From an agricultural perspective, drought refers to an unusual deficiency of plant available water in the root-zone of the soil profile. This paper focuses on evaluating the benefit of assimilating soil moisture retrievals from the Soil Moisture Active Passive (SMAP) mission into the USDA-FAS Palmer model for agricultural drought monitoring. This will be done by examining the standardized soil moisture anomaly index. The skill of the SMAP-enhanced Palmer model is assessed over three agricultural regions that have experienced major drought since the launch of SMAP in early 2015: (1) the 2015 drought in California (CA), USA, (2) the 2017 drought in South Africa, and (3) the 2018 mid-winter drought in Australia. During these three events, the SMAP-enhanced Palmer soil moisture estimates (PM+SMAP) are compared against the Climate Hazards group Infrared Precipitation with Stations (CHIRPS) rainfall dataset and Normalized Difference Vegetation Index (NDVI) products. Results demonstrate the benefit of assimilating SMAP and confirm its potential for improving U.S. Department of Agriculture-Foreign Agricultural Service root-zone soil moisture information generated using the Palmer model. In particular, PM+SMAP soil moisture estimates are shown to enhance the spatial variability of Palmer model root-zone soil moisture estimates and adjust the Palmer model drought response to improve its consistency with ancillary CHIRPS precipitation and NDVI information. Timely and routine knowledge of expected crop yield production is important for farmers, agricultural agencies, insurance companies, aid organization and other end-users because it drives food supply/price projections, impacts trade markets, and identifies food insecure areas. However, yield forecasting using physically-based crop growth models is challenging and requires accurate knowledge of a variety of environmental parameters  and plant available water  . Important operational USDA-FAS goals include maintaining global food security and commodities market development. In particular, USDA-FAS's Office of Global Analysis (USDA-FAS/OGA) serves as a major source of objective and reliable global agricultural production information for the USDA's monthly World Agricultural Supply and Demands Estimates (WASDE) report—the primary source of the USDA's global commodity outlook. The monthly WASDE report provides public access to information affecting world food security and is crucial for supporting decisions affecting U.S. agriculture, trade and food aid policies—as well as aiding economic decisions made by stakeholders, policymakers, and governments. USDA-FAS/OGA uses a variety of data products at regional, national and subnational scales to operationally monitor and analyze monthly changes in global crop production. The analysis of RZSM patterns, and their relationship to climatological expectations, is an important part of this analysis. Within the United States, an analogous domestic monitoring role is played by the USDA National Agricultural Statistical Service (USDA NASS).Prior to 2014, USDA-FAS RZSM information was generated using a modified two-layer Palmer model (PM). The PM is a simple soil moisture accounting model driven by daily meteorological data (including daily precipitation estimates and temperature observations) provided by the U.S. Air Force 557th Weather Wing (USAF). It applies a simple water balance formulation to estimate temporal variations in RZSM. However, this approach shows less skill in the case of poor-quality forcing data. In particular, random errors in daily precipitation forcing propagate through modeled soil water balance physics and can greatly reduce the accuracy of the model-generated soil moisture estimates  mission  assessing the impact of SMAP on the USDA-FAS's soil moisture estimates and (2) examining the change in skill (if any) of the SMAP-enhanced PM model (PM+SMAP) for capturing the extent, duration and severity of agricultural drought events. To this end, the performance of the USDA-FAS's soil moisture information (without and with SMAP) will be examined for its capability to detect RZSM deficiency over three agricultural regions that have experienced major agricultural drought since the launch of SMAP in early 2015: (1) the 2015 drought in California (CA), USA, (2) the 2017 drought in South Africa, and (3) the 2018 mid-winter drought in Australia. RZSM deficiency will be established by evaluating the behavior and accuracy of the model standardized soil moisture anomalies in relation to change in anomalies in precipitation and the Normalized Difference Vegetation Index (NDVI).Therefore, this paper is organized as follows. Section II provides background on the physics of agricultural drought and its impact on crop growth and yield production—as well as describing available soil moisture-based indices with demonstrated value for agricultural drought monitoring. Section III focuses on the soil moisture, precipitation, and NDVI datasets and provides a description of the study domains and the drought events listed above. Results will be presented/discussed in section IV and summarized in section V.Agricultural drought is generally associated with a decline in precipitation that causes insufficient plant water availability and reduced soil water storage. Its adverse effect can be accelerated by the simultaneous occurrence of high air temperatures and strong winds, which causes further drying. Boken et al.  describeA large number of indices have been developed to monitor drought and quantify its impact. Mishra and Singh  offer a Here our primary focus will be on soil moisture-based indices. Narasimhan and Srinivasan  proposedSA) used here is computed as:Another alternative is the calculation of standardized anomaly indices that express current soil moisture conditions relative to a climatological expectation. This can be useful to convey degree and duration of drought across several climatological regions and multiple soil and vegetation types over time. If standardized by a long-term standard deviation, such an index represents standardized anomalies that summarizes the deviation of the current soil moisture conditions in terms of standard deviations relative to long-term climatological expectations for a given month. The monthly Standardized Anomalies  and measurements reflecting vegetation status . Since the RZSM product is an important part of the official product suite currently generated for USDA-FAS, an anomaly analysis carried out as described above should provide useful insight into the utility of this product for the USDA-FAS crop analysts. Note that the interpretation of (1) is typically based on an implicit assumption of a Gaussian RZSM distribution. More robust non-parametric percentile or return interval approaches are also possible but require longer sampling periods than the relatively short data records provided by existing global RZSM products (see below).Here, the As discussed above, the USDA-FAS soil moisture product is based on the modified 2-layer Palmer model (PM) Palmer, . The topThe SMAP satellite was launched in January of 2015 and began providing scientific data on March 31, 2019. It is an L-band mission that observes the Earth's surface at about 40-km resolution twice a day at 6 a.m. and 6 p.m. . SMAP was designed to carry aboard two microwave instruments, a radar (centered at 1.26 GHz) and a radiometer (centered at 1.5 GHz). Unfortunately, the SMAP radar failed in July 2015. However, the passive microwave radiometer has continued to generate a nearly continuous data record since late March 2015.SMAP generates several different global soil moisture products using various radiative transfer-based algorithms and methodologies. Of particular interest here is the Level-2 passive-based only soil moisture product (L2_SM_P) ONeill, . The L2_The current operational USDA-FAS SMAP-based RZSM product is derived based on the assimilation of the SMAP L2_SM_P soil moisture product (section 3.1) into the 2-layer PM (section 3.1) to filter random errors that degrade PM RZSM estimates. This assimilation is based on an Ensemble Kalman filtering (EnKF) approach. The EnKF, its background and application in hydrology—as well as its specific USDA-FAS implementation—have been well-documented by previous studies  and the observation covariance matrix R (which reflects our degree of confidence in the accuracy of assimilated observations). Q and R are generally assumed constant in time here—see Mladenova et al.  ground stations. Given the general understating that gauge-based correction is important for ensuring the quality of precipitation forcing data, Q was modeled as an increasing function of the distance between the model grid pixel and the nearest gauge station—thereby lending more confidence to background PM forecasts over areas with greater station density coverage  team has evaluated SMAP soil moisture retrievals using very comprehensive and well-calibrated ground-collected datasets  values provided by the SMAP Cal/Val team for specific vegetation classes  should allow for the representation of more realistic soil moisture patterns than the baseline USAF-forced PM. Therefore, one technique for demonstrating the value of a data assimilation-based system combining both satellite-based precipitation and soil moisture observations is to carefully analyze the spatial and temporal agreements between the datasets , as well as the datasets used in their production, and compare them to a higher-accuracy precipitation dataset . This approach is followed here. Specifically, we compare both the PM and PM+SMAP results with the independent CHIRPS precipitation dataset.An additional comparison analysis against NDVI anomalies is conducted to evaluate the impact of water shortage on vegetation health as captured by NDVI. Is it well-known that, in mid-latitude agricultural regions during the growing seasonal, negative anomalies in RZSM tend to produce a time-lagged corresponding negative anomaly in NDVI  the Climate Hazards group Precipitation climatology (CHPclim), (b) the satellite-only Climate Hazards group Infrared Precipitation (CHIRP), and (c) the station blending procedure that produces the CHIRPS. The global monthly climatologies are based on station data obtained from the Agromet Group of the Food and Agriculture Organization of the United Nations (FAO) and the Global Historical Climate Network (GHCN). In addition to the gauge data, CHPclim incorporates elevation, latitude and longitude information as well as monthly long-term mean values acquired from Tropical Rainfall Measuring Mission 2B31 microwave precipitation estimates, CMORPH microwave-plus-infrared based precipitation estimates, monthly mean geostationary infrared brightness temperatures and land surface temperature estimates. CHPclim uses a moving window method to build tile specific regression models that are consequently fit to the FAO climatology. Station specific biases are then computed against the GHCN data. Lastly, CHIRP is blended with station observations from several public regional archives. Merging is done by computing bias ratios between the CHIRP data and the nearest 5 stations. These bias ratios are used to compute a correction factor that is used to adjust the original CHIRP values. Final CHIRPS estimates are a weighted combination of the original CHIRP and the adjusted CHIRP, where the weighing function is determined based on the agreement of each product with the nearest station. A detailed description of the CHRIP/S methodology and validation results can be found in Funk et al.  dataset. CHIRPS is distributed at 0.05° and offers a quasi-global coverage (50°S-50°N). CHIRPS incorporate global climatologies, several different satellite-based products and k et al. , Paredesk et al. , and Rivk et al. .CHIRPS precipitation is an independent data set as it was not used to run the PM and is considered to be of relatively high-quality (vs. the USAF precipitation product used to drive the PM) due to its more complex blending algorithms, the use of global precipitation climatology and the much larger number of gauge data incorporated into the CHIRPS product, as discussed above. However, as mentioned, it a quasi-global data set and does not provide full global coverage (50°S-50°N). In addition, there is considerable latency in data availability  show that the CHIRPS temporal and spatial response is consistent with other precipitation data sets such as the Parameter-elevation Relationships on Independent Slopes Model (PRISM) and the South African Weather Service data. However, both of these products have only regional coverage  and cannot support a global analysis.NDVI anomalies were used here as a proxy of crop status and vegetation health. The Moderate Resolution Imaging Spectroradiometer (MODIS) NDVI data used in this study was processed by the NASA/Goddard Space Flight Center's Global Inventory Modeling and Mapping Studies (GIMMS) Group through funding support of the Global Agricultural Monitoring project by USDA-FAS. It is generated using the maximum-value compositing technique . Therefore, PM* is RZSM SA of the Palmer model alone and ENKF* refers to SA produced via the assimilation of SMAP into the PM (PM+SMAP). Likewise, CHIRPS* and NDVI* refer to monthly SA anomalies acquired from the CHIRPS precipitation and the GIMSS NDVI products, respectively.The standardization procedure described in (1) is applied to develop monthly standardized precipitation and NDVI standardized anomalies. A “As mentioned above, our three study domains of interest are: California (USA), the Western Cape (South Africa) and New South Wales  . Each ofAlong with the WASDE report, USDA-FAS routinely releases Commodity Intelligence Reports (CIR), and World Agricultural Production (WAP) Circulars. These briefs describe changes in crop status and expected yield variations for a specific country or agricultural area in the context of an ongoing weather or climate event. The impact of the 2017 drought in South Africa and the 2018 mid-winter drought in Australia were extensively described by the USDA-FAS briefs. Likewise, the Californian drought is described by USDA NASS reports. These reports are referenced below to provide context concerning the impact of our three selected drought events on large-scale agricultural productivity.https://ipad.fas.usda.gov/highlights/2018/02/SouthAfrica/index.pdf).Our first case study focuses on the impact of a prolonged drought in the Western Cape province of South Africa. The Western Cape is located in the south-western edge of South Africa. It is the country's largest wheat producing region and operates on an austral winter wheat calendar with planting in May and harvest in November. The agriculture in the area is predominantly rain-fed. Climate in the Western Cape is characterized by hot/dry summers and cold/wet winters. Average annual rainfall is 185 mm, which is significantly lower than the South African national average of 380 mm (statistics are based on the 1981–2018 CHIRPS data record). The Western Cape Province has experienced below-average rainfall since 2014/15—reaching near-record lows during the 2017 growing season, which was the lowest recorded since either 1981 (based on CHIRPS data record) or 1933  province, located in the south-eastern corner of Australia, is one of the major agricultural production areas in Australia. Its climate varies from arid to semi-arid, in areas to the west of the Great Dividing Range, to more oceanic and humid subtropical in the east. Average annual rainfall is about 365 mm (based on the 1981–2018 CHIRPS data record). Wheat, canola and barley are the major commodities cultivated in the area. Winter crops are planted between May and July and harvested between late October and early January. However, specific planting dates are highly dependent on winter rainfall amounts. Numerous studies have found that Australia is prone to inter-annual drought due the impact of several major climate phenomenon such as El Niño/Southern Oscillation (ENSO), Pacific Decadal Oscillation (PDO), and the Indian Ocean Dipole (IOD) , as of early April 2015, 44% of CA was experiencing exceptional drought conditions . This percentage increased to almost 47% by mid-May  typically receives most of its annual precipitation during the winter season (November through April). However, the 2013/2014 winter season was the 6th driest since 1985 . An important characteristic of CA agriculture is its heavy reliance on irrigation, which supports the growth of high-value cash value crops such as nuts and vegetables. As a result, the state of CA has the largest number of acres of irrigated farmed land in the U.S. . This lack of inter-annual variability highlights the importance of irrigation in CA and its ability to moderate drought impacts on plant growth and lower agricultural crop productivity.CA is one of the major agricultural areas in the US. Commodities grown in the area are diverse and include a large variety of fruits, nuts and vegetables—as well as additional field crops (*), EnKF-based RZSM (ENKF*), precipitation (CHIRPS*), and vegetation health (NDVI*) standardized anomalies are shown in * and both PM* and ENKF* RZSM time series are summarized in Our analysis focuses on exploring the agreement between PM RZSM products (acquired both with and without SMAP data assimilation) with independent estimates of rainfall and vegetation health captured by CHIRPS and GIMSS MODIS NDVI, respectively. For all three locations over the entire SMAP data record , time series of the standardized anomalies of PM-only RZSM (PMhttps://ipad.fas.usda.gov/cropexplorer/Default.aspx).The convergence of evidence approach employed by the USDA-FAS crop analysts is based on evaluating current crop status relative to some expected normal level using a variety of geospatial variables linked to agricultural productivity . As shown in * RZSM, PM* RZSM, CHIRP* precipitation, and NDVI* standardized anomalies over South Africa, Australia and the western half of the United States are shown in 8. Specific results for each of our three case study events are summarized in the next three sub-sections.Note that the plots for the Western Cape and NSW reflect the austral winter crop growing season (roughly November to May). Spatial variability in ENKF* RZSM, PM* RZSM, CHIRPS* precipitation, and NDVI* in *). However, assimilation of SMAP data (used to generate ENKF* results) introduces additional temporal variability not captured by the original model-only PM* product—see the black outlined boxes in * product demonstrating enhanced temporal correlation, as compared to model-only PM* results, vs. the CHIRPS* precipitation baseline  in terms of soil moisture over the Western Cape, South Africa , precipitation (CHIRPS*), and NDVI* anomalies over South Africa for two growing seasons (2016 and 2017) are shown in * and ENKF* results show different spatial patterns . In particular, ENKF* more closely adheres to spatial variability displayed in CHIRPS anomalies—suggesting that the assimilation of SMAP observations is correcting for spatially erroneous rainfall information used to generate the model-only PM* product. This is especially clear in the May-July 2017 imagery where PM* results contain an obvious spatial artifact  corrects model-only PM* results in a way that better reflect spatial CHIRPS* patterns. As in the Southern African case, the total temporal agreement between ENKF* and CHIRPS* is higher than that sampled between PM* and CHIRP* . This agrees with the CHIRPS precipitation. Thus, the relatively good vegetation status in May 2017  soil moisture and vegetation conditions were below normal  information via the assimilation of SMAP Level 2 surface soil moisture retrievals into the USDA-FAS Palmer model (PM). The resulting PM+SMAP assimilation system is one of the first operational systems to use SMAP data products in a decision support context  and as our NDVI analysis demonstrated, exploiting this information to predict future change in crop health may be challenging. The complex plant-weather relationship and the adaptive mechanism plants have to handle environmental stresses complicate direct inter-comparisons between NDIV and SM and precipitation. Our NDVI-based results showed some temporal offset between the soil moisture and NDVI responses to drought; however, this relationship was not immediately apparent and varied between sites. This indicates that the use of root-zone soil moisture dynamics to verify and predict NDVI variability is not straightforward and requires further study. One possible approach would be to consider a more complex methodology, where the precipitation driven variability in RZSM is evaluated relative to air temperature, water levels, snow melted water, wind speed, etc.SMAP began operational data production in early 2015 and the SMAP data record is still relatively short. This complicates the calculation of interannual anomalies. Despite this complication, the analyses presented here demonstrate that the ENKF data outperform the PM-only run and that SMAP adds additional variability and information, which effectively improves the quality of RZSM information operationally available to the USDA-FAS. However, the short duration of the operational passive-based satellite sensors such as SMAP makes it challenging to set up a stable data assimilation system, compute dependable climatological anomalies and sample statistically significant differences in performance metrics.One of the main assumptions of data assimilation is that the systematic differences between the model and the satellite observations are accounted for prior to assimilation. This is often achieved using long-term, climatology-based statistical rescaling techniques. Furthermore, while a large number of approaches are applied to detect and track drought, the most commonly used indices are anomaly-based  and appear to provide complimentary information-since the value of each variable for crop monitoring changes throughout the growing season .All data sets analyzed in this study are publicly available. The NASA-USDA soil moisture products generated from the SMAP-enhanced Palmer model can be found here: IM has processed the datasets and conducted the analysis presented in the paper. IM have worked on integrating the SMAP satellite observations into the Palmer model and worked with NS on setting up the operational data assimilation system. IM, WC, and JB have worked collaboratively on structuring and writing the paper. WC and JB have helped with reviewing the manuscript and discussing the results. NS has run the Palmer model and helped with initial data processing. CR have provided insides related to the use of the SMAP-enhanced Palmer output by USDA-FAS as well as its value for the agency's crop monitoring activities.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.


Dear EditorRecently, we read with interest the valuable article entitled “Anticancer Effect of Cisplatin-Loaded Poly (Butylcyanoacrylate) Nanoparticles on A172 Brain Cancer Cells Line” that has been published in Asian Pacific Journal of Cancer Prevention . The paper has pointed out that cisplatin loaded on poly (Butylcyanoacrylate) nanoparticles with this range of size, was more efficient than the free form of cisplatin in treating A172 cancer cell line that helps to elucidate the role and the mechanism of antitumor activity of NC- cisplatin. Among the most important findings, were nessesery several comments to complete, that the authors have ignored them in their article:1) The nano-carrier stability of cisplatin loaded on poly (Butylcyanoacrylate) nanoparticles could monitor the time-dependent changes in particle size and drug content. To test the chemical stability, the content of Cisplatin loaded on poly (Butylcyanoacrylate) nanoparticles in sample could be determined via high-performance liquid chromatography (HPLC) . 2) In vitro cellular uptake of the free and Cisplatin loaded on poly (Butylcyanoacrylate) nanoparticles could be determined by HPLC from lysates of cancer cells .3) Eke, the morphology measuring of nano-capsulated need be analyzed by a more accurate method, such as microscopic electron techniques (transmission electron microscopy (TEM), scanning electron microcopy (SEM)) that this is a neccessery as a charectristic drug-loaded nanocapsules . 4) The DAPI staining could examine the cell nucleus morphology in normal and apoptotic cells by fluorescence microscopy and the percentage of the apoptotic cells can be estimated by annexin V/propidium iodide staining that will be helpful.5) Finally, migration ability of the cells can be measured using a wound-healing assay. Asad Vaisi-Raygani, Mozafar Khazaei, Mitra Bakhtiari, Elham Arkan, and Faranak Aghaz declare that they have no conflict of interest.   Dear Editor In response to very useful and stand comments of the letter regarding our paper titled “Anticancer Effect of Cisplatin-Loaded Poly (Butylcyanoacrylate) Nanoparticles on A172 Brain Cancer Cells Line”.  We have to say that, the focus of this paper was mainly on the anticancer activity of Cis-NPs and we would have looked at other properties such as time- dependent stability and NPs morphology or other experiments however, due to limited resources the possibility was none. We do also recommend in future research such properties should be address provide enough resources is available.


To the Editor:Prone position ventilation has been shown to improve oxygenation and survival in patients with severe acute respiratory distress syndrome (ARDS) . Facing PP Team consisted of five volunteers: a senior medical non-intensivist physician placed at the patient’s head to secure the endotracheal tube and four medical fellows or medical students placed at each side of the bed. For patients treated with VV-ECMO, a supplementary physician was added to secure the lines. Since PP is a complex procedure and has many potential adverse events requiring adequate and well-trained staff, volunteers received previously a theoretical training and a hands-on ad hoc training session. PP teams followed the guidelines for PP placement .This retrospective observational study was performed in our extended ICU (from 22 to 46 beds), from the first day of deployment of PPT .n = 63) are presented in Table The main characteristics and outcomes of prone positioned patients  observed in Guérin et al. study [This innovative management allowed three major benefits: (i) critical relief of permanent intensive care team’s workload; (ii) reduction of the nurse-to-patient ratio, permitting also the reassignment of critical care nurses to newly created ICUs; and (iii) devoid of any self-censorship for fear of overwork and burn-out, intensivist physicians were able to strictly follow PP guideline recommendations, ensuring the best standard of care for ARDS patients.Since the pathophysiology is poorly understood , 5, the


The Brain Health Study (BHS) of the Baltimore Experience Corps Trial (BECT) examined whether a randomized, controlled trial of an intergenerational social volunteer program, entitled Experience Corps, increased subregions of the amygdala related to socioemotional memory and risk for Alzheimer’s disease in aging adults. We further assessed functional correlates of these intervention-related changes and changes in aging adults’ developmental need to be generative, or, to give back to the well-being of others. The BHS simultaneously randomized 112 men and women  within BECT to evaluate intervention impact on biomarkers of brain health at baseline and annual follow-ups during the two-year trial. Intention-to-treat analyses revealed program-specific increases in the shape of the centromedial and basomedial regions of the left amygdala (p’s≤0.05 adjusted), which were correlated with increases in generativity (p’s =0.06). Meaningful social engagement buffered amygdalar declines important to preservation of emotionally salient memory and risk for dementia. Part of a symposium sponsored by Brain Interest Group.


Angiogenesis is the growth of new capillaries from the preexisting blood vessels. Glioblastoma (GBM) tumors are highly vascularized tumors, and glioma growth depends on the formation of new blood vessels. Angiogenesis is a complex process involving proliferation, migration, and differentiation of vascular endothelial cells (ECs) under the stimulation of specific signals. It is controlled by the balance between its promoting and inhibiting factors. Various angiogenic factors and genes have been identified that stimulate glioma angiogenesis. Therefore, attention has been directed to anti-angiogenesis therapy in which glioma proliferation is inhibited by inhibiting the formation of new tumor vessels using angiogenesis inhibitory factors and drugs. Here, in this review, we highlight and summarize the various molecular mediators that regulate GBM angiogenesis with focus on recent clinical research on the potential of exploiting angiogenic pathways as a strategy in the treatment of GBM patients. Gliomas arising from the glial cells in the central nervous system of adult brain are the most common primary intracranial tumors and account for 70–80% of all brain tumors –3. BasedPhysiological angiogenesis is a highly regulated process and is an essential one for the adequate supply of nutrients and oxygen to developing or healing tissues . It is cAngiogenesis is essential for tumor growth and progression. The tumor cells away from vessels experience hypoxia due to deficiency of blood and oxygen. Hypoxic environment induces cancer stem cells (CSCs) to differentiate toward endothelial progenitor cells and mature endothelium, which in turn generates new blood vessels inside the tumor. Tumors generate abnormal and functionally immature blood vessels due to deregulated factors such angiogenic growth factors, angiogenesis inhibitors, and other genetic factors by a process known as pathological angiogenesis . Blood vBrain tumor progression is closely associated with the formation of new vessels. Brain tumor angiogenesis is mediated through the action of many angiogenic factors, some of which are involved in normal angiogenesis Fig. . The besAngiogenesis is fueled by several pro-angiogenic cytokines in malignant glioma, among which VEGF is the most important signaling molecule. This family of cytokines has six VEGF isoforms  . VEGF-A VEGF plays an important role in the survival and proliferation of gliomas. VEGF mRNA expression was observed in low-grade gliomas with further upregulation in high-grade gliomas , 55. GliFGF is another pro-angiogenic growth factor, which is both present the tumor cells and as well as stored in the vascular basement membrane for sustained release and is upregulated during angiogenesis. Two forms of FGFs, FGF-1 or acidic FGF (aFGF or FGF1) and FGF-2 or basic (bFGF or FGF2), bind most commonly to the receptor tyrosine kinases FGFR-1 or FGFR-2 . FGF binFGF-2 is implicated in brain tumor progression and localizes in the microvasculature as well as in the tumor cells in human gliomas –66. bFGFPDGF family proteins are 45-kDa molecules and consist of four polypeptide chains , PDGF-C, and PDGF-D) and were originally purified from platelets. All the PDGF family polypeptides have a highly conserved growth factor domain, called the PDGF/VEGF homology domain involved in forming bisulphite bridges to form the PDGF dimers PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD . PDGF prSeveral studies demonstrate that gliomas express all the PDGF ligands –75. It wHepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding mesenchyme-derived cytokine consisting of a 60-kDa α-chain and a 30-kDa β-chain. It transduces signals by binding to its receptor and is a transmembrane tyrosine kinase encoded by c-MET. SF and c-MET are strongly increased in several tumors and is often associated with poor prognosis . HGF is SF/HGF and its receptor tyrosine kinase c-MET are expressed in brain tumors and were shown to promote tumor proliferation, migration, invasion, and angiogenesis. This ligand-receptor pair expression levels correlate with tumor grade, tumor blood vessel density, and poor prognosis . InhibitThe angiopoietins are glycosylated proteins that bind to Tie-2  receptors . Four tyAng-1 mRNA was localized in tumor cells while Ang-2 mRNA was detected in endothelial cells and causes blood vessel dissolution/destabilization, and it is identified as one the early marker of glioma-induced neovascularization , 91. AngC. elegans and D. melanogaster) to regulate the expression of TGF-β target genes [The TGF-β family of structurally related polypeptides and control several pro-tumorigenic functions like proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and angiogenesis. They signal through heteromeric complexes of type I  and type II (TβRII) transmembrane serine/threonine kinase receptors serine/threonine kinase receptor complexes which in turn triggers phosphorylation of the intracellular effectors, Smads  and gelatinase-B (MMP-9) are highly expressed in patients with WHO grade III brain tumors . Both thIt has been previously mentioned that angiogenesis is one of the most obvious hallmarks of most tumors including adult brain tumor (GBM), which significantly contrasts GBM from normal brain tissues , 113. HeIt has been reported that hypoxia-inducible gene 2 (HIG2) is a marker of hypoxia and it can serve as a diagnostic biomarker for several cancers including GBM, as a potential target for anti-angiogenesis therapy . FurtherA study reported by Francescone et al.  showed tA study reported that the PTEN molecular signaling act as a tumor suppressor gene, and it is often inactivated in several cancers including GBM . This stMore and more emerging studies have suggested that the targeted gene knockout techniques with well-designed experimental strategy could be effective in the treatment of GBM patients and other human diseases. Moreover, newly designed targeted drug delivery systems circumvent multidrug resistance and demonstrated an enhanced efficacy for GBM patient , 133. AdSeveral preclinical studies suggested that anti-angiogenic therapeutic agents enhance the efficacy of conventional treatments. A number of anti-angiogenic therapies have been evaluated in clinical trials as an alternative or complementary to conventional cancer treatments. Table The first anti-angiogenesis agent approved for clinical use for brain cancer is a drug called bevacizumab or avastin . Bevacizumab is a monoclonal antibody, and it functions like the physiological antibodies that the human body naturally produces as part of the adaptive immune system. Bevacizumab binds to VEGF and blocks signaling of the molecule and suppresses the formation of new blood vessel growth. Several phase II clinical trials have studied the therapeutic efficacy of bevacizumab as a single agent or in combination with chemotherapy or radiation for recurrent GBM. Bevacizumab as a single agent had significant anti-glioma activity in patients with recurrent glioblastoma  Table 22. A phasSome of these clinical trials also suggested that the anti-angiogenic therapeutic agents  Table  enhance More recent phase 2 trial suggested that the combination of bevacizumab and lomustine did not confer a survival advantage over treatment with lomustine alone in patients with progressive GBM . A randoAs discussed above, although anti-VEGF treatment indeed altered several abnormal characteristics of tumor vessels and was generally well tolerated leading to devascularization that limits tumor growth, a large fraction of patients develops toxicity and resistance to this treatment. Moreover, prolonged exposure to anti-angiogenic drugs blocks blood supply to the tumors leading to hypoxic environment which in turn is known to induce chemo-resistance and tumor progression. Therefore, the dose and time of initiation of anti-angiogenic treatment could play a significant role on the therapeutic benefit as the angiogenic inhibitors suppress the tumor growth by inhibiting the growth of blood vessels but does not necessarily kill cancer cells. Single-agent bevacizumab seems to have significant effects on vascular permeability and cerebral edema, suggesting that future trials should focus on the role of bevacizumab as the initial treatment of GBM before starting the chemotherapy treatment . The ass


An intraoperative real-time respiratory tumor motion prediction system with magnetic tracking technology is presented. Based on respiratory movements in different body regions, it provides patient and single/multiple tumor-specific prediction that facilitates the guiding of treatments.A custom-built phantom patient model replicates the respiratory cycles similar to a human body, while the custom-built sensor holder concept is applied on the patient’s surface to find optimum sensor number and their best possible placement locations to use in real-time surgical navigation and motion prediction of internal tumors. Automatic marker localization applied to patient’s 4D-CT data, feature selection and Gaussian process regression algorithms enable off-line prediction in the preoperative phase to increase the accuracy of real-time prediction.Two evaluation methods with three different registration patterns  were used quantitatively at all internal target positions in phantom: The statical method evaluates the accuracy by stopping simulated breathing and dynamic with continued breathing patterns. The overall root mean square error (RMS) for both methods was between The built system is proposed to predict respiratory motions of internal structures in the body while the patient is breathing freely during treatment. The custom-built sensor holders are compatible with magnetic tracking. Our presented approach reduces known technological and human limitations of commonly used methods for physicians and patients. The advantages of surgical tracking technology are used for real-time tumor or organ motion prediction aiming to guide the surgeries or therapies with minimal damage to the surrounding tissue around the target. In particular, treatments in stereotactic ablative radiotherapy (SABR) or stereotactic body radiation therapy (SBRT) while the patient is breathing freely are an important concern in clinical workflows for the safe and effective provision of precision radiotherapy, computer-assisted tumor surgery and biopsy interventions –4. ExistWe present a patient-specific approach that predicts internal tumor motions using real-time tracked skin sensors with magnetic tracking while giving to patient relaxed freely breathing condition. The respiratory cycle of the patient and thus the 3D temporospatial movements of the internal targets are observed from patient’s 4D-CT preoperatively. Our optimization technique  and custThis section describes the hardware and software components of the respiratory motion prediction system, possible clinical workflow and the implementation of respiTrack.To replicate the human respiratory system artificially and to predict the tumor motion based on the respiratory simulation, a custom-made realistic phantom model was built Fig. . The staSeveral real-time movement prediction techniques apply external surface sensors –8. HowevThe concept of the custom-made SH can improve the real-time prediction accuracy in intraoperative phase by optimizing the spatiotemporal distribution and alternating number of surface markers to use for each patient and multiple tumor movement prediction with respect to their predictive power in the preoperative phase. The improved SH design enables switching the tracking sensors while maintaining the same sensor origin and provides off-line prediction preoperatively using surface fiducials in SH and the pre-trained predictors with magnetic tracking during the intervention after the known relative transformation between the surface fiducials and the inserted real-time tracker sensor.The main component of the SH consists of a X-Spot CT skin fiducial , centered in a sensor attachment point. During the preoperative phase, Rhinospider (RS) is a novel registration technique used in combination with magnetic tracking to determine the accurate fiducial localization and optimize the workflow for patient-to-image registration . In thisA plugin-based prototype software system (respiTrack) featuring preoperative planning (off-line prediction), intraoperative registration, surgical navigation and real-time prediction was developed. All the required modules  were impThe individual steps Fig.  in respiFor the 4D-CT, a scanner  at the University Clinic for Radiology in Medical University of Innsbruck was used.The phantom model with 20 SHs within 7 targets was placed into the CT gantry and held at fully inhaled position by adjusting air in the balloon. , while less movements were observed in y (AP-anterior/posterior) and x planes (LR-left/right), respectively. The total movements assure consequently that internal marker movements are replicating very similar respiratory organ motions with internal organs of a human body, such as heart, lung, liver, trachea, prostate and spine [The detected marker locations for each 4D-CT phase were exported (input and target data) and used for training data during prediction. The observations represent the respiratory cycle of the patient and the 3D temporospatial movement variance of all surface and target markers for a half breathing cycle in 12 discrete time steps  during the GA search is represented by a chromosome of a k-dimensional binary vector nth bit (gene) in chromosome represents whether the nth SH marker is used for prediction 1 or not 0.An individual M is the number of enabled markers within the individual. For each I, the fitness function is defined by multi-objective function E(I) is the average RMS error between the predicted and target locations using X as the input feature set over a threefold cross-validation on the T time steps, S(I) is the number of features enabled, K is the maximum preferred number of enabled surface markers, and K enabled sensors. The GA in respiTrack was configured with generation size 60 (termination criteria), population size 600, crossover proba 0.5, mutation proba 0.2, cv independent proba 0.5 and mu independent proba 0.05.If a SH marker is selected to use, its 3D positional coordinates within the CT reference frame are added to the input coordinate set used for prediction. This yields I, the predictions were evaluated using 3 Gaussian process regressors (GPR)  for an individual target y) and patient maintains a fixed position relative to the field generator with or without breath held. The combined sensors and SH marker coordinates were matched The intraoperative image-to-patient registration was established, while 50 sensor location readings (relative to DRF) were averaged for every attached single sensor (dependent on the number of recommended sensor list or (FRE) .R is a y with read real-time test data During real-time prediction, each observed sensor readings ion Fig. . The GPRFor each target, the recommended number of SHs and their identified locations were used, respectively. The patient was then positioned in the FOV of tracker, and real-time sensor data (test data) were observed. The prediction accuracy was validated using RS ball within located sensor, which was intended to use as a tracked target marker .Load first patient dataset into respiTrack  Fig. , top.Fill air in the model until marked position on the handle regarding number of loaded dataset and perform patient-to-image registration.Perform real-time prediction for all targets, respectively, while holding the handle on the fixed position without changing the air in the model.Repeat same experiment for half inhaled (6th) and fully exhaled (12th) dataset.In dynamical method, the prediction was determined with the same steps (except 3) above while changing the amount of air in the patient between handle positions 1 and 12 repetitively   was applInstead of recommended SHs, randomly selected SH locations were used to cross-validate the results and to investigate different location of SHs on the accuracy effect between the motions of SHs and a target under various registration patterns Tables  and 5.TaIn this paper, we proposed a real-time respiratory motion prediction system that uses surface sensors to predict internal tumor motions Fig. . For magOur internal tests with the system serve reliable prediction accuracy and show a promising potential to be used in SABR and SBRT treatments or tumor and biopsy surgeries. The system overcomes many of the limitations of common clinical approaches and can be integrated into the existing clinical workflows in the medical environment.More rigid respiratory system designs (due to temporal expansion of the balloon’s volume, Table


Deep learning has become the dominant technology for protein contact prediction. However, the factors that affect the performance of deep learning in contact prediction have not been systematically investigated.ab initio approach of parsing domains from MSAs alone without using known protein structures was a simple, fast approach to improve contact prediction. Finally, we showed that predicting the distribution of inter-residue distances in multiple distance intervals could capture more structural information and improve binary contact prediction.We analyzed the results of our three deep learning-based contact prediction methods  in the CASP13 experiment and identified several key factors  that influenced the contact prediction accuracy. We compared our convolutional neural network (CNN)-based contact prediction methods with three coevolution-based methods on 75 CASP13 targets consisting of 108 domains. We demonstrated that the CNN-based multi-distance approach was able to leverage global coevolutionary coupling patterns comprised of multiple correlated contacts for more accurate contact prediction than the local coevolution-based methods, leading to a substantial increase of precision by 19.2 percentage points. We also tested different alignment methods and domain-based contact prediction with the deep learning contact predictors. The comparison of the three methods showed deeper sequence alignments and the integration of domain-based contact prediction with the full-length contact prediction improved the performance of contact prediction. Moreover, we demonstrated that the domain-based contact prediction based on a novel https://github.com/multicom-toolbox/DNCON2/.Bioinformatics online. Due to the advancement in the DNA/RNA sequencing technology (Apart from the direct correlated mutation (or coevolutionary) analysis, deep learning is a major technological innovation to improve contact prediction. After deep learning contact prediction was first introduced in 2012 , differeIn this work, we analyzed the results of our three deep learning-based contact prediction methods in the CASP13 experiment and explained why they significantly outperformed the coevolution-based methods (e.g. CCMpred). We demonstrated how the contact distance distribution prediction helped improve the performance of contact prediction and investigated how the Neff in MSAs, MSA generation protocols and domain parsing method contributed to the contact prediction improvement.Our MULTICOM contact predictors were based on the same deep learning architecture of DNCON2 trained on the same dataset . If some alignment contains ≥5L sequences (L: target sequence length), the one at the lowest E-value threshold was used; otherwise, the alignment at E-value of 1 was used. MULTICOM-CONSTRUCT first ran HHblits  domain, otherwise template-free modeling (FM) domain. For each FM domain, the two predictors searched the domain sequence against the databases to generate MSA for the domain as they did for the full-length target sequence. The full-length MSA was used to predict full-length contact maps and the domain-based MSA was used for predicting the domain-based contact maps. The predicted contact probabilities in the full-length contact map were replaced by their counterparts in the domain-based contact map if the latter were larger than the former. We also implemented the same domain splitting approach on DNCON3 that applied PSIBLAST and Jackhmmer to generate alignments. Our human contact predictor MULTICOM averaged contact predictions from our four server predictors. However, because DNCON3 and MULTICOM missed some CASP13 targets, they were not discussed in this work.The template-based domain parsing is time consuming and complicated. During the CASP13 experiment, we tested a simple method to directly detect domains or more strictly regions that have a significantly lower number of sequences than other regions in an MSA, aiming to search the individual domain/region against the sequence database again to collect more homologous sequences in order to generate better coevolutionary features for them. Specifically, we computed the number of sequences covering each residue position of a target sequence in an MSA. Using the median of the numbers as a cutoff, we defined a consecutive sequence fragment (with the length at least 30 residues) in the full-length sequence as a hard domain if the number of sequences of all the residue positions in the fragment was less than the cutoff value. The contact prediction of a domain was integrated with the full-length contact predictions by MULTICOM-CLUSTER and MULTICOM-CONSTRUCT as in Section 2.2.https://predictioncenter.org/). The emphasis of the evaluation was placed on the precision of long-range contacts with sequence separation ≥24 residues.We evaluated our contact predictors on all these 108 structural domains of 75 official CASP13 targets, including 43 FM and FM/TBM domains. To be consistent with the CASP convention, contact predictions were evaluated at domain-level. We used ConEVA , Neff, to estimate the quality of alignments. It was calculated as the following function:β atoms in the native structure is below 8.0 Å. A contact is considered long-range if the sequence separation between the two residues of the contact is at least 24 residues away in the protein sequence. A contact with sequence separation between 12 and 23 residues is at medium range and between 6 and 11 residues at short range. We focus on evaluating the precision of top L/5, L/2 and L predicted long-range contacts ranked by contact probability scores. L is sequence length. We compare our deep learning predictors with three coevolution methods, including CCMpred (based on pseudo-likelihood maximization), Freecontact  and PSICOV (sparse inverse covariance estimation). The results are shown in We follow the CASP definition that a pair of residues are in contact if the distance between their CIt shows that the deep learning-based methods outperformed the coevolution-based methods on all ranges  for top L/5, top L/2 and top L predicted contacts. For instance, for top L/5 long-range predicted contacts, the precision of the best performing predictor—MULTICOM-CLUSTER was 70.7%, substantially higher than 43.4% of CCMpred, 36.2% of Freecontact and 38.1% of PSICOV. One reason that the deep learning predictors perform much better is that the CNN is able to detect the correlation between contacts within a certain region in the input matrices (e.g. a group of contacts between two beta strands). The size of the region depends on the size of the total receptive field captured by convolutions . For insP-value is 6.5E-8 under the hypothesis that the correlation coefficient is 0, indicating the correlation between Neff and contact precision is significant.The coevolution-based feature is the most important input feature for contact prediction. The reliable calculation of coevolutionary scores requires a large number of diverse homologous sequences in an MSA. We found that deeper alignment with more diverse homologous sequences (higher Neff) usually resulted in higher contact prediction precision for the deep learning predictors, which is expected because higher Neff generally leads to better coevolutionary input features for them. Neff of MSAs depends on the alignment methods used with the deep learning predictors. To compare the quality of MSAs generated by the three predictors, we ran CCMpred, Freecontact and PSICOV on their alignments to generate coevolution-based contact predictions and evaluated the precision of top L/5 long-range predicted contacts. It has been shown that integrating domain-level contact predictions with full-length contacts can improve contact prediction precision, especially when domain boundaries can be accurately identified . The reaab initio method) to split the full-length sequence of a target into domains. We evaluated the performance of two domain-parsing methods with MULTICOM-CLUSTER along with its full-length contact prediction on the domains of all 65 CASP13 FM, FM/TBM and TBM-hard domains  at the first stage, which was used as input together with the original input features to predict the final contact map at the second stage. On the 108 domains of 75 CASP13 targets, we compared the contact prediction precision of using or not using the predicted contact distance distribution as the extra input .The result shown in The size of protein sequence databases affects how many homologous sequences may be found for a target. After the CASP13 experiment, we noticed that some groups used the metagenomics sequence database not used with our predictors to find more homologous sequences for some CASP13 targets than our methods. After CASP13, we updated the alignment generation pipeline MULTICOM-CLUSTER to include an extra search on a large metagenomic protein sequence database Metaclust50 that was built from 1.6 billion metagenomic sequence fragments with ≤50% sequence identity . MULTICOThe deep learning predictors generally tend to work well if there is a sufficient number of diversely related homologous sequences available. However, the sufficiency is target-specific. When there are fewer homologous sequences available for a target, they can still leverage weak signals in shallow alignments and perform well in some cases. Moreover, a larger Neff in the alignment does not always lead to the increase of prediction accuracy with our deep learning predictors. For example, MULTICOM-NOVEL overperformed MUTICOM-CLUSTER by 22 percentage points (94.44% versus 72.22%) on T1015s1-D1 according to the precision of top L/5 contact predictions , while tWe further applied two external methods, CCMpred and ResPRE , which iWe evaluated the performance of our three CASP13 deep learning-based contact prediction methods  and investigated the key factors that affected their performance. We showed that leveraging residue–residue interactions and contact correlations within an area  in the input matrices captured by multi-layers of convolutions was a key reason that the deep learning methods substantially outperformed the local contact prediction methods that treated each pair of residues independently. Through multiple layers of convolutional feature extraction, the deep learning methods could capture the long-range interactions between residues and correlations between contacts to improve contact prediction. Our experiment also demonstrated that predicting the distance distribution of inter-residue distance in multiple distance intervals was able to capture more structural information than a binary contact map at a single distance threshold. Leveraging the distance distribution can improve contact prediction.The accuracy of contact prediction also depends on the number of effective (true) homologous sequences. Therefore, the sensitive sequence search protocol is important for further improving contact prediction. The Neff is also related to the size of protein sequence database. We confirmed that the metagenomics sequence database contained some sequences not in widely used Uniref90 and Uniclust30 databases and should be used if necessary.Domain parsing is also important to improve contact prediction, which is especially useful for domains for which few homologous sequences are found during the full-length sequence search. We demonstrated that a fast, simple domain-based contact prediction methods based on MSAs alone could consistently improve contact prediction accuracy over the full-length contact prediction, even though it was less accurate than the domain-based contact prediction based on the template-based domain parsing.It is worth noting that another key factor that affects the accuracy of inter-residue contact prediction is the architecture of deep learning models and how they are trained, which are not investigated in this work. In the CASP13 experiment, some external deep learning methods performed better than our predictors, partially due to the difference in the architecture design and training strategy . The selMoreover, in the future, we will design more advanced deep learning architectures to predict more detailed inter-residue distance relationships  and apply them to build protein structures from scratch, and rank protein structural models (btz679_Supplementary_DataClick here for additional data file.


Transpedal access is increasingly utilized for the treatment of peripheral artery disease (PAD). Femoral-popliteal artery chronic total occlusions (CTOs) are some of the most difficult lesion subsets that sometimes require the use of re-entry support devices during percutaneous intervention. Limited data is available on the use of re-entry devices when treating femoral-popliteal CTOs via transpedal access. The aim of this study was to demonstrate the feasibility of using the Outback® Elite re-entry device for the treatment of femoral-popliteal CTOs via the transpedal approach in an outpatient based lab setting.Seventeen patients presented with femoral-popliteal CTOs in which treatment required the use of the Outback® Elite re-entry device. All procedures were performed in a single outpatient based lab. Patients were followed at 1 week and 1 month post-procedure, with lower extremity arterial duplex ultrasound assessment during the 1 month follow-up.The average patient age was 78 years-old, with 71% being males. Most patients presented with Rutherford class IV symptoms. Procedural success was achieved in all patients with no requirement to convert to femoral artery access in any of the cases. No immediate post-procedural complications nor at any time during follow-up were observed. Ultrasonography at 1 month follow-up showed patent intervention sites and access site vessels in all patients.The use of the Outback® Elite re-entry device for the treatment of femoral-popliteal CTOs via transpedal access is a feasible option and may have potential benefits by avoiding risks associated with traditional femoral artery access. Peripheral arterial disease (PAD) is a common and debilitating condition that affects an estimated 202 million people worldwide  and subsequent cross-over, or ipsilateral antegrade CFA access. However, femoral access site complication rates have been reported to be as high as 2.3% and comprise a significant proportion of overall procedural related complications  in the superficial femoral artery (SFA) or popliteal artery remain one of the hardest lesion subsets to treat and sometimes require re-entry from a dissection plane back into the vessel true lumen. In this case series, we show the feasibility of using the Outback® Elite re-entry device for the treatment of femoral-popliteal CTOs via transpedal access.Seventeen patients who failed conservative management for lifestyle limiting claudication or critical limb ischemia (Rutherford class III or higher) were identified and underwent diagnostic angiograms which demonstrated femoral-popliteal CTOs. Following discussion of possible treatment options, including vascular bypass, a collective decision was made to proceed with percutaneous endovascular intervention for each patient. All procedures were performed via transpedal access in a single outpatient based lab setting. The transpedal approach was selected due to known prior difficulty and failed standard CTO revascularization attempts in each of the patients.All patients were brought to the catheterization laboratory and prepared in standard fashion for a diagnostic unilateral peripheral angiogram. An ultrasound was performed to determine which vessel – anterior tibial artery (ATA), posterior tibial artery (PTA), or peroneal artery would be the appropriate access site. The pedal area on the ipsilateral side of the affected leg was then prepared in sterile fashion and a 21-gauge micropuncture needle was used for arterial access under ultrasound guidance followed by placement of a 4-Fr Glidesheath (Terumo). After confirming arterial flow, 5000 units of heparin were given intravenously and an antispasmodic cocktail of nitroglycerin 100 μg and verapamil 2.5 mg was administered into the sheath. To achieve an activated clotting time (ACT) > 300 s, additional heparin was given if needed. A routine diagnostic angiogram was performed and a femoral-popliteal CTO was encountered in each case. Secondary arterial access was obtained via the RA for antegrade injections. All patients received conscious sedation (fentanyl and/or midazolam) as well as local anesthesia.The Outback® Elite re-entry device (Cordis) was used after initial wire escalation attempts failed to re-enter into the true lumen of the stenotic lesion. For each procedure, radial access was obtained using a 4-Fr sheath, which was eventually upsized to a 6-Fr Slender Glidesheath (Terumo) to allow use of the Outback re-entry device. Final treatment of the CTO with angioplasty and/or stenting was performed at the discretion of the operator. Procedural success was defined as successful re-entry into the true vessel lumen with < 20% residual stenosis at the target lesion by the end of the procedure. Based on our prior success and low complication rates using the TR band (Terumo) and VasoStat  devices to achieve hemostasis at different transpedal puncture sites, we implemented the same previously described technique in all the cases  trunk into the proximal peroneal artery CTO with zero vessel runoff was identified . Pedal vessel selection and determining the appropriateness of the access site should be guided by duplex ultrasound. In addition, it is important to be aware of potential procedure complications such as vessel perforation, and dissection of the treated or accessed vessel. For these reasons, the contralateral femoral site should be always prepared in case of bailout.This is a small, single center retrospective series of selected patients and larger studies are necessary to better evaluate safety and efficacy. For the purposes of this paper, follow-up was limited to 1 month and our results cannot be extrapolated to determine long-term vessel patency using this approach. Furthermore, the procedures were performed by operators familiar with transpedal access and the results may not be generalizable to those with less experience in the transpedal technique especially since ultrasound guided access may be difficult and time-consuming to operators unfamiliar with the approach.While radial access was still necessary to visualize the proximal cap and length of the CTO, smaller 4-Fr sheaths are still utilized and the femoral artery is still avoided which will result in less complications. Furthermore, Clark et al. reported a case of transpedal only access for treatment of a superficial femoral artery CTO - which highlights the fact that in some cases the filling of the proximal cap through collaterals may be sufficient  (Clark et al. The treatment of femoral-popliteal CTOs can be successfully performed using the Outback® Elite Re-entry device via the transpedal approach – an innovative access site that may help with the current healthcare trend of cost containment while increasing patient safety.


Background and Objectives: Acne, an inflammatory disorder of the pilosebaceous unit associated with both physiological and psychological morbidities, should be considered a chronic disease. The application of self-regulation theory and therapeutic patient education has been widely utilized in different health-related areas to help patient with a chronic disease to attain better behavioral modification. The present study aims at investigating the treatment efficacy of combining a self-regulation-based patient education module with mobile application in acne patients. Materials and Methods: This was one-grouped pretest–posttest design at a single tertiary referral center with the enrollment of 30 subjects diagnosed with acne vulgaris. Relevant information was collected before (week 0) and after (week 4) treatment in the present study, including the Acne Self-Regulation Inventory (ASRI), Cardiff Acne Disability Index (CADI), and Dermatology Life Quality Index (DLQI) that involved a questionnaire-based subjective evaluation of the patient’s ability in self-regulation and quality of life as well as clinical Acne Grading Scores (AGS) that objectively assessed changes in disease severity. To reinforce availability and feasibility, an individualized platform was accessible through mobile devices for real-time problem solving between hospital visits. Results: Thirty subjects completed the designed experiment. An analysis of the differences between scores of pretest and posttest of ASRI demonstrated substantial elevations (p < 0.001). The questionnaire survey of CADI and DLQI dropped significantly after the application of a self-regulation-based patient education module with a mobile application, revealing substantial reductions in both parameters (p < 0.001). The sign test demonstrated a remarkably significant difference in AGS , indicating notable improvement in the clinical severity of acne after treatment. Conclusions: After incorporating modern mobile application, a self-regulation-based therapeutic patient education module could significantly improve treatment outcomes among acne patients. Like other chronic diseases, acne has recently been categorized as a chronic  inflammaMany studies have reported successful therapeutic experience through combining medical treatment with a well-designed patient education program . Self-reThrough utilizing a mobile application incorporated with SRT and TPE, the present study attempted to build a therapeutic module that would benefit acne patients as well as dermatologists and nurse practitioners who care for this patient population. It focused on 4-week follow-ups of acne outpatients whose treatment course can easily be traced and analyzed by their mobile devices. To reinforce availability and feasibility, an individualized platform was accessible for real-time problem solving by a live chat bot through the mobile application.From December 2018 to December 2019, all participants visiting a single tertiary referral center  with a confirmed diagnosis of acne made by qualified dermatologists were enrolled. All patients had attended scheduled study follow-up visits at the dermatology outpatient clinic and signed informed consent forms for participation in the study.The inclusion criteria were: (a) ≥14 years old; and (b) diagnosed with acne by qualified dermatologists of E-Da Hospital. The exclusion criteria were: (a) illiterate; (b) diagnosis of systemic diseases, endocrinologic and psychiatric disorders; (c) pregnant; (d) subjects taking isotretinoin or systemic corticosteroids within 30 days; (e) those taking systemic medications likely to aggravate or abate acne such as oral phenytoin or any other epileptic, finasteride, spironolactone, or flutamide, or testosterone; (f) individuals receiving facial procedures such as chemical peeling, laser, microdermabrasion, or phototherapy within 30 days.The current study adopted a one-grouped pretest–posttest design at a single medical care center with the enrollment of 30 subjects diagnosed with acne vulgaris. The study duration was 4 weeks with visits at week 0 (baseline) and week 4. Relevant information was collected before (week 0) and after (week 4) treatment, including an objective assessment of acne severity by dermatologists with the Acne Grading Scores (AGS) as well as patients’ subjective evaluation of their self-adjustment ability using the Acne Self-Regulation Inventory (ASRI) and the negative impacts on their life quality using the Cardiff Acne Disability Index (CADI) and the Dermatology Life Quality Index (DLQI).The self-regulation-based therapeutic patient education module was a four-step process . The aimhttps://mobile.facebook.com/profile.php? id = 2329997470545842, titled Acne Expert, accessed from 01 December 2018. The study protocol was approved by the institutional review board (IRB) of E-Da Hospital and conducted in compliance with the Declaration of Helsinki .Additionally, during the 4 weeks before the final visit, a Dermatological Live Chat Bot (DLCB)  was buil(a)Acne Grading Scores (AGS): A very simple grading of clinical acne severity was described in the 2003 report from the Global Alliance for better outcomes of acne treatment . This ba(b)Acne Self-Regulation Inventory (ASRI): ASRI comprises in total 31 items based on four subscales of the self-regulation theory, including self-monitoring (6 items), a self-judgment subscale (6 items), a self-reaction subscale (12 items), and self-motivation (7 items). A 4-point Likert scale was used to assess the subjects’ responses to their understanding of the disease and treatment method as well their compliance to the proposed therapeutic strategy . The sco(c)Cardiff Acne Disability Index (CADI): The index is a brief and simple 5-item questionnaire designed to assess the disability caused by acne regarding the negative emotional and social impacts of acne on patients’ daily lives. Hence, the questionnaire is a patient’s subjective assessment of acne-induced disability, and provides relevant information to dermatologists . The hig(d)Dermatology Life Quality Index (DLQI): The index is the most widely used quality of life instrument for patient self-evaluation of dermatological problems. The testing subjects are asked to choose the most appropriate answers to ten questions involving the emotional, social, and physical aspects affecting their quality of life by the disease ,28. The p < 0.05 was considered statistically significant.All statistical analyses were executed using the SPSS software . Paired-sample t tests and sign tests were applied to evaluate the significance of difference between pretest and posttest scores for the continuous  and categorical (AGS) variables, respectively. A The thirty participants mentioned in p < 0.001)  , suggestp < 0.001)  , suggestp < 0.001)  , indicatAcne, a pilosebaceous inflammatory disorder  related Because the concept of SRT suggests that human behaviors are the result of interactions between the individual, environment and behavior, the module of the present study was developed in three dimensions: (1) dermatologists for acne outpatient assessment; (2) nurse practitioners for the clarification of educational objectives; and (3) patients for the completion of objective questionnaires. The results of the current study showed that combining the three-dimensional interventional approach with an internet live chat bot platform that not only provided unrestricted patient access to acne treatment information but also allowed real-time feedback from the patients could significantly reinforce treatment efficacy. Furthermore, the mobile device-assisted self-regulation-based therapeutic patient education module could be applied to other typically incurable chronic skin diseases, such as atopic dermatitis or psoriasis vulgaris, taking into consideration its time-effectiveness and the importance of minimizing social contacts to reinforce the policy of social distancing during the period of a viral pandemic . There are several limitations to this study. Firstly, the number of study subjects was relatively small. Secondly, all patients were enrolled from a single medical institute; therefore, the results may not be globally applicable. However, the results demonstrated significant improvements, highlighting the therapeutic effectiveness of combining a self-regulation module with a mobile application for patients with acne in both physical and psychological aspects; not only could it alleviate the clinical severity of acne but it could also enhance the patients’ self-regulation capability as well as improve their acne-induced disability and their quality of life.It is necessary for dermatologists to educate their patients that acne is a chronic disease instead of a self-limiting disorder. By utilizing an internet platform on mobile devices, the implementation of an effective self-regulation-based therapeutic patient education module for acne patients could be a time- and cost-effective measure that enables constant modifications of education and therapeutic strategies through real-time bilateral interactions to meet therapeutic goals without the restrictions of time and space.


In recent years, cell-free extracts (or lysates) have (re-)emerged as a third route to the traditional options of isolated or whole-cell biocatalysts. Advances in molecular biology and genetic engineering enable facile production of recombinant cell-free extracts, where endogenous enzymes are enriched with heterologous activities. These inexpensive preparations may be used to catalyse multistep enzymatic reactions without the constraints of cell toxicity and the cell membrane or the cost and complexity associated with production of isolated biocatalysts. Herein, we present an overview of the key advancements in cell-free synthetic biology that have led to the emergence of cell-free extracts as a promising biocatalysis platform. Evolution has bestowed enzymes, nature’s catalysts, with remarkable catalytic prowess which is unrivalled by man-made catalysts  prepared from engineered recombinant cells as an inexpensive source of all requisite enzymatic activities H. In in vitro reactions, these expensive compounds act as co-substrates and are required in prohibitive stoichiometric amounts. Biochemists have overcome this obstacle by coupling the reaction of interest with an auxiliary enzymatic reaction which regenerates the spent cofactor using an inexpensive substrate Fig.  Zhao an. This enSeminal work in cell-free protein synthesis applications identified the possibility of utilising endogenous enzymes, already present as inert contaminants in the cell-free extract, to catalyse cofactor recycling. Spirin and co-workers reported that the requirement of ribosomal protein synthesis for ATP and GTP could be met through endogenous recycling with the same inexpensive substrates proposed by Whitesides  were achieved with ~900 turnovers of the NADH cofactor necessary for the final reduction of acetoin to 2,3-butanediol. The same group also employed this approach for the production of mevalonate, an important intermediate in the synthesis of isoprenoids NTP mixtures for direct use in biotechnologically important polymerase-catalysed syntheses of mRNA (cell-free protein synthesis) or DNA (PCR) Fig.  Alissan. Endogen−1 h−1 yield, from simple and inexpensive feedstocks, namely, sugar and nucleobase  in g L−1 h−1 citrulline. As before, the acetyl phosphate is produced from acetic anhydride and inorganic phosphate in a separate reaction  into nitrogen-rich citrulline (Alissandratos et al. ion Fig. . ImportaVibrio natriegens (Des Soye et al. The ever-growing interest in cell-free synthetic biology and the accompanying development of new tools and methodologies holds great promise for future application of cell-free extract biocatalysts (Bundy et al. The application of cell-free extracts in industrial biocatalysis will require readily scalable straightforward production methodologies and stable formulations. Cell-free extracts are already generated as intermediates in the production of isolated commercial biocatalysts; therefore the necessary bioprocesses are already available at scale (Tufvesson et al. All in all, the future appears bright for this emerging cost-efficient biocatalysis platform that has already been applied successfully for the synthesis of an array of important platform and fine chemicals. Nonetheless, widespread application of such cell-free systems will also require a better understanding of the physiochemical interactions involved. As recently illustrated, changes in reaction parameters may strongly impact the performance of cell-free extract-catalysed transformations (Karim and Jewett


Transposition of the great arteries is a congenital heart defect defined by an abnormal connection between the aorta, pulmonary artery, and the ventricles, resulting in parallel systemic and pulmonary circulations. Long-term follow-up data of patients who underwent correction via an arterial switch operation have recently shown that as a result of re-implantation of the coronary arteries in the neo-aorta, coronary stenosis and occlusion are relatively common complications. In this report, we discuss two cases illustrating the added value of myocardial perfusion imaging (MPI) and cardiac CT for the assessment of these patients. Based on the available literature we conclude that MPI and cardiac CT are excellent non-invasive methods to evaluate coronary anatomy and myocardial function also in this specific group of patients.The online version of this article (10.1007/s12350-019-01738-4) contains supplementary material, which is available to authorized users. The venous blood is re-introduced in to the systemic circulation, without crossing the pulmonary circulation for oxygenation. Because of the separate pulmonary and systemic circulation, children present with severe arterial desaturation at birth. To support life there has to be a connection between the 2 circulations, either via an atrial septal defect (ASD), a VSD, or patent arterial duct. The neonate oxygen saturation of the systemic circulation is completely dependent on shunting through these connections.When TGA is diagnosed, prostaglandins are used to prevent the arterial duct from closing. In addition, the resistance in the pulmonary vascular bed is lowered after birth. This results in an increased left-right shunt and thus improved pulmonary flow. In turn this leads to increased volume and pressure in the left atrium and thus left-right shunt on atrial level (given an ASD or VSD), creating an increased and oxygen-rich blood inflow from the left atrium and as a result higher oxygen saturation in the systemic circulation.Surgical treatment of TGA is one of the most successful achievements in the history of congenital heart defects surgery. Without treatment, 30% of the children die within 1 week after birth, 50% in one month, and 90% within one year. After surgical repair, mortality and morbidity rates decrease dramatically.3First step in treatment is stabilization by creating a shunt possibility on the atrial level, usually through balloon septostomy .2In 5%-15%, long-term complications occur; the most important being pulmonary hypertension caused by stenosis of the pulmonary artery or in other levels of the right ventricular outflow tract (RVOT).10We present two cases of teenage patients with a history of transposition of the great vessels and arterial switch procedure.A 13-year-old boy presented with signs of ischemia on ECG during exercise stress test. Exercise testing was performed according to the Bruce protocol. ST-segment changes were observed after 12-15 minutes of exercise. There was ST depression in leads V4-V6 and II, aVF. The patient had no clinical complaints and exercise test was performed on routine clinical evaluation.99mTc-tetrofosmin (stress) and 487 MBq 99mTc-tetrofosmin (rest).Gated single-photon emission computerized tomography (SPECT) myocardial perfusion imaging (MPI) after symptom limited bicycle ergometry and at rest was performed to rule out myocardial ischemia (2-day stress rest protocol). Patient exercised for 9 minutes with a stress/exercise tolerance of 123 Watt and a maximum heart rate of 181 beats/minute (87% of the age-predicted maximum heart rate). Rest ECG showed no abnormalities. On stress ECG ST depression was seen at the end of the exercise (V4-V6), with normalization during recovery , approximately involving 10% of the left ventricle Figure . There wContrast-enhanced cardiac CT showed a normal aspect and course of the RCA. There was an occlusion at the origin of the LCA. More distal there was filling of the LAD and Cx, probably by collaterals and retrograde filling via the RCA Figure . CoronarAfter multidisciplinary consultation a CABG was performed (LIMA-LAD). MPI was repeated after CABG and showed significant improvement of myocardial perfusion, with only a small area of inducible hypoperfusion remaining in the mid-anterior wall  Figure . There wA 15-year-old boy with a history of arterial switch for TGA presented with reduced exercise tolerance.99mTc-tetrofosmin stress/rest myocardial perfusion was performed to rule out ischemia (2-day stress rest protocol). Patient exercised during 11 minutes with a stress/exercise tolerance of 87 Watt and a maximal heart rate of 150 beats/minute (73% of the age-predicted maximum heart rate). Exercise was discontinued because of recognizable dyspnea complaints. Rest ECG showed a sinus rhythm with indifferent cardiac axis and a complete right bundle branch block. There were high amplitudes in the right precordial leads indicating a right ventricle hypertrophy. There were no evident signs of ischemia on stress ECG . This patient is still in follow-up and doing fine (6-month follow-up).Coronary artery complications are relatively common after an arterial switch procedure. In a study of Bonnet et al., evaluating 64 patients who underwent an arterial switch procedure, 12% of the patients had stenosis or occlusion of the coronary arteries on long-term follow-up i.e., 7 years). years.7In young childhood, these coronary artery lesions do not  cause ischemia because the formation of an extensive collateral network maintains left ventricular blood supply. As patients grow older, collateral network may fall short, resulting in ischemia.In our patients, the presence of a significant collateral circulation from the RCA to the left coronary arterial system maintained perfusion in LAD territory at rest. At stress however, the collateral network failed, causing myocardial ischemia. 14All individuals with congenital heart disease (CHD) require some sort of follow-up to monitor cardiac function, disease progression, and the occurrence of complications whether or not related to surgical correction. Transthoracic echocardiography (TTE) is, because of its widespread availability and low cost, the mainstay for follow-up for most CHD. TTE has several limitations, mostly related to limited field of view, which may inhibit the visualization of essential structures such as the great vessels. Usually cardiac MRI is the first choice when information from TTE is incomplete, especially in younger patients. However, when small structures such as coronary arteries are the subject of investigation contrast-enhanced cardiac CT is a better option because of its superior spatial resolution and fast acquisition time.15Early studies opted that non-invasive screening tools for coronary artery insufficiencies in patients with an arterial switch procedure were inadequate because of relatively high radiation doses and low sensitivity and that screening should be performed by invasive coronary angiography.20In favor of using MPI in these patients is the known relation between the outcome of exercise MPI and cardiovascular risk. In patients with complaints or new ECG abnormalities after an arterial switch procedure, MPI and cardiac CT are essential in the functional and anatomical evaluation of coronary arteries. Furthermore, it is important to realize that prominent visualization of the right ventricle on post-stress myocardial perfusion scintigraphy as the only sign of diffuse left ventricular ischemia also occurs in children and young adults.Late outcome of the arterial switch procedure in TGA may be influenced by complications concerning the coronary arteries. Complete occlusion may occur early in life and is often counterbalanced by extensive collateral perfusion. As patients grow older, this collateral network may fall short, resulting in (diffuse) ischemia of the left ventricle. With recent CT developments, especially on dose reduction, CT and myocardial perfusion scintigraphy (MPS) are excellent non-invasive methods to assess coronary anatomy and function. Furthermore, it is essential to be aware that prominent visualization of the right ventricle on post-stress MPS may be the only sign of diffuse left ventricular ischemia .Supplementary material 1 (MP4 9437 kb)Supplementary material 2 (MP4 12016 kb)Below is the link to the electronic supplementary material.


A combitivation . Producttivation . GI tracAmong the lifestyle factors most strongly implicated in PD pathogenesis are diet and physical activity. Consumption of a Western diet is a risk factor for PD whereas diets high in fiber are associated with reduced risk. While diet has many effects on the body , diet robustly impacts the intestinal microbiota. Consumption of a Western diet promotes pro-inflammatory intestinal microbiota dysbiosis, characterized by a high relative abundance of LPS-containing bacteria and low relative abundance of SCFA-producing bacteria , which cHow does dysbiotic microbiota trigger/promote neuroinflammation? The microbiota has many features that can influence inflammation, but compelling evidence indicates that low SCFA and high LPS [via binding to toll like 4 receptor (TLR) leading to activation of the NLRP3 inflammasome] are important. SCFA are thought to be anti-inflammatory with an inverse relationship observed between SCFA levels and pro-inflammatory cytokines such as IL-6, IL-12, and TNF-α . SCFA caThis special issue will present evidence demonstrating the critical role of the intestinal microbiota and the immune system in PD pathogenesis, as well as how diet and physical exercise might impact PD disease course . This special issue highlights the potential importance of the bi-directional relationship of the brain and intestinal microbiota and microbiota/immune system in PD underscoring the need to better understand the microbiota-gut-brain axis in PD in order to identify potential therapeutic target(s) to design scientifically-based, gut/microbiota-directed disease modifying therapeutics to prevent and/or treat PD and positively impact PD disease course.GA conceived the idea of this topic and managed most of the reviews. Consequently, he developed a first draft of this contribution, reporting the highlights of the topic, and gave specific aspects about physical activity. AK supervised this work and gave a significant contribution about the role of GA. SA supervised the contribution and offered specific aspects about immune system. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.