomitant neurodevelopmental delays begun to be addressed in these specialty clinics.Deformational plagiocephaly (DP), also termed positional plagiocephaly, and craniosynostosis (CS) are two of the most common cranial anomalies encountered in craniofacial clinics. Both conditions can significantly distort the closed cranial vault anatomy in which the developing brain presides. Coincidentally, both conditions are associated with neonatal developmental delays yet it remains indeterminate whether the relationship is causative or correlative. This question has focused recent research efforts to study the impact that the cranial vault shape has on normal brain function and development.DP is the most common neonatal head shape anomaly affecting 13–48% infants less than 1 year of age  and results from early fusion of fibrous cranial sutures which serve as growth centers separating immature, growing cranial bones. Premature ossification and union of individual cranial bones, according to Virchow's rule, results in abnormal cranial growth parallel to the fused suture(s). CS requires surgical correction and often cranial vault expansion/remodeling to restore the “normal” infant head shape and aesthetics. Both the timing and the specific operative technique to restore normal cranial anatomy are surgeon-dependent, creating a confounding factor that permeates the literature on this topic.It is well established that syndromic variants of CS are often associated with neurologic delay. In addition, non-syndromic CS has also been associated with developmental delay but much less commonly. In 2000, Renier et al. first demonstrated that neurodevelopment was delayed in non-syndromic infants with single suture CS  to objective measures requiring infant participation, such as the Bayley Scales of Infant and Toddler Development III. A common problem with all these measures is that they are limited to certain age ranges and correlation with adolescent and/or adult development is modest at best. One plausible solution is to utilize to utilize a battery of other developmental tests as an initial screening and longitudinal assessment tool (Hashim et al., For several years our craniofacial team has been investigating neurodevelopmental problems associated with both DP and CS. We have conducted prospective studies involving both conditions. Our team has demonstrated that surprisingly, the severity of DP cannot be used to predict either the presence or degree of infant developmental delays (Fontana et al., There are several problems and criticisms of the medical literature concerning the relationship of developmental delay with DP and CS. First, most studies are retrospective and/or observational in design. This limits the conclusions that can be drawn from their results and at best the relationship remains correlative not causative. Second, as stated earlier, there is no uniformly accepted developmental screening tool to utilize and assess outcomes among differing institutions. Since centers use different developmental assessments it is difficult to compare results amongst institutions. Finally, all current DP and CS studies are from single institutions only with no multi-center studies or meta-analyses available to interpret. To obtain more useful information a large multi-center study or database is required. These knowledge gaps create a large hole in the medical literature. Further work is needed to better understand the relationship between cranial bone growth patterns and infant neurodevelopment. Many groups, including our own, have demonstrated that abnormal skull growth associated with both DP and CS significantly increases the likelihood of developmental delays. While the cause of these delays occur is yet poorly understood, there does seem to be a trend toward normalization in infants with CS who have surgical correction.Both BA and SF were involved in the data collection, review of literature and the writing of this paper.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.