Early diagnosis of oral cancer is critical to improve the survival rate of patients. The current strategies for screening of patients for oral premalignant and malignant lesions unfortunately miss a significant number of involved patients. Optical coherence tomography (OCT) is an optical imaging modality that has been widely investigated in the field of oncology for identification of cancerous entities. Since the interpretation of OCT images requires professional training and OCT images contain information that cannot be inferred visually, artificial intelligence (AI) with trained algorithms has the ability to quantify visually undetectable variations, thus overcoming the barriers that have postponed the involvement of OCT in the process of screening of oral neoplastic lesions. This literature review aimed to highlight the features of precancerous and cancerous oral lesions on OCT images and specify how AI can assist in screening and diagnosis of such pathologies. Medical imaging is an inseparable part of medical diagnosis and plays a pivotal role in cancer screening and follow-up of treatments. In the specific field of oncology, imaging provides valuable anatomical and functional information that can preciously improve the results of screening, diagnosis, treatment, and follow-up . ComputeEarly diagnosis of tumoral changes not only ensures appropriate timing for surgical intervention and subsequent treatment and increases the survival rate but also decreases postsurgical morbidity, especially in invasive and malignant tumors, because less tissues are involved. Definite cancer diagnosis relies on histopathological assessment that requires tissue preparation and is time-consuming. Moreover, in large tumors, several samples from different sites need to be excised. Besides, in the process of surgical removal of a tumor, surgeons need to examine the excised margins several times to ensure leaving clear and tumor-free margins. In such cases, immediate and precise histopathological examination may not be practically possible . ArtificApproximately 300,000 new cases of oral cancer are diagnosed annually worldwide which are responsible for over 145,000 deaths per year. Oral cancer ranks the sixth most common cancer worldwide, with an increasing incidence rate but constant survival rate during the past decades because of delayed detection and reliance on traditional screening methods. The importance of early detection of oral cancer is further understood when comparing the 5-year survival rate of 80–90% in case of early diagnosis and treatment with 30% rate in cases diagnosed in advanced stages , 7. Oralμm and 17–22 μm, respectively). An 8 μm axial resolution and a 2 μm axial and lateral resolution are reported as state of the art. OCT is fast, repeatable, and well tolerated by patients [Optical coherence tomography (OCT) is a noninvasive real-time imaging modality that delivers three-dimensional (3D) high-resolution microscale images )) AND  OR (machine learning) OR (deep learning) OR ). The inclusion criteria included studies that investigated oral precancerous or cancerous lesions on OCT images by any AI algorithm. Relevant articles were initially included based on their title and abstract and subsequently by their full text. The reference lists of relevant articles were also explored to find possibly missed articles.A comprehensive search was conducted in PubMed for articles published in English up to August 28, 2021, using this query:  OR (OCT)) AND  is a spectrum of light with deepest penetration into biological tissues  . The beax-axis and z-axis to create 2D views. C-scans or enface images are also 2D views obtained from the x-axis and y-axis. Volumetric data are reconstructed by 2D scanning of the layers [OCT consists of a broadband light source, an imaging system, a transducer, a data processor, and a computer to control the entire scanning process and image visualization . The imae layers –30.The optical characteristics of a sample dictate the optical path and penetration depth of OCT beam, and OCT images reflect the coefficient of transmission information of a sample . The penOCT devices can be time-domain or frequency-domain devices based on their reference arm optics. The frequency-domain devices are of two types as well, spectral OCT and swept source OCT, based on the receiving compartments and output properties. The swept source OCT uses ultrahigh speed  laser beam which enhances the sensitivity of the system, penetration depth, resolution of the system, and scanning rate (1 second or less imaging speed), resulting in a shorter acquisition time , 34–37. OCT can accompany probes and catheters to image internal organs and structures . It shouAlthough OCT is fundamentally a label-free modality, different contrast agents are studied to target specific cells or tissues including magnetic nanoparticles, gold nanoparticles, and encapsulating protein-shell microspheres –44. VessOCT has proven its novel capabilities in some fields of medicine such as ophthalmology and cardiology; however, it has not been widely used in dentistry. OCT has been employed as a valuable tool for assessment of the anterior part of the visual pathway, optic nerve characterization, and visualization of cellular layers of macula . FunctioDifferent sites of the oral cavity and hard-to-reach areas require customized applicable probes. For some pathological lesions, greater depth and a larger field of view may be required for a more comprehensive assessment of the tissues , 57.The first designed OCT device for dental applications was hoped to be used for imaging of gingival margins, periodontal attachments, and pockets . OCT hasOCT does not have a large field of view or high penetration depth, but its microresolution and high soft tissue contrast due to differences in scattering properties make it an ideal nonsurgical modality to spatially differentiate cell layers and tissues. It has been widely used in oncological studies in vivo and in vitro , 73–75. Three-dimensional cell colonies are developed to aid in investigation of tumorigenesis mechanism and drug response with no need for animal models. OCT can monitor such samples periodically and repeatedly. It has been demonstrated that OCT has the ability to detect dead cells based on their scattering properties . OCT is μm in different sites and can be imaged by OCT with 2–3 mm penetration depth and 10–12 μm resolution [Measurement of epithelial thickness on OCT images is valid, reliable, and practicable. The normal epithelial thickness is 75–550 solution , 79, 80.Neoplastic changes are characterized by cells that are abnormal in shape and size and have enlarged nuclei. Such changes at the cellular and subcellular levels change the optical scattering properties of OCT, which enhances their detection. Some important histological indicators of malignancy in the epithelial tissue include expanded dysplastic cells, irregular epithelial stratification accompanied by broadened rete pegs, basal hyperplasia, and elongated papilla core , 81. DysResearchers have tried to find some indicators to differentiate intact, premalignant, and neoplastic tissues in epithelial mucosa, subepithelial tissue, and basement membrane of oral mucosa on OCT images. Thickening of basement membrane is a sign of tumor invasion and can be considered as an indicator of malignant changes. In a previous study, the mean epithelial layer thickness was the highest in microinvasive carcinoma, followed by carcinoma in situ, dysplasia, and benign lesions . AnotherA clear boundary between the epithelium and lamina propria could not be identified on B-mode scans of cancerous lesions . The epiThe epithelial and subepithelial changes following dysplastic transformation result in stronger light scattering and fluctuation of spatial distribution. The mean intensity of spatial reflection is greater in dysplastic oral epithelium in comparison with normal tissue. Moreover, collagen deposition in lamina propria results in a reduction in SD level .There is a distinctive contrast in signal intensity between the epithelium and lamina propria (bright epithelium and brighter lamina propria) in oral premalignant tissues; subsequently, this boundary can be precisely identified . Lee et There are some drawbacks related to the oncological applications of OCT such as limited penetration depth, limited area and volume of scans, demand for higher resolution to visualize more cellular and subcellular details, too much noise, difficult image interpretation, and the training required for image interpretation . InterprAutomatic processing of the features of OCT images not only saves the time of analyzing abundant volume of data but only will digitize the data that could not be interpreted subjectively . MachineArtificial neural networks are machine learning algorithms made of associated working units known as neurons. The neurons are arranged in layers and acquire a value based on the activation frequency. When the neuron layers extend to more than 2–3 layers, it is known as deep learning artificial neural network. Deep learning convolution neural network is a model with multiple neural layers that administrate template-matching of input data with ground truth. Convolution neural network can be trained by continuous introduction of structured data and can upgrade its operation ability . ConvoluDeep learning algorithms have shown promising results in ophthalmology such as macular edema detection, retinal thickness measurement, and retinal layer segmentation , 99–105.A marvelous preponderance of image translation by AI is that AI can quantify variations which could not be even detected by inspection. Specific characteristics of the tissue texture could not be quantified by the naked eye. Moreover, AI is able to integrate multiple data variables including imaging, geographical, clinical, pathological, and electronic health data as well as risk factors, resulting in a more comprehensive and analytical diagnosis .Appending a diagnostic algorithm to the OCT system eliminates the operator training considerations as well as inter- and intraoperator diagnostic errors and nullifies subjectivity in interpretation of images. It can speed up the analysis of large amounts of datasets as well.There are few studies that utilized computational algorithms for normal or cancerous tissue characterization , 85. LeeThe statistics demonstrated that OCT-based diagnosis of malignant and dysplastic oral lesions integrated with AI had comparable results (93–96% sensitivity and 74–49% specificity) to the biopsy. Heidari et al.  deployedA cloud-based platform has been launched for remote machine learning of OCT image analysis that could be employed for analysis of tumor images. Open access to this platform will nourish the algorithms with more diverse data, leading to enhanced performance .High cost and limited availability limit the extensive application of OCT in the clinical setting, leading to less available necessary data to enrich and enhance AI algorithms. Affordable OCT devices not only provide accessibility to this modality but also would supply the image analysis algorithms with more datasets. Since the diagnosis of oral cancer and precancerous lesions, interpretation of OCT images, and development of AI algorithms for automated OCT image interpretation require profound expertise, qualified teams with experts from all related fields are required to collaborate interactively to achieve the desirable results. These requirements decrease the pace of employing AI algorithms in oral cancer screening and diagnosis by OCT images. Further studies are required to analyze and improve the efficiency and accuracy of AI algorithms for detection of cancerous changes before we could use such automated interpretation systems in the clinical setting.AI algorithms have rendered hopeful outcomes in interpretation of OCT images of oral mucosa and discrimination of normal oral epithelium from precancerous and cancerous lesions. Progressive evolution of AI algorithms for interpretation of OCT images (which requires continuous data feed as ground information) paves the way towards automated oral cancer screening by OCT, even though it might be a long road to bring the integration of OCT and AI into the clinical setting. In addition to the need for further studies to provide OCT imaging data for AI algorithms, the existing challenges such as standardization of labeling, validation of automated interpretations, and development of infrastructures for application of AI in oral cancer screening and diagnosis must be addressed to enable the application of AI in OCT for the aforementioned purposes and enhance early detection of oral mucosal cancerous changes with no need for physical presence of experts.


Rice plant architecture and stress tolerance have historically been primary concerns for rice breeders. The “Green Revolution” and super-rice breeding practices have demonstrated that ideal plant architecture can effectively improve both stress tolerance and yield. The synergistic selection and breeding of rice varieties with ideal architecture and stress tolerance can increase and stabilize yield. While rice plant plant architecture and stress tolerance are separately regulated by complicated genetic networks, the molecular mechanisms underlying their relationships and synergism have not yet been explored. In this paper, we review the regulatory mechanism between plant architecture, stress tolerance, and biological defense at the different level to provide a theoretical basis for the genetic network of the synergistic regulation and improvement of multiple traits. Global climate extremes profoundly affect human social and economic behavior, especially agricultural production in fragile ecosystems. In recent years, China’s rice production and food security have been challenged by natural disasters such as cold damage, high temperatures, and drought stress. Therefore, improving the stress tolerance of rice is important for overcoming these issues and ensuring food security.The concept of ideal crop architecture was first proposed by Donald in 1968 . Ideal pSd1 in rice breeding, which is the first variety to greatly increase production by reducing rice plant height and improving lodging resistance. It is also the first time to improve rice resistance by improving the plant type (HTD2 (D88/D14) encodes an esterase that regulates cell growth and organ development through the strigolactone pathway. In rice, it inhibits the meristem and negatively regulate the tiller number, which helps regulate rice plant architecture , double-stranded RNA binding protein (DsRBP), and Heat shock protein (HSP) have been successfully cloned, which has clarified the synergistic regulatory functions of rice plant development, stress tolerance, and biological defense.In recent years, in addition to the studies of PROG1 encodes a C2H2-like zinc-finger protein and plays an important role in the domestication of stolon or slope growth to upright growth in rice. PROG1 from both wild and cultivated rice has transcriptional activation activity, and the loss of PROG1 function in cultivated rice not only improved rice plant architecture but also increased the spike number, significantly increasing yield  contain two functional or catalytic domains and can participate in multiple regulatory pathways , such asolerance . Currentolerance . Of themelopment , while Ozae Cav .. Analyelopment . As we kelopment . The expterature . This prNal11 and OsHSF18 are involved in regulating rice plant type. Nal11 encodes the small molecule heat shock protein HSP40. The disruption of the DNAJ domain in mutant nal11 affects the mRNA splicing pattern and leads to premature termination of translation, which affects agronomic traits such as the tiller, leaf width, and panicle length in rice  caused by climate change poses a serious threat to rice production. The typical high and stable yield of rice is determined by its genotype and external environmental conditions. As a “smart” plant, rice constantly changes its plant type to adapt to different environmental conditions. For example, under high temperature conditions, rice plant reduces transpiration by promoting leaf curling, thereby enhancing resistance ; in coldsd1 in “Dijiaowujian” realized the dwarfing profile of rice plants, which improved the lodging resistance of rice and catalyzed the first “Green Revolution” of rice production. It is easier to transfer good genes from wild rice because it is the ancestor of cultivated rice. Several genes and QTLs related to cold tolerance and drought resistance, such as SRFP1  can overcome pleiotropy among quantitative traits and provide a new source of targets for breeding beneficial traits, while the study of agronomic gene CRR systems will reveal more critical transcriptional regulatory networks, thus providing key information to guide the creation of novel elite alleles in plant breeding . In 2021Rice plant development and stress tolerance are complex agronomic traits controlled by multiple genes. To improve the synergistic regulatory network between plant development and stress tolerance, more genes must be identified. So far, plant breeding has made the leap from manual selection breeding, hybrid breeding to molecular breeding. In future r,esearch on rice production, it would be necessary to investigate the genetic network and signaling regulatory mechanism of rice plant development and stress response and apply them to breeding practice in a short period of time by combining various research methods. This includes QTL localization or Genome-Wide Association Studies (GWAS) to explore genes for superior agronomic traits and resistance genes, and multi-omics analyses such as transcriptomics, proteomics, metabolomics and epigenomics to investigate the regulatory network of plant development and resistance from a comprehensive perspective to achieve gene prediction and accurate breeding . To enabHZ and XL are the main writers of the article, JW participates in the production of the article pictures, and QQ and GZ participate in the correction of the article and provide fund project support. All authors contributed to the article and approved the submitted version.


Heart rate variability (HRV) is a psychophysiological variable that is often used in applied analysis techniques to indicate health status because it provides a window into the intrinsic regulation of the autonomic nervous system. However, HRV data analysis methods are varied and complex, which has led to different approaches to data collection, analysis, and interpretation of results. Our scoping review aimed to explore the diverse use of HRV methods in studies designed to assess health outcomes in outdoor free-living contexts. Four database indexes were searched, which resulted in the identification of 17,505 candidate studies. There were 34 studies and eight systematic reviews that met the inclusion criteria. Just over half of the papers referenced the 1996 task force paper that outlined the standards of measurement and physiological interpretation of HRV data, with even fewer adhering to recommended HRV recording and analysis procedures. Most authors reported an increase in parasympathetic (n = 23) and a decrease in systematic nervous system activity (n = 20). Few studies mentioned methods-related limitations and challenges, despite a wide diversity of recording devices and analysis software used. We conclude our review with five recommendations for future research using HRV methods in outdoor and health-related contexts. The outdoors is a place commonly utilized by adventure seekers and explorers; however, recent evidence suggests there is a relationship between contact with nature and an improvement in health and well-being ,4,5,6,7.In 1996, a joint task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology published standards and recommendations for measurement, analysis, and interpretation of HRV data . The firFollowing the task force recommendations, evidence began to emerge after 1996 showing the health benefits of immersion in outdoor contexts using HRV as a psychophysiological variable. Studies related to Shinrin-yoku (forest bathing)  and greeClinically, HRV analysis is particularly helpful in understanding cardiovascular health ,12,18,19When HRV data are collected in an outdoor field setting, the data can be analyzed and interpreted in different ways based on the methodological approach used see . HoweverA scoping review method was selected to address our purpose and research questions based on the diversity and complexity of HRV data collection techniques for health-related outcomes in outdoor contexts. According to Munn et al., scoping reviews are “useful tools to investigate the design and conduct of research on a particular topic” . They arTwo searches were conducted: the first occurred on 27 October 2018, and the second on 15 May 2022. The second search followed the same protocols and used the exact search string as the first search, and it was completed to update the study before submission for publication. The following indexes were searched: PubMed, Web of Science, EBSCO Platform, and CINAHL Platform. No limits were set during the initial search. However, papers prior to 1996 and those published in any language other than English were removed by the reviewer(s) upon the initial screening. Initial search terms were selected based on a review of relevant/associated papers and were compared against relevant MESH terms. The final derived search string used to obtain studies was created iteratively to ensure that only relevant terms were used, and other keywords excluded  to ensure irrelevant studies were not included. The final search string used in the initial PubMed index search appears in ; it was Date range: Studies published from 1996 to 15 May 2022 (date of our last search) to reflect the year when HRV standards were first published (1996) ;Empirical studies: Systematic reviews and original studies involving primary data collection related to the three variables ;Outdoor environment: The setting was in a wilderness, outdoor, or natural environment; contact with nature was the primary context for the intervention or program. The immersive experience had no minimum or maximum limit of duration;HRV methods: Methods involved HRV devices, data collection, and analysis techniques;Health outcomes: Primary outcomes were associated with therapeutic or holistic health-related benefits; these outcomes were derived from HRV data and analysis.The initial eligibility assessment focused on screening titles and abstracts and removing duplicates; a single researcher completed it. Following full-text extraction of the remaining studies, they were assessed by the researcher for inclusion and then screened by a second author until consensus was achieved on the included studies. A final citation chaining process identified relevant papers from the reference lists of the included systematic reviews. The screening and selection process used five inclusion criteria:A single researcher performed the initial data extraction and charting. The following extraction fields were obtained from each paper: title, author(s), date of publication, type of study design, population size, outdoor context, intervention, control/comparison, HRV data collection methods and analysis, setting, challenges, limitations, ethical considerations, and risk of bias. Extracted data were charted in a Microsoft Excel spreadsheet to provide a visual map of the extracted fields for all the included studies.To address RQ1, data analysis involved using summary counts and percentages for method characteristics from extraction fields containing quantitative data  or data that could be quantified . To address RQ2, data were analyzed and summarized quantitatively (counts and percentages) for the characteristics of HRV analysis procedures and outcome variables in terms of time domain or frequency domain analysis See . OutcomeInitial search results identified 17,505 records. Search records were imported using a reference manager (Zotero); 13,199 records remained after removing 4716 duplicates. The flow diagram of the screening process is portrayed in The descriptive characteristics of HRV studies in this review are summarized in TM 3 [The primary HRV device used was the Activetracer (AC301A), and twelve studies reported the use of this device ,43,44,55TM 3 ,53, ActiTM 3 ,51, and TM 3 ,49. TherAlmost every study used other physiological or psychological measures in their study, however five studies did not report the use of any other measures ,45,46,57Out of the 34 studies, 14 different types of software were used for HRV analysis. The most prominent software used was the MemCalc/Win, GMS, with thirteen studies using it ,44,54,57Only 27 of the 34 empirical studies reported health-related HRV outcomes, and Four studies used HRV methods in a high-altitude hypoxic setting ,57,59,60Eight systematic reviews were included in this review, and five focused on the health benefits of forests and outdoor environments ,66,67,68Our scoping review aimed to explore and compare the diverse methodological approaches used by empirical studies focusing on health-related impacts in outdoor contexts that used HRV-derived variables and analysis. This review was designed to address the scarcity of knowledge about the best practices for HRV analysis in immersive outdoor natural environments. The following three sections present a discussion related to each of the three RQs: (1) characteristics of studies using HRV methods; (2) types of HRV analysis and outcome measures; and (3) challenges and limitations reported by study authors.Studies using HRV methods to identify the health benefits in outdoor contexts are increasing since over 80% of the studies included in this review have been published within the last ten years. This was not unanticipated, given the technological advancements resulting in the emergence of many portable/wearable devices that are available for relatively convenient and non-invasive HRV data collection . In addiIn terms of study designs, there were no Randomized Control Trial (RCT) studies, and most studies followed a within-subject counter-balanced design with small sample sizes, often with less than twenty participants. The small sample size was an additional limitation, and the authors of those studies identified this in eight studies in our review. Future directions for studies investigating HRV variables in an outdoor context should seek larger sample sizes and more robust experimental designs such as Randomized Control Trials (RCTs). Additionally, future studies should explore and compare different design features such as recording before and after vs. during the intervention, optimal length of recording time, and the impact of a pre-intervention relaxation period.TM 3 [guidelines for reporting articles on psychiatry and heart rate variability (GRAPH), with the goal of standardizing the reporting of HRV research to develop a reliable psychiatric biomarker that improves the interpretation and reproducibility of HRV studies in psychiatry [The HRV devices used were varied; however, most studies (38.2%) used the Activetracer (AC301A). This device is manufactured in Japan and was primarily used in the studies related to forest bathing. Interestingly, only four studies referenced the reliability and validity of the device used and these included the Actiheart , Zephyr TM 3 , Polar ETM 3 , and HeaTM 3 . In addiTM 3 , and farTM 3 ,72,73. TTM 3 . The Quiychiatry ,72,73.The intervention exposure times varied tremendously from six minutes to 80 days; however, most studies had intervention or exposure times of 15–60 min. Surprisingly, most studies did not describe a relaxation (baseline) period before starting the HRV recording. It is known that exercise can affect HRV acutely and hours after exercise, and by not allowing for a relaxation period it is hard to determine whether the HRV results were influenced by a previous physiological or psychological state . The HRVAs the 1996 task force recommended, most studies used an analysis epoch of one minute or five minutes in length for analysis . HoweverThe methodological challenges reported in these studies included: HRV sensor errors, exercise affecting HRV data, psychological factors, and air pollution. HRV sensor errors occurred in two studies, and in these studies the leads connecting the portable HRV device became disconnected. Exercise affects cardiovascular activity, and an increase in physical activity increases heart rate. This increase in heart rate from activities as simple as walking in a forest environment also impacts HRV . Given tBiophilia is a theory that suggests humans have an inherent curiosity to seek connections with nature and other forms of life, and contrarily, biophobia is simply a fear of nature resulting in an aversion from it [One psychological factor that could influence HRV data is related to the concepts or psychological states of biophilia and biophobia.  from it . Several from it ,64,76. A from it .There were 10 distinct limitations identified by the authors of most of the included studies; however, no limitations were identified in 12 of the studies. Many studies in our review contained small sample sizes, and this precluded sub-analysis by age and gender . The sam(1)Researchers should follow the standards of HRV analysis outlined in the 1996 task force paper and should also refer to more recent standards such as those provided by Sassi et al., 2015, Quintana et al., 2016, and Shaffer et al., 2017. To our knowledge, these are the most current standards on HRV collection, analysis, and interpretation. To increase the validity and replicability of future results, new studies should adhere to these guidelines.(2)It is also recommended that studies increase their methodological rigor by increasing sample size and implementing stronger study designs such as randomized control trials with more varied populations (other than university students).(3)Validity and reliability confirmation need to be completed and reported on the devices being used for HRV recordings as well as the analysis software interpreting the collected data. There were many devices and analysis software used, and very few studies reporting or referencing validation of their use.(4)Many studies identified the biophilia/biophobia theory yet had no psychological evaluation or assessment in place to account for it. More research should be devoted to investigating this theory and the possible impacts it can have on results, considering its potential influence on stress and relaxation states. It should also be noted that there were a wide range of self-report psychological and confirmatory scales used, and the psychometric properties of these scales should be reported.(5)Finally, there is a limited understanding of the effect of exercise on HRV while in free-living conditions such as being in nature. Given the outdoor context and intervention  in most of these studies, a greater understanding is required to identify the interaction effect between the outdoor environment and varying levels of physical activity and how they interact to impact HRV.Our scoping review identified a wide variety of methodological approaches using HRV collection and analysis in outdoor contexts. The findings summarized the characteristics of HRV studies used in outdoor contexts, the methods used for HRV collection and analysis, and the limitations and challenges identified by the authors in the included studies. From our scoping review, five recommendations were created by our research team for consideration in future research study designs using HRV methods in outdoor and health-related contexts: HRV methods do hold promise in the future for determining health-related outcomes in outdoor free-living contexts, but caution is warranted in reviewing current study claims.


Stroke is one of the leading causes of disability worldwide. Early diagnosis and treatment of stroke are important for better clinical outcome. Rapid and accurate diagnosis of stroke subtypes is critical. This review discusses the advantages and disadvantages of the current diagnostic and assessment techniques used in clinical practice, particularly for diagnosing acute ischemic stroke. Alternative techniques for rapid detection of stroke utilizing blood based biomarkers and novel portable devices employing imaging methods such as volumetric impedance phase-shift spectroscopy, microwave tomography and Doppler ultrasound are also discussed. Current therapeutic approaches for treating acute ischemic stroke using thrombolytic drugs and endovascular thrombectomy are discussed, with a focus on devices and approaches recently developed to treat large cranial vessel occlusions. Stroke is the second largest cause of mortality worldwide, only surpassed by ischemic heart disease . AccordiOcclusions of internal carotid artery (ICA), M1 or M2 segment of the middle cerebral artery (MCA), or vertebro basilar arteries called large vessel occlusions (LVO) represent 11%-29% of AIS , 4. BraiThe most common stroke symptoms people present with are facial numbness and weakness, visual impairment, weakness of the upper or lower limbs on one side of the body, impaired balance, nausea, abrupt severe headache of an unknown cause and speech impairment . These tFor rapid diagnosis and triage, various field triage stroke scales have been developed. These scores have been validated for clinical use and allow rapid diagnosis of patients suspected to be suffering from acute ischemic stroke . Based oThe current gold-standard approach to assessment of stroke requires brain and neurovascular imaging, in addition to the clinical assessment of stroke severity using National Institute of Health Stroke Scale (NIHSS). Advantages and disadvantages of all imaging techniques used for assessment of stroke are summarized in Non-contrast computed tomography (NCCT) of the head is fast, widely available, and cost effective. It is used as the primary imaging in patients with suspected AIS to eliminate acute hemorrhage . NCCT imCT angiography (CTA) and CT perfusion (CTP) are routinely used for diagnosis and selecting patients for endovascular therapy (EVT) . MultimoSingle phase CT angiography (sCTA) is useful for the rapid evaluation of LVO, and is also useful for evaluation of collateral circulation. Good collaterals on sCTA correlate with reduced ischemic core growth, although no correlation between collateral status and clinical outcome was observed . NCCT isMultiphase CTA (mCTA) gives three time-resolved gray-scale images of the cerebral vasculature, with 8 and 16 s delays. Thus, the reader needs to link these images together for visualization and interpretation, which necessitates a high degree of expertise. mCTA provides consistent evaluation of pial artery filling in AIS imaging and has good interrater reliability as well as predicts clinical outcome with remarkable accuracy . Color-cCT perfusion (CTP) provides comparable diagnosis and prognosis capabilities to mCTA and is often preferred as the color maps used are easier to interpret . CTP alsCTP assesses blood flow at the capillary tissue level using data from repeated cerebral CT scans. Perfusion parameters utilized in identifying core and penumbra comprise cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and time to maximum (Tmax). Although there is no clear consensus in the literature on the exact parameters or thresholds to be used for characterizing core and penumbra, brain tissue with severely reduced CBV or CBF predicts infarcted core, and regions with prolongation of the MTT or its derivatives, the TTP or Tmax, determine the penumbra , 33.Digital subtraction angiography (DSA) is an old technology that requires invasive action and is not widely used today. In DSA pre-contrast images taken on fluoroscope are subtracted from the contrast images for better visualization of vasculature. DSA can also be used to determine occlusion location and evaluate collateral circulation, most commonly during EVT. DSA is more invasive than CTA and the interrater reliability of CTA-determined occlusion type has been reported to be better than DSA-determined occlusion type, so CTA is more widely used .Magnetic resonance imaging (MRI) has greater sensitivity than any other imaging techniques for AIS detection. However, it is not as widely available as other imaging modalities and it is mostly utilized as follow-up imaging . Prompt Diffusion MRI or diffusion-weighted imaging (DWI) is the gold standard for the imaging diagnosis of AIS, detecting it as early as 30 min after the beginning of symptoms. In DWI, diffusion of protons in the tissue is shown and tissues with delayed or restricted proton movement with a low apparent diffusion coefficient (ADC) appear bright. By using intravoxel incoherent motion imaging (IVIM), DWI can be employed to obtain the perfusion fraction, which is related to the cerebral blood volume (CBV) . While NSusceptibility-weighted imaging (SWI), fluid attenuated inversion recovery (FLAIR) and T2-weighted MRI, can be utilized for accurate identification of hemorrhage and other stroke mimics , 42. MR Magnetic resonance angiography (MRA) can be used as an alternative tool to CTA to assess brain perfusion, although it is not as widely used as CTA. Both sCTA and MRA permit quick detection of large vessel occlusion (LVO) . OverallThe 2018 Guidelines for Management of Acute Ischemic Stroke from the American Heart Association/ American Stroke Association now recommends that CTP, diffusion-weighted imaging (DWI)- MRI, and/or MRI perfusion (MRP) be included as part of a standard imaging evaluation for patients within 6–24 h of symptom onset . DiagnosAlthough there is some agreement on the parameters that define favorable and unfavorable perfusion profiles, the selection criteria for intervention continues to be ambiguous. CTP and MR perfusion characteristics denote complex metabolic changes during AIS in a simplistic manner. Thus understanding of how these characteristics are associated with patient outcome is required . For exaCT and MRI, while widely employed for diagnosing AIS, are not available in every healthcare facility. There is considerable ongoing research and development for novel, practical, portable, economical and complementary instruments to the currently used diagnostic techniques in acute care units. A variety of novel portable devices are being developed for diagnosis of stroke with good sensitivity and specificity. Diagnostic devices in development employ alternative imaging methods such as volumetric impedance phase-shift spectroscopy, microwave tomography and Doppler ultrasound and are in various stages of prototype development and testing , 50, 51.Strokefinder MD100 developed by Medfield Diagnostics AB  is a microwave based device that fits on a stretcher and can identify intracranial hemorrhage with high sensitivity (100%) and specificity (75%) , 52. MicTranscranial Doppler ultrasound based technology measures cerebral blood flow velocity. The Lucid™ Robotic System using transcranial Doppler ultrasound  has been reported to differentiate patients with LVOs with high sensitivity (100%) and specificity (86%) from healthy controls . It alsoThe SONAS® , also utilizes transcranial ultrasound to detect LVOs. SONAS® helps in unilateral and bilateral assessment of cerebral blood perfusion . HoweverTM) based Visor® device by Cerebrotech , showed high sensitivity (93%) and specificity (92%) and was able to differentiate severe stroke from minor strokes caused by LVO in a study with 248 subjects  is also an impedance based imaging technique that is portable, safe, and economical . EIT creEIT of brain is being studied for its potential to identify the location of epileptic foci , and alsA panel of accurate blood biomarkers could be an important additional diagnostic tool –73. The During stroke, blood brain barrier dysfunction reduces the compartmentation between the fluids of the brain and periphery, thereby allowing movement of brain-derived factors into the blood that would normally be prevented. Necrosis in the infarct core can result in the release of glial structural proteins in to the blood stream at considerably higher than normal levels. Glial proteins such as glial fibrillary acidic protein (GFAP), and S100β, which are both structural astrocytic proteins, are two very promising blood biomarkers that could be indicative of stroke in patients presenting with symptoms of acute neurological dysfunction. Furthermore, evidence suggests that levels of GFAP and S100β could distinguish between AIS and brain hemorrhage. GFAP is considered the best candidate to date for differentiating hemorrhagic and ischemic stroke . SeveralFinally, several studies and meta-analyses have described other possible biomarkers for stroke diagnosis, including matrix metalloproteinase 9 (MMP-9) , 84, BraTo date, the only therapeutic approaches approved for treatment of AIS are the administration of a thrombolytic therapy and the mechanical removal of the occlusive clot through endovascular mechanical thrombectomy (MT) –95.Blood clot formation is a physiological response to vessel injury starting with formation of a loose platelet plug, followed by activation of the coagulation cascade that results in the formation of a fibrin mesh that strengthens the clot and allows the injured vessel to be repaired. Clot dissolution then naturally occurs over the next several days as the wounded blood vessel wall heals, through the activation of plasminogen to plasmin, a serine protease that is a powerful fibrinolytic. Tissue plasminogen activator (tPA) is responsible for the cleavage of plasminogen to plasmin, which is slowly released by endothelial cells at the site of injury.The first record of the use of molecules naturally implicated in the normal clot dissolution to treat acute ischemic stroke occurred in 1958 . Three pvia the groin, threading it through the heart to reach the cerebral vessel occluded by the blood clot and mechanically removing it, allowing the restoration of the natural blood flow to the brain. Five clinical trials in 2015 demonstrated the effectiveness of mechanical thrombectomy as an AIS treatment, and it is fast becoming the gold standard. However, initial attempts to mechanically manipulate the clot using microcatheters and percutaneous balloon angioplasty devices highlighted the risk of distal embolization .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 Food and Agriculture Organization of the United Nations (FAO) in 2018 provided a definition of “food systems” highlighting that they “encompass the entire range of actors and their interlinked value-adding activities involved in the production, aggregation, processing, distribution, consumption, and disposal of food products that originate from agriculture, forestry or fisheries, and food industries, and the broader economic, societal and natural environments in which they are embedded”. The COVID-19 pandemic has imposed a stop that has caused the population to rethink their lifestyles, production, and consumption, also accelerating the transformation progress necessary in light of the objectives of the 2030 Agenda for Sustainable Development—adopted by all United Nations Member States in 2015—which provides a shared blueprint for the peace and prosperity of people and the planet, now and in the future. Actual food systems account for nearly one-third of global GHG emissions; consume large amounts of natural resources; result in biodiversity loss and negative health impacts (due to both under- and over-nutrition); and do not allow fair economic returns and livelihoods for all actors, in particular, for primary producers. With regard to these observations, innovations should aim to develop the following food systems:Inclusive: ensuring economic and social inclusion for all food system actors, especially smallholders, women, and youth;Sustainable: minimizing negative environmental impacts, conserving scarce natural resources, and strengthening resiliency against future shocks;Efficient: producing adequate quantities of food for global needs while minimizing post-harvest loss and consumer waste;Nutritious and healthy: enabling the consumption of a diverse range of healthy, nutritious, and safe foods.These are ambitious goals that will require multidisciplinary effort—from engineering to life sciences, biotechnology, medical sciences, social sciences, and economic sciences. New technologies and scientific discoveries are the solution to the increasing demand for sufficient, safe, healthy, and sustainable foods influenced by the increased public awareness of their importance. This Special Issue is composed of 11 papers.Jing Xu and his collaborators  focused Giordano Stella and co-authors  discusseMaiorano et al.  addresse2). Titanium dioxide is commonly used in food, cosmetic, and pharmaceutical industries as a white pigment due to its extraordinary light scattering properties and high refractive index. However, as evidenced by recent reports, there are overriding concerns about the safety of nanoparticles of TiO2. As an alternative to TiO2, Mg-Al layered double hydroxide (LDH) and their composite containing casein and carboxymethyl cellulose (CMC) were synthesized using wet chemistry and compared with currently used materials (food grade TiO2 (E171), rice starch, and silicon dioxide (E551)) for its potential application as a white pigment. These particles were characterized for their size and shape (Transmission Electron Microscopy), crystallographic structure (X-ray Diffraction), agglomeration behavior and surface charge (Dynamic Light Scattering), surface chemistry (Fourier Transform Infrared Spectroscopy), transmittance (UV–VIS spectroscopy), masking power, and cytotoxicity. their results showed the formation of typical layered double hydroxide with flower-like morphology which was restructured into pseudo-spheres after casein intercalation. Transmittance measurement showed that LDH composites had better performance than pristine LDH, and the aqueous suspension was heat and pH-resistant. While its masking power was not on a par with E171, the composite of LDH was superior to current alternatives such as rice starch and E551. Sustainability score obtained by MATLAB® based comparison for price, safety, and performance showed that LDH composite was better than any of the compared materials, highlighting its potential as a white pigment for applications in food.Estee Ngew and her research team  studied Caterina Palocci and collaborators  presente−1) appeared as the main compound, although relevant amounts of an isomer of the 3-hydroxytyrosol glucoside (4.3 μg mL−1) and quinic acid (4.1 μg mL−1) were also detected. LOMW was able to greatly inhibit ABTS radical , displaying, in the aqueous medium, an increase in its scavenger properties by almost one order of magnitude compared to the organic one. Lyophilized olive mill wastewaters reactive species and tara gum chains were involved in an eco-friendly grafting reaction to synthesize a polymeric conjugate that was characterized by spectroscopic, calorimetric, and toxicity studies. In vitro acute oral toxicity was tested against 3T3 fibroblasts and Caco-2 cells, confirming that the polymers do not have any effect on cell viability at the dietary use concentrations. Antioxidant properties of the polymeric conjugate were also evaluated, suggesting its employment as a thickening agent, in the preparation of pear puree-based pudding. High performance of consistency and relevant antioxidant features over time (28 days) were detected in the milk-based foodstuff, in comparison with its non-functional counterparts, confirming lyophilized olive mill wastewaters as an attractive source to achieve high-performing functional foods.Gianfranco Spizzirri  and its Vincenzo Russo et al.  studied Tao et al.  wrote anSimone Mancini with the research team  discusseClodoveo and her collaborators  presenteThe last paper of this collection has been written by Clodoveo et al. . and is As summarized above, the collection of 11 articles that make up this Special Issue devoted to “Innovations in the Food System: Exploring the Future of Food” underscores the progress that has been made toward a better understanding of the trends in the global food industry, oriented to a sustainable production assisted by economic and technological tools. surely these first evidences will be developed and enriched in the near future and additional studies are expected to cover a broad range of approaches to the design of innovation in the Food systems.


E. coli and S. cerevisiae, and many synthetic circuits have been developed and poised to transform those cells into productive tools in the biotechnology and medicine industry , representing the application of synthetic cellular/genetic circuits in vertebrate systems. Another work combined GBM cell culture with biocompatible elastic materials to build a synthetic encephaloid model for brain stiffness mimicking and drug screening, representing the contribution of abiotic materials to the engineering and modeling of complex biological systems . Beyond this topic, other researchers may pick up these synthetic blocks and make their own synthetic models for different purposes and applications.In the research topic, Wang Zhu’s laboratory reviewed their progress in using multi-target CRISPR/Cas9 technology to generate animal models of prostatitis and prostate cancer (PCa), and employing synthetic circuits to genetically trace the cell-of-origin of PCa (In general, engineering of synthetic biology in vertebrate systems remains challenging, including multiple levels of regulation, fluid cell fate determination, and complex multicellular interactions. Nevertheless, the current elements of synthetic biology have formed a foundation or library for studying the spatiotemporal dynamics of diseases and for developing relevant diagnostic or therapeutic approaches, and we are looking forward to much more significant progress in their clinical and preclinical translational applications.


Palliative care for persons experiencing homelessness who reside in social service facilities is often late or lacking. A threefold intervention was implemented to improve palliative care for this population by increasing knowledge and collaboration between social service and palliative care professionals. This consultation service comprised: 1) consultations between social service professionals and palliative care professionals; 2) multidisciplinary meetings involving these professionals; and 3) training of these professionals. This study aims to evaluate the perceived added value of this threefold consultation service in three regions in the Netherlands.A mixed-methods evaluation study using structured questionnaires for consultants, requesting consultants, and attendees of multidisciplinary meetings, semi-structured group and individual interviews with social service and palliative care professionals involved, weekly diaries filled out by consultants, and an implementation diary. Qualitative data were analyzed following the principles of thematic analysis. Quantitative data were analyzed descriptively.Thirty-four consultations, 22 multidisciplinary meetings and 9 training sessions were studied during the implementation period of 21 months. Social service professionals made up the majority of all professionals reached by the intervention. In all regions the intervention was perceived to have added value for collaboration and networks of social service and palliative care professionals , the competences of especially social service professionals involved , and the quality and timing of palliative care .The threefold consultation service particularly helps social service professionals connect with palliative care professionals. It helps them to identify palliative care needs in good time and to provide qualitatively better palliative care to persons experiencing homelessness. Persons experiencing homelessness often live lives characterized by poor health, frequently in combination with psychiatric diseases, intellectual disabilities, behavioral issues, and/or substance use –3. The oSeveral international studies and commentaries have shown a need to strengthen multidisciplinary collaboration between palliative care professionals and social service professionals in order to improve the access and quality of palliative care for persons experiencing homelessness –29. We dIn our previous focus-group study, we explored the need for a consultation service intervention in which professionals of different disciplines work together in order to increase collaboration and the exchange of knowledge between social service professionals and palliative care professionals . ParticiIn the Netherlands, palliative care is generally delivered by generalists who are supported by healthcare professionals specialized in palliative care. Consultation with a palliative care consultant is a commonly used method to increase palliative care knowledge among healthcare professionals, and it has been shown to lead to the delivery of palliative care starting earlier , 35. OurTherefore, over a period of 21 months a threefold intervention involving consultation, multidisciplinary meetings, and training sessions was developed and implemented in three Dutch regions and the added value evaluated. The intervention was aimed at both professionals working in the field of social services for people experiencing homelessness and healthcare professionals working in the field of palliative care. We aimed to improve the quality of care by increasing collaboration and knowledge, and ensuring that palliative care starts earlier for people who are homeless.How was the threefold consultation service received by social service professionals and palliative care professionals, and which professionals and patients did the intervention reach?What is the perceived added value of the threefold consultation service for collaboration between social service and palliative care professionals, professionals’ competences, and the timing and quality of palliative care for persons experiencing homelessness, according to the social service professionals and palliative care professionals?In this evaluation study, we aim to provide insights into the intervention’s added value. The research questions were:The intervention is described in Table The mixed-methods evaluation study consisted of structured questionnaires, semi-structured topic-list guided interviews, and diaries. Table n = 10, one face to face and one by video call); two semi-structured group interviews about the training ; five telephone interviews with consultants; and one implementation diary.The data consisted of: 216 structured weekly digital diaries recorded by the consultants; 34 questionnaires filled out by consultants after consultations; 14 questionnaires completed by professionals who had requested a consultation; 22 questionnaires about multidisciplinary meetings (MDMs) filled out by the palliative care consultant; eight semi-structured individual interviews with managers at organizations involved in the intervention; two semi-structured group interviews about MDMs  and multidisciplinary meetings (n = 32). Most of them were male (80%). Almost all patients (93%) were 70 years of age or younger. A majority of patients had Dutch nationality (59%) and resided in long-term shelters (57%). The most common diagnoses were cancer or lung disease (including COPD) and severe substance use.Table Consultations between social service professionals and palliative care professionals lasted on average 56 minutes (range 10–120) and were mostly held at the bedside (59%). For practical reasons or due to COVID-19 restrictions, some consultations were by phone (32%). On average, 3.23 symptoms (range 1–6) were mentioned in a consultation request; these were mainly fatigue, pain, and weight loss. On average 1.79 domains (range 1–4) were covered in the consultation requests per patient. These requests mostly concerned somatic aspects (30/34) and the patient’s future well-being, pain treatment, or support and comfort in daily life. To a lesser extent, consultation requests concerned the psychological domain (7/34), for example patients being withdrawn or defensive. Some consultation requests were in the social domain (6/34), concerning the involvement of family members, isolation, or behavior. Lastly, consultation requests were in the existential domain (5/34), concerning future wishes, how to discuss incurability with the patient, isolation, and suffering. Consultants reported on average 2.23 (range 1–4) advice per consultation; these were mostly somatic care advice (29/34), and to a lesser extent advice on substance use (10/34), psychosocial aspects (19/34), and existential aspects (9/34).On average MDMs lasted 75 minutes (range 30–90) and were attended by an average of 6.86 persons (range 4–9). In terms of disciplines, most attendees were general practitioners (GPs) and practicing or trainee medical specialists (34%), nurses and social workers in social services (21%) and to a lesser extent, in-shelter care coordinators (11%), nurses specialized in palliative care or psychiatric care (20%), or professionals of other disciplines (14%). The training sessions as part of the threefold consultation service lasted on average 132 minutes (range 30–300) and were attended by an average of 12.43 persons (range 7–16). Training sessions were provided on an introduction to palliative care, palliative sedation, handling complicated behavior, and taking care of caretakers.The use of the intervention differed per region and strongly depended on what options for consultation, MDMs, and training were already available within the region and whether there were needs within the region. Table The intervention mainly had perceived added value for collaboration between social service professionals and palliative care professionals and the competences of these professionals, which in turn was thought to improve the timing and quality of palliative care. The data revealed seven themes reflecting the added value of the intervention.The intervention resulted in reciprocity between healthcare professionals and social service professionals. For all intervention elements, reciprocity was of added value in equipping especially social service professionals as caregivers to provide palliative care in the physical, psychological, social, and spiritual domains to a complex population. Reciprocity provided these social service professionals with additional knowledge, skills, and understanding that helped them take care of this population. Social service professionals also gained awareness about options for palliative care provision that they had not been aware of before, which is illustrated in Table Mainly because of the MDMs and training sessions, the intervention resulted in new formal networks and new forms of teamwork encompassing professionals in social services and palliative care. The main added value of these networks and this teamwork was in knowing how to find one another, the ‘strategic partnerships’ Table , and famBoth social service professionals and palliative care professionals felt better supported in providing palliative care to patients coping with complex issues in all domains of palliative care. Advice in consultations and MDMs on medication, and symptom management provided in consultations by palliative care professionals helped social service professionals feel more competent in detailed, early and comfortable palliative care provision. Training helped them feel better equipped in applying knowledge, guidelines, and protocols. These tools, knowledge and skills were applied to signal deterioration of the patient and decide about subsequent policy and actions and to monitor the resident. An example of recognizing deterioration and whether or not to send someone to the hospital for further treatment is exemplified in Quote 5, Table Being able to request a consultation or ask for a second opinion on suspicions or actions that had been taken was perceived as of great importance for the professionals involved in the intervention. Social service professionals in particular reported that being able to consult a palliative care specialist whom they already knew helped them feel emotionally supported, gave them self-confidence and let them provide tailored care to the patient. Another perceived benefit was self-efficacy due to feeling better equipped, feeling supported when making decisions, and being able to ask for help, which we illustrate in Quote 7 Table . Quote 8Social service professionals and palliative care professionals saw added value for the quality of life and quality of death of patients from the regular use of all three elements of the intervention. They felt that the involvement of a palliative care consultant, the knowledge gained or refreshed in training, and the discussions of patients in MDMs with other professionals helped social service professionals offer residents more comfort and prioritizing comfort when someone is detoriating, which is illustrated by Quote 9, Table In line with the previous theme, the training sessions and consultations in particular helped social service professionals use advance care planning for all their residents, as many of them are vulnerable, and look ahead. Quote 11 Table  illustraAs a recovery-oriented and person-centered approach was shown to be common among social service professionals who participated in this study, they often lack knowledge and awareness on the possibility of palliative care and especially attention for the somatic domain (illustrated by Quote 13, Table All three elements of the threefold consultation service were used by all three regions, although regional differences in the way of use were found. Consultations mainly involved palliative care professionals advising social service professionals. Social service professionals mainly posed questions about somatic issues, whereas the provided advice often covered somatic as well as psychosocial aspects. In all regions social service professionals and palliative care professionals perceived an added value of the intervention on collaboration, competences, and quality and timing of palliative care.Our findings reveal that the intervention is of perceived added value regarding the detection of possible palliative care needs and quality of palliative care. All three elements of the three-faceted intervention contributed to the perceived added value of the intervention as a whole, combining equipping social service professionals with knowledge, raising awareness, and facilitating collaboration. In terms of improving the quality of palliative care, our study revealed several aspects that have been identified as determining quality in palliative care by the Dutch Quality Framework for palliative care, namely recognition, proactive care planning, coordination and continuity, expertise, and personal balance of the professional . TherefoOur study shows that collaboration between different organizations helps social services to deliver palliative care covering the somatic, spiritual, social, and psychological domains as defined by the WHO , rather In addition to our findings on collaboration, timing and quality, and competences, our study highlights the emotional support needed by especially social service professionals when providing palliative care to this population. This is also found in other studies –47, whicThe diversity in use of the intervention but comparable perceived added value confirms the importance of a context-sensitive approach. Moreover, a context-specific approach per region using the basic elements of collaboration. Competences, and quality and timing of palliative care is relevant in other regions and countries. However, the success of implementing an intervention is also highly dependent on the process of implementation. Implementation of the intervention took time and effort, and some social service and palliative care professionals involved said that it was too early to assess the efficacy of the intervention or that more time was needed for better implementation. The COVID-19 pandemic made it particularly difficult to build new collaborations. A process evaluation is needed to gain more insight.An important strength of this study is that it evaluates a new, regionally tailored intervention aimed at improving the quality and timeliness of palliative care for persons experiencing homelessness. Another strength of this study is the intervention explored and designed in close collaboration with persons experiencing homelessness, guided by our previous focus group study in which persons experiencing homelessness indicated that both social service and healthcare professionals serving them needed more knowledge, training and collaboration when providing palliative care . The desA limitation of this study is that persons experiencing homelessness who were the subject of consultations were not interviewed themselves due to COVID-19 visiting restrictions, although this had been intended in the study protocol. We recommend to conduct research into evaluation of this intervention from the perspective of those who experienced the intervention while measuring patient-centered outcomes. Another limitation can be seen in the use of the intervention within social services, which might have resulted in a relatively old, mainly Dutch patient population receiving care. Our study population is probably not generalizable to the entire homeless population in need of palliative care in the Netherlands, because a small number of seriously ill people live on the streets, are undocumented or do not use social services , 5.A threefold consultation service can help especially professionals in social services to connect with palliative care professionals. It is perceived to help professionals in social services better identify palliative care needs, and collaboratively provide timely palliative care of better quality. It is recommended to further study future use of the intervention in other regions and countries.


The degradation of ecosystems threatens the provision of ecosystem services and limits human well-being. This systematic literature review evaluates the threats surrounding cultural ecosystem services (CES), namely recreation and landscape aesthetics in European permanent grasslands. We identified underlying causes, direct threats, consequences and suggested solutions for threat mitigation. The most common threats were land-use and management change processes, followed by social attitude, industrial developments and natural threats. However, recreational activities also created negative feedback, affecting the ecosystem, biodiversity and CES, most frequently in the form of various touristic activities. Suggested solutions were most commonly socio-economic and institutional measures to enhance rural communities, as well as improving communication with relevant stakeholders. CES play a crucial role in reconnecting people with nature, and their consequent acknowledgement and incorporation into future ecosystem service frameworks and agri-environmental policy developments are key elements in supporting future sustainable grassland management.The online version contains supplementary material available at 10.1007/s13280-022-01755-7. Humans are facing significant challenges due to the degradation of ecosystems, a trend exacerbated by climate change that continued even during the COVID-19 pandemic IPBES . An unde2 (40%) of the agricultural area  provided by European permanent grasslands?What are the most common direct threats to the CES provided by European permanent grasslands?What are the most common threats to European grasslands and the ecosystem services generated by grassland-associated recreational activities and tourism?What are the consequences of threats to CES in European permanent grasslands?What are the consequences of threats from CES to European permanent grasslands and feedback to their cultural ecosystem services?What suggested solutions are available to address these aspects and mitigate the identified threats?In this systematic review, we aim to evaluate what threats to recreation and landscape aesthetics have been described in the literature, what consequences they may have and what solutions have been suggested for their mitigation. Considering the diverse types of threats, we formulated the following research questions , the Scopus and CAB abstract databases were searched on 5 November 2019 for grassland CES in Europe . The resulting 17 979 papers were uploaded into the EPPI reviewer 4 tool (http://eppi.ioe.ac.uk/cms), a systematic review analysis software. Finally, after removing duplicates, 13 719 articles remained for screening.As part of the SUPER-G project . In the first round of screening, 13 523 papers were excluded . As a second step, the full texts of the remaining 196 papers were scanned, of which 71 papers were selected that contained at least one of the following aspects:threats to CES and permanent grasslands,threats to grasslands from CES,solutions to prevent or reverse threats.As a first step, titles and abstracts were screened on relevance and filtered based on a set of exclusion criteria (see Supplementary Appendix S2) were read, and data were extracted into a data extraction form (Table S2a/b). The selected papers contained 77 studies, with four papers including two or more studies from different countries, which were analysed separately. The elicited data included bibliographical information, country and region of the study, spatial scale , grassland type, threat type, underlying causes and consequences and suggested solutions. The paper selection was made independently by the two first authors, and in divergent cases, a consensus was developed.The selected 71 papers , we compared our findings on direct threats to the direct threats classification on biodiversity by the IUCN-Conservation Measures Partnership . Following our conceptual framework .Fifty-one studies taken from 47 papers on threatened CES were included in the analysis , of which socio-economic factors had the highest frequency (39 cases). They included economic aspects related to a lack of profitability and motivation of the local population to continue farming, as well as detrimental market forces, for example, against local products that can reduce income from farming. The second-most frequent underlying cause (27 cases) were institutional aspects, including strict regulations controlling recreational activities and other related regulations  that do not support CES. In other cases, the lack of regulations led to land speculation and the related conversion of grasslands into built-up areas. In close connection with pure economics, the loss of governmental financial support led to a decrease in grassland areas, as they were abandoned. The loss of culture and traditions (11 cases) was commonly mentioned together with socio-economic changes. However, culture also had a controversial role, for example, when locals avoided a nature reserve due to negative memories or when there were conflicts between different groups about their perceptions of aesthetic landscapes. Demographic factors (11 cases) included the emigration of young people and an ageing population, leading to an unbalanced age structure. The related disrupted continuity of farming families led to the abandonment of traditional farming activities. On the other hand, urbanisation and the demand for residential buildings in grassland areas were caused by a growing population. Infrastructure (7 cases) was reported to be insufficient for tourism development and local access, restraining CES usage, or overabundant with roads supporting high traffic volumes in natural areas. Industrial and economic influences (5 cases) included large industrial or agricultural developments, the construction of renewable energy plants and technological changes. Finally, climate change (5 cases) was mentioned in the context of rising temperatures. In 19 cases, no underlying causes were mentioned targeting specific threats.Based on the IPBES classification IPBES , seven tA total of 95 direct threats provided an insight into the diversity of threats affecting the function and CES of European grasslands. Based on the IUCN-CMP direct threat classification IUCN-CMP , four maThe second-largest group of threats was related to social attitude (12 cases), a category with no equivalent in biodiversity science. Nature conservation measures were disapproved in four cases, as they were perceived as limiting recreational activities. Poor recreational services (4 cases) resulted from insufficient infrastructural development in the region, which could threaten recreation because of poor access to otherwise attractive places and a lack of local services. The lack of appreciation for cultural values posed a threat to a continued CES supply in two cases. In a further two studies, people had negative sentiments towards a place because of its history.The third threat group incorporated industrial and economic activities (8 cases). In three studies, wind farms and solar panels impaired landscape aesthetics, and in two cases, mining and quarrying induced threats to both recreational activities and aesthetics through water-borne, air-borne and noise pollution. Industrial air pollution (1 case) caused both air pollution and aesthetic damage to the landscape. In one case each, military exercises and waste deposition were reported as threats to recreational activities and aesthetic values.The fourth threat category was natural threats (6 cases), namely retreating glaciers and snow-deficient winters, spontaneous afforestation in place of melting glaciers and natural hazards in thawing permafrost areas. All the threats in this category affected both landscape aesthetics and recreational activities such as hiking.The reported consequences of these threats could be divided into two major groups: First, the reduced appeal of grasslands for recreation, and second, the decreased aesthetic value because of a homogenous landscape. Many threats affected recreation and aesthetics simultaneously. The loss of landscape aesthetics was the more dominant consequence with 81 cases, followed by reduced recreational appeal in 49 cases, restricted recreational activities in eight cases and hampered tourism development in four cases. Consequences of abandonment were the economic loss for the tourism industry and negative effects for hikers due to landscapes with reduced access for walking. It also had negative aesthetic effects through a reduction or a complete loss of panoramic views. In fact, both more intensive and too little management (abandonment) led to decreased cultural values . The loss of aesthetic and recreational appeal, including hampered tourism development, lowered the frequency of tourist visits, while restrictions (due to nature protection or private property) to prevent access induced conflicts. They all led to tourists looking for other destinations, a reduced length of stay or a decreased willingness-to-pay (WTP) for local services. Yet, it was also mentioned that when places of high natural value are threatened, the exclusion of tourists may be necessary. In other situations, however, such strict regulations threatened the livelihood of farmers when their primary source of income was tourism or when management was no longer profitable, leading to further abandonment and the loss of CES.Socio-economic solutions were by far the most widely suggested solution type (46 cases) and covered a wide range of mitigation measures for the development of rural areas. The solutions encompassed financial support from governments , the stimulation of employment in rural areas, farm income diversification , improved market access, but also conservation measures and the development of sustainable rural tourism. All these approaches were reported in the reviewed literature to ensure local livelihoods, preserve a healthy environment and help to develop a sustainable, local socio-economic system for the given socio-economic context. The proper organisation of tourism may help to maintain traditional landscapes and activities. Communication was the second-most suggested solution (19 cases), including both transfer of knowledge and education. That covered various aspects, such as increased cooperation between stakeholders, their incorporation into landscape planning and decision-making, and enhanced valuation of CES. The education of locals and tourists was proposed to promote their understanding of the importance and functions of grassland ecosystems. Institutional solutions (17 cases) were typically regulations such as restricted industrial development in sensitive areas, adapted conservation strategies and governmental regulations ensuring sustainable maintenance and harmonising tourism and conservation. The suggested infrastructural investments (14 cases) included the development of tourism in response to environmental changes, with improved access to remote areas; the use of artificial snow at lower elevations or creating pistes at higher elevations; and the construction of new hiking trails and recreational ‘furniture’ . Finally, the restoration of the ecosystem functions  was suggested in three cases and purely economic development in one case. In 15 cases, no suggestions were made to reduce threats to CES.S5).An overall 37 reviewed studies (in 36 papers) contained threats caused by CES . The second-most frequently mentioned underlying cause was economic factors (8 cases). All were related to tourism becoming more economically profitable than agriculture. Institutional backgrounds, such as defective regulations or lack of regulations, were discussed as the underlying cause of two threats. Climate change was mentioned once in the context of decreasing snow reliability, suggesting that the creation of artificial snow will be intensified to ensure the continued provision of CES.Based on the IUCN-CMP direct threat classification (IUCN-CMP 2019), seven main threat categories could be distinguished. The most abundant threats were disturbances and pressures by tourism (29 cases), where four subcategories were differentiated, namely (1) general disturbances on ecosystems and people ; (2) hiking and related trampling effects; (3) skiing, with similar effects like hiking, together with the disturbance of bird species in the surrounding areas; and (4) recreational vehicles for activities such as motorised sports (e.g. snowmobiling) or biking, where the physical impact was the main disturbance, together with noise and air pollution and impacts on wildlife. The second threat category was the development of tourist facilities , followed by the building of accommodation for tourists , as a specific type of urban development competing with grasslands (7 cases). Minor threats were hunting tourism (3 cases) and gathering plant souvenirs (1 case) as sources of disturbance in grasslands. Abandonment of grassland management because of more lucrative jobs in tourism, land modification for recreational activities, and grassland eutrophication due to using artificial snow were each mentioned once.The most frequent consequences were land degradation processes (37 cases), such as reduced aboveground biomass, vegetation cover, species frequency and composition, and changes in the cellular structures of trampled plants. Furthermore, land degradation was connected to soil erosion and compaction, soil nutrient changes and sometimes even the total disappearance of grasslands due to buildings or recreational activities. Biodiversity loss was the second-most mentioned consequence (24 cases), often co-occurring with land degradation. Minor consequences were the loss of traditional cultural landscape (9 cases), the negative impact on tourism (5 cases) and aesthetic values (2 cases), and finally, the negative impact on residents of an increase in tourist numbers (1 case).The regulation of tourism and economic development were suggested most often, using institutional and economic tools to avoid the overuse of the ecosystem (20 cases). Several reviewed studies suggested limiting visitors or implementing a frequentation management plan in sensitive areas or according to season to prevent negative impacts of human trampling. Alternatively, it was suggested to concentrate tourists on a few areas rather than let them spread or to monitor the negative effects with sensitive indicator species. The second-most frequently mentioned solutions were the regulation of urban development through land-use planning, conflict management and collaborations, among others (10 cases). Habitat restoration was noted in seven cases as an important tool to mitigate the negative impacts of CES. The unfavourable impacts of ski pistes were suggested to be restored by reseeding and mowing management. Infrequently suggested solutions were the development of an appropriate conservation strategy, the protection of the landscape, the increase of landscape multifunctionality, improved communication and education, the reconstruction of routes relieving sensitive natural areas and the diversification of income through a combination of part-time farming and working in tourism. Seven studies did not report any obvious solutions.CES are generally not as well understood as most other ecosystem services  to be the most important threats caused by recreation, mainly affecting vegetation, soil and wildlife. Typically, such effects become larger with increasing use, although the additional impact weakens at higher intensities Cole .The threats to a region or landscape were typically related to the development of tourist facilities (e.g. roads and ski lifts) and the building of tourist accommodation. An increasing number of ‘day trips’ in rural and remote areas has increased the volume of transit traffic and the associated negative impact of roads and vehicles on the environment EEA . With toIn the face of climate change and related increasingly snow-poor winters, the demand for artificial snow production will grow . Several papers suggested new agri-environmental programmes, which are especially important in marginal areas and should be incorporated into the new Common Agricultural Policy (CAP) , are a common tool in Europe to promote recreation in such areas . Although highly relevant for CES, the exact spatial scale was rarely mentioned or identifiable implicitly  and urban and other commercial development . “Social attitudes” in the direct threats, and “communication” and “restoration” in the suggested solutions were views not previously categorised in literature. One plausible reason could be that the classification systems used targeted biodiversity, while this systematic review addressed CES. We recommend developing categories that specifically take cultural and social aspects  into account. We consider CES to be the crucial link in balancing supply and demand of ecosystem services, not least because the foundation of values, attitudes, and beliefs lies in culture and traditions and directly affects how ecosystems and their services are perceived Nassauer .Existing habitat categorisations do not focus on ecological processes and services, including landscape aesthetics. Therefore, it is necessary to explore the delineation of habitat qualities for CES, and to improve the understanding of how ecological processes provide continued CES supply Below is the link to the electronic supplementary material.


Purpose: As the number of patients with chronic obstructive pulmonary disease continues to increase, it is increasingly important to understand the impact of cardiovascular risk on the progression of chronic obstructive pulmonary disease, which can provide guidance for clinical medication and recommendations for patient care and rehabilitation. The purpose of this study was to investigate the relationship between cardiovascular risk and the progression of chronic obstructive pulmonary disease (COPD). Methods: Selected COPD patients admitted to hospital from June 2018 to July 2020 were included in the study for prospective analysis, and patients who showed more than two instances of moderate deterioration or severe deterioration within one year before the consultation were defined as COPD patients, and all participants underwent relevant tests and assessments. Results: Multivariate correction analysis showed that a worsening phenotype improved the risk of carotid artery intima-media thickness exceeding 75% by nearly three times, and it had no relation with the degree of COPD severity and global cardiovascular risk; in addition, the relationship between a worsening phenotype and high carotid intima-media thickness (c-IMT) was more pronounced in patients under 65 years of age. Conclusions: The existence of subclinical atherosclerosis is individually related to the worsening phenotype, and the difference is more obvious in young patients. Therefore, the control of vascular risk factors in these patients should be strengthened. Patients with an acute aggravation of chronic obstructive pulmonary disease (AECOPD) typically die from cardiovascular disease. Studies have shown that carotid atherosclerosis is associated with the severity of chronic obstructive pulmonary disease (COPD) ,2,3. AccInclusion criteria: ① Diagnosed as AECOPD; ② Age ≥ 18 years; ③ AECOPD diagnosis in accordance with the 2017 GOLD guidelines. Exclusion criteria: ① Combined with hyperblood pressure, hyperlipidemia, diabetes, and rheumatic immune diseases; ② Combined with blood fluid disease; ③ Patients with tumors and other lung diseases; ④ Liver function not complete. Age and gender did not significantly differ between the two groups (p > 0.05). The study was approved by the hospital ethics committee.Selected COPD patients who visited our hospital from June 2018 to July 2020 were included in the study for prospective analysis. Patients with a history of COPD who had uncontrolled dyspnea or exacerbations even with medical handling, or who had progressive illness necessitating further treatments, including oxygen therapy, or consideration of lung transplantation, which were excluded. The diagnosis of COPD was made according to the treatment guidelines. The diagnosis of coronary artery atherosclerosis was based on the clinical diagnostic criteria of coronary artery atherosclerotic heart disease in the first National Academic Conference of Internal Medicine of Chinese Medical Association in 1980. ® system in accordance with SEPAR guidelines [® high-resolution device with 5–10 MHz linear converter frequency; measurement of common carotid artery, internal carotid artery, and carotid bulb. Carotid IMT was measured at each of these segments, and patients with subclinical carotid AT were considered to have an average IMT greater than 75% [(1) A unified registration form was used to collect basic information of the subjects, including age, gender, chronic medical history , tobacco and alcohol history, etc. (2) Biochemical indexes: Fasting venous blood was collected, and routine biochemical indexes such as blood lipids were detected using a biochemical analysis system. (3) Serum ultra-sensitive C-reactive protein was detected using an immunoassay system. (4) We used the Framingham Global Cardiovascular Risk Score , SCORE Ridelines . 6) Paridelines . (7) Car Paridelithan 75% .t-test. p < 0.05 was regarded as statistically significant when the association was examined using Person and Spearman correlation analysis.Software statistics were performed using SPSS16.0, and measurement data were reported as (p = 0.018). More patients had diabetes  and hypertension ; oral hypoglycemic  and inhaled steroid use rates  were significantly higher, and patients had significantly lower diastolic blood pressure (DBP)  and FVC%  and CVR  severity, compared with non-deteriorating patients, the worsening phenotype was associated with subclinical carotid atherosclerosis , and there was a trend for higher CVR values.COPD is a progressive lung disease that is ranked as the third leading cause of death worldwide. It is one of the most common diseases in the elderly population in China, and the number of deaths from COPD increases sharply with age in people over 70 years of age . COPD isp = 0.017) and hypertension . Likewise, a higher rate of vasodilator and diuretic drug use in exacerbated patients could explain the trend toward lower DBP. Furthermore, no statistically significant change in LDL-cholesterol was observed. However, according to an observational study [A systematic review showed  that IMTal study , an incrInflammatory reaction is the main pathogenesis of atherosclerosis, specifically as follows: (1) inflammatory reaction caused by vascular endothelial cell injury is the initiating factor in atherosclerosis; activation of T lymphocytes and macrophages stimulates cytokine release, increasing induced endothelial cell adhesion molecule expression, leading to the circulation of the blood cells attached to the wall and migration to the vascular intima; (2) in the inflammatory response, the expression of scavenger receptors in monocytes/macrophages is increased, lipid uptake is increased, and foam cells secrete cytokines, which promotes the development of atherosclerotic plaques, and then affects the occurrence and development of atherosclerosis; (3) CRP can inhibit the process of nitric oxide synthase, affect the function of vascular endothelial cells and the generation of plasminogen activators, damage the fibrinolytic function of endothelial cells, and then promote the rupture of atherosclerotic plaques and thrombosis ,19,20,21In conclusion, this research was based on the presence of subclinical atherosclerosis as determined by the thickness of the carotid intima-media. After adjusting for COPD severity (measured by the BODE index) and global cardiovascular risk including COPD CoRi, CVR was independently associated with a worsening phenotype, and these differences were more pronounced in younger patients. This suggests that the advantages of clinical preventative measures would be greater for this population.


Biological disease-modifying anti-rheumatic drugs (bDMARDs) are widely used for the management of rheumatoid arthritis, although their benefits are counterweight by an increased risk of infections. In the present study, we used administrative data to compare the risk of severe infections among different classes of bDMARDs. A retrospective cohort study was conducted using Administrative Health Databases of the Piedmont Region, Italy. Relevant data were obtained from: (1) the inhabitants registry, (2) hospital discharge records, and (3) the co-payment exemption registry and (4) drug claims registry. Fine and Gray competing risk models were fitted to evaluate the association between the use of different types of bDMARDs and occurrence of severe infection accounting for treatment interruption as competing risk. A total of 1780 new users of bDMARDs were identified. Among them, 50 hospitalizations for infection occurred during the study period. The use of Tocilizumab was associated with an increased risk of infection, compared to tumor necrosis factor (TNF) inhibitor drugs , whereas no difference in the risk of severe infection was found for abatacept . bDMARDs treatment is generally safe in clinical practice with slight but important differences among classes. The increased risk of infection associated with tocilizumab use should be taken into account when balancing the risk and benefits of starting a treatment with this drug. In 1999, a trial firstly proved the clinical benefit of adding etanercept, a tumor necrosis factor inhibitor (TNFi), to methotrexate in Rheumatoid Arthritis (RA) patients who did not respond to the standard of care . The curA retrospective cohort study was conducted using the administrative health databases of Piedmont Region, Italy . Relevant data were obtained from: (1) the inhabitants registry ; (2) hospital information system, including hospital discharge records from public or private hospitals; (3) co-payment exemption registry; (4) and drug claims registries, including records of the drug prescriptions reimbursable by the Italian National Health Service dispensed by hospital and local pharmacies. These databases can be linked through a unique encrypted identifier and have largely been used for epidemiological research ,11,12. AThe use of bDMARDs in clinical practice is nowadays largely widespread. One of the most relevant concerns related to their use is the risk of severe infections, which may vary among the different biological target addressed. In this paper, using the administrative data of a large Italian region, we found that tocilizumab was associated with a higher risk of infections than abatacept and TNFi. In 2010, the European League Against Rheumatism (EULAR) released the first version of the recommendations for the management of RA with synthetic and biological DMARDs . This doIn conclusion, our study confirms that bDMARDs treatment is generally safe in clinical practice with slight but important differences among classes. In particular, tocilizumab is associated with a greater risk of infection, along with age, comorbidities, and use of steroids.