As life expectancy continues to increase worldwide, age-related dysfunction will largely impact our societies in the future. Aging is well established to promote the deterioration of cognitive function and is the primary risk factor for the development of prevalent neurological disorders. Even in the absence of dementia, age-related cognitive decline impacts specific types of memories and brain structures in humans and animal models. Despite this, preclinical and clinical studies that investigate age-related changes in brain physiology often use largely different methods, which hinders the translational potential of findings. This review seeks to integrate what is known about age-related changes in the brain with analogue cognitive tests used in humans and rodent studies, ranging from “pen and paper” tests to virtual-reality-based paradigms. Finally, we draw parallels between the behavior paradigms used in research compared to the enrollment into clinical trials that aim to study age-related cognitive decline. The steady increase in life expectancy was projected to globally slowdown in the latter half of this century, compared to the increase observed from 1990 to 20172. This deceleration is predicted to be more pronounced in countries that already show high life expectancies, than in developing countries. Therefore, estimations towards the end of the century point to an overall global convergence of life expectancies2.One of the prime accomplishments of modern societies is the steady increase in longevity. In one century alone, we have evolved from almost no countries with life expectancies over 50 years, to currently having over 40 countries with life expectancies that exceed 80 years of age3. Accordingly, it is well established that cognitive function is affected during aging, as about 40% of individuals aged 65 years or above suffer from some form of memory loss7. While it is widely acknowledged that aging is the primary risk factor for the development of progressive neurodegenerative disorders like Alzheimer’s disease (AD), it is important to note that the neurobiological changes that occur during aging which result in cognitive deficits are vastly distinct from those observed in AD. For instance, while both aging and AD are associated with brain volume loss, research conducted on humans and animals suggests that the atrophy observed during normal aging primarily results from synaptic loss, rather than cell loss. In contrast, AD is characterized by significant neuronal and synaptic loss8. Several studies have shown that mild cognitive impairment (MCI) affects approximately 16% of individuals over the age of 70, while around 14% of people in the same age group experience dementia14. Furthermore, it is estimated that about 15–20% of patients with MCI may eventually develop dementia16. Importantly, aged individuals encounter difficulties in performing daily activities and show deterioration as they age, in a gender-specific pattern, even in the absence of disease18. Notably, the severity of cognitive impairment is strongly linked to hospital admissions18. Elderly patients without MCI, but with cognitive impairment, are more prone to frequent hospitalizations compared to those with intact cognitive function18. These individuals also face an increased risk of adverse outcomes during their hospital stay20.The increase of chronological age is generally accompanied by several factors that impair the health quality during the final years of life. Older populations show a higher risk and prevalence of age-associated disorders such as cancer, arthritis, heart, and neurodegenerative disorders15.In conclusion, understanding the prevalence and characterizing cognitive impairment spared of disease in the elderly population is crucial to identify and address the healthcare needs of individuals experiencing cognitive decline, as well as for implementing appropriate strategies to mitigate the risk of adverse outcomes during hospitalization21. Limited social and/or financial support might also hinder the enrollment to studies and introduce recruitment bias. Lastly, the intrinsic design of aging longitudinal studies may take several decades to complete. The prolonged duration of these studies can lead to many participants opting out before the study concludes, for numerous reasons. These include the inability to participate due to new arising incapacities, geographical relocation or changes in life-style that make them inadequate for the inclusion criteria of the study. These limitations underlie the need for complementary research options to study age-related cognitive decline and associated brain alterations. Animal models show several advantages as they largely decrease variability and allow a more detailed and cost-effective evaluation of the underlying changes associated with age-related cognitive decline. These preclinical studies are also useful to trim down candidate changes and mechanisms to be later evaluated in human studies.However, human aging studies are challenging to design and to complete. For example, selection bias in recruiting participants that already display advanced age-related comorbidities can easily result in reduced enrolment in the study. The opposite can also occur, as healthy, active subjects might decline participation in studies due to lack of time23. Therefore, animal models of cognitive aging are highly relevant to complement human aging studies.In the past decades, it has become clear that mechanisms leading to cognitive dysfunction associated with aging are largely conserved in a wide range of animal models, such as primates and rodents26. Interestingly, this decline in memory function in animals is not accompanied by significant neuronal loss, much like in humans. Instead, it appears to be primarily linked to synaptic changes, including the loss of synapses and alterations in synaptic efficacy27. An example of this can be seen in the hippocampal long-term potentiation (LTP), a process that mirrors synaptic learning, which becomes more challenging to induce and decays faster in aged animals29. These changes in animal models during normal aging reflect the translatability of impairments in cognitive performance to observations seen in humans.Animal models of aging, such as rodents, canines, and nonhuman primates, exhibit a decline in cognitive function similar to that observed in humans as they age Fig. . This de30.The use of an array of animal models is important to investigate the complexity of brain alterations during aging. In particular, rodents share significant genetic and physiological similarities with humans and have a relatively short lifespan compared to larger model organisms. This enables the study of age-related changes and cognitive decline over a shorter time span. Mice and rats also exhibit cognitive abilities and behaviors that are, to some extent, comparable to humans, making them suitable for assessing learning and memory. Moreover, rodents are highly amenable to genetic manipulations, allowing researchers to explore the effects of specific gene modifications or interventions on cognitive aging. Finally, rodent animal models do not spontaneously develop AD-like histopathological hallmarks, which potentially allows the study of age-related cognitive decline without interference from AD-like phenotypeThe use of robust animal models to study cognitive aging remains crucial for understanding the implications of research findings. While human research is undoubtedly the most directly applicable, it faces ethical limitations in terms of manipulation and comprehending the temporal progression of events that could contribute to cognitive impairments during aging. Consequently, translational research aimed at enhancing human health during advanced stages of life relies heavily on the utilization of animal models, specifically rodents and nonhuman primates, to model age-related cognitive decline.In this review, we will outline the current understanding of cognitive dysfunction in human and rodent models as an effort to facilitate knowledge interchange. This review will focus on specific modifications that occur at a cognitive level, without disease, and behavior analysis conducted in preclinical and clinical settings. We will not focus on molecular and synaptic plasticity modifications that have been described to also occur during the aging process. First, we will discuss the main memory types that are known to be affected during aging, as well as the brain regions that show altered function. Next, we will debate on the methods commonly used to test cognitive performance in humans and animal models, and how they can potentially be compared to better understand the aged brain. Lastly, we will discuss the main methodologies used in age-related clinical trials.32. Cognitive abilities are differentially impacted by age, as some are resistant to modifications, while others tend to decrease or even further develop. For example, vocabulary function is particularly unaffected by aging and tends to improves over time33. On the other hand, conceptual reasoning, processing speed and memory decline progressively as age advances36. Cognitive changes are inherent to the aging process, although individuals experience different rates of cognitive decline. However, the acceleration and consequent deterioration of cognitive abilities is linked to the inability to continue daily routines and the development of age-related disorders, such as Alzheimer’s disease and vascular dementia, the two most common forms of dementia that affect the aged population37. Moreover, individual levels of cognitive decline are present not only in humans, but also in animal models. This heterogeneity results in good and poor aged performers, which stresses the importance of sensitive cognitive tasks that can accurately distinguish both populations.Modifications in cognitive performance during aging are well documented in the scientific literature38. This effort resulted into two types of classification which are still largely used: crystalized intelligence and fluid intelligence39. Crystalized intelligence comprises skills that are learned over time. Noteworthy examples include acquisition of vocabulary and general knowledge, that become stable or even increase during aging31. Older adults outperform younger adults in tasks that directedly rely on this type of intelligence. Moreover, procedural memories  are largely spared with age. On the contrary, fluid intelligence encompasses abilities of problem-solving and reasoning applied to the processing of novel information, which is less dependent on familiar experiences. Abilities such as processing speed, memory formation and retention peak during early adult age and tend to decrease during aging40  in the environment relative to each other . In human studies, this classification is attributed to temporary formation of memories required for task performance in the range of seconds to minutes, while working memory refers to the manipulation of short-term memories62. Recollection of LTM formed years or decades ago in humans is largely spared, which suggests that aging mostly impacts the acquisition of new information, which would be consolidated into LTM, but not the retrieval of LTM. One recent study evaluated healthy aged individuals´ performance in a cognitive examination over a period of 30 min or 4 weeks. They found that while at the 30 min test individuals showed overall good performance, 4 weeks later they detected accelerated long-term forgetting63. These findings indicate that evaluating long-term cognitive performance is a sensitive way of assessing age-related cognitive decline. Clinical and animal studies usually do not evaluate such long-term memory deficits. These studies mostly focus on age-dependent changes associated with the formation of recent memories. Moreover, longitudinal studies that accompany memory decay from middle to advanced age are underperformed in rodent studies. This is in part due to the requirement of inducing learning in middle-aged rodents and assessing memory recall after their age advances, which are time-consuming experiences to perform. As discussed in the next sections, most of the behavior paradigms used do not induce memories that would persist for several months. One exception would be tests that form associative memories based on aversive stimuli. It is not advised to retrain animals several times in cognitive tasks, as this process might introduce confounds of memory reconsolidation processes and/or reinforcement due to the repeated exposure to learning cues. A detailed discussion of behavior paradigms that can be used for these studies is presented in section 2.3 Cognitive tests used to evaluate age-related cognitive decline and is summarized in Fig. Activity between several brain regions during long periods of time is required for memory consolidation and consequent formation of long-term memories (LTM). The formation of LTM is prone to disruption during aging in humans and rodents31. These alterations are accompanied by functional impairments that hinder brain plasticity and function.There is extensive evidence of structural changes during aging in the brain, such as loss of synaptic complexity and reduced white matter volumes66. Nonetheless, these initial findings did not consider that young individuals tend to outperform aged individuals, which might lead to different patterns of brain activity independently of aging. Further work addressed this issue by separating aged individuals based on their performance in a spatial memory task and comparing their patterns of brain activity to young individuals67. The authors found that aged good performers and young individuals displayed similar patterns of brain activity evaluated by blood oxygen level-dependent signal. These findings indicate that patterns of activity predict the performance level in cognitive tasks and that activity may become less specific with age  is one of such alternatives and since then has become widespread in clinical practice83 78 Fig. . This qu94. These paradigms have been used to evaluate cognitive function in physiological conditions and neurological disorders. Moreover, several tests have been established or adapted to study age-related cognitive decline. Criteria have been proposed for assessing the sensitivity of behavior tasks to study cognitive decline during aging97. Particularly, behavior rodent tasks should: (1) be sensitive to detect memory deficits, when comparing old and young animals; (2) avoid bias from other processes that might affect the outcome of the test; (3) avoid the use of dietary restrictions or stressors that might hinder the performance of aged animals; (4) detect memory deficits in young animals, when lesions occur brain regions that model deficits observed in aged animals; (5) be consistent across several animal strains and multiple species, such as humans and rodents; (6) be sensitive to established pharmacological approaches that are known to improve behavior in clinical trials with aged humans and; (7) depend on brain regions that support learning and memory formation. Based on these criteria, over the years several behavior paradigms have been developed that can, to some extent, be applied to rodents and humans. We will expand on tests that rely on spatial associative learning based on aversive or non-aversive cues.In the past decades, clinical researchers have used an array of tasks that can assess deficits in spatial memory formation and navigation strategies using rodent models99. Variations of these tasks, that heavily rely on intact hippocampal function, such as trace fear conditioning are more sensitive in detecting spatial memory deficits in aged rodents100. In humans, it is challenging to establish fear conditioning protocols that model studies in rodents92.Associative learning relies on pairing between two independent stimuli as a measure of learning and memory. In classical conditioning paradigms, a neutral stimulus such as a chamber  or sound (cue fear conditioning) is presented in combination with an aversive stimulus (foot-shock) to induce associative learning Fig. . After t103. Aged rodents also show impairments in this task, similarly to humans. One study compared young and aged mice that have intact auditory function in contextual or trace fear conditioning and eyeblink classical conditioning. They found that aged mice had impairments in eyeblink associative learning, although no age-related differences were observed in fear conditioning paradigms75. The authors concluded that cerebellar functions show earlier signs of senescence compared to the hippocampus. One possible limitation of this paradigm is that depends on an auditory tone as a neutral stimulus. It has been proposed that there is an age-dependent decrease in auditory function, which can potentially introduce bias104.Another associative task used to evaluate age-related memory deficits is delay eyeblink conditioning Fig. . In this105. This variation of classical fear conditioning introduces a trace period that separates each conditioning trial, which increases the role of connections between the medial prefrontal cortex and the hippocampus for memory106. Nonetheless, these findings are consistent with the sensibility of eyeblink classical conditioning to evaluate cognitive decline associated with cerebellar dysfunction, which is consistent with other animal studies107. The combination of behavior paradigms evaluating different brain regions that are required for associative learning is useful to track age-related differences over time. The paradigms discussed so far induce association between fear responses and spatial component or reflexes. Therefore, it is possible that they can introduce unwanted confounds. These associative tasks highly depend on hippocampal  or cerebellar function (delay eyeblink conditioning), regions that are known to be mostly affected during aging. Therefore, the use of these tasks, particularly in rodents are useful to investigate cellular and molecular alterations associated with age-related dysfunction in these regions.As discussed, fear conditioning paradigms might introduce confounds, due to their dependence on brain regions besides the hippocampus and altered anxiety-like behavior. An alternative to these studies is trace fear conditioning, which is accepted as a more sensitive test to evaluate hippocampal function in aged miceIn the next section, we will layout alternative strategies that are not based on Pavlovian conditioning.109. Since then, the Morris water maze has become one of the golden standards for evaluating spatial learning and memory performance in rodents  in comparison with young participants that navigate by reference to cues present in the room . These findings have been replicated in other studies demonstrating that older adults display a robust shift for egocentric performance116. Similarly, another study using a real-space analogue of the Morris water maze found selective impairments in allocentric navigation in aged individuals, but preserved egocentric strategies117. In this study, however, they did not detect any differences in overall memory performance between the different age groups, which might suggest that a shift between allocentric to egocentric strategies might compensate performance in these tasks117. Recent findings separated aged good from poor performers and evaluated navigation strategies using virtual versions of the maze. The authors speculated that aged poor performers might be unable to adapt new navigation strategies to compensate altered neuronal subtracts118. Future human and rodent studies should couple navigational strategy and performance with imaging, to understand the engagement of distinct brain regions in allocentric and egocentric strategies during aging. For detailed reading on age-related egocentric and allocentric alterations during aging we recommend this systematic review49. This evaluation would represent a significant advancement in the field to develop target therapies for brain region specific impairments during aging. The Morris water maze depends on swimming-induced stress as a motivator for escaping, therefore age-associated changes in stress response might bias performance119. Moreover, cerebellar age-associated dysfunction can hinder swimming performance of aged rodents and influence performance, independently of altered memory capacity.In 1981, Richard Morris developed a spatial behavior task based on a water-maze for rats120. Contrarily to the Morris water maze this task evaluates spatial memory formation without major aversive stimuli as it is a dry maze. Nonetheless, both tests induce an increase in the levels of stress hormones compared to naïve animals, but corticosterone levels are significantly higher in the Morris water maze compared to the Barnes maze121. Therefore, the Barnes Maze is accepted to be sensitive for spatial memory deficits, but requires less physical effort. This test was initially developed to evaluate age-related cognitive performance in aged rats that show impaired performance121. Versions of this task have also been applied to study aged mice28. Over the years it has shown to be a reliable tool to access memory performance during aging  for navigation in this virtual maze, similarly to what has been shown in mice and human studies135. In summary, there is a wide-range of behavior tests available in clinical settings and in behavior laboratories. These evaluate different components of age-related cognitive decline and therefore can be used in combination to understand alterations associated with specific brain regions. The development of virtual-reality-based tests shows a high potential for future standardization of screening aged adults in the clinics without the need for spatial tasks that are difficult to implement in a clinical setting. Moreover, these methods can potentially generate comparable tasks to be developed for animal models which might bring closer together the data generated in preclinical and clinical studies.Novel technological advances allow the development of user-friendly tasks that can be easily implemented into clinical setting. Particularly, the emergence of virtual-reality-based tests that analyze spatial performance are novel powerful tools that can potentially bridge findings from human studies and animal modelsIn the previous sections, we discussed common tests to evaluate cognitive performance during aging in mice and humans. Several tests show selective sensitivity, which is useful to discriminate specific impairments associated with aging. Therefore, it would be reasonable that clinical trials used as inclusion criteria the “best” possible paradigms to evaluate novel approaches to delay/treat deterioration of cognitive abilities during aging. We characterized the available clinical trials available in the clinicaltrials.gov under the category of “Age-Related Cognitive Decline” Fig. . Only trIn this review, we discussed recent findings on altered brain activity during aging in humans and rodent models. We pointed to the main strategies to diagnose/investigate age-related cognitive decline and we contrasted their use in clinical settings and the laboratory. Lastly, we interrogated whether there was a wide variety of tests being currently used to select elderly patients for clinical trials enrollment. Many behavior paradigms have been successfully developed and most are used in rodent’s animal models and humans. The interdisciplinary versatility of these tests is crucial to develop therapeutic approaches that can be applied to patients that suffer from age-related cognitive decline. Moreover, these tests can also be used to understand the circuit and molecular alterations in cognitive abilities that affect the elderly. The spread of virtual-reality based tests is an opportunity to implement reliable and sensitive testing in the clinics and laboratory. Finally, clinical scientists should take advantage of the availability of sensitive cognitive tests beyond the classic “pen and paper” strategies particularly for admission into clinical trials.


When used as an alternative to or in addition to aspirin, clopidogrel has been demonstrated by some but not all randomized controlled trials to be effective in secondary prevention of cardiovascular (CV) events in patients with (1) coronary artery disease (CAD), (2) acute coronary syndrome (ACS), and (3) coronary stent placement. However, a drawback to clopidogrel therapy is the cost to patients and the health care system. Clinical studies have also demonstrated that when clopidogrel is used in addition to aspirin, the combination has an increased bleeding risk compared with aspirin alone. Cost-effectiveness analysis may aid in developing strategies for optimal use of clopidogrel.To review and evaluate published pharmacoeconomic analyses on the use of clopidogrel in secondary prevention of CV events in patients who have known CAD, have ACS, or are undergoing percutaneous coronary interventions (PCIs).English-language peer-reviewed articles or abstracts were identified from MEDLINE and the Current Contents database  using the search terms clopidogrel and pharmacoeconomics or clopidogrel and cost analyses. Citations from available articles were also reviewed for additional references.Multiple cost-effectiveness analyses of clopidogrel were available for review. These pharmacoeconomic studies were performed using different clinical databases from randomized controlled trials as well as observational databases. Cost was from the perspective of different health care systems and society; it was expressed in varying cost-effectiveness terms . Although direct comparison among studies was difficult, clopidogrel appeared to be cost effective when used for up to 12 months in combination with aspirin  in patients with ACS or in those undergoing PCIs, using different societal perspectives  per QALY]). In contrast, when used as an alternative to aspirin for secondary prevention of CAD, clopidogrel had mixed results in cost-effectiveness analyses . A major limitation of the models cited is the extrapolation of outcomes far beyond the duration used in the clinical trial database.On the basis of current cost-effectiveness data, clopidogrel should be used in addition to aspirin therapy for up to 12 months in all patients with non-ST elevation ACS as well as in those who received coronary stents. For secondary prevention of CAD, clopidogrel should be used only in those who cannot tolerate aspirin therapy.


Heterosis is already manifested early in root development. Consistent with the dominance model of heterosis, gene expression complementation is a general mechanism that contributes to phenotypic heterosis in maize hybrids.1-hybrids outperform their parental inbred lines, a phenomenon known as heterosis. Utilization of heterosis is of paramount agricultural importance and has been widely applied to increase yield in many crop cultivars. Plant roots display heterosis for many traits and are an important target for further crop improvement. To explain the molecular basis of heterosis, several genetic hypotheses have been proposed. In recent years, high-throughput gene expression profiling techniques have been applied to investigate hybrid vigor. Consistent with the classical genetic dominance model, gene expression complementation has been demonstrated to be a general mechanism to contribute to phenotypic heterosis in diverse maize hybrids. Functional classification of these genes supported the notion that gene expression complementation can dynamically promote hybrid vigor under fluctuating environmental conditions. Hybrids tend to respond differently to available nutrients in the soil. It was hypothesized that hybrid vigor is promoted through a higher nutrient use efficiency which is linked to an improved root system performance of hybrids in comparison to their inbred parents. Recently, the interaction between soil microbes and their plant host was added as further dimension to disentangle heterosis in the belowground part of plants. Soil microbes influenced the performance of maize hybrids as illustrated in comparisons of sterile soil and soil inhabited by beneficial microorganisms.Highly heterozygous F This phenomenon was first described in tobacco by Joseph Kölreuter , as a typical outcrossing species, achieve for instance 50–100% yield increase in comparison to open-pollinated maize varieties (Kutka Oryza sativa L.) display only a yield increase of 10–20% in comparison to their corresponding inbred line varieties  gene, which mediates yield heterosis in tomato, or a very short root phenotype in wheat (Krieger et al. Furthermore, the overdominance model suggests that the effect of heterosis relies on the interaction of heterozygous alleles in the hybrid, which is much stronger than between homozygous alleles Shull . In addiFinally, epistasis, i.e., interactions in the hybrid between non-allelic genes at one or more loci result in superiority, was proposed as an explanation for heterosis Richey .There are several examples supporting either hypothesis, but it is apparent that none of the classical genetic hypotheses can explain heterosis alone. Hence, some other models try to explain heterosis by an overall improvement in the energy utilization of the hybrid: in line with the gene balance hypothesis it was proposed that hybrids might have more favorable gene dosage balances than their parental inbred lines (Birchler et al. From a molecular perspective, there is increasing evidence that variation of transcriptional regulation relates to the enhanced phenotypic performance of hybrids (Botet and Keurentjes In a transcriptomic study of maize, an extreme instance of gene expression variation was observed in which hundreds of genes were expressed in the hybrids, but only in one of its two parental inbred lines: an expression pattern denoted as single-parent expression (SPE; Fig. SPE complementation was proposed as a potential link to translate genetic distance of parental inbred lines into phenotypic heterosis. The number of identified SPE genes varies among genetically diverse hybrids Table  but reflAmong the different maize hybrids and tissues investigated in the different transcriptomic studies Table , no unifThe introduction of hybrid varieties, in combination with more efficient agricultural practices, including the application of synthetic fertilizers, resulted in remarkable yield increases Fig. . NitrogeRoots are the main plant organ to absorb nutrients, thus an efficient root system is essential. In the past 100 years of maize breeding with the aboveground target of yield increase, genotypes with a more shallower and deeper root system with less nodal roots, but longer lateral roots were selected (York et al. Hybrids are more efficient in the absorption of nutrients in comparison to inbred lines (Wei et al. The rhizosphere is the narrow region of soil of only a few millimeters that is directly influenced by root exudates and influences the root system via the associated microorganisms. These microorganisms are collectively designated as the root microbiome (Bai et al. A comprehensive understanding of the molecular principles of heterosis is the basis to accelerate crop improvement and to optimize breeding. Transcriptomic studies have been widely applied to investigate the gene expression landscape of hybrids. Employing transcriptomic data as biomarkers for predicting hybrid performance can efficiently increase the selection response to support breeding programs (Zenke-Philippi et al.


Most of these species demonstrate social or aggressive behavior toward mirrors. Although mice have poor vision and predominantly use olfaction to gather information from the surrounding environment, visual stimulation through mirrors appears to be effective also in this species. Research investigating the effects of mirror exposure in mice found that the presence of mirrors has similar effects to the presence of cage mates. Restraint in a small holder induces hyperthermia (stress-induce hyperthermia: SIH) in mice but a restrained mouse surrounded by similarly restrained cage mates shows less SIH  can be evaluated through a two-choice preference test. Research demonstrated that bright lights and unnatural reflected images are anxiogenic factors that can produce bias in the preference test and hence should be avoided. However, under unbiased conditions , mirrors appear to be rewarding for mice, that show a clear preference for mirrors over opaque control objects (Watanabe, On the other hand, the reinforcing value of a mirror in operant conditioning can be assessed by measuring, for example, lever pressing to access a mirror. The strength of its reinforcing value should be measured by a progressive ratio schedule in which the number of responses required to receive reinforcement is gradually increased until the subject stops responding.Mirror-based tests could become a new class of animal-friendly learning tests. Indeed, mirrors could be employed as animal-friendly reinforcers to study learning and memory processes. Investigation of mirror-induced conditioning could lead to the development of new behavioral tests that do not require punishment or prior stressful conditions, such as food or water deprivation.SW conceived and wrote the manuscript, created the figures, and acquired funding.


Azospirillum, Trichoderma, Glomus, and Pseudomonas. This article evaluates the effects of applying Trichoderma as a model microbe for assessing microbial growth-promotion, biological control activity, and modulation of gene expression under the conditions created by SRI practices. Information about the molecular changes and interactions associated with certain effects of SRI management suggests that these practices are enhancing rice plants’ expression of their genetic potentials. More systematic studies that assess the effects of SRI methods respectively and collectively, compared with standard rice production methods, are needed to develop a more encompassing understanding of how SRI modifications of crops’ growing environment elicit and contribute to more robust and more productive phenotypes of rice.The system of rice intensification (SRI) is an extensively-researched and increasingly widely-utilized methodology for alleviating current constraints on rice production. Many studies have shown physiological and morphological improvements in rice plants induced by SRI management practices to be very similar to those that are associated with the presence of beneficial microbial endophytes in or around rice plants, especially their roots. With SRI methods, grain yields are increased by 25-100% compared to conventional methods, and the resulting plant phenotypes are better able to cope with biotic and abiotic stresses. SRI management practices have been shown to be associated with significant increases in the populations of certain microorganisms known to enhance soil health and plant growth, e.g.,  SRI praThere is considerable evidence that using SRI’s methods results in improved rice phenotypes compared to rice plants of the same genotype that are grown with conventional methods . These dUnder SRI management, paddy soils are maintained mostly under unflooded conditions, receiving additional oxygen through soil-aerating mechanical weeding that is conducive for the growth of aerobic soil microorganisms . Also, wPseudomonas and mycorrhizal fungi while suppressing pathogenic microorganisms  discusses molecular mechanisms that could be enhancing rice plant performance under SRI management with respect to plant-microbe interactions and the modulation of gene expression.This paper (i) reports on the diversity and dynamics of soil microbial communities as influenced by using SRI methods, (ii) compares rice phenotypes under SRI vs. non-SRI management, both with and without inoculation with 2Azospirillum) living within the roots of rice plants , this study evaluated the effects of this diazotrophic bacteria in response to SRI management practices, respectively and collectively, compared to conventional rice cultivation methods. Under SRI management, there was a huge increase in the populations of root-endophytic op yield . The colIn a later study done in China , the larIn the test plots under conventional management with continuous flooding, raising the share of N soil amendment from 25% organic to 100% organic enhanced the number of actinomycetes by 78%, by only about one-quarter as much as with SRI management and unflooded soil. Populations of actinomycetes were thus seen to respond quite differently to SRI vs. conventional irrigation and to organic vs. inorganic sources for soil nutrition .In trials conducted in northern Thailand, the community structures of bacteria and archaea showed significant changes under SRI practice as compared with what was found in conventionally-managed rice fields. Community compositions of these soil microbes started to change during the vegetative phase of rice growth, just after the practice of alternating wetting and drying of SRI plots began; and the microbial communities continued to diverge between the two respective strategies until the water management for both systems was made the same again just before harvesting . This inGlomus and Acaulospora, whereas with conventional cultivation, only one genus (Glomus) could be detected in the roots of rice plants  present, colonizing rice plant roots, e plants . These ce plants . But to In another study, this one done in India, fluorescent pseudomonads, plant‐beneficial bacteria that reside in the rhizosphere around plant roots, were found in abundance in an SRI field compared to a non-SRI field . These bPseudomonas and Clostridium were found to be the most dominant genera in SRI plots compared to other plots  plants grown under SRI methods without T. asperellum inoculation, and (b) plants grown conventionally and inoculated with T. asperellum  under SRI management without T. asperellum SL2 inoculation, or (b) with conventional methods whether with or without this inoculation. The data indicated that the combined effects of T. asperellum SL2 inoculation and SRI methods synergistically boosted the rice plants’ resistance toward sheath blight disease . Other genes that were significantly up-regulated in Trichoderma-inoculated, SRI-grown plants included two genes involved in stress tolerance (CYP38 and CYP20-2); one gene regulating the synthesis of the critical phytohormone gibberellin (OsGAE1); a gene for tillering (MOC1); one regulating the uptake of phosphorus (OsPHR2); another related to root elongation (OsARF12); and a gene that controls crown root emergence (OsCAND) – compared to rice plants that had been inoculated with Trichoderma but grown conventionally, and to SRI-grown plants that had no Trichoderma inoculation  the application of SRI practices and (b) with inoculation with Little research thus far has directly assessed SRI management practices as an independent variable having demonstrable effects on plants’ molecular signaling and gene expression, however. And we are not suggesting here that SRI effects are attributable only to microbial activity. Wider spacing of plants reduces shading and contributes to increased light interception even with much-reduced plant density. It affects rice plants’ physical architecture, with tillers more horizonal and leaves more vertical. And stopping continuous flooding of rice paddies avoids necrosis and stunting of roots due to hypoxia. SRI is difficult to evaluate because its multiple effects, and any associated synergy among them, complicate both research design and analysis. But there is reason to conclude that more systematic and in-depth studies at the molecular level should be undertaken to assess the effects of SRI practices in terms of particular cellular and molecular processes affected, which we consider next.4Plants’ microbiomes play significant roles in their nutrient acquisition and mobilization as well as in conferring protection against various environmental stresses . Plant gBacillus amyloliquefaciens under saline soil conditions has been found to increase the inoculated plants’ growth and salt-tolerance as there is modulated expression of at least 14 identifiable genes related to the plants’ defense mechanisms  in the stressed rice plants. Such reactions could be triggered by having been inoculated with symbiotic microbes. For example, the inoculation of rice plants with chanisms .T. harzianum have been shown to exhibit greater drought-tolerance as compared with untreated control plants , meaning that significantly more (or fewer) proteins are synthesized inoculated plants than in uninoculated plants. Proteins related to photosynthesis are up-regulated in the leaf sheaths and leaves of inoculated rice plants, while proteins involved in defense mechanisms are up-regulated particularly in the roots  are induced in the shoots of the rice plant, ones that are essential for phytohormone production, photosynthetic efficiency, carbohydrate metabolism, cell division, and cell wall expansion.Further research has shown that the molecular mechanisms affected by interactions between the rice plants and This recognition and transduction modulate cell-cycle regulator genes that lead to accelerated cell division. The plant-microbe interactions also enhance other processes that culminate in greater plant growth resulting from an intensification of physiological processes like energy metabolism, phytohormone production, and cell wall expansion . As rice5SRI practices for growing irrigated rice have been seen repeatedly to result in improved morphology of rice plants and in physiological processes that result in better growth and higher grain production. However, these assessments have been conducted without reference to or examination of the molecular processes that were occurring inside the rice plants’ cells. Observable effects on rice plants’ growth and performance must have some causal processes that are occurring concomitantly at the cellular, molecular, and genetic levels.The beneficial interactions that take place between rice plants and their associated microbiomes are becoming of ever-greater interest. It is clear that beneficial microbes play a pivotal role in the functioning of rice plants by influencing physiological and molecular processes. Transcriptome and proteome profiling of rice plants following their inoculation with certain microbes has identified specific genes that are involved in key physiological and molecular processes in rice plants being up-regulated or down-regulated compared to uninoculated control plants. This was evidently in response to the inoculation because other factors were being controlled.These changes result in greater or lesser synthesis of certain proteins, including enzymes, within plant cells. This would differ perhaps in kind but not in degree from the effects of certain endophytic microorganisms that are already resident in plants, these microbes being affected by management practices that determine the environment of plants (and microbes). It is unlikely to be just coincidence that the effects of SRI management practices and of microbial inoculation are so similar.Trichoderma suggests that SRI methodology may itself be affecting the microbial populations in, on, and around rice plants, and that these communities in turn affect their hosts’ growth and physiological characteristics, as well as the molecular processes that underlie plant growth and development as well as the plants’ sickness and health. The results of rice plant inoculation have corresponded very closely to the effects observed with SRI practices, so it is anticipated that these practices are inducing similar dynamics and effects at the molecular level that are mediated by the plant’s microbiome.The finding that the accelerated/improved performance of rice plants being grown with SRI management correlates strongly with the effects of inoculating rice plants with certain endophytic microbes like However, much research remains to be carried out, to elucidate the effects of SRI management at the molecular level, compared with such effects from non-SRI practices. It will be interesting for future studies to analyze the patterns of gene expression and protein synthesis in rice plants grown under SRI management vs. conventional practices through comprehensive use of transcriptomic and proteomic analysis. Such a study has been initiated in Indonesia by researchers from Meiji University in Japan, and their findings should advance our understanding of what is going on at the molecular level in SRI-grown rice plants. Multi-omics approaches can provide a systems-level view of the complex interactions and regulatory networks that occur in plant growth and performance, helping to identify key biological processes and pathways associated with SRI-related crop improvements.Conceptualization, FD. writing—original draft preparation, FD, NU, MM, NS, and MSM. writing—review and editing, FD, NU, MM, NS, MSM, RS, NR, and AA. visualization, FD, and AA. funding acquisition, FD. All authors contributed to the article and approved the submitted version.


A new study in Genome Biology and Evolution reveals that egg yolk proteins may have been co-opted to provide maternal nutrition in live-bearing sharks and their relatives.Genome Biology and Evolution, a team of researchers led by Shigehiro Kuraku, previously Team Leader at the Laboratory for Phyloinformatics at RIKEN Center for Biosystems Dynamics Research in Japan, set out to address this gap. Their study identified egg yolk proteins that were lost in mammals after the switch to viviparity but retained in viviparous sharks and rays , or transferring nutrients via a placenta.VTG), a major egg yolk protein synthesized in the female liver in egg-laying species. Regardless of their reproductive mode, all cartilaginous fish species had at least two copies of VTG, while all copies of VTG have been lost from mammals . Next, the authors searched for homologs of the VTG receptor; while mammals retain a single copy of this receptor, Kuraku and his colleagues identified two ancient tandem duplications giving rise to three copies of the receptor in cartilaginous fishes. The authors note that this finding was unexpected. “We predicted the retention of egg yolk protein genes in the shark genomes because live-bearing sharks rely partly on nutrition supply from the egg yolk,” says Kuraku. “What surprised us the most was that cartilaginous fish including sharks have more copies of the egg yolk protein receptor genes.” This suggested that these proteins may provide a novel function in this viviparous lineage.To better understand these various mechanisms, the authors searched genomic and transcriptomic data from 12 cartilaginous fishes for homologs of vitellogenin  and two viviparous sharks. The frilled shark is a viviparous species that provides no maternal nutrients to the developing embryo, while the spotless smooth-hound has a placenta. In the egg-laying cloudy catshark, VTG is primarily expressed in the liver, and its receptors are primarily expressed in the ovary. In contrast, in the two viviparous sharks, VTG was expressed not only in the liver but also in the uterus. Interestingly, the VTG receptor was also expressed in the uterus in these species. This suggests that VTG proteins may not only function as yolk nutrients but may also be transported into the uterus, where they may play a role in providing maternal-based nutrition in some cartilaginous fishes.As noted by the authors, this intriguing possibility remains to be confirmed through functional studies. They also hope to expand this analysis to a genome-wide survey of factors associated with the various reproductive modes of cartilaginous fishes. Unfortunately, such experiments are difficult in these species given the challenge in obtaining biological samples. Kuraku and his collaborators, however, hope to change this. “This study was enabled by networking among individuals with various types of expertise who recognize the biological potential of cartilaginous fishes,” says Kuraku. “It also led to the launch and development of the Squalomix consortium,” an initiative launched in 2020 to promote genomic and molecular approaches specifically targeting shark and ray species . The con


Current fertility preservation options are limited for cancer survivor patients who wish to have their own biological children. Human in vitro gametogenesis (IVG) has the hypothetical ability to offer a unique solution to individuals receiving treatment for cancer which subsequently shortens their reproductive lifespan. Through a simple skin punch biopsy, a patient’s fertility could be restored via reprogramming of dermal fibroblast cells to induced pluripotent stem cells, then from primordial germ cell-like cells into viable oocytes and spermatocytes which could be used for embryogenesis. Induced pluripotent stem cells could also be used to form in vitro environments, similar to the ovary or testes, necessary for the maturation of oogonia. This would allow for the entire creation of embryos outside the body, ex vivo. While this area in stem cell biology research offers the potential to revolutionize reproduction as we know it, there are many critical barriers, both scientific and ethical, that need to be overcome to one day see this technology utilized clinically. Fertility preservation remains one of the most important and dynamic areas of focus for reproductive endocrinology and fertility specialists. There are approximately 1.9 million people diagnosed with cancer each year in the United States (US), the most frequent being breast cancer with nearly 290,000 people diagnosed per year . PresentUnfortunately, current fertility preservation options are limited for cancer survivor patients of reproductive age. Current female fertility preservation options include suppression of the hypothalamic–pituitary–ovarian axis with gonadotropic-releasing hormone (GnRH) agonists, as well as oocyte, embryo (requiring sperm donor), and ovarian tissue cryopreservation. Certain cancer diagnoses require urgent initiation of treatment, in which cryopreservation of oocytes or embryos risks delaying initiation of chemotherapy due to the time required to complete controlled ovarian hyperstimulation ,6. In adAn exciting area of current research which may one day help to overcome these obstacles is human in vitro gametogenesis (IVG). IVG is the process of making gametes outside the body. IVG uses either 46XX or 46XY somatic cells to make an oocyte or sperm cell from those somatic cells in the lab and fertilizing them with gametes of the opposite biologic sex in order to make an embryo. The ability to generate gametes without the use of natural gametes presents a unique opportunity within reproductive medicine with particular applications for the field of oncofertility as well as for possible future opportunities of non-gamete dependent reproduction using induced pluripotent stem cells (iPSC).While IVG holds great potential, quality measures have yet to be established to safeguard from its inappropriate advancement. Therefore, an important area of future investigation is to ensure the biologic integrity of oocytes in each stage of maturation in IVG. This will require careful validation studies for the integrity of each step of the process. Given the restrictive environment of human embryology research, initial studies will occur in mouse models, testing the ability of oocyte in vitro maturation (IVM) to develop from blastocysts into healthy pups. Despite decades of research, IVM has been a particularly challenging hurdle for which there remains no widely adopted clinical technique. Continued IVG research will enhance our current understanding of assisted reproductive technology (ART). This includes potentially improving outcomes for patients with infertility who would not require IVG to procreate. For example, if a patient with cancer wishes to preserve her fertility prior to chemotherapy, radiation and/or surgery, they may elect to proceed with tissue cryopreservation followed by surgical autologous transplantation which would be required for oocyte maturation. IVG research could strengthen our understanding of IVM to the point where primordial follicles from cryopreserved ovarian tissue could be used for the in vitro creation of embryos without the risk of reimplantation of potential cancer cells back into the patient.Human IVG has the potential to offer a unique solution to individuals receiving treatment for cancer which subsequently shortens their reproductive lifespan. Once available clinically, IVG could allow patients to first focus on their cancer treatments without additional medications, procedures or surgeries between time of diagnosis and initiation of treatment. These patients would have a skin punch biopsy performed and preserved for subsequent IVG to restore their reproductive potential. Therefore, this method could address several of the shortcomings of current fertility preservation methods. One patient population with unique limitations in fertility preservation is the pre-pubertal cancer patient. In males, spermatozoa are not formed until puberty, making the collection of semen used for sperm cryopreservation not possible. Pre-pubertal testicular tissue preservation remains experimental, as there have not been live births seen as a result of this technique. In pre-pubertal women, oocytes are not responsive to the medications used for oocyte maturation used in in vitro fertilization (IVF). This excludes them from the commonly utilized option of controlled ovarian hyperstimulation followed by oocyte cryopreservation for fertility preservation in post-pubertal women. IVG could offer a unique solution to pre-pubertal males and a less invasive alternative to ovarian tissue cryopreservation in pre-pubertal females. IVG could theoretically be performed after completion of a patient’s cancer treatment, thereby allowing patients additional time to plan for the acquisition of resources required for treatment; thus, making IVG a more widely available and timely solution when they are less likely to be distracted by a new cancer diagnosis and its current possibility of a childless future.In this review, we summarize the current state of IVG, the various optional methodologies that could be utilized as well as future necessary research to achieve its promising applications in preservation and possible restoration of fertility in cancer survivors. We also explore some of the ethical concerns associated with this transformative approach.Mammalian gametogenesis is the process of germ cells differentiating into dimorphic gametes, oocytes, and spermatozoa. The haploid female oocyte fuses with the haploid male spermatozoon to form a diploid zygote which subsequently begins embryogenesis . In ordeOne form of IVG utilizes embryonic stem cells (ESCs) collected from the inner cell mass of the blastocyst after fusion of the female oocyte and the male spermatozoon. These cells are pluripotent and can develop into cells of all germ layers but not extraembryonic structures . These cells must be collected before implantation. The process of culturing ESCs is conducted by collecting cells from the inner cell mass of the blastocyst on approximately day 4 of development after fertilization. Isolation and collection of these ESCs typically takes place in an embryology lab specialized in in vitro fertilization. Alternatively, induced pluripotent stem cells (iPSCs) are obtained after implantation. iPSCs are created through the introduction of genes into somatic cells, inducing de-differentiation (known as reprogramming), causing them to become pluripotent  12]..12].Adult stem cells (ASCs) are found in differentiated tissue that retains the ability to renew themselves and generate new cells in response to damage or dying cells. These are synonymous with somatic stem cells (SSCs). The major distinction is that both ASCs and SSCs are non-reproductive cells . One well-known multipotent stem cell line consist of hematopoietic stem cells (HSC), which are used in bone marrow transplant patients to replete and replace malignant blood cell lines . The HSCReprogramming differentiated somatic cells into induced pluripotent stem cells (iPSCs) relies on cell reprogramming. In a mouse model, reprogramming focuses on downregulation of p53 and increase of oncogenes Myc and Klf4 (Kruppel-like factor 4). However, in that mouse model, these changes may increase the risk of mutations and could possibly lead to cancer or congenital birth defects in the developed organism . To reprIn 2011, the first successful in vitro development of mouse haploid sperm and mouse haploid oocytes from iPSCs was completed . This scFunctional oocytes have been generated from pluripotent stem cell-derived primordial germ cell-like cells (PGCLCs) when cultured with embryonic ovarian somatic cells in a mouse model . The sigIVG research in animal models may serve to benefit both animals and humans. It has been proposed that IVG may be a solution to prevent endangered species from becoming extinct . For exaFigla, Sohlh1, Lhx8, Nobox, Stat3, Tbpl2, Dynll1 or Sub1), which have been shown to drive the primordial to primary oocyte transition and prompt the capacity for oocyte growth ..28].Forty-five years have passed since Lesley Brown bravely gave birth to her daughter, Louise, the first baby conceived by IVF, and shocked the world by its novelty. Today, the apprehension around the ‘test-tube baby’ has passed and the percentage of babies born from IVF each year is rapidly increasing. The science of reproductive medicine continues to evolve and IVG is one of the most exciting areas that has largely developed over the past decade. The excitement within reproductive endocrinology and infertility regarding progression to the future clinical use of IVG is understood across the field.IVG has the opportunity to address the limited reproductive potential of millions of cancer survivors in addition to the other unique patient populations it may serve. With approximately 1.9 million people diagnosed with cancer per year in the US and an estimated 26 million cancer survivors by 2040, IVG could have wide and lasting impact on cancer survivors . Some pr


In this review, we summarise new insights into diagnostic approaches and treatment strategies for coronary artery disease (CAD) in patients with diabetes mellitus (DM). Despite the improvements in therapy, the clinical management of DM patients remains challenging as they develop more extensive CAD at a younger age and consistently have worse clinical outcomes than non-DM patients. Current diagnostic modalities as well as revascularisation treatments mainly focus on ischemic lesions. However, the impact of plaque morphology and composition are emerging as strong predictors of adverse cardiac events even in the absence of identified ischemia. In particular, the presence of vulnerable plaques such as thin-cap fibroatheroma (TCFA) lesions has been identified as a very strong predictor of future adverse events. This emphasises the need for an approach combining both functional and morphological methods in the assessment of lesions. In particular, optical coherence tomography (OCT) has proven to be a valuable asset by truly identifying TCFAs. New treatment strategies should consist of individualised and advanced medical regimens and may evolve towards plaque sealing through percutaneous treatment. The incidence and prevalence of diabetes mellitus (DM) are increasing and it has currently become the most common global metabolic disorder , 2. DM iDM patients are at increased risk for developing acute coronary syndrome (ACS). Consequently, this increased risk has resulted in DM having a prevalence of 25–40% among patients presenting with ACS , 11, 12.Despite advances in percutaneous coronary intervention (PCI) with the utilisation of modern drug-eluting stents (DES), studies have continued to show a trend towards higher rates of adverse cardiovascular events in DM patients than non-DM patients presenting either with or without ACS –20. The During the choice of the revascularisation strategy it is of crucial importance to acknowledge that patients with DM often present with CAD at a younger age than their non-DM counterparts. Therefore, maintaining these patients free of cardiac ischemia over a longer period of time becomes challenging. While CABG is indeed the treatment of choice for complex multivessel disease in this patient population, it is known that (venous) grafts also have a limited patency that hardly extends over a decade; therefore, PCI has an important role in delaying the time that these patients ultimately receive CABG . In concMultifactorial pathophysiological processes in patients with DM contribute to an increased risk for developing both CAD and ACS. Persistent hyperglycemia and insulin resistance induce metabolic disarrangements and oxidative stress through diverse molecular processes that stimulate the accelerated development, progression and instability of atherosclerotic plaques , 30. TheThese complex disturbances are divided into three main functional categories: endothelial dysfunction, plaque alteration and platelet activation with coagulation disturbances. These processes are schematically illustrated in Fig. When the dysfunctional endothelium or the fibrous cap comes into contact with the bloodstream, it activates platelets that adhere to the vessel wall. The proposed mechanisms for this phenomenon are an interplay between diabetic-induced elevated concentrations of pro-coagulant factors and a reduction in endothelial antithrombotic properties in combination with the previously mentioned presence of reactive oxygen species and inflammatory stimuli. Activated platelets further release numerous mediators within their granules leading to an accelerated vicious cycle of plaque destabilisation. Finally, both intrinsic and extrinsic (by tissue factor-induced) coagulation pathways are activated, which produce a blood clot.The presence of metallic devices may mechanically distort and constrain the stented segment of the coronary vessel, thus preventing the normalisation of vasomotion and autoregulation. In-stent restenosis may also be imposed by the presence of foreign material , 32. ThiThe currently most implemented catheterisation laboratory assessment of ischemic properties of coronary lesions is effectuated either by a visually directed quantitative coronary angiography or by hemodynamic measurements. Fractional flow reserve (FFR) is the most accurate technique to assess ischemia during hyperemia induced by adenosine injection; however, other rest pressure assessment techniques, such as the instantaneous wave-free ratio or resting full-cycle ratio are also widely adopted and do not require adenosine injection , 34. For2 are independent predictors of adverse cardiac events [Historically, the concept of a vulnerable plaque was described several decades ago and opened a broad new era of research to enhance our knowledge of precursor determinants of adverse cardiac events . In genec events , 47. Nonc events .Fig. 2MaA TCFA itself is defined as any coronary lesion with predominantly lipid-rich non-calcified plaque, a large necrotic core and foamy macrophage infiltration, for which the thinnest part of the atheroma cap measures ≤ 65 μm , 48. TCFPrevious studies have shown that the prevalence of TCFAs in a population presenting with ACS is higher than that in patients with stable CAD, which may suggest that TCFA presence might be a strong predictor of culprit plaque rupture responsible for ACS . These rWhen evaluating the clinical consequences of CAD in DM patients, it is of great importance to uphold a distinction between ischemic symptoms and prognostic determinants. Under appropriate medical therapy, non-ischemic vulnerable lesions may still be relevant in terms of prognosis, while not all (symptomatic) ischemic lesions are deemed prognostically unfavourable, as was shown in a DM substudy of the ISCHEMIA trial . This paRecently, the COMBINE OCT-FFR trial was conducted to address this approach of combined functional and visual assessment of coronary lesions . This anAs predicted from this natural history study hypothesis, the results demonstrated that the presence of a TCFA in FFR-negative lesions was associated with a fivefold higher risk for adverse cardiac events. Second, TCFAs were present in only 25% of FFR-negative lesions but contributed to > 80% of adverse cardiac events. Finally, all new MI events originated from the TCFA lesions. Importantly, this increased risk of adverse events persisted during a long-term follow-up . FurtherBoth intravascular ultrasound (IVUS) and OCT have been implemented for visualising vulnerable plaques . In addiIVUS provides two-dimensional cross-sections that enable the visualisation of the lumen and stent struts as well as the dimensions of the coronary vessel wall. Despite its usefulness, IVUS remains limited in the assessment of certain plaque characteristics, for example lipid content, due to the inherent properties of sound waves, leading to a relatively low spatial resolution. On the other hand, NIRS imaging offers outstanding ability to detect a lipid-rich core in the plaque. This technology is based on the ability of tissue to absorb and scatter light at different intensities and wavelengths. However, NIRS alone also has limitations as it is unable to produce information about the lumen and plaque depth. The combination of IVUS and NIRS provides a hybrid imaging modality that is capable of detecting high-risk non-obstructive lesions with high lipid content and large plaque burden as was shown in the PROSPECT II trial . HoweverThe OCT technique uses a low-coherence infrared light source that is directed at the vessel wall and produces tissue imaging with backscattered light. It does require the clearance of blood by contrast injection, as red blood cells are able to attenuate light. OCT has a higher spatial resolution than IVUS but less depth penetration. Therefore, OCT is currently the most accurate method for visualising and measuring the thickness of the fibrotic cap and thus detecting true TCFAs . The relMedical therapy is the treatment of choice for stable CAD in DM patients. The BARI 2D trial, and more recently, the ISCHEMIA trial showed the non-inferiority of a medical approach compared to percutaneous treatment , 53. NotTreatment with statin therapy has been widely proven to improve clinical outcomes, especially in the setting of secondary prevention. Although the direct effects of statin therapy on reducing coronary stenosis diameter are limited, the beneficial effects include creating plaque stability. In addition to their lipid-lowering properties, statins induce pleiotropic effects by enhancing endothelial function and decreasing inflammation. On a coronary level, data from longitudinal imaging studies suggest that atherosclerotic plaque morphology may change over time, as it is able to both gain and lose features of vulnerability –69. It hThe pursuit of the optimal antidiabetic therapy is extensive. In addition to conventional antidiabetic agents, newer glucose-lowering drugs have also been shown to reduce the incidence of major cardiovascular events as was shown in the LEADER, SUSTAIN-6 and EMPA-REG trials –75. GlucThere are multiple substrates of GLP1 agonists, as they are responsible for glucose-dependent secretion of insulin, the inhibition of glucagon secretion and delayed stomach transit, all effects that favour cardiovascular protection. Indeed, these beneficial cardiovascular effects are unlikely to be driven only by a modest glycemic difference but rather by lowering blood pressure, body weight loss and by exerting favourable effects on lipid profiles , 77.SGLT2 inhibitors are active by inducing reversible inhibition of the SGLT2 transporter with the result of glucose secretion and osmotic diuresis that in turn reduces preload and afterload with particularly favourable effects on heart failure. The beneficial cardiovascular protective effects might be related to the preservation of kidney function, increased uric acid excretion, reduction of epicardial adipose tissue, improved endothelium function and more efficient mitochondrial activity , 77. IndThe benefit of more potent antiplatelet therapies has been shown consistently in various clinical settings . To a grIdentifying patients with higher clinical risk is also possible by determining the duration and control of DM. Advanced DM that requires insulin prescription has been previously identified as a risk factor for the development of major adverse cardiovascular events in both FFR deferred lesions as well as those treated with PCI , 53, 86.Percutaneous coronary treatment is still the most utilised strategy in DM patients presenting with MI as well as in those with stable CAD. Newer-generation DES are associated with better safety and efficacy outcomes than bare metal stents or first-generation DES –91. FurtThe ISCHEMIA trial showed that performing ischemia-guided revascularisation reduces angina frequency and improves quality of life but is insufficient to reduce prognostic endpoints such as cardiovascular mortality and MI when compared to an approach with optimal medical treatment . It mustGiven the results from the COMBINE OCT-FFR trial and those of other previously mentioned studies, it is plausible that PCI treatment could be reserved for a small subgroup of lesions with an intermediate to severe degree of diameter stenosis and vulnerable features even in the absence of ischemia , 52. WhiDespite the major advantages of novel DES with good general performance, ongoing restenosis and thrombotic events remain problematic with metallic DES in these generally younger DM patients. Biodegradable polymer DES were introduced to counteract this mechanism by developing a polymer that is prone to dissolving with the advantage of only leaving the bare metal stent. Nevertheless, new-generation durable polymer DES have proven to be very thrombo-resistent and outperformed these biodegradable polymer DES, mainly in the setting of DM and ACS , 96. In A major downside of metallic DES is that repeated percutaneous interventions at target lesions lead to a critical loss in vessel diameter, thus shortening the time span where CAD can still be managed with PCI. Confronted with these conditions, bioresorbable scaffolds (BRS) have been developed to overcome these shortcomings through completely resorption within three years, with the additional hypothesis that vessel restoration and late remodelling after (non-layering) implantation might be associated with more beneficial long-term outcomes than metallic DES.The multicentre ABSORB DM Benelux trial evaluated the utilisation of BRS in an exclusively all-comer DM population . If implConsidering the young DM patient group and the dynamic plaque formation of vulnerable (ruptured) thin-capped lipid-rich soft plaques such as TCFAs as well as the downsides of permanent foreign material in the vessel wall caused by metallic DES, more optimised BRS with safer profiles could yet be particularly appealing in these DM patients. A similar method was already harnessed in the PROSPECT ABSORB trial, in which non-obstructive lesions with high plaque burden underwent revascularisation through the implementation of BRS with favourable long-term angiographic results when compared to standalone medical therapy . The resIn modern interventional cardiology, CAD in patients with DM remains challenging as these patients develop more extensive vessel disease at a younger age and have consistently worse clinical outcomes for all current treatment strategies. As most validated methods are well established to determine ischemic lesions, they are unsuited to distinguish non-ischemic high-risk morphological plaque features such as TCFAs. Henceforth, this paradigm emphasises the need for a combined approach of both functional and morphological methods in the assessment of CAD in this specific patient category. In particular, OCT has proven to be a valuable asset. The treatment of these non-ischemic high-risk lesions should include individualised medical treatment strategies and may evolve towards plaque sealing through PCI, in which hypothetically the implementation of improved BRS might prove to be particularly beneficial.


The use of urine dipstick tests in people who are more likely to have asymptomatic bacteriuria (ASB) can lead to the over-diagnosis of urinary tract infection (UTI) and unnecessary antibiotic prescribing. As a result, urine dipsticks are not recommended in those over the age of 65 years, or those with a urinary catheter in UK primary care guidelines. However, due to variation in prevalence estimates for ASB and the age of some of the existing prevalence studies it is unclear whether the use of age 65 as a cut-off for dipstick testing remains appropriate.This systematic review aims to identify and synthesize more recent evidence around ASB prevalence and other risk factors relevant to a UK community context, in order to improve how UK primary care UTI diagnostic guidance addresses asymptomatic bacteriuria.The protocol for this systematic review is registered with PROSPERO. Inclusion criteria are: study participants aged ≥18 years; prospective studies recruiting from a primary care relevant population; studies that measure ASB prevalence and risk factors; and studies from the Organization for Economic Co-operation and Development member countries. Exclusion criteria include: studies from inpatient hospital settings (including the emergency department); studies exclusively including people who are pregnant, who have urinary catheters, who are post renal transplant or who have structural urological abnormalities; animal studies; laboratory studies; studies published before 1990; and studies not written in English. Searches were conducted in CINAHL, Embase and Medline using MeSH and free text words adapted for each database including terms for bacteriuria AND asymptomatic disease. The Cochrane Collaboration Covidence platform is being used for the management of screening and assessment of studies. Two authors are independently completing screening, data extraction and quality assessments.The initial search identified 3891 studies. After screening, 685 are currently undergoing full text review. Overall findings will be reported in a narrative synthesis. We will describe the studies identified, including how ASB has been defined within each of the studies. If sufficient data are available we will complete a meta-analysis. Using standard meta-analysis methods we will generate forest plots showing prevalence and 95% CIs for each study. If possible, we will estimate pooled prevalence of ASB from the reported prevalence of eligible studies, by age group and gender.The results of this review may highlight where new evidence around ASB prevalence and risk factors relevant to a UK primary care population is needed.


Based upon an extended Technology Acceptance Model (TAM), this study aims to investigate the factors influencing the behavioral intention to adopt Fintech from the perspective of Indonesian women. The research data were collected from 409 Indonesian female respondents and analyzed using the SEMinR statistical data analysis tool. Structural equation modeling (SEM) was used to assess this research’s measurement model and structural model. The result shows that perceived usefulness, perceived ease of use, user innovativeness, attitude, trust, and brand image significantly positively impact behavioral intention to adopt Fintech among Indonesian women. Meanwhile, perceived ease of use, financial literacy, and government support are found to have indirect relationships with behavioral intention. In addition, moderation analysis revealed that the saving habits of women during the COVID-19 pandemic reduced the relationship between their innovativeness and behavioral intention to adopt Fintech. Based on these results, we recommend practical suggestions to the government, policymakers, and aspiring Fintech service providers further to enhance women’s empowerment through digital financial inclusion. The World Bank  reveals The arrival of financial technology (Fintech) has the potential to close the gender gap in women’s access to financial services  has established the Regional Financial Access Acceleration Team (Tim Percepatan Akses Keuangan Daerah/TPAKD) to promote financial inclusion, including access to financial services for people in rural areas and women, who are considered vulnerable groups affected by the economic crisis and play an important role in household financial decisions OJK . FurtherSeveral recent empirical studies have assessed the customers’ behavior/satisfaction in adopting or using financial services , perceived ease of use (PEU), user innovativeness (UI), attitude (AT), trust (TR), brand image (BRI), government support (GS), and financial literacy (FL) are observed in this study, and these variables are associated with Fintech adoption through behavior intention (BI). Furthermore, the saving habit is also examined as intervening and moderating variable for the driver factors of Fintech adoption during the COVID-19 pandemic.Davis et al.  define pPerceived usefulness positively impacts behavior intention to adopt Fintech.The concept of Perceived ease of use (PEU) pertains to an individual’s level of effort required to use new technology  and behavior intention to adopt Fintech is moderated by saving habits in the COVID-19 pandemic.This study obtained primary data to answer the research hypotheses. Respondents with basic information about Fintech were qualified to take part in this survey. The original English-language online survey questionnaire was translated into Indonesian by qualified native Indonesian speakers. Data collection through questionnaires was carried out in three stages. First, the researcher developed the questionnaire items based on the theoretical construct  values  in the relationship between various factors and behavior intention to adopt Fintech. Results from the bootstrapping Table  show savTo assess the interaction effect in moderation, the study calculated f-Sq effect size (Hair et al. The results reveal that almost all investigated variables have a significant relationship with behavior intention to adopt Fintech, excluding government support and financial literacy, which positively impact behavior intention through the mediating effect of user innovativeness.The most striking result of the study is that perceived ease of use has a significantly negative impact on behavior intention to adopt financial technology services in the case of Indonesian women. This result is inconsistent with the conclusion from the TAM model conducted by Agyei et al. ; Chawla The statistical analyses show that perceived usefulness is still among the important factors in the decision to adopt Fintech among Indonesian women. This result is consistent with most findings from TAM research. As one of the most significant factors, customers have an intention to adopt new technology if they feel this technology would benefit their performance (Singh et al. Although government support and financial literacy have no direct impact on behavior intention to adopt Fintech services, these factors influence user innovativeness. It seems that higher knowledge in finance would stimulate female Fintech users to discover and test new Fintech products. Moreover, Indonesian women tend to be more innovative in Fintech services supported and promoted by governmental policy. The insignificantly results from the impact of government support on behavior intention to adopt Fintech reveal that even though the Indonesia govern involving in the Fintech development during the COVID-19, it seems the support does not yet generate significant results. To accelerate digital financial inclusion, the Indonesian government, through OJK and working with all governors, create the Acceleration of Access to Regional Finance in every province in Indonesia. Related to the reverse impact on financial literacy toward Fintech adoption, it may reveal that in Indonesia, Fintech may promote financial inclusion by allowing people with limited financial literacy to use financial technologies (Nathan et al. Trust, attitude and brand image positively impact the behavior intention of Indonesian female customers. Similar findings have also reported by the other previous literatures (Setiawan et al. Our result from statistical analysis demonstrates that the higher saving behavior during the COVID-19 pandemic reduced the relationship between user innovativeness and behavior intention to adopt Fintech among female customers. This result seems consistent with the functional performance of Fintech providers in Indonesia. COVID-19 could be seen as a motivating force for developing new mobile services. Moreover, COVID-19 leads to higher demand for a loan and a higher risk profile; therefore, some innovative Fintech providers select to reduce their portfolio and aim to provide their services to lower-risk customers with a better income.In conclusion, understanding the essential variables for adopting Fintech by women in Indonesia is valuable for closing the gender gap in accessing and democratizing financial services for all segments of society. Furthermore, an empirical study conducted by D’espallier et al.  indicateThe study revised the efficiency of the TAM model in explaining the intention of women customers to adopt Fintech services. The findings of this article suggest that perceived usefulness, attitude, user innovativeness, brand image, and trust are among the good indicators. Meanwhile, as customers are getting more knowledge in related-technology services, perceived ease of use would negatively impact the decision to adopt new technology and become a barrier. Furthermore, in the context of the COVID-19 pandemic, customers often pay attention to higher saving habits, as the results will impact the relationship between user innovativeness and behavior intention to adopt Fintech services.The results have important implications for financial firms and technology developers. Fintech companies should improve customers’ attitudes because this factor is the most important factor influencing the decision to adopt Fintech services. In order to achieve a higher attitude from customers’ perspectives, Fintech providers should create more attractive Fintech applications, provide more interesting customer relationships, and broaden their service ecosystem. Moreover, to be successful, Fintech services should be more complete and secure to attain the attention of female customers. This means that they could need to regularly update their applications and provide more secure systems to protect customers’ information and transactions. Moreover, the pursuit of women’s adoption of Fintech must go cohesive with equal participation in the creation and improvement of these financial technologies through incentives for women’s participation in the industry.Furthermore, this work leads to implications for governments through public policies to achieve higher financial inclusion and reduce the gender gap in access to financial services by promoting the usage of Fintech services. Governments can indirectly influence individual decisions through two channels. First, raising public awareness of financial topics would be essential. Furthermore, the government could provide more training courses to the older and younger generation of women to help them build confidence in approaching financial services. Secondly, the government should improve a transparent policy and sandbox to support new Fintech companies. Receiving technical and administrative assistance from governmental authorities increases the success of Fintech entrepreneurs and improves Fintech’s reputation among users. The COVID-19 situation may reduce the role of customer innovativeness; however, Fintech providers may overcome this problem by creating monetary incentives for using Fintech services.Although this study provides significant results, some limitations should be mentioned. The explanatory power is 70%, so other important factors should be included in future research. As this is a sample study of a large and diverse population, we accept a certain degree of error. The methodology of empirical analysis and solutions can be adopted in other countries and technological services, considering that the results are affected by the cultural characteristics of the country. For future work, it is also important to conduct a study that examines the drivers and barriers factors for the adoption and use of Fintech, including evaluating the role of Fintech in increasing financial inclusion in Indonesia. Furthermore, the longitude research should investigate how customers’ behavior changes after the COVID-19 pandemic.