The role of medical image computing in oncology is growing stronger, not least due to the unprecedented advancement of computational AI techniques, providing a technological bridge between radiology and oncology, which could significantly accelerate the advancement of precision medicine throughout the cancer care continuum. Medical image processing has been an active field of research for more than three decades, focusing initially on traditional image analysis tasks such as registration segmentation, fusion, and contrast optimization. However, with the advancement of model-based medical image processing, the field of imaging biomarker discovery has focused on transforming functional imaging data into meaningful biomarkers that are able to provide insight into a tumor’s pathophysiology. More recently, the advancement of high-performance computing, in conjunction with the availability of large medical imaging datasets, has enabled the deployment of sophisticated machine learning techniques in the context of radiomics and deep learning modeling. This paper reviews and discusses the evolving role of image analysis and processing through the lens of the abovementioned developments, which hold promise for accelerating precision oncology, in the sense of improved diagnosis, prognosis, and treatment planning of cancer. To better understand the evolution of medical image processing in oncology, it is necessary to explain the importance of measuring tumor appearance from medical images. Medical image processing approaches contain useful diagnostic and prognostic information that can add precision in cancer care. In addition, because biology is a system of systems, it is reasonable to assume that image-based information may convey multi-level pathophysiology information. This has led to the establishment of many sophisticated predictive and diagnostic image-based biomarker extraction approaches in cancer. In more detail, medical image processing efforts are focused on extracting imaging biomarkers able to decipher the variation within individuals in terms of imaging phenotype, enabling the identification of patient subgroups for precision medicine strategies . From thBased on the above considerations, the extraction of quantitative parameters characterizing size, shape, texture, and activity can enhance the role of medical imaging in assisting in diagnosis or therapy response assessment. However, in clinical practice, only simpler image metrics  are often used in oncology, especially in the evaluation of solid tumor response to therapy . Both RECIST and WHO evaluation criteria rely on anatomical image measurements, mainly in CT or MRI data, and were originally developed mainly for cytotoxic therapies. Such linear measures suffer from high intra/inter-observed variability, which in some cases can compromise the accurate assessment of tumor response, since some studies report inter-observer RECIST variability of up to 30% . SeveralIn the 1990s, one of the first challenges in medical image analysis was to facilitate the interpretation of mammograms in the context of national screening programs for breast cancer. In the United Kingdom, the design of the first screening program was undertaken by a working group under Sir Patrick Forrest, whose report was accepted by the government in 1986. As a consequence, the UK screening program was established for women between 50 and 64 in 1990 [As a result, the radiologist’s task became more complex, since the interpretation of a mammogram is challenging, due to the projective nature of mammography, while at the same time the need for early and accurate detection of cancer became pressing. To address these needs, medical image analysis became an active field of research in the early nineties, giving rise to numerous research efforts into cancer and microcalcification detection, as well as mammogram registration for improving the comparison of temporal mammograms. However, early diagnostic decision support systems suffered from low precision, which in turn could potentially lead to a negative impact in the number of unnecessary biopsies. In a relevant study , the posWith the advent of more sophisticated imaging modalities enabling functional imaging, medical image analysis efforts shifted towards the quantification of tissue properties. This opened new horizons in CAD systems towards translating image signals to cancer tissue properties such as perfusion and cellularity and developing more intuitive imaging biomarkers for several cancer imaging applications. For example, in the case of MRI, complex phenomena that occur after excitation are amenable to mathematical modeling, taking into consideration tissue interactions within the tumor microenvironment. In the context of evaluating a model-based approach, the model can be regarded reliable when the predicted data converges on the observed signal intensities and at the same time provides useful insights to radiologists and oncologists. MRI perfusion and diffusion imaging has been the main focus of such modeling efforts, not least due to fact that MRI is ionizing radiation-free.Diffusion weighted MRI (DWI-MRI) is based on sequences sensitized to microscopic water mobility by means of strong gradient pulses and can provide quantitative information on tumor environment and architecture. Diffusivity can be assessed in the intracellular, extracellular, and intravascular spaces. Apparent diffusion coefficient (ADC) per pixel values derived from DWI-MRI theoretically have an inverse relationship to tumor cell density. In addition, with the introduction of the intravoxel incoherent motion (IVIM) model, both cellularity and microvascular perfusion information could be assessed after parametric modeling . Figure DWI-MRI has been tested in most solid tumors for discriminating malignant from benign lesions, to automatize tumor grading, and to predict treatment response and post-treatment monitoring .However, there is still a lack of standardization and generalization of these results, as well as validation against histopathology. While in clinical routine, in-depth DWI-MRI biomarker validation is difficult, recent pre-clinical studies have found that derived parametric maps can serve as a non-invasive marker of cell death and apoptosis in response to treatment . To thisIn a similar fashion, in dynamic contrast-enhanced MRI (DCE-MRI), T1-weighted sequences are acquired before, during, and after the administration of a paramagnetic contrast agent (CA). Tissue-specific information about pathophysiology can be inferred from the dynamics of signal intensity in every pixel of the studied area. Usually this is performed by visual or semi-quantitative analysis from the signal time curves in selected regions of interest. However, with the use of pharmacokinetic modeling, e.g., between the intravascular and the extravascular extracellular space, it became possible to map signal intensities per pixel to CA concentration and then fit model parameters describing, e.g., interstitial space and transfer constant (ktrans). This enabled the generation of parametric maps, e.g., for ktrans providing more quantitative representation of tumor perfusion and heterogeneity within the tumor image region of interest. Although promising, e.g., for assessing treatment efficacy, such approaches have found limited use in clinical practice, not least due to the low reported reproducibility of model parameter estimation. One aspect of this problems is presented in the example shown in In conclusion, the clinical translation of DWI and DCE MRI is hampered by low repeatability and reproducibility across several studies in oncology. To address this problem initiatives such as the Quantitative Imaging Biomarkers Alliance (QIBA) propose clinical and technological requirements for quantitative DWI and DCE-derived imaging biomarkers, as well as image acquisition, processing, and quality control recommendations aimed at improving reproducibility error, precision, and accuracy . It is aTraditional cancer medical image analysis was for decades based on human-defined features, usually inspired by low-level image properties, such as intensity, contrast, and a limited number of texture measures. Such methods were successfully used. e.g., in cancer subclassification, but it was hard to capture the high-level, complex patterns that an expert radiologist uses to define the presence or absence of cancer .However, with the advancement of machine learning and the availability of more powerful, high-performance computational infrastructures, it became possible to exhaustively analyze the texture and shape content of medical images in an effort to decipher high-level pathophysiology patterns. At the same time the evolution of texture representation and feature extraction, through a growing number of techniques during the last decades, played a catalytic role in better capturing tumor appearance through medical image analysis . Last buAll these factors played a central role in the advancement of radiomics, where in analogy to genomics high-throughput feature extraction followed by ML enabled the development of significant discriminatory and predictive signatures, based on imaging phenotype. Radiomics have been enhanced with deep learning techniques, offering an alternative approach to medical image feature extraction by the learning of complex, high-level features in an automated fashion from a large number of medical images that contain variable instances of a particular tumor. Recent advancements in AI driven medical image processing can have a positive impact in national cancer screening programs, alleviating the heavy workload of radiologists and aiding clinicians to reduce the number of missed cancers and to detect them at an earlier stage. Compared to the initial efforts mentioned in previous sections, recent AI-driven image processing can exceed the limits of human vision and potentially reduce the number of cancers missed in screening, as well as cope with inter-observer variability.Regarding lung cancer screening, early nodule detection and classification is of paramount importance for improving patient outcomes and quality of life. Despite the existence of such screening programs the majority of lung cancers are detected in the later stages, leading to increased mortality and low 5-year survival rate . To thisRegarding breast cancer screening technologies, it is argued that AI may provide the means to limit the inherent drawbacks of mammography and enhance diagnostic performance and robustness. In a prospective clinical study, a commercially available AI algorithm was evaluated as an independent reader of screening mammograms, and adequate diagnostic performance was reported .During the last decades CAD-driven precision diagnosis has been the holy grail of medical image processing research efforts. However, the clinical interest in such applications has significantly grown only recently with the advancement of AI-driven efforts to generalize performance across diverse datasets. AI systems have reported unprecedented performance regarding the segmentation and classification of cancer. A recent study reported increased performance in segmenting and classifying brain tumors into meningioma, glioma, and pituitary tumors .In addition, a growing number of studies are concerned with automated tumor grading, which is a prerequisite for optimal therapy planning. Yang et al. presented a retrospective glioma grading study (grade II and grade III concerning low grade glioma and high grade glioma) on one hundred and thirteen glioma patients and used transfer learning with AlexNet and GoogLeNet architectures, achieving up to 0.939 AUC .At the same time, the quest to decode imaging phenotype has given rise to efforts to correlate imaging features with molecular and genetic markers in the context of radio-genomics . This prThere are many challenging problems in optimizing treatment for cancer patients, such as accurate segmentation of organs at risk (OAR) in radiotherapy and prediction of neoadjuvant chemotherapy response. Intelligent processing of medical images has opened new horizons to address these clinical needs. In the case of nasopharyngeal carcinoma radiotherapy planning, a deep learning organs-at-risk (OAR) detection and segmentation network provides useful insights for clinicians for the accurate delineation of OARs . RegardiWhile promising, radiomics methodologies are still in a translational phase and thorough clinical validation is needed towards clinical translation. To this end, when these technologies are tested and reviewed, a number of important limitations becomes apparent. In a recent review on MRI based radiomics in nasopharyngeal cancer , the autContrary to common belief, medical image processing has been evolving for the last few decades and its main application is cancer image analysis. Traditional medical image processing was founded on classical image processing and computer vision principles, focusing on low-level feature extraction and simple classification tasks, e.g., benign vs. malignant, or in the geometrical alignment of temporal images and the segmentation of tumors for volumetric analyses. This early stage in the 1990s was an important milestone for further development, since several radiologists and oncologists understood the future potential and helped in the creation of a multidisciplinary community on medical image analysis and processing. More importantly, it laid the foundations of radiomics by proposing the shape and textural analysis of tumors as useful patterns for detection, segmentation, and classification. However, the main limitation was the high degree of fragmentation in such efforts, the limited computational resources, and the very low availability of cancer image data; usually being mammograms or MRIs.Functional imaging was another important milestone for medical image computing, since the idea of transforming dynamic image signals to tissue properties paved the way for the discovery of reliable and reproducible image biomarkers for oncology. To achieve this goal, non-conventional medical image processing was deployed based on compartmental models to link the imaging phenotype with microscopic tumor environment properties, based on diffusion and perfusion. Such model-based approaches include compartment pharmacokinetic models for DCE-MRI and the IVIM model for DWI-MRI, often requiring laborious pre-processing to transform the original signal to quantitative parametric maps able to convey perfusion and cellularity information to the clinician. It is argued that this is still an evolving research field and that the potential for clinical translation is significant, especially since techniques such as DWI-MRI do not involve ionizing radiation or the administration of contrast agent. That said, significant standardization efforts are still required in order to converge on stable imaging protocols and model implementations that will guarantee reproducible parametric maps and robust cancer biomarkers. Another limitation when comparing to modern radiomics/deep learning efforts is that the processing of such functional data with compartmental models is a very demanding task, requiring a deeper understanding of imaging protocols, as well as of numerical analysis methods for model fitting.The gradual advancements of high-performance computing and machine learning and neural networks have revolutionized research in the field, especially during the last decade. The field of radiomics has extended the cancer medical image processing concepts regarding texture and shape descriptors to massive feature extraction and modeling. Such radiomics approaches have also been enhanced by convolutional neural networks, which outperformed the traditional image analysis methods in tasks such as lesion segmentation, while introducing more sophisticated predictive, diagnostic, and correlative pipelines towards precision diagnostics, therapy optimization, and synergistic radio-genomic biomarker discovery. The availability of open access computational tools for machine and deep learning, in combination with public cancer image resources such as the Cancer Imaging Archive (TCIA), has led to an unprecedented number of publications, AI start-ups, and accelerated discussions for the establishment of AI regulatory processes and clinical translation of such technologies. At the same time, the main limitation of these impressive technologies has been their low explainability, which came as a tradeoff for the impressive performances in oncological applications throughout the cancer continuum. Low explainability also contributed to reduced trust in these models, while the vast number of features explored made generalization difficult, especially due to the large variability of image quality and imaging protocols across vendors and clinical sites.Medical image processing is still evolving and will continue to provide useful tools and methodological concepts for improving cancer image analysis and interpretation. Data science approaches focusing on radiomics have paved the way for accelerating precision oncology . However


Over the past decades, an ever growing body of literature has explored the anatomy, connections, and functions of the habenula (Hb). It has been postulated that the Hb plays a central role in the control of the monoaminergic system, thus influencing a wide range of behavioral responses, and participating in the pathophysiology of a number of psychiatric disorders and neuropsychiatric symptoms, such as aggressive behaviors. Aggressive behaviors are frequently accompanied by restlessness and agitation, and are commonly observed in patients with psychiatric disorders, intellectual disabilities, and neurodegenerative diseases of aging. Recently, the Hb has been explored as a new target for neuromodulation therapies, such as deep brain stimulation, with promising results. Here we review the anatomical organization of the habenula and discuss several distinct mechanisms by which the Hb is involved in the modulation of aggressive behaviors, and propose new investigations for the development of novel treatments targeting the habenula to reduce aggressive behaviors. The habenula (Hb) is an epithalamic structure that presents rich connections with several cortical and subcortical structures, including the limbic system, and areas responsible for the production and regulation of monoamines  –5. TheseAggressive behaviors can be verbal and physical insults directed toward oneself , others, or objects , and areThe neurocircuitry underlying aggressive behaviors include prefrontal cortical regions and areas of the mesolimbic system, especially the hypothalamus, amygdala and periaqueductal gray matter –17, 26. In this review, we explore the anatomical organization of the habenula, describe the relevant literature on the involvement of the Hb in the modulation of aggressive behaviors and discuss future perspectives and novel therapies.via the medial stria medullaris comprise the main afferent projections to the MHb , the posterior commissure , and the stria medullaris of the thalamus .The MHb can be further divided into five subregions, namely superior (MHbS), inferior (MHbI), central (MHbC), lateral (MHbL), and commissural (MHbCo) parts . The MHbThe LHb is significantly larger than the MHb and is subdivided into medial (LHbM) and lateral (LHbL) parts . Each of−/− mice present null expression of GPR3 in the Hb, high levels of aggressive behavior and accentuated reduction of serotonin, noradrenaline and its metabolites in the hypothalamus and frontal cortex  present absence of aggressive behavior and accentuated reduction in oxytocinergic innervation in the lateral habenula -nucleus accumbens (nAcc) network that results in increased dopamine release in the nAcc when animals are expecting a conditioned aggressive encounter (The reward value of aggressive behaviors is also mediated ncounter . Moreovencounter –54. In lncounter , 56 and ncounter  reportinncounter .There is a strong body of evidence on the role of the Hb in regulating the circadian cycle, thus influencing internal physiology, brain activity patterns and day-night behavioral rhythm –62. AnatVia GABAergic interneurons, the LHb modulates the activity of serotonergic neurons in the dorsal raphe nucleus (Among the various neurotransmitters, neuropeptides, and neurohormones involved in the modulation of the circadian cycle, dysfunctions in serotonin transmission are thought to be central in the association between poor sleep and aggressiveness.  nucleus , 71, tha nucleus , 73. The nucleus , thus covia antagonizing dopaminergic receptors or selectively inhibiting serotonin reuptake enzymes (Excessive aggressive behaviors are highly prevalent, particularly among patients with psychiatric disorders and presents a major obstacle for patient care, increasing institutionalization rates and reducing patients' quality of life , 17. The enzymes . However enzymes , 75, 76.Focused ultrasound is being intensively investigated as a novel non-invasive tool for neuromodulation that could be used to deliver pharmacological agents to localized brain areas, without the need of a systemic distribution . By repuvia the application of an electrical current that can be precisely titrated (Deep brain stimulation is a neuromodulation therapy that involves the precise placement of electrodes into deep brain structures to modulate neuronal activity titrated . Althougtitrated , depresstitrated , 83, obstitrated , and biptitrated . New clititrated ]. ConsidIn this article we provide a detailed review of the anatomical organization of the Hb, by describing cell characteristics and connections of the lateral and medial aspects of the Hb and its subdivisions. We discussed several distinct mechanisms by which the Hb modulates aggressive behavior, detailing studies investigating transgenic models, neuronal modulation and neuroimaging, and the literature about the involvement of the Hb in reward-related behaviors and regulation of circadian cycle. We concluded this review discussing how innovative neuromodulatory techniques could be investigated in the context of Hb and aggressive behaviors to improve patient outcome.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The first WHO guidelines for risk reduction of cognitive decline and dementia marked an important milestone in the field of dementia prevention. In this paper, we discuss the evidence reviewed as part of the guidelines development and present the main themes emerged from its synthesis, to inform future research and policies on dementia risk reduction. The role of intervention effect-size; the mismatch between observational and intervention-based evidence; the heterogeneity of evidence among intervention trials; the importance of intervention duration; the role of timing of exposure to a certain risk factor and interventions; the relationship between intervention intensity and response; the link between individual risk factors and specific dementia pathologies; and the need for tailored interventions emerged as the main themes. The interaction and clustering of individual risk factors, including genetics, was identified as the overarching theme. The evidence collected indicates that multidomain approaches targeting simultaneously multiple risk factors and tailored at both individual and population level, are likely to be most effective and feasible in dementia risk reduction. The current status of multidomain intervention trials aimed to cognitive impairment/dementia prevention was also briefly reviewed. Primary results were presented focusing on methodological differences and the potential of design harmonization for improving evidence quality. Since multidomain intervention trials address a condition with slow clinical manifestation—like dementia—in a relatively short time frame, the need for surrogate outcomes was also discussed, with a specific focus on the potential utility of dementia risk scores. Finally, we considered how multidomain intervention could be most effectively implemented in a public health context and the implications world-wide for other non-communicable diseases targeting common risk factors, taking into account the limited evidence in low-middle income countries. In conclusion, the evidence from the first WHO guidelines for risk reduction of cognitive decline and dementia indicated that “one size does not fit all,” and multidomain approaches adaptable to different populations and individuals are likely to be the most effective. Harmonization in trial design, the use of appropriate outcome measures, and sustainability in large at-risk populations in the context of other chronic disorders also emerged as key elements. The number of people with dementia is projected to triple within the next 30 years . The lacsocial activity and hearing loss, preventing the definition of specific recommendations.The guidelines were developed during 2018 based on the evidence available at the time on twelve modifiable risk/protective factors identified within recent systematic reviews (SRs) , 4 and gThe aim of this paper is to critically discuss the main themes that emerged from the evidence review and based on this, to inform the most effective directions for future research on dementia risk reduction. The future development of more robust evidence for the best strategies for dementia risk reduction, together with new evidence reported since the publication of the guidelines, will help refine the recommendations in the next update of the guidelines, not only for factors already included, but also by potentially including new factors and, thus, improve public health policies aimed at dementia prevention.The systematic review and quality assessment of the evidence was based on the “Grading of recommendations, assessment, development, and evaluations” (GRADE) methodology . The higocial activity and hearing loss are not included since recommendations could not be formulated. However, further results from RCTs are expected for hearing loss  su00–0.47; , the fordiabetes prevention it has been suggested that lifestyle interventions could be at least as effective as pharmacological treatments    suggest dyslipidaemia are a typical example. Although static use was found to be significantly associated with decreased risk of dementia  in observational studies  a substantial body of observational evidence contrasted with a total lack of evidence from RCTs, partly due to the ethical issues posed by potential randomization to risk factor exposure or placebo/control.In other cases, relatively large associations in observational studies did not translate into any significant intervention benefit in RCTs  and the  studies , no sign studies . In moreThe underlying causes of such mismatches are not fully clear. One key clue could lie in the duration of observational studies, which can span a much longer period of time, compared to RCTs. This can potentially affect not only the size of the association/effect reported but, more importantly, determine the choice of feasible outcomes. Clinical endpoints for slowly developing dementia are routinely used in longitudinal studies , but rarely achievable in the timeframe of RCTs. Cognition assessed through standardized tests is the preferred surrogate option, but the application of other indirect risk-estimation tools, such as well-established risk scores, could also be effective , 20 and hypertension, for which RCT evidence broadly aligns with observational data   , but werticular) , 37, altAs proposed for CVD , a threstobacco consumption and nutrition. The association between smoking and risk of AD or vascular dementia (VaD) has been inconsistent (Most of the systematic reviews considered do not discriminate among dementia pathologies and disease specific studies focus consistently on Alzheimer's Disease (AD). Additionally, many studies consider primarily clinical diagnosis of different dementia types. Some evidence has been collected from observational studies for nsistent  althoughnsistent . Observansistent , 41, butnsistent  and reprThe evidence linking risk/protective factors to individual pathologies is, in general, incomplete. Several biological mechanisms have been proposed for dementia risk factors , but their potential links with specific brain pathologies have not been fully elucidated. Until recently, non-pharmacologic RCTs only sporadically included assessment of biomarkers such as cerebrospinal fluid or brain imaging .social engagement, hearing loss, and, to a certain extent, overweight/obesity) that are thought to act as proxy for others  that are more tightly linked with specific biologic mechanisms of neurodegeneration. In these cases, a better understanding of the link with specific brain pathologies could provide key information on biologic mechanisms and the best preventive/therapeutic targets.From a preventive perspective, identifying the strategies that work best could be deemed more important than understanding exactly how they work. Moreover, recommendations for dementia risk reduction could still be developed based on available evidence. However, in the long-term, research would considerably benefit from elucidation of the links between individual risk factors and specific brain pathologies. This is particularly relevant for those factors  or ethnic  group and diverse population subgroups may respond differently to differing patterns of risk factor exposure and interventions  result in higher risk scores. Eighteen studies were identified in a SR examining the impact of comorbid modifiable risk factors for dementia . DespiteFinally, the findings of the cumulative impact of increasing number of risk/protective factors raises the question of whether specific combinations of medical conditions or health behaviors have different long-term impacts on the risk of dementia. In addition, specific combinations of environmental and genetic  risk factors may affect the risk of dementia. For example, the investigation of whether the beneficial effects of physical activity interventions on cognition are modified by APOE genotype is ongoing. Understanding the interactions among risk factors will lead to better targeted intervention. Multidomain interventions can also be implemented with a higher degree of flexibility and, therefore, more easily tailored to single individuals or specific target populations, based on their risk factors patterns, needs and lifestyle.Population attributable risk prediction models suggested that about 40% of dementia cases are attributable to modifiable factors  and 7% tGiven the multifactorial etiology of dementia, interactions between genetics and combinations of environmental  factors can potentially provide more relevant insights for risk reduction strategies. However, studies focusing on individual factors are much more common . In thisWithin the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) study, the late-life risk of dementia was reported to increase in ApoE-ε4 carriers with an unfavorable (non-genetic) risk profile at midlife . RecentlThe importance of risk profiles, especially at midlife, has been explored in detail over the past years. Risk modification at midlife has been shown to be associated with lower risk of cognitive decline and dementia , but it In the context of multidomain interventions, the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial , the FinMore evidence is needed from multidomain RCTs to elucidate the complex interaction between genetics and environment and help define the most suited target population also based on genetic risk.Given the recent scientific advances in diagnostic criteria  and lessThis includes, for example, multi-nutrient interventions ; interveMore recently, a newer generation of multidomain trials has been established .The preDIVA trial tested a 6-year multidomain intervention in an unselected primary care population of older adults . No signpost-hoc analyses showed beneficial effects of the multidomain intervention regardless of supplementation status or on individuals with an increased risk of dementia [i.e., participants with a CAIDE score of 6 or more; , compared the efficacy of a 2-year intensive multimodal lifestyle intervention in patients with ischemic stroke vs. standard stroke care in reducing the risk cognitive decline. No effects were observed on the primary outcomes , which cThe KENKOJISEICHI trial tested a 24-week intervention combining physical, cognitive, and social activity against health education in 83 people with MCI. The primary outcome was cognitive function and significant intervention benefits were reported for spatial working memory .The Brain Body Life for Cognitive Decline (BBL-CD) trial evaluated the effects of an 8-week multidomain diet, exercise, and cognitive training program against an education only program in older adults with subjective cognitive decline or MCI. The intervention showed positive effects on overall cognition .Finally, the FINGER trial, tested a 2-year multidomain lifestyle intervention in older adults at increased risk of dementia. The intervention showed beneficial effects on overall cognition , which wpost-hoc analysis reported beneficial effects in specific subgroups, emphasizing the importance of targeting at-risk or selected populations and tailoring strategies to people with different risk profiles. Larger RCTs are, therefore, warranted to test such interventions  of lifestyle-based intervention trials delivered to relatively fit, albeit at-risk, populations. Cognitive function measured e.g., through a neuropsychological battery covering various cognitive domains and sensitive to subtle age- and neuropathology-related changes is currently used as surrogate outcome in cognitively normal older adults  or MCI pIn the context of dementia risk reduction, tools specifically aimed to risk estimation, such as dementia risk scores, may be also considered as a plausible alternative for surrogate outcomes. Dementia risk scores can potentially be more sensitive to change than cognitive outcomes in middle-aged populations, long before the onset of the symptomatic phase of cognitive decline or dementia. Furthermore, their assessment is generally less demanding than that of neuropsychological tests measuring cognitive function, making their application in the context of large-scale intervention more feasible and a good complementary assessment.post-hoc analyses of the first three, large dementia prevention multidomain intervention trials, FINGER, MAPT, and preDIVA, with promising results , and several NCDs are also risk factors for dementia . Interventions targeting multiple factors across multiple NCDs are likely to lead to the most cost-effective and sustainable solutions. For example, primary prevention policies for dementia can be built onto existing programmes or campaigns related to other NCDs, including population health promotion in the areas of increased physical activity, healthy diet, tobacco cessation, management of weight, and alcohol use disorders, as well as specific strategies addressing cognitive stimulating activities, socially active lifestyles, and adequate childhood or formal education. The WHO Global Action Plan on the public health response to dementia 2017–2025 encourages this multi-sectorial approach in response to dementia, including alignment of dementia prevention activities to existing NCDs, mental health, and aging efforts world-wide. Researchers, policy makers and health professionals should be encouraged to develop, deliver, and promote evidence-based multidomain interventions at the population, community, and individual level that target both common and dementia specific risk factors when treating NCDs.Implementing multidomain interventions may be the most effective way to increase the health of whole populations , 74. ManThe development of the first WHO guidelines for the risk reduction of cognitive decline and dementia through a rigorous review of the best quality evidence available  was a laBox 1population with the highest potential for improvement, both in terms of individual benefit and number of people who can benefitIdentify the Multidomain approach: targeting more risk/protective factors at onceTailored approach: flexible intervention characterized by a core of common principles which are adapted individually based on what is realistically achievable by each participant in terms of lifestyle changessurrogate outcomes Explore the validity and potential use of Prospective harmonization of trial design, especially concerning the intervention design and outcome measuressustainabilityIdentify strategies to support post-trial time to act within the life and disease courseIdentify the most appropriate optimal intensity levels for each interventionIdentify specific bran pathologiesInvestigate more closely the link between interventions and genetic risk, sex, and ethnic differences in modifying the response to preventive interventionsInvestigate the effect of in the context of other NCDsOptimize the implementation of interventions The field of dementia prevention through lifestyle-based non-pharmacological interventions is still in its early phase and, compared to other age-related disorders , has been the subject of a relatively small number of large RCTs. Many opportunities and lines of investigation are open and, as highlighted by the recently published 2020 report of the Lancet commission for Dementia prevention, intervention and care , fillingRS, MB, RP, AS, KA, and MK conceived and designed the study. RS, MB, and RP drafted the manuscript. NE, LZ, and JL wrote sections of the manuscript. All authors contributed to the revision of the manuscript, read, and approved the submitted version.This work was supported by the European Research Council (ERC) (Grant No. 804371), the Academy of Finland , the European Union Joint Programme—Neurodegenerative Disease (JPND) project EURO-FINGERS (Academy of Finland Grant No. 334804), Stiftelsen Stockholms Sjukhem, Center for Innovative Medicine (CIMED) at Karolinska Institutet, Knut and Alice Wallenberg Foundation, the Swedish Research Council for Health, Working Life and Welfare, Alzheimerfonden, Region Stockholm grants , Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse, the Finnish Cultural Foundation, the National Health and Medical Research Council (NHMRC) (Grant Nos. 1102694 and 1100579), the NHMRC Dementia Centre for Research Collaboration, the Australian Research Council (ARC) (Grant No. FL19000011), Public Health England, and the Center for Disease Control and Prevention, United States of America.The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.KA is an advisor to Staying Sharp. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This paper considers a case that Chinese healthcare organizations in China leverage mobile smart cloud platform (MSCP) to build a self-sustaining healthcare ecosystem, which presents an evolutionary process of three phases. Multiple elements have been involved in the system, which has reinforced one another. Finally, an ecosystem is formed, which is economically sustainable and scalable nationwide. The study adds to the understanding of the ecosystem-based approach to address complex problems. It offers important implications for designing healthcare MSCPs which may help transform the healthcare industry. As is well known, China is the most populous country in the world as well as one of the fastest-growing markets in the world. At present, China's healthcare industry is facing many problems that other developed countries faced in the past or are even facing to this day. In terms of China's social environment, the issue of an aging population is worsening (China is the only country with more than 100 million elderly persons and the largest aging population in the world), the number of people with chronic diseases continues to increase, and people's health management awareness has been increasing as well. In the industrial environment, the high concentration of high-quality medical resources is concentrated in few big cities. The whole country faces the challenges of unbalanced structure of healthcare service system, inefficient implementation of graded medical services, shortage of healthcare workers, increasing medical costs, and inefficient risks of implementing national medical insurance system which have exacerbated the existing crisis in China's healthcare service industry. There are information and communication technologies (ICTs) and Internet-enabled solutions to these issues. As an example, the mobile smart cloud platform (MSCP) has been used to improve healthcare services, including, e.g., in professional online healthcare treatment, health counseling, and telemedicine services for outpatients.In the 1980s, countries like the UK started to promote the use of Internet-based technologies in healthcare. As an example, a doctor can track and provide consultation to his patients equipped with intelligent wearable devices when locating at home or in public places [This paper focuses on MSCP in healthcare from the ecosystem perspective. The ecosystem concept was initially used to analyze the applications of ICTs, which involved the collaboration of a broad range of actors . In receThis article focuses on MSCP-enabled ecosystem in healthcare, a kind of service ecosystem, which takes the healthcare cloud service as the core asset, connects the stakeholder of healthcare through internet technology, forms a virtual organism that interacts with each other and promotes each other, the social actors that depended on each other, seeks the dynamic balance of the system in the competition, and finally realized the value increment of the whole system. Through a case study, we will address such a research question: at the macro-, meso-, or microlevels, how do relevant societal actors collaborate to use MSCP to form a healthcare ecosystem?To understand the evolution of healthcare service ecosystems, we consider a pioneering case of MSCP based healthcare project in China. A case study design is proper for addressing how to type research question.The research originated from the author's participation in the healthcare project, which was initiated by the healthcare authority of A City, and entrusted B Company and P University to develop a mobile smart cloud platform (MSCP) in the way of school-enterprise cooperation. Company B is willing to share the relevant information of the smart healthcare project. City A is a second-tier city located in the south-central region. The rural population is mostly, and the city's information base is weaker than that of developed cities along the eastern coast. In order to test the MSCP platform, the government healthcare administrations in City A established 24 small-scale healthcare clinics and identified 6 medium-scale basic hospitals and 1 large-scale and high-level hospital as pilot healthcare institutions. Through the analysis of the case, we can explore the use of a mobile intelligent cloud platform to build a self-sustaining healthcare ecosystem for similar cities in China. In order to solve the problems of reducing healthcare costs, making up for healthcare shortcomings, adjusting the structural distribution of healthcare resources, etc., the first experience and revelation are provided. To collect data, we carried semistructured interviews with sponsors and leaders of the project to develop a preliminary understanding of the various stages through which MSCP has progressed. The interviews help us to understand the key actors in the healthcare ecosystem, including patients, healthcare service providers, health insurance agencies, and government healthcare administrations. Among them, the healthcare service providers include the local doctor in the small-scale healthcare clinics, online doctors in the medium-scale basic hospitals, the specialist doctors in the large-scale and high-level hospitals, pharmaceutical companies, healthcare equipment companies, and third-party developers. Before each interview, the researcher would carefully design an outline according to relevant research questions and who the interviewee was. After the outline was laid out, the interview was recorded for future analysis. After the interview was conducted, the recorded file would be transcribed into a text summary and issued an identification number. The field interview process began in January 2017 and concluded in December 2017, covering 28 interviewees. The interview arrangements are illustrated in Except for interviews, there are mainly two data sources: internal documents including the project implementation plan and project process documentation; data from online channels such as the government authorities' websites and news media. In order to improve the reliability and validity of the research results , researcThe case study results are summarized in In January 2017, MSCP engaged with the doctor in the medium-scale basic hospitals and all the patients to understand their needs and gauge demand for the platform. In this stage, the doctors in 6 medium-scale basic hospitals can diagnose online by the MSCP platform, and 24 small-scale healthcare clinics were established in urban residential communities and rural areas according to the geographical division. The telemedicine equipment was set up, with the help of the local doctor in the small-scale healthcare clinics, patients used telemedicine equipment to collect health data and complete the process of seeking healthcare treatment directly with online doctors in the medium-scale basic hospitals by video. This new healthcare pattern diagnosed diseases through remote consultation, remote ECG, remote imaging, and remote inspection and gives an electronic prescription online; at the same time, a personal electronic health archive was established. Services provided by small-scale healthcare clinics to patients through the platform include generation and cancellation of appointments online, telemedicine, home health monitoring, self-care, health training, health management, first aid nursing, and public health information. Patients can receive health check-ups via the small-scale healthcare clinics as well. In the same time, the MSCP's extended functions include treatment through prevention and rehabilitation of chronic diseases including providing health assessments, health interventions, and health promotion services. Customer-downloaded apps may be used to guide patients with reasonable exercise, diets, accommodations, and so on.Technically, the small-scale healthcare clinics are characterized by the large number and wide geographic distribution. Due to the small flow of patients and the small amount of data in a single small-scale healthcare clinic, the SSL VPN is the simplest and safest solution to the remote user access data. The medium-scale basic hospitals are characterized by the small number and a larger flow of patients. Due to a large amount of data, the connection stability requirements, the IPSec VPN is the main mode of connection, which is a relatively complete system of VPN technology and provides a series of protocol standards.In the first stage, MSCP provides technology to extend the healthcare service of the medium-scale basic hospitals to the small-scale healthcare clinics through MSCP. The government healthcare administrations in City A established 24 small-scale healthcare clinics. Patients can be treated directly by the doctor online via video. The local doctors in the small-scale network healthcare clinics help patients collect and monitor all kinds of health indicators through physical examinations and offer daily health management services, general health management, and disease prevention for a subhealth population. The online doctors in the medium-scale basic hospitals undertake outpatient clinical services online, make a diagnosis, and give an electronic prescription according to the patient's own description of the illness, the test results collected by telemedicine equipment. Patients and doctors establish cooperative relationships to cope with the disease and complete the online diagnosis and treatment process.As a result, the treatment of common diseases, frequently occurring diseases, and chronic diseases can be achieved online at local small-scale healthcare clinics. 80-90% of patients with diseases can be treated remotely online via the platform, without going to the large-scale and high-level hospitals.In village clinics, I can communicate with a doctor from the network hospital conveniently. I do not need to worry about to travel to a faraway big hospital for a small health problem. (Patient)The patients can be diagnosed and treated in their own community hospital and directly take needed medicine or injections, they can skip going to a big hospital to wait in line and conduct various tests, which saves the time and energy. (Online doctor)The patients suffering from chronic diseases such as diabetes mellitus and hypertension can conduct real-time examinations directly from community hospitals and collect health indicators to complete the referral rehabilitation without traveling to a large hospital far away. (Online doctor)In April 2017, the large-scale and high-level hospitals were connected to the MSCP in this stage. The online hierarchical healthcare service system was established based on MSCP, which consisted of with the small-scale network healthcare clinics, the medium-scale basic hospitals, and the large-scale and high-level hospitals, which established the division and cooperative relations, and healthcare resources could be reasonably distributed. Patients can be registered into the system, and prediagnosis will be based on the patient's conditions when finding a suitable healthcare service provider. After the patient's initial visit, they will receive diagnostic results back online and complete their referral remotely. The hospital decentralization has been promoted, and the patient resources of big hospitals have been diverted according to the graded diagnosis and treatment system. Only patients with critical illness need to be hospitalized at the large-scale and high-level hospitals, thereby relieving workloads in the large-scale and high-level hospitals, which can concentrate on research and healthcare services for difficult diseases. The MSCP can provide data sharing and assist hospitals at all levels to implement linkages throughout the network, including remote consultation and healthcare service/supply exchanges. In-person healthcare services would be extended to all levels of health institutions' network via the Internet and a proprietary app.Technically, the healthcare information system of every given pilot hospital will be transformed to accommodate the MSCP. One common information standard should be constructed to merge pilot hospital information systems and break down data barriers. Existing healthcare information systems were independently constructed by major hospitals. They need to conform to a new standard so that data would be transferable throughout the new system. Process management through business process reengineering and optimization is conducted. Issues arising from discrepancies in personnel, assets, business management, patient service, and online interaction with healthcare insurance agencies between each location have been addressed. Utilizing data exchange technology, the original HIS, LIS, PACAS, and EHR systems of the pilot hospitals were connected to the MSCP. Based on unified data standards, the data could be merged successfully. Information and resources may be effectively shared among all-level hospitals. The large-scale and high-level hospitals are also characterized by a relatively small number and a larger flow of patients. Due to a large amount of data, taking into account the demand for image data sharing, the flow is 5 to 10 times of the general small-scale healthcare clinics and the medium-scale basic hospitals; the connection mode is dominated by MPLS VPN. MPLS VPN refers to the use of MPLS technology to build enterprise IP network to achieve cross-regional, security, high-speed, reliable multiservice high-quality communication methods.In the second stage, the government healthcare administrations in City A identified 6 medium-scale basic hospitals and 1 large-scale and high-level hospital as pilot healthcare institutions. MSCP provides technology to be compatible with all the systems in all-level hospitals and establishes the online hierarchical healthcare service system. For rare cases of illness, the specialist doctors in the large-scale and high-level hospitals would be responsible for the diagnosis and treatment of critically ill patients and the guidance of basic hospitals and the patients can get valuable advice from well-known experts in the large-scale and high-level hospitals. The patients could spend the least amount of money and time to make full use of healthcare resources of the online hierarchical healthcare service system. The doctors in all levels of hospitals aim to achieve up and down linkages and upgrade diagnosis and treatment services for the patients.The patients can make full use of the large-scale and high-level hospitals and expert medical staff throughout the network to share healthcare resources. For rare cases of illness, the patients can get valuable advice from well-known experts in the large-scale and high-level hospitals. (Online doctor)I can quickly and cheaply choose the best diagnosis and treatment using the online system. (Patient)Technically, the healthcare information system of every given pilot hospital will be transformed to a given hospital's healthcare information system which is usually built internally by the hospital, causing such systems to be incompatible with one another. A comprehensive system would improve the overall work efficiency of healthcare staff and managers. (Developer of the SMCP)The establishment of unified data standards is conducive to the sharing of information and resources of the online hierarchical healthcare service system. (Developer of the SMCP)In July 2017, the MSCP provided improved access services, software services, hardware services, and platform services to the third-party healthcare institutions, integrates the hospital resources, and gradually opens up the upstream and downstream resources such as pharmaceutical provider, manufacturers of the healthcare equipment, third-party developers of healthcare cloud services, healthcare insurance agencies, and government health administrations. The functions of MSCP transformed traditional professional solutions to the healthcare service ecosystem step by step. The industrial chain is integrated into the system to improve the wealth of wisdom within the healthcare service platform's service portfolio and increase healthcare institutions' cooperation in the field of development.The drug and the equipment decentralization have been pushed forward; the process of medicine, healthcare equipment, and diagnostics are separated. MSCP also provides medical big data for government healthcare administrations and healthcare insurance agencies. The medical big data obtained through personal electronic health archive include drug data, clinical medical data, healthcare expenses and healthcare insurance fund data, and personal health management data. Applications developed by third-party developers based on market demand can be directly released to users on the cloud service platform, or services to support the background of the cloud service platform management system.In the third stage, the pharmaceutical provider is allowed to sell prescription drugs to patients online. The manufacturers of the healthcare equipment could sell healthcare equipment online to patients and all-level hospitals. MSCP provides the openness of technological interfaces and freely accessible data on cloud service platforms to all actors in the healthcare service ecosystem. Third-party developers develop healthcare applications which meet market demand, in turn, improve the quality of services provided on the platform. The government healthcare administrations will provide policy support, strengthening healthcare quality management, healthcare procedure assessment, and healthcare outcome assessment going forward using MSCP in building a self-sustaining online ecosystem. The government health administrations at all levels of cities, districts, and county administration can provide health management services through dynamic collection, analysis, and evaluation of residents' daily health data, control the spread of epidemics more quickly by monitoring infectious diseases early on, at the same time, scientifically assess healthcare expenses, quality measures, control healthcare facility costs, and ensure healthcare service quality. The healthcare insurance agencies may formulate the reimbursement policy for drugs on the market based on the outcome of treatment and its corresponding social and economic benefits, detect fraud risks, waste, and abuse of resources, and help speed up the healthcare insurance claim process. The patients could get more convenient and efficient service from other actors in the healthcare service ecosystem.MSCP will eventually form a self-evolving and self-enriching healthcare service ecosystem of its own, leading to new wisdom in the realm of healthcare applications and business models. The establishment of the healthcare service ecosystem can free up precious healthcare resources and push efficiency to a greater extent, helping to solve problems within healthcare equality applications and business models. The establishment of the healthcare service ecosystem can free up precious healthcare resources and push efficiency to a greater extent, helping to solve problems within healthcare equality.After the patient completes the online diagnosis and treatment process, purchases the medicine directly online according to the electronic prescription, it is very convenient. SMCP have opened to healthcare equipment suppliers, including sensor technology manufacturers and health measurement equipment manufacturers to provide more accurate and higher-quality services for hospitals at all levels. Relying on the open interface of the healthcare service platform, openness of network data, and so on, healthcare applications with nuanced functions may be developed in line with demand. These applications can be released directly to members of the service platform or simply utilize the service platform as back-end infrastructure. (Third-party developers)The current direction of development of healthcare services should be from high-quality healthcare resources concentrated in the large-scale and high-level hospitals to the medium-scale basic hospitals, ending at the small-scale network healthcare clinics. (Government Officers)The healthcare service industry has gradually changed its direction from government control to the market. (Government Officers)Collaboration between doctors and hospitals is seen as a means of improving the quality and efficiency of care, which can create a personalized experience for patients. (Government Officers)The process of providing healthcare services starts with traditional treatment as the core, and then, it gradually develops to include the entire industrial healthcare chain such as prevention and rehabilitation. (Government Officers)We can obtain medical data from the MSCP and develop the new insurance products and find new customers. The medical data can help us promptly detect fraud risks, waste, and abuse of resources and speed up the healthcare insurance claim process. The cost of health management services will be paid by all levels of government, along with a gradual increase in the number of the small-scale network healthcare clinic associated with telemedicine technology, which is expected to account for 65% of the total healthcare costs. (Government Officers)The study discusses below how the relevant actors of the ecosystem address complex issues in healthcare in a coordinated manner. It offers important implications for designing healthcare MSCPs which may help transform the healthcare industry by suggesting a blueprint for the implementation of a sustainable healthcare service ecosystem.The service ecosystem is proposed to consider as the micro-, meso-, and macrolevels which are shown in In the studied case, this paper has documented the emergence and evolution of the MSCP-enabled healthcare service ecosystem, which evolved in three phases and integrated relevant actors in complementary fields, including patients, healthcare service providers, health insurance agencies, and government health administrations . Among tAt the microlevel, the actors include patients, local doctors, and online doctors. According to Akaka and Chandler , interacAt the mesolevel, drawing on the conceptual framework proposed by Tsiotsou , indirecAt the macrolevel, the multiple participants may be expanded to involve government health administrations, and health insurance agencies . They dePractice actors at three levels interact to build the MSCP-enabled healthcare service ecosystem. In each level, the number and types of actors engaged in healthcare services, as well as the breadth of services provided, differ. Multiple elements of the ecosystem have progressively evolved and reinforced one another to create a dynamic system. The case MSCP ecosystem in China is economically sustainable and scalable and can accelerate transformation.The case study suggests that the mobile smart healthcare cloud platform could enable the development of an ecosystem capable of unleashing multipronged, integrated improvements to address complex problems, which would help address the increasingly serious service crisis and promote the evolution and restructuring of the healthcare industry in developing countries. The case study offers insights into the evolution of the MSCP, enabling a healthcare service ecosystem of key actors and their impact. This paper offers an empirical inquiry into the process of healthcare ecosystem evolution and its consequences in an effort to uncover the value added by technologically enhanced healthcare services, which is based on Internet ICTs, at the same time, which has conducted the healthcare service ecosystem to direct the future medical model and shift focus towards development. In future research, we should focus on the formation of such an ecosystem, which requires efforts from multiple actors ; actors who operate within the healthcare system create value at different ecosystem levels; they strengthen each other through their cooperation, each leveraging its core competencies, but doing so in collaboration with others for self-sustaining, maximum impact.


Nanotechnology has made a great impact on the pharmaceutical, biotechnology, food, and cosmetics industries. More than 40% of the approved drugs are lipophilic and have poor solubility. This is the major rate-limiting step that influences the release profile and bioavailability of drugs. Several approaches have been reported to administer lipophilic drugs with improved solubility and bioavailability. Nanotechnology plays a crucial role in the targeted delivery of poorly soluble drugs. Nanotechnology-based drug delivery systems can be classified as solid lipid nanoparticulate drug delivery systems, emulsion-based nanodrug delivery systems, vesicular drug delivery systems, etc. Nanotechnology presents a new frontier in research and development to conquer the limitations coupled with the conventional drug delivery systems through the formation of specific functionalized particles. This review presents a bird's eye view on various aspects of lipid nanoparticles as carriers of bioactive molecules that is, synthesis, characterization, advantage, disadvantage, toxicity, and application in the medical field. Update on recent development in terms of patents and clinical trials of solid lipid nanoparticles (SLNs) and nanostructure lipid carriers (NLCs) have also been discussed in this article. The main objective of designing an effective drug delivery system is to deliver the therapeutic molecules to target site by minimizing premature drug degradation, maintain optimum amount of drug at the tissue of interest to produce better therapeutic outcomes, and to prevent harmful side effects. The conventional methods of drug administration have several limitations, such as increased chances of dose missing, fluctuations in drug levels, poor bioavailability, undesirable side effects, poor patient compliance, rapid metabolism, and drug toxicity. However, these limitations can be overcome by using target-specific nanocarrier systems, such as solid lipid nanoparticles (SLNs), niosomes, liposomes, ethosomes, bilosomes, transferosomes, colloidosomes, pharmacosomes, herbosomes, layerosomes, sphingosomes, ufosomes, and polymeric nanoparticles. Since the disclosure of cosmetic applications of non-ionic surfactant vesicles by L'Oreal in 1975, the development of nanomaterials for drug delivery and biomedical applications is growing exponentially  have gained the tremendous interest of formulation scientists during the past two decades. Solid lipids are gaining popularity over the liquid oils in the preparation of controlled release of nanoformulations due to the low mobility of drug molecules in a solid lipid matrix  and the surface stabilizers; other components include co-surfactant, preservatives, cryoprotectant, and charge modifiers  Mishra . The matThe SLNs are crucial in the site-specific targeting of the drug and improve the stability of the drug incorporated into it  may lead to stability problems.The loading of the drug in the SLNs depends on various factors, such as the interaction of the drug with the lipid melt, nature of lipid matrix, drug miscibility with lipid matrix, and the drug being distributed or dissolved in the lipid matrix , solvent evaporation/emulsification, etc. have been reported to produce SLNs. Solid lipid component of SLNs may contain ingredients, such as partial glycerides (imwitor), triglycerides (tristearin), fatty acids (stearic acid), waxes , and steroids (cholesterol). Egg lecithin, polysorbates, soybean lecithin, poloxamers, and phosphatidylcholines are commonly used emulsifiers in the production of SLNs. Organic solvents are not required to produce SLNs, whose production yield is high, and scale up is easy than the other type of nanoparticles. Despite these advantages, SLNs production has several limitations, such as pressure-induced drug degradation, gelation, change in the physical state of lipid (formation of supercooled melt), stability problem issues due to the increase in particle size, and drug expulsion  methods requiring high energy, (ii) methods requiring low energy, and (iii) methods that utilize the organic solvent.High-Pressure Homogenization Technique. This is the most widely used, dependable, and effective technique for the preparation of SLNs and NLCs. In this technique, high-pressure homogenization takes place which pushes the liquid with high pressure  through a few microns gap. Hot homogenization technique and cold homogenization technique are the two methods by which high-pressure homogenization can be achieved.Hot Homogenization Technique. In the hot homogenization technique, the drug is added to the lipid. The temperature is maintained at 5–10°C above the melting point of lipid. The mixture is added by stirring in an aqueous surfactant solution maintained at the same temperature to form a pre-emulsion. The resulting oil dispersed in water (o/w) microemulsion is homogenized and cooled to room temperature to form SLNs  and does not require sophisticated equipment  to obtain SLNs. Easy manufacturing and control of particle size by varying process parameters are the major advantages of this technique.Solvent Emulsification-Evaporation Technique. In this method, the drug and lipid are dissolved in a non-polar organic solvent . Emulsification is carried out in an aqueous phase using a high-speed homogenizer. The organic solvent is evaporated by stirring at room temperature (25°C) under reduced pressure at 40–60 mbar. Precipitation of lipid leads to the formation of SLNs . The organic phase is injected through an injection needle at a constant rate into an aqueous phase with or without surfactant under constant stirring and the dispersion is filtered. The use of pharmacologically acceptable organic solvent, easy handling, and fast production process without using technically sophisticated equipment are the major advantages of this method.All these preparation techniques have their own advantages and disadvantages . The hotSterilization is a mandatory process when the formulation is administered parentally , zeta potential, percentage drug entrapment efficiency, drug crystallinity, and stability  populations of nanocarriers of a certain size ] and separation techniques . These techniques allow the quantification of the active ingredient. Entrapment efficiency is measured by two major methods, namely direct and indirect methods. In the direct method, the encapsulated drug is directly measured whereas, in the case of indirect method, the amount of unencapsulated drug in the supernatant is measured . DSC is an analytical technique in which heat is required to determine the nature of the lipid particles. It is a fast and accurate method for establishing the degree of crystallinity of lipids based on the enthalpy of the lipid. The major disadvantage of DSC is that it is a destructive technique. The non-destructive method which is used to determine the crystallinity of the lipid and to analyze the crystal structure of SLN and NLC is powder X-ray diffractometry (PXRD)  or reversible (flocculation) phase separation. Gelling of the formulation can occur during storage. Surfactants are used to overcome the aggregation and gelling of formulation which stabilizes NLC suspension by electrostatic repulsion. Cationic or anionic surfactants can increase zeta potential value, and non-ionic surfactants can act as steric stabilizers  homogenous matrix model, (ii) drug enriched shell-core shell model, and (iii) drug enriched core-core shell model -coated SLNs. A fast release profile of doxorubicin was observed at pH 4.7 as compared to pH 7.4. The enhanced rate of drug release at low pH may be due to the decreased electrostatic attractions among the negatively charged lipid core and the positively charged doxorubicin  is the cationic surfactant that can be used at 1 mg/ml without affecting cell viability. But there are some reports which showed that the cationic surfactants affect the integrity of the cell membrane (Xue et al., No DNA damage in A549 cells has been reported by the negatively charged SLNs. The study reported that there was no DNA fractionation in gel electrophoresis (Dolatabadi et al., Hemolysis assay is performed to determine the damage of red blood cells when a foreign material or a drug is injected through an intravenous route. Intravenously administered SLNs/NLCs do not damage RBCs. Lakkadwala et al. reported that the SLNs composed of glycerol monostearate and polysorbate 80 have limited hemolysis even at 1 mg/ml dose (Lakkadwala et al., In the past, nanoparticles were commonly administered through the parenteral route; however, now scientists are exploring various other dosage forms containing nanocarriers. Some of the patents are shown in SLNs and NLCs are nanocarriers that provide benefits in the administration and delivery of bioactive molecules. SLNs and NLCs have been reported as a good option for targeted drug delivery. The present review discusses the recent advances in SLNs and NLCs, including technological progress in the delivery of old and new drugs, process of preparing the same, and their characterization methods. SLNs and NLCs as drug carriers offer benefits in the administration and delivery of both natural and synthetic bioactive molecules. Despite the progress in the field of lipid nanoparticle research, there is still a long way to go before achieving the clinical success of lipid nanoparticle formulations. Though a lot of research and studies are done on the fabrication, storage, and toxicity of the SLNs and NLCs, still some of the problems persist. The scale-up issues, long-term stability issues upon storage, and toxicity are the areas of concern in the development of lipid nanoparticles. The science of SLNs and NLCs is currently among the most appealing areas of research. A lot of research in this field in the last 5 years has already led to the filling of <2,000 patents and completion of few clinical trials across the world. Thus, nanotechnology is expected to introduce new vistas in biomedical science utilizing the advantage of its small size.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In human patients with hypertension, existing therapeutic treatments show a low successful rate to control blood pressure. This is mainly because cardiovascular problems are closely associated with other physiological parameters, including metabolic complications. Indeed, metabolic syndrome, a world spreading health concern, includes metabolic disorders, such as obesity, hyperinsulinemia, insulin resistance, and diabetes, as well as cardiovascular problems including stroke and hypertension. Therefore, the metabolic and cardiovascular systems are reciprocally associated with each other, and impairment in one system can directly affect pathophysiological development on the other side.Needless to say, understanding of where and how reciprocal interaction between the metabolic and cardiovascular systems occurs is critical to develop better treatment for metabolic syndrome. In this regard, accumulating investigations have pointed a role for the central nervous system (CNS) in mediating functional crosstalk between the metabolic and cardiovascular signaling molecules, and further an implication of the CNS mechanisms in normal cardio-metabolic homeostasis as well as in the development of the metabolic syndrome. A focus of the proposed Research Topic entitled “Crosstalk between the metabolic and cardiovascular systems in the brain” was to cover a broad spectrum of biomedical research within the CNS, from molecular level to local and regional networks, involved in the cardio-metabolic homeostasis, and this Research Topic consists of two original research articles and four reviews.Mohsin et al. in this Research Topic addressed this question using the postmortem brain samples from normotensive and hypertensive humans. What they found using an immunohistochemical approaches is that the expression of PPR in both the PVN and RVLM was (1) exclusively observed only in neuronal populations; (2) increased with hypertension; and (3) positively correlated with age and systolic blood pressure. These molecular and anatomical findings strongly suggest an active involvement of the brain PRR mechanisms in the development of pathophysiological cardiovascular conditions, such as hypertension, in humans.A key feature of essential hypertension is neurohumoral dysfunction, characterized by elevations in sympathetic outflow and hormonal imbalance. For example, a chronic overactivation of the renin-angiotensin system (RAS), characterized by elevations of angiotensin-II (Ang-II) in circulation, drives hypertension development. Importantly, the brain establishes intrinsic RAS system and an overactivation of the brain RAS system is also strongly implicated in the development of hypertension. Accumulated evidence have suggested that a local production of brain Ang-II can be initiated by the (pro)renin receptor (PRR) that is abundantly present in multiple cardiometabolic brain regions, including the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM). However, the molecular and clinical evidence of the PRR in these brain nuclei in relation to cardiovascular diseases in humans have not been characterized yet. Studies by Zhang et al. reports the molecular mechanism of how VEGF expression level is regulated appropriately after oxygen-glucose deprivation (OGD), a model of stroke. They found that OGD increases tube formation of brain microvascular endothelial cells (BMVECs) by increasing MYB expression, which is a transcriptional factor to regulate angiogenesis. They also found that MYB induces miR-150 expression, which is an inhibitory regulator of VEGF, and miR-150 also suppresses MYB expression as a negative feedback loop in BMVECs after OGD. The data suggests that the feedback loop between MYB and miR-150 may achieve the fine-tuning of VEGF expression and thus affects the pathophysiological process of stroke.One of the most life-threatening complications in metabolic syndrome is stroke. After cerebral ischemia occurs, the brain tries increasing angiogenesis to get enough blood supply to survive. Vascular endothelial growth factor (VEGF) is an important regulator for angiogenesis after stroke. However, an overdose of VEGF expression increases the permeability of the blood-brain barrier, which leads to edema and neuroinflammation. Therefore, an elaborate control of VEGF expression is needed for brain survival. The article by Including these two research articles as mentioned above, all articles presented in this Research Topic represent a central role of the CNS mechanisms in cardio-metabolic physiology, by mediating reciprocal communication between the metabolic and cardiovascular signaling molecules.JJ and CT developed a draft of manuscript. All authors have equally contributed to modify 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This study aimed to develop a risk of psoriatic arthritis (PsA) predictive model for plaque psoriasis patients based on the available features.Patients with plaque psoriasis or PsA were recruited. The characteristics, skin lesions, and nail clinical manifestations of the patients have been collected. The least absolute shrinkage was used to optimize feature selection, and logistic regression analysis was applied to further select features and build a PsA risk predictive model. Calibration, discrimination, and clinical utility of the prediction model were evaluated by using the calibration plot, C-index, the area under the curve (AUC), and decision curve analysis. Internal validation was performed using bootstrapping validation. The model was subjected to external validation with two separate cohorts.Age at onset, duration, nail involvement, erythematous lunula, onychorrhexis, oil drop, and subungual hyperkeratosis were presented as predictors to perform the prediction nomogram. The predictive model showed good calibration and discrimination . The AUC of this prediction model was 0.7578092. Excellent performances of the C-index were reached in the internal validation and external cohort validation . The decision curve indicated good effect of the PsA nomogram in guiding clinical practice.This novel PsA nomogram could assess the risk of PsA in plaque psoriasis patients with good efficiency. Psoriasis is an immune-related chronic inflammatory disease mediated by genetic background, affecting 2%–3% of the population . PsoriasAccumulating research revealed that severe psoriasis severity, nail involvement, structural entheseal lesions, enthesitis, dactylitis, and type 2 diabetes are predictive of the development of PsA in patients with psoriasis –14. ReceIn this study, we establish an effective but simple prediction model for plaque psoriasis patients to predict the risk of PsA by using characteristics and clinical manifestations easily available when patients visit. This prediction model helps in the education and personalized treatment of patients with high-risk PsA and improves psoriasis patients’ overall life quality.Patients were recruited from outpatients of the Department of Dermatology of Xiangya Hospital of Central South University from January 2017 to January 2020, and they came from all over China. External validation cohort 1 was recruited from the Department of Dermatology of Xiangya Hospital of Central South University from September 2020 to September 2021. External validation cohort 2 was recruited from Dalian Dermatosis Hospital, Dalian, China, from November 2020 to December 2020. All the patients completed a detailed investigation, including demographic characteristics, waist-to-hip ratio (WHR), body mass index (BMI), family psoriasis history, smoking history, and alcohol intake. And their skin lesions, the disease severity (psoriasis area and severity index (PASI)) , and naiNail clinical manifestations are classified according to previous researches . Pittinghttps://www.R-project.org). All the factors mentioned above were included in the least absolute shrinkage and selection operator (LASSO) method to reduce the dimensionality of the data . Statistical analysis was performed using the R software   . The C-iTo verify the clinical benefits of the nomogram, that is, the net benefits of plaque psoriasis patients , we condAccumulating research has confirmed the close relationship between psoriatic nail involvement and the development of PsA –31. It hvia univariate logistic analysis, which was similar to the research from Yan’s research  and Hunan Provincial Innovation Foundation for Postgraduate (CX20200120).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Recently, distraction osteogenesis has been suggested as the treatment of choice for overcoming the limitations of conventional orthognathic surgery; (2) Methods: A new custom-manufactured dental-anchored distractor was built and anchored in the first molar and lower canine. It consists of a stainless-steel disjunction screw, adapted and welded to the orthodontic bands through two 1.2 mm diameter connector bars with a universal silver-based and cadmium-free solder; (3) Results: The distractor described can be a useful tool to correct mandibular retrognathia and is better tolerated by patients, especially in severe cases; (4) Conclusions: The dental-anchored distractor increases the anterior mandibular bone segment without affecting the gonial angle or transverse angulation of the segments and avoids posterior mandibular rotation, overcoming the limitations of conventional surgical treatment. Mandibular hypoplasia is the most common growth disorder of the facial skeleton in Western Europe. With a prevalence ranging from 41% to 56%, this condition is commonly associated with an Angle class II occlusion, convex profile, and mandibular deficiency .Mandibular deficiency has a variety of causes, ranging from embryogenesis to various postnatal causes. This condition can occur isolated or in association with congenital malformation syndromes and, depending on its severity, can require orthodontic-surgical-orthognathic treatment .Several studies have reported that certain malocclusions, including skeletal Class II, are associated with decreased masticatory efficiency, abnormal speech, pain, and decreased social interaction . BernabéThe surgical and orthodontic treatment of mandibular deficiency progressed significantly in the second half of the twentieth century with the introduction of new techniques and materials. These procedures have the primary goal of restoring dental occlusion, masticatory function, respiratory function, and harmony in patients with class II skeletal malformations ,6.For the correction of this deformity, the most frequent treatment encompasses a conventional orthodontic-surgical-orthognathic protocol which is divided into four stages. The first is the presurgical orthodontic phase. This step is crucial as it is set to eliminate tooth compensation, harmonize the dental arches, and place the teeth in a stable position regarding the bone bases. This is followed by the surgical phase comprised of a bilateral sagittal split osteotomy (BSSO) which is the most commonly performed technique . The post-surgical stage is a combination of recovery and orthodontic refinements. The final stage is an optional surgical intervention to remove the osteosynthesis plates.The surgery itself is performed under general anesthesia and usually requires four to six weeks of rigid or non-rigid maxillomandibular fixation. As for the post-surgical orthodontic phase, it takes around six months on average. During this period, bone tissue is consolidated and the dental occlusion is adjusted in an attempt to prevent or camouflage small skeletal relapse.Although this protocol is very commonplace, it is not exempt of risk or handicaps. This intervention will generally increase the overall treatment time. As mandibular premolar extractions are usually required in order to allow for dental compensation correction, the surgery is only recommended to be performed on adult patients . It also presents itself with a high relapse rate and is an expensive and temporarily incapacitating procedure ,8. To ovThe American Association of Oral and Maxillofacial Surgeons and other researchers have reported several situations for which distraction osteogenesis should the chosen procedure for mandibular elongation. These include hemifacial microsomia ; mandibular body segmental defects due to trauma or tumor entity; class II syndrome caused by mandibular position (retrognathia) or dimension insufficiency (brachygnathia); micrognathia caused by trauma and temporomandibular joint ankylosis; vertical alveolar distraction for occlusal plane correction and deficiencies in the position and dimension of the alveolar ridges for dental implant rehabilitation; and for mandibular elongation in obstructive apnea syndrome ,14,15,16p = 0.004), and the authors’ findings showed that distraction osteogenesis significantly reduced the incidence of neurosensory disturbance of the inferior alveolar ramus after lengthening of the retrognathic mandible when compared to BBSO. However, these findings could not be confirmed in other studies. Akkerman et al. [Several authors have attempted to compare BSSO and DO procedures. However, the reported results were contradictory. Al-Moraissi et al.  conducten et al.  conducten et al. ,18.The available experimental and clinical studies mostly concern external distractors. Despite their biomechanical advantages, external distractors have more side effects from the patients’ point of view. As it is more disabling, psychosocial problems can arise due to the distractor’s visibility and volume. There is also perceptible scarring on the face. The disadvantages do not end there, as there is instability in distractor fixation and a risk of dental and/or nerve injury ; edema is generally present, and the wounds are propitious to localized infections ,21,22,23All of these limitations often resulted in the rejection of the external distractors, requiring the development of alternative mechanics. The intraoral distractors that were nothing more than miniaturizations of existing external devices and/or adaptations of orthodontic devices for maxillary disjunction.McCarthy et al.  in 1992 Regarding dental-anchored distractors, Guerrero used an intraoral distractor to correct mandibular deformities for the first time in 1990, using a modified Hyrax-type appliance cemented to the first premolars and lower molars . RazdolkThe aim of this study is to describe a new custom-manufactured dental-anchored distractor anchored in the first molar and lower canine to perform the sagittal distraction of the mandible as parallel to the occlusal plane as possible.A new custom-manufactured dental-anchored distractor design was elaborated and anchored in the firs molar and lower canine. It consists of a stainless-steel disjunction screw, adapted, and welded to the orthodontic bands through two 1.2 mm diameter connector bars, with universal silver-based and cadmium-free solder, 0.1 mm in diameter . The mecSurgically, the cortectomy is performed between the lower premolars, with slight deviation to preserve the continuity of the inferior alveolar neurovascular bundle.A 21-year-old female presented a skeletal and angle Class II malocclusion, a deviation from the dental midline, and a crowding in the lower arch. ®2 Dentaurum, Turnstrabe 31, Ispringen, Germany) for six months in order to provide enough interdental space to perform the osteotomies without damaging the adjacent teeth. A dental-anchored distractor was placed and the surgery was performed under general anesthesia with nasoendotracheal intubation . The distractors anchored to the teeth and parallel to the occlusal plane allow for a significant increase of the anterior bone segment without any side effects at the gonial angle or alteration of the transverse angulation of the bone segments . TherefoDuring the active period of distraction (14 days), a mechanical force is applied to the soft callus, preventing fracture healing and creating a unique and highly dynamic microenvironment. The soft tissues, such as the epidermis, dermis, blood vessels, tendons, muscles, and nerves, gradually follow bone growth as a result of the tension forces applied to the bone segments  24,27,2,227,28. Due to the enormous potential of distraction osteogenesis in the treatment of dentofacial deformities, the interest and use of this technique in orthodontics and maxillofacial surgery has grown significantly in recent years. Its late appearance in orthopedics can be explained in part by the anatomical characteristics of the craniofacial region, which make distraction devices difficult to apply. Indeed, the morphology of the bones of the facial mass is more complex, the scars are less tolerable than in other parts of the body, and conventional maxillofacial surgery techniques allowed for the resolution of a large portion of the severe facial deformations.The main interest of distraction osteogenesis lies in its regenerative nature. The gradual and controlled elongation that allows tissue regeneration and repair occurs not only in the bone skeleton but also in soft tissue associated with it including the muscles, subcutaneous cellular tissue, and skin. This feature is particularly important in the treatment of dento-skeletal deformities that require mandibular advancement and in determining the choice of distraction osteogenesis technique over conventional orthognathic surgery, as well as substantially reducing the risk of relapse caused by strong soft tissue tensions ,29,30,31Dental-anchored distractors are only used intraorally and are bonded to the teeth. Despite having significant advantages, such as having little psychosocial impact on patients, reduced dimensions, no risk of infection, being less invasive and requiring no surgical intervention in placement and removal, and having less morbidity and greater stability in the anchorage, they have been poorly studied for use in sagittal dentoskeletal deformities and have been primarily used to treat transverse jaw deformities ,34,35. VThe use of a dental-anchored distractor allows its placement and removal without demanding surgery. The osteogenic distraction using a dental-anchored distractor is efficient in the sagittal lengthening of the jaw. Therefore, this procedure represents a new orthodontic surgical treatment approach alternative to the mandibular bilateral sagittal split osteotomy and should be considered as a treatment option for mandibular hypoplasia.