Endometriosis is caused by the growth or infiltration of endometrial tissues outside of the endometrium and myometrium. Symptoms include pain and infertility. Surgery and hormonal therapy are widely used in Western medicine for the treatment of endometriosis; however, the side effects associated with this practice include disease recurrence and menopause, which can severely influence quality of life. Angiogenesis is the main biological mechanism underlying the development of endometriosis. Numerous natural products and Chinese medicines with potent anti-angiogenic effects have been investigated, and the molecular basis underlying their therapeutic effects in endometriosis has been explored. This review aims to describe natural products and compounds that suppress angiogenesis associated with endometriosis and to assess their diverse molecular mechanisms of action. Furthermore, this review provides a source of information relating to alternative and complementary therapeutic products that mediate anti-angiogenesis. An extensive review of the literature and electronic databases, such as the China National Knowledge Infrastructure, PubMed, and Embase, was conducted using the keywords ‘endometriosis,' ‘traditional Chinese medicine,' ‘Chinese herbal medicine,' ‘natural compounds,' and ‘anti-angiogenic' therapy. Anti-angiogenic therapy is an emerging strategy for the treatment of endometriosis. Natural anti-angiogenic products and Chinese medicines provide several beneficial clinical effects, including pain relief. In this review, we summarize clinical trials and experimental studies of endometriosis using natural products and Chinese medicines. In particular, we focus on anti-angiogenic products and alternative and complementary medicines for the treatment of endometriosis and additionally examine their therapeutic efficacy and mechanisms of action. Anti-angiogenic natural products and/or compounds provide a new approach for the treatment of endometriosis. Future work will require randomized trials with larger numbers of subjects, as well as long-term follow-up to confirm the findings described here. In vitro and in vivo evidence suggests that pathogenesis may be related to abnormalities in nerve fibers, abnormal expression of nerve growth factors, and/or abnormal expression of inflammatory factors. Recent studies also suggest a link between angiogenesis and the growth of new nerve fibers, which together affect endometriosis associated pain [Endometriosis is a gynecological disease in which functional endometrial glands and stroma are implanted outside of the uterine cavity. This is a common benign disease in women of reproductive age , 2. The ted pain . Neurovaɑ (TNF-ɑ), and anti-angiogenic factors are new treatments for endometriosis [At present, endometriosis is difficult to cure, with only symptomatic forms of treatment available. These main treatments include surgery, drug treatment, and long-term comprehensive individual treatment . Traditietriosis , 10. Theetriosis . It is ietriosis . ConsequComplementary and alternative medicines may provide new strategies for the management of chronic pelvic pain associated with endometriosis. Several anti-angiogenesis treatments have been shown to shrink lesions, loosen pelvic tissue adhesions, reduce pelvic congestion, relieve pelvic pain, and improve ovarian function . In endo in vivo and in vitro studies were included. However, it is important to note that this study incorporates research based on basic research and is not a systematic review.A literature search was performed in China National Knowledge Infrastructure, PubMed, and Embase for original articles written in English or Chinese and electronically listed before May 2018. The search included the following key words: ‘endometriosis,' ‘angiogenesis,' ‘anti-angiogenic,' ‘angiogenesis inhibitor,' ‘ectopic endometrium,' ‘natural product,' ‘natural compound,' ‘Chinese medicine,' ‘alternative and complementary,' and ‘Chinese medical practitioners.' Basic and clinical research, andThe mechanistic basis for endometriosis is most likely to represent a complex network process that includes immune responses , inflammVEGF and its receptor, VEGFR, are powerful angiogenic factors that play important roles in tumor formation and other angiogenesis-associated diseases. VEGF affects endothelial cell proliferation, migration, and permeability , 19. Theɑ, cyclo-oxygenase (COX), and hypoxia-inducible factor 1α (HIF-1). MMPs degrade the extracellular matrix and are key components of endometrial adhesion and angiogenesis [ɑ promotes angiogenesis during the progression of endometriosis. There is a strong relationship between the TNF-α gene promoter region -1031T/C polymorphism and endometriosis [κB) may also be involved in the endometrial biological alterations associated with endometriosis [Furthermore, immune and inflammatory proteins are closely linked to angiogenesis . Numerouogenesis , 27. TNFetriosis . COX inhetriosis . Prostagetriosis . Toll lietriosis . These fNeuro-angiogenesis and angiogenesis are essential for the development of endometriosis. Anti-angiogenic compounds may inhibit early-stage or post-surgical endometriotic lesions . Numerou GnRH analogues  has been shown to induce apoptosis and reduce angiogenesis by increasing the expression of Bax and Fas-ligand (FasL) and decreasing Bcl-2, VEGF-A and interleukin-1 beta (IL-1β) in eutopic endometrial cell cultures [ Dienogest  is a novel progestin that is highly selective for progesterone receptors and inhibits endometriosis. Dienogest has been shown to reduce proliferation, aromatase expression and angiogenesis, and increase apoptosis in human endometriosis cells [The role ofcultures . Dienogeis cells .Angiogenesis inhibitors  are substances that antagonize or inhibit the development of new blood vessels, and target angiogenesis-related targets. These inhibitors specifically target either angiogenic factors or tyrosine kinases involved in the regulation of angiogenic pathways. Bevacizumab is a humanized anti-VEGF monoclonal antibody used in the treatment of cancer. There is some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signaling cascades described above. The anti-VEGF antibody, bevacizumab, was as effective as GnRH agonists in the regression of endometriotic lesions in a rat endometriosis model, and significantly inhibited cell proliferation in lesions, reduced vascular density, increased the proportion of apoptotic cells, and reduced VEGF levels in the peritoneal fluid of female BALB/c mice [B/c mice –39. RaniB/c mice . ThalidoB/c mice , 42. SunB/c mice –45.Statins, known as 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitors, are a class of lipid-lowering medications and represent a promising drug for the treatment of endometriosis because they have anti-proliferative, anti-angiogenic, antioxidant, and anti-inflammatory properties and can inhibit matrix metalloproteinase activity [α(HIF-1α) [activity –48. Simv(HIF-1α) , 50. Sim(HIF-1α) .Dopamine and its agonists,  such as cabergoline (Cb2), decreased in the percentage of active endometriotic lesions and cellular proliferation index in female nude mice implanted human endometrium fragments. Activation of the dopamine (Dp)/dopamine receptor 2 (Dp-r2) pathway was involved in the VEGF/VEGFR-2 signaling process and can reduce neoangiogenesis [ogenesis . Cabergoogenesis . Compareogenesis . Quinagoogenesis . These d in vitro and in vivo studies of several potential drugs that reduce angiogenesis and endometriotic implant size have been reported in mice ,–58, in vin mice –61), pri, pri in in mice , and huin mice . See TaEndometriosis research focuses upon reducing the side effects of treatment as well as understanding the mechanistic basis for the therapeutic effects of these treatments. Anti-angiogenic drugs represent a new direction for the treatment of endometriosis. However, clinical evidence for their efficacy and safety is not yet available. Most anti-angiogenic drugs show efficacy in preclinical models (as well as for the treatment of cancer), but are generally not useful in the clinic. Angiogenesis inhibitors show promise in the treatment of endometriosis, but these anti-angiogenic agents are effective in inhibiting pathological angiogenesis; they also have serious side effects that preclude their use in many patients. For example, bevacizumab may have potential adverse effects such as proteinuria, hypertension, thromboembolism, and hemorrhage . Angioge Please refer to Table 2 for a list of natural-product angiogenesis-inhibitors for endometriosis.Some plants and their active compounds/natural products, in combination with standard therapies, may improve medical treatment for endometriosis. These may include Ayurvedic products, homeopathic products, dietary modifications, and herbal therapies. Many of these are phytochemicals that have been shown to have anti-cancer and anti-angiogenic effects. These include polyphenols, flavonoids, alkaloids, terpenoids, and tannins as antioxidants. Melatonin, resveratrol, xanthohumol, and epigallocatechin-3-gallate have been reported as new and effective compounds for the long-term treatment of endometriosis –70. PleaEpigallocatechin Gallate (EGCG),  which is derived from green tea, has powerful anti-angiogenic properties. It may be effective against endometriosis through inhibition of angiogenesis, adhesions, and invasion by endometriotic lesions on an endometriosis mouse model transplanting human eutopic endometrium [β1-stimulated activation of mitogen-activated protein kinase (MAPK) and Smad signaling pathways in endometrial and endometriotic stromal cells [β1-stimulated endometrial and endometriotic stromal cells. EGCG and prodrug of green tea epigallocatechin-3-gallate (pro-EGCG) significantly reduced the size and weight of endometriotic lesions via the induction of apoptosis [ometrium . EGCG seometrium . EGCG alal cells . EGCG alpoptosis . Pro-EGCpoptosis . In vitrpoptosis . EGCG anResveratrol,  3,4,5-trihydroxy-trans-stilbene, a phytoalexin derived from grapes and other food products, is a plant-derived polyphenolic phytoalexin that inhibits angiogenesis in peritoneal and mesenteric endometriotic lesions, significantly reduces micro-vessel density, inhibits proliferation, and increases apoptosis [ in vitro invasiveness of endometriotic stromal cells (ESCs) and suppress the inflammatory response [ɑ levels in plasma and peritoneal fluid [ɑ (ESRɑ) [poptosis , 78. Furresponse . Resveraal fluid . Resveraal fluid . Resveraɑ (ESRɑ) . Resveraɑ (ESRɑ) .Resveratrol has potent antioxidant properties , anti-inPalmitoylethanolamide (PEA) is an endogenous fatty acid amide that has anti-inflammatory and neuro-protective effects. Co-micronized palmitoylethanolamide/polydatin (PEA/PLD) inhibited the development of endometriotic lesions in a rat model of surgically induced endometriosis. PEA/PLD could also decrease angiogenesis (VEGF), nerve growth factor (NGF), intercellular adhesion molecule (VCAM-1), MMP-9, and lymphocyte accumulation, and reduce peroxynitrite formation (poly-ADP) ribose polymerase activation, Ik-Bɑ phosphorylation, and NF-κB translocation [location .Achillea biebersteinii Afan.:  the aerial components of A. biebersteinii were collected from the Beynam Forest. The therapeutic effect of an ethyl acetate (EtOAc) extract of A. biebersteinii was attributed to the flavonoid aglycones found in the extract. This EtOAc extract reduced the post-treatment volumes of endometrial foci in non-pregnant Sprague Dawley rats and reduced levels of TNF-α, VEGF, and IL-6 in the peritoneal fluid [al fluid .Viburnum opulus L.:  the fruits of V. opulus L. (Wu Beizi) have been used to treat endometriosis, primary and secondary dysmenorrhea, and ovarian endometriosis. Active extracts were analyzed by high-performance liquid chromatography (HPLC), and chlorogenic acid was found to be the main active compound. Both EtOAc and methanol(MeOH)extracts of V. opulus L. showed significant inhibition of TNF-α, VEGF, and IL-6 levels in a rat model of surgically induced endometriosis [etriosis .Flavonoids  are a class of secondary plant and fungus metabolites that includes flavones, flavonols, flavanones, anthocyanins, and isoc acid was found to be the main active compound. Over 5000 naturally occurring flavonoids have been characterized from various plants. Flavonoids have anti-angiogenic properties in several diseases and may have potential for the treatment of endometriosis [etriosis , 90.Genistein  is a type of isoflavone. Isoflavones have been shown to exhibit anti-microbial, anti-mutagenic, anti-oxidant, anti-inflammatory, and anti-angiogenic activities [α in mice, increase the expression of estrogen receptor β, and decrease the expression of VEGF and HIF-1α in peritoneal tissues using immunohistochemical techniques, reaching levels comparable to that of a group of mice treated with leuprolide acetate; in this study, genistein also regulated inflammation and angiogenesis by modulating inhibition upon the estrogen receptor in a murine model of peritoneal endometriosis [tivities . Doses oetriosis .Xanthohumol  is a natural product found in the female inflorescences of humulus lupulus. Xanthohumol could act as a pleiotropic chemopreventive agent for cancer due to its anti-proliferative, anti-inflammatory, and anti-angiogenic properties. For example, xanthohumol was shown to effectively reduce the size of cancerous lesions and reduce the level of phosphoinositide 3-kinase protein (PI 3-kinases) in a BALB/c mouse model of endometriosis; additional analysis showed that treatment with xanthohumol could significantly decrease the microvessel density (MVD) and did not affect the histomorphology, proliferation, or vascularization of the uterine horn and ovary during such treatment [reatment .Sea buckthorn and St. John's wort  Sea buckthorn (Hippophae rhamnoides L.) and St. John's wort (Hypericum perforatum L.) are used for the treatment of uterus inflammation and endometriosis. A mixture of sea buckthorn and St. John's wort oils (HrHp oil) significantly decreased the volumes of endometriotic implants and reduced the levels of TNF-α, vascular VEGF and IL-6 in peritoneal fluids in a surgically induced endometriosis rat model [at model .Numerous plant-based products are known to have anti-inflammatory, anti-proliferative, analgesic, antispasmodic, and antioxidant properties. As such, these products represent potential treatments for endometriosis and provide a source of drugs for future anti-angiogenesis studies of endometriosis. in vivo in a zebrafish model and in vitro in a human umbilical vein endothelial cell (HUVEC) model by blocking the VEGFA/VEGFR2-MAPKs signaling pathway [Flavonoid natural compounds may represent a particularly good potential source of drugs for endometriosis. Naringenin belongs to the family of flavanones that includes six categories of flavonoids. Naringenin is a phytoestrogen that exhibits estrogen and antiestrogenic activity and is mainly extracted from citrus fruits. This phytoestrogen could suppress proliferation and increase apoptosis via depolarization of mitochondrial membrane potential and the generation of reactive oxygen species (ROS) in human endometriosis cell lines (VK2/E6E7 and End1/E6E7) . Naringe pathway . HoweverKushecarpin D (KD),  a novel flavonoid isolated from the traditional Chinese herbal medicine Kushen (the dried root of Sophora flavescens Ait) exerted anti-angiogenic effects by inhibition of cell proliferation, cell migration, cell adhesion, and tube formation [ Marsdenia tenacissima could inhibit the proliferation of human umbilical vein endothelial cells (HUVECs) by blocking cell cycle progression from G1 to S phases and by blocking migration and tube formation in HUVECs [ Wild Chrysanthemum and Uniflower Swiss Centaury Root have also been shown to have anti-angiogenic effects in zebrafish by influencing both pro-angiogenic mechanisms and negative regulation of angiogenesis [ Radix bupleuri and may also have potential therapeutic effects against angiogenesis [ (bFGF), HIF-1α, and the VEGF signal pathway [In addition,ormation . Marsdenn HUVECs . Wild Chogenesis . Saikosaogenesis . Sulfate pathway .Recently, a growing number of natural products have been shown to possess anti-angiogenic activities with multiple molecular mechanisms of action. Anti-angiogenic therapy using natural compounds has been extensively studied in tumors and angiogenic diseases. Endometriosis features tumor-like angiogenic behavior and the related targets and signaling pathways are therefore similar. Anti-angiogenic natural compounds could also represent a potential treatment for endometriosis. However, for many of these compounds, the mechanism of action is unclear and clinical trials have not yet been completed. Furthermore, the safety and pharmacotoxicity of these compounds also need further evaluation. Natural compounds therefore require significant development for medical application. See Table 3 for a list of Chinese herbs commonly used to treat blood circulation problems associated with endometriosis.Chinese herbal medicine (CHM), which comprises a variety of compounds and has a long history of use in China, is emerging as a treatment choice for numerous therapeutic applications, including anti-angiogenesis. Many Chinese herbs and formulas promote blood circulation, reduce blood stasis, and have anti-platelet effects, thus eliciting anti-angiogenic effects. Blood-activating and stasis-resolving herbals, tonifying qi herbals, as well as heat-clearing and detoxifying herbals, have anti-angiogenic effects, and their mechanism of action is related to the regulation of angiogenesis-related factors and signaling pathways. Due to the complexity of Chinese herbs, the active ingredients of such herbs are of increasing interest for medical application. The core compounds of traditional Chinese medicine may represent the key to pharmacological action. Due to the large number of compounds in traditional Chinese medicine, we only focus here on the main pharmacodynamic compounds identified to date.Curcumin and Curcuma longa (Jianghuang):  a rhizomatous plant of the ginger family has been associated with profound anti-inflammatory and antioxidative functions for centuries. Curcumin is also the active ingredient in the turmeric plants Rhizoma curcumae (E'zhu), Rhizoma sparganii (Sanleng), and Curcuma rcenyujin (Yujing) and a variety of traditional Chinese herbs. Several studies have demonstrated the anti-inflammatory, anti-oxidant, anti-tumor, anti-angiogenesis, and anti-metastatic activities of curcumin. The anti-angiogenic activity of curcumin has been assessed in vivo and in vitro. Curcumin has been found to decrease the MVD and VEGF protein expression in the heterotopic endometrium in a rat model of endometriosis [κB and MMP-3 by influencing signaling pathways and increasing the secretion of associated proteins in human endometriotic stromal cells, thus mediating the regression of endometriosis [etriosis . Followietriosis . Furtheretriosis . Curcumietriosis . Curcumietriosis . Curcumietriosis . Therefoetriosis .Radix ginseng (Renshen):  the dry root of Panax ginseng C.A. Mey. has been traditionally used as herbal medicine. The chemical components of ginseng include polysaccharides, ginsenosides, peptides, polyacetylene alcohols, and fatty acids. Ginsenoside Rg3 has various biological activities including immune enhancement, anti-oxidant, anti-inflammatory, neuro-protective, and anti-metabolic syndrome [syndrome . The antsyndrome , 112. Gisyndrome . Rg3 hassyndrome .Pueraria lobata (Gegen)   is a frequently used Chinese medicine. Puerarin, one of several known isoflavones, is derived from the root of Pueraria lobata (Gegen). It has been widely used for the treatment of cardiovascular and cerebrovascular diseases, diabetes, diabetic complications, Alzheimer's disease, and endometriosis [etriosis . Puerarietriosis .Puerarin, a phytoestrogen with a weak estrogenic effect, binds to estrogen receptors and competes with 17-estradiol to produce an anti-estrogenic effect [α as well as limiting that of co-activators in endometriotic stromal cells (ESCs) [c effect . Pueraric effect . High les (ESCs) . Anothers (ESCs) .Salvia miltiorrhiza (Danshen), a traditional Chinese herb, contains a number of compounds, including salvianolic acid , dihydrotanshinone, tanshinone I, and tanshinone II A, widely used as blood-activating herbals for a variety of diseases including cardiovascular disease. Tanshinone II A, which is a major diterpene quinone compound present in S. miltiorrhiza, induces angiogenesis by inducing the VEGF/VEGFR2 pathway and CD146 (melanoma adhesion molecule) both in vitro and in vivo. Tanshinone II A modulated angiogenic functions in HUVECs and dramatically suppressed VEGF-promoted cell migration and tube formation in human bone marrow-derived endothelial progenitor cells (EPCs) through the phospholipase C(PLC), protein kinase B(Akt), and c-Jun N-terminal kinase (JNK) signaling pathways. This is a promising natural product with potential for the treatment of cancer and other angiogenesis-related pathologies [hologies , 122.ζ in EESCs. The overexpression of 14-3-3ζ restores cell viability, migration, and invasion, but has no effect on apoptosis. The effects upon cell viability, migration, and invasion were shown to be mediated in a 14-3-3ζ-dependent manner, whereas the effects of apoptosis were mediated in a 14-3-3ζ independent manner [Tanshinone II A, combined with the method of warming yang, removes blood stasis, effectively increasing serum p53 and p21 protein levels. Furthermore, this compound reduces the levels of murine double minute2 (MDM2), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1(sVCAM-1), and CA125 in patients with uterine endometriosis within three menstrual cycles . Tanshint manner . S. miltiorrhiza have also shown promise in treating endometriosis by markedly reducing the serum levels of CA125 and the levels of IL-18 and TNF-α, by significantly increasing the levels of IL-13 in the peritoneal fluid in a rat model [ S. miltiorrhiza could inhibit ectopic stromal cell proliferation by inhibiting MMP-9 mRNA and protein expression [ S. miltiorrhiza may be involved in the anti-angiogenic process of endometriosis, but this requires further investigation.Extracts ofpression . Other aPaeonia lactiflora Pall (Chishao)  is a species of herbaceous. Paeoniflorin, the core component of P. lactiflora., is commonly used in Chinese medicine prescriptions for gynecological diseases such as dysmenorrhea and irregular menstruation endometriosis. Common prescriptions such as Danggui Shaoyao and Danggui Sini decoctions are used for endometriosis-associated pain. Paeoniflorin has anti-inflammatory, analgesic, antipyretic, and platelet-inhibitory effects, and could influence the function of estrogen receptor-α (ESRα) and HIF-1α at network pharmacological and pharmacodynamic levels [c levels .Andrographis paniculata (Chuanxinlian)  is an annual herbaceous plant in the family Acanthaceae and has been traditionally used to treat infections and some diseases. Andrographolide is a labdane diterpenoid isolated from the stem and leaves of Andrographis paniculata (Chuanxinlian). Andrographolide, as a NF-κB inhibitor, possesses anti-tumor activity and inhibits tumor angiogenesis. Andrographolide has been shown to reduce lesion size and improve in generalized hyperalgesia in a dose-dependent manner in an endometriosis rat model. This effect was mediated via COX-2, tissue factor (TF) and the phosphorylation of p50 and p65. Andrographolide dose could also suppress proliferation and cell cycle progression, reduce DNA-binding activity of NF-κB, and inhibit COX-2 and TF expression in endometriotic stromal cells [al cells .Lithospermum erythrorhizon (Zicao)  is a Chinese herbal medicine with various antiviral and biological activities. Shikonin, an ingredient of L. erythrorhizon, has been shown to have wound healing, antimicrobial, anti-inflammatory, and antioxidant activities and is effective for several tumors; the underlying mechanism involves the inhibition of angiogenesis and has been observed both in vivo and in vitro [ in vitro [in vitro . Shikoniin vitro .In Chinese medicine, anti-angiogenic effects are mediated via multiple interdependent processes such as the modulation of gene expression, signaling pathways, and enzyme activities .Blood-activating and stasis-relieving drugs are widely used in Chinese medicine and are commonly applied in the treatment of various angiogenesis-related diseases. Several blood-activating and stasis-removing drugs have been associated with anti-angiogenic effects, although the regulatory mechanisms underlying these effects require further clarification in endometriosis. In the next section, we discuss the potential anti-angiogenic mechanisms of commonly used Chinese medicines.Ligusticum chuanxiong (Chuanxiong)  is an extremely common traditional, edible, medicinal herb. L. chuanxiong exerts therapeutic effects and has been applied in the treatment of both cardiovascular and cerebrovascular diseases. Approximately 174 compounds have been isolated and identified from L. chuanxiong; phthalides and alkaloids have been identified as the main bioactive ingredients with pharmacological properties [operties , 133.Angelica sinensis (Danggui)  is one of the most commonly used drugs for gynecological diseases; n-butylidenephthalide (BP) has been identified as the bioactive component in a volatile oil of Radix A. sinensis (VOAS), and exerts angiogenic effects, both in vitro and in vivo [ in vivo .Heat-clearing and detoxifying drugs, such as other Chinese medicines, have also been associated with anti-angiogenic effects. Scutellaria baicalensis(Huangqin) is a widely used for inflammation, diabetes, hypertension, cancer and virus related diseases. High dosage of baicalin or baicalein showed anti-angiogenesis effect through induction of apoptosis, but low dosage of baicalin promoted angiogenesis through increasing cell proliferation [ Pulsatilla chinensis (Baitouweng)  extracts have anti-tumor activity against undifferentiated thyroid cancers via their apoptotic and anti-angiogenic effects [feration . Pulsati effects . The mec Panaxatriol saponins [ Emodin [ Hedyotis diffusa Willd and M. tenacissima are suggested to have anti-angiogenic effects [Potential anti-angiogenic natural compounds and Chinese herbs may provide anti-angiogenic drugs. For example, the following have all been associated with anti-angiogenic effects: Vitexins ; Luteolisaponins ; Actein saponins ; Emodin [ Emodin ; Paeonol effects .In conclusion, several types of natural Chinese medicinal herbs are natural inhibitors of angiogenesis. It is therefore essential to understand their mechanistic basis for potential application in the treatment of endometriosis. For example, VEGF/VEGFR signaling plays a fundamental role in inducing vascular endothelial cell proliferation, migration, and angiogenesis. Many different types of Chinese medicine are also shown as natural inhibitors of angiogenesis. These also show a range of complexities. Collectively, these characteristics make it very difficult to carry out investigative research on such compounds. The the mechanism of these anti-angiogenic Chinese herbs in endometriosis needs further study. It is therefore essential to understand their mechanistic basis for potential application in the treatment of endometriosis.In traditional Chinese medicine, blood stasis syndrome (BSS) is an important pathology and is known to underlie many diseases . The mai A list of Chinese medicine compounds used in the treatment of endometriosis treatment is provided in In 1991, the Professional Committee of Obstetrics and Gynecology of the Chinese Association of Integrative Medicine published its integrative medicine standards for the diagnosis and treatment of endometriosis. The therapeutic plan for endometriosis was designed according to the age of the patient, her symptoms, the location and range of the lesion, and her requirement for fertility. The use of Chinese herbals in the treatment of endometriosis is based upon their anti-angiogenic effects. The use of traditional Chinese medicine includes the administration of pills, capsules, granules, and herbal decoctions. The following Chinese medicines had been reported to be effective for endometriosis treatment.Guizhi Fuling Wan., a mixture of five herbal plants, is a classic formulation. Guizhi Fuling Wan, consists of Cinnamomum cassia (Guizhi), Poria cocos (Fuling), Moutan Cortex (Mudanpi), Prunus persica (Taoren), and Paeonia lactiflora (Chishao); these were identified in the classic monograph of traditional Chinese medicine “Jingui Yaolue ” [r, SGC)” . Guizhi r, SGC)” .α in the peritoneal fluid of rats model [α and VEGF in ectopic endometrium and eutopic endometrium in endometriosis patients for one month treatment [Guizhi Fuling Wan has been shown to significantly inhibit the expression of proliferating cell nuclear antigen (PCNA) and platelet endothelial cell adhesion molecule-1(CD31) in the ectopic endometrium and significantly reduce the expression of VEGF and HIF-1ts model . Other rreatment .Futhermore, Guizhi Fuling Wan was shown to play an important role in the regression of endometriotic implants by immunological regulation in a rat model of endometriosis . Guizhi Xiaochaihu Tang (XCHT)  is also described in a “Treatise on Cold Pathogenic and Miscellaneous Diseases”, and comprised seven crude drugs:Bupleurum chinense (chaihu), Scutellaria baicalensis (Huangqin), Ginseng root (Renshen), Pinellia ternata (Banxia), Glycyrrhiza uralensis (Gancao), Zingiber officinale (Shengjiang), and Ziziphus jujuba (Hongzao). XCHT inhibited the growth and angiogenesis of the ectopic endometrium in a rat model. XCHT has been shown to reduce the level of VEGF and MVD in ectopic endometrium and decrease the level of IL-8 and TNF-α in blood and peritoneal fluid [al fluid . XCHT waal fluid .Sanleng Wanwas first reported in the Chinese medical monograph “Experiential effective prescription (Jingyan Liangfang)” in Qing dynasty. This medicine is composed of traditional Chinese medicinal herbs found in Sparganium stoloniferum (Sanleng) and Curcuma aeruginosa (E'zhu) and is used for the treatment of dysmenorrhea. Sanleng Wan has been shown to reduce micro-vessel density (MVD) and inhibit VEGF, TNF-α protein, and mRNA levels in the ectopic endometrium in a rat model [at model .Jiawei Sanleng Wan consists of Sparganium stoloniferum Buch. (Sanleng), Curcuma phaeocaulis (E'zhu), and Astragalus membranaceus (Huangqi). Jiawei Sanleng Wan has been shown to decrease the secretion of E2 by eutopic endometrial cells; an anti-angiogenic effect was obtained by reducing the level of VEGF in the eutopic endometrial cells during endometriosis [etriosis , 158.Shaofu Zhuyu Decoction(SZD) originally recorded in the “Correction of Errors in Medical Classics (Yiling Gaicuo)”, a monograph compiled by Qingren Wang in the Qing dynasty. Shaofu Zhuyu Decoction (SZD) consists of ten commonly used herbs and has been widely used in clinical practice to relieve symptoms of endometriosis. SZD significantly reduced the size of ectopic lesions inhibited cell proliferation, increased cell apoptosis, and reduced MVD, HIF-1α and CD34 expression in the ectopic endometrium in a rat model [at model .Sanjie Zhentong Capsules,  a well-known traditionally prescribed Chinese medicine, consists of Daemonorops draco draco Bl. (Longxuejie), Panax notoginseng (Sanqi), Fritillaria thunbergii (Zhebeimu), and Coix lacryma-jobi (Yiyiren). These capsules, which are used for the treatment of endometriosis, effectively reduce endometriosis- and adenomyosis-associated pain, with few side effects [α in the peritoneal fluids in an endometriosis rat model [ effects . Using u effects . Sanjie  effects . The twoat model . Sanjie at model .Eleng Capsules, patented by the Guangdong Provincial Hospital of Chinese Medicine, have been used in the treatment of endometriosis for over 10 years now . We conducted clinical and basic research on the Eleng capsule, which is composed of Sparganium stoloniferum (Sanleng), Curcuma phaeocaulis (E'zhu), Slavia miltiorrhiza (Danshen), Curcuma wenyujin (Yujin), Trionyx sinensis (Biejia), Hirudo nipponica (Shuizhi), and Citrus aurantium (Zhike). Long-term clinical and basic research confirmed that Eleng capsules are able to significantly and effectively relieve pain while also restoring fertility and inhibiting the recurrence of endometriosis by countering adhesion, invasion, and angiogenesis. Eleng capsules are also able to significantly relieve the symptoms and signs of endometriosis and blood stasis syndrome, potentially by down-regulating serum levels of prolactin (PRL), CA125, and anti-endometrial antibody (EMab) [y (EMab) . Eleng cy (EMab) . Other sy (EMab) .Dan'e Fukang Decoction  is composed of Slavia miltiorrhiza (Danshen), Curcuma phaeocaulis (E'zhu), Panax notoginseng (Sanqi), Paeonia lactiflora (Chishao), Angelica sinensis (Danggui), Sparganium stoloniferum (Sanleng), Cyperus rotundus (Xiangfu), Corydalis yanhusuo (Yanhusuo), Bupleurum chinense (Chaihu), and Glycyrrhiza uralensis (Gancao). Dan'e Fukang decoction is known to reduce the expression of VEGF and TNF-α in the ectopic endometrium during endometriosis, while also inhibiting the invasion and proliferation of endometrial cells [al cells ; it alsoal cells . Dan'e Fal cells .α in serum [α in the endometriotic lesions and decreasing concentration of VEGF in peritoneal fluid [Many traditional Chinese medicine decoctions have been shown to have anti-angiogenic effects. Bushen Wenyang Huayu decoction reduced levels of VEGF and CA125 in the serum of endometriosis patients . Xiaozhein serum . Clearinin serum . Taoren in serum . Huayu Xin serum . Wenshenal fluid .Herbal extracts and Chinese medicines are therefore of significant value for the treatment of endometriosis, largely due to their anti-angiogenic properties and their ability to directly affect cell function. Furthermore, the individualized use of herbal treatments is designed to meet the needs of each patient.Endometriosis is a complex gynecological disease. Endometriosis is not a potentially life-threatening disease, and most of the affected patients are young women of reproductive age. Current medical treatments mainly address the patient's symptoms such as pain, fertility, and recurrence. However, emerging therapeutic approaches, including GnRH antagonists, aromatase inhibitors, anti-angiogenic drugs, or alternative medicines, provide new tools for the treatment of endometriosis , 9. MostIn particular, research into the treatment of endometriosis needs to address the protection of ovarian reserve, the prevention of recurrence, and the reduction of side effects and to seek to develop long-term treatment options. From this perspective, anti-angiogenic agents are particularly promising because they have favorable safety profiles and could act as antiangiogenic treatments aimed at inhibiting new vessel formation. Targeting angiogenesis could be a suitable method with which to prevent recurrent endometriosis conditions associated with current pharmacological and surgical treatment modalities. Understanding the roles of angiogenesis in the pathophysiology of endometriosis is essential for the development of novel therapeutic approaches.However, existing information relating to the efficacy of exclusive and most inclusive anti-angiogenic compounds has been obtained from animal models . AnotherAlternative medicines for the treatment of endometriosis are widely used in China, where these treatments improve patient symptoms effectively, although large-scale studies have not yet been completed. Natural compounds, along with complementary and alternative medicines, are significant because of their multi-target characteristics, which provide new sources for difficult and chronic diseases. The mechanistic basis for the anti-angiogenic effect of many natural compounds and traditional Chinese medicines, along with complementary and alternative medicines, is still unclear. There are still many compounds and treatments that are unidentified and worthy of further exploration . The mechanisms underlying the action of natural compounds and Chinese herbs are summarized in Alternative and complementary medical treatments primarily consist of natural compounds and herbals, which have fewer side effects and are suitable for long-term treatment and are acceptable to patients. Supplementary alternative medicine is widely used worldwide, particularly in Asian countries. Targeting natural compounds may provide a new direction for finding new targets for endometriosis treatment. Traditional Chinese medicine treatment is based on compounds with multi-target regulation characteristics and can intervene in the disease process via multiple pathways. In terms of angiogenesis, natural medicines and traditional Chinese medicines are involved in the regulation of multiple pathways and are associated with pathways such as inflammation and immunity to jointly regulate the process of angiogenesis. Natural compounds and traditional Chinese medicine for the treatment of endometriosis have multi-channel and multi-target regulatory characteristics, which are mainly related to the down-regulation of VEGF. Practice Guidelines for the Treatment of Endometriosis with Chinese Herbal Medicine were developed using the Delphi Process in 2007 [ Endometriosis Collaborative Group of the Chinese Medical Association Obstetrics and Gynecology Branch, mentioned dysmenorrhea also can consider Chinese medicine treatment [Chinese medicine treatments have been used for the symptoms of endometriosis for more than two thousand years. These treatments have been demonstrated to be beneficial in relieving dysmenorrhea, in regulating menstruation to assist pregnancy, and in reducing pelvic mass. According to the theory of Chinese medicine, endometriosis is caused by blood stasis. Blood stasis forms a mass in the body, which causes pain, dysmenorrhea, and infertility . As repo in 2007 . Guidelireatment . Most ChIn summary, our literature review indicates that Chinese medicine mainly regulates angiogenesis-related factors and angiogenesis pathways, reduces angiogenesis, and reduces the density of microvessels. VEGF/VEGFR signaling pathways and related signaling pathways represent specific foci for current research. Furthermore, Chinese medicine may play a synergistic role with other regulatory mechanisms.There are five other mechanisms that should be considered.  First, the analgesic effect: clinical studies suggest that Chinese herbals can alleviate the pain symptoms of patients with endometriosis, and that this might be related to the regulation of prostaglandin-related receptors [ See Figure 2 for a summary of Chinese medicine compounds that show complex regulatory mechanisms. eceptors , 171; seeceptors , 170; theceptors ; fourth,eceptors . Chineseeceptors . There mAt present, studies on the anti-angiogenesis activities of monomer and Chinese herbal extracts are very transparent; however, basic research on compounds remains in its infancy. In the theory of TCM, formulae with multiple combinations of herbs are more frequently used for clinical therapy . The comThe bioavailability of these compounds is low because many of these molecules have poor solubility; therefore, only negligible concentrations of these natural compounds can reach the peripheral circulation and the desired sites affected by disease. We also need to identify the biological target(s), disease pathway(s), and the active compound(s) that are responsible for the modification of endometriosis. Furthermore, there is a lack of confirmatory therapeutic studies that establish the molecular mechanistic basis for therapies; this requires further investigation and confirmation.From retrospective TCM compound clinical research, we can see that there is a clear lack of literature relating to multi-channel and signaling pathway mechanisms. Notably, the mechanisms underlying the anti-angiogenic therapeutic activities of traditional Chinese medicine still remain unclear. Furthermore, the clinical practice of TCMs has not yet been reviewed and examined in the context of modern medical knowledge, and there is a clear lack of lack of large, randomized, and controlled trials. For example, one meta-analysis study was shown that Chinese Medicine Bushen Huoxue Prescription (BSHXP) significantly improved endometriosis-related symptoms and syndromes. But the evidence is inconclusive because of the low methodological quality of the included RCTs . ClinicaIt is also poor trial outcomes and the lack of transparency in endometriosis, as well as in alternative and complementary medicines in endometriosis treatment. Several completed clinical trials on endometriosis did not publish their results, and presumably failed. Elucidating the causes for failed clinical trials may improve future researches .Natural compounds and Chinese herbs are capable of regulating multiple targets, with potential applications in complex diseases. New methods must be adopted to investigate Chinese compounds. Network pharmacology can predict the target profiles and pharmacological actions of herbal compounds, reveal drug-gene-disease comodule associations, and thus allow us to screen synergistic multi-compounds from herbal formulas using high-throughput evaluation. Network pharmacology and systems pharmacology should therefore be used more effectively to identify herbal ingredients and their related properties to establish compound-target relationships and target-disease relationships –188.Genome-wide association studies have demonstrated several reproducible loci associated with endometriosis. Such studies could identify informative subtypes of endometriosis that will enhance our understanding of the pathogenic mechanisms of endometriosis . It is pFurthermore, clinical endometriosis research, featuring high-quality Chinese herbal compounds, needs to focus on evidence-based medicine. The phenotypes of patients with endometriosis are different, and the further application of precision medical methods, combined with the use of complementary or alternative medicines, is expected to provide personalized forms of treatment for patients with endometriosis . Future  in vitro research or animal models. Furthermore, there is not enough convincing clinical evidence for the potential use of these herbs for the treatment of endometriosis. In the era of evidence-based precision medicine, more clinical trials are now necessary to prove the efficacy and safety of these therapies in patients with endometriosis, as well as to explore the mechanistic basis of their therapeutic effect. Future research should also be performed to establish pharmacological evidence for phytochemical effects using pharmaco-genomics, -proteomics, -transcriptomics, and -metabolomics. Studies should also investigate the efficacy and effectiveness of the herbal combinations and therapeutic strategies used in current herbal practice.Endometriosis is both a gynecological and chronic disease. Angiogenesis is a primary mechanism involved in endometriosis. In experimental studies, various anti-angiogenic agents have induced the regression of endometriotic lesions by targeting their blood supply. Angiogenesis inhibitors may therefore become new targets for the treatment of endometriosis , 194. Mo


Introduction: Patients with Multiple Sclerosis exhibit disturbed dexterity, leading to difficulties in fine motor skills such as buttoning a T-shirt or hand-writing. Consequently, activities of daily living and quality of life are affected. The aim of the present study is to investigate the effectiveness of a tablet app-based home-based training intervention to improve dexterity in patients with Multiple Sclerosis.Methods: An observer-blinded randomized controlled trial will be performed. Seventy patients with Multiple Sclerosis with self-reported difficulties in dexterity while executing activities of daily living will be recruited. After baseline assessment, participants are randomized to either an intervention group (n = 35) or control group (n = 35) by a computerized procedure. Blinded assessments will be done at baseline, post-intervention (after 4 weeks) and 12 weeks follow-up. The home-based intervention consists of a 4-week tablet app-based dexterity program. The app contains six dexterity games in which finger coordination, tapping, pinch grip is required. The control group will receive a Thera-band training program focused on strengthening the upper limb. The primary outcome is the Arm function of Multiple Sclerosis Questionnaire, a measure of patient-reported activities of daily living related dexterity. Secondary outcomes are dexterous function, hand strength, and quality of life.Discussion: This study will evaluate the effects of tablet app-based training for dexterity in patients with Multiple Sclerosis. We hypothesize that a challenging app-based dexterity program will improve dexterity both in the short term and the long-term. The improved finger and hand functions are expected to generalize to improved activities of daily living and quality of life. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and the most common cause of non-traumatic disability in young adults –3. It isImpaired dexterity is a frequently observed impairment, affecting up to 76% of PwMS , 9. AnatTo obtain an optimal training effect, work load must be “shaped” (adjusting the task difficulty to the subjects' performance), and the intensiveness of training should be progressive and challenging. Based on these motor learning principles, Bonzano et al.  found in©,” by a team of experts including an occupational therapist , graphic designer, and IT expert. The app is already available to be downloaded from Google Play store or Apple Store (see for more details: www.fingers-in-motion.de). The app specifically contains six dexterous exercises, which are explained more in the methods. The exercises are goal oriented, repetitive, give direct feedback and most importantly are fun to to. To ensure constant improvement, the speed and difficulty of the exercises are progressively adapted to the individuals' performance limit. To our knowledge the efficacy of this tablet app-based training has not been investigated in MS.With recent technological innovations, such as the development of applications (apps) for mobile phones and/or tablets there are new possible treatment options. The advantages of such apps, certainly build on the premise that these are often mentally stimulating, are game-based, attractive, fun, all aspects which are fundamental to possibly stimulate neuroplasticity in MS. Training with mobile apps may also allow flexible training at home, so PwMS can exercise whenever they want at a convenient time of the day. Recently such an app, called COGNI-TRAck, was developed to train cognition in MS, which was found to be feasible, highly motivating and well-accepted among PwMS . A folloThe aim of the present study will therefore be to investigate the effectiveness of a tablet app-based dexterity home-based intervention in MS (TAD-MS). The short and long-term benefits of this training program will be compared with a Thera-band® training program. For these purposes, an observer-blinded proof-of-concept RCT will be performed. We hypothesize that TAD-MS will improve dexterity, leading to improved ADL, and HrQoL in PwMS.http://www.consort-statement.org/.An observer-blinded RCT will be performed with random allocation of intervention, with pre- (baseline) and post-intervention measurements, at 4 weeks immediately after intervention and a follow-up 12 weeks later, after finishing the training. The study flow chart is shown in see We aim to recruit 70 PwMS. The inclusion criteria are as follows: males and females, age 18–75, diagnosis of MS  following the revised McDonald criteria . In addip-value of 0.05 for detecting 20% difference between groups on the Arm Function in Multiple Sclerosis Questionnaire (AMSQ) in favor of the App-based dexterity group. Based on mean expected baseline values of 50.2 ±14.0  of the whole group, a 20% difference would reflect a 10-point improvement. Following Cohen's guidelines  will execute a balanced (1:1 ratio) group allocation using a computerized randomization protocol. Two clinicians , with experience in the field of MS rehabilitation, will be responsible for the assessments and instruction of both interventions. All outcome measures  will be videotaped and rated by an independent rater blinded to randomization procedure and group allocation.Two home-based treatment conditions are investigated in this study: the experimental condition (TAD-MS) and the control condition (Thera-band®). Patients will receive instructions for their home-based training programs by a trained clinician . Both groups will train 5 days per week (approximately 30 min per day) for 4 weeks. All exercises will be performed with both hands. Besides therapist instructions, for each exercise the app contains a demonstration video and a text explaining how to perform the exercises. The app is linked with a website in which a clinician can log in and track the patient's performance, so compliance to the protocol can be monitored. Patients exercising with Thera-band® receive a booklet explaining all exercises with pictures and text instructions. This booklet also contains a diary to document if an exercise is performed and, if applicable, the time needed to accomplish the exercise.PwMS allocated to the TAD-MS will receive a tablet with the app on it. The app contains six different exercises. During a first training session PwMS receive instructions about the log-in procedure and functionality of the web-interface and exercise app. The therapist can pre-select the exercises for the patient. For more information about TAD-MS a step by step manual is presented in PwMS allocated to the control group will receive Thera-band-exercises on paper [see ]. PwMS wThe AMSQ measures manual dexterity in MS patients and shows good validity, test-retest reliability and inter-observer reliability . RecentlThe 9HPT is a reliable, valid and sensitive test to quantify impaired dexterity, and has been validated in patients with MS . While sThe Coin rotation Task (CRT) is a sensitive measure to quantify fine coordinated finger movements in MS . ParticiThe hand-held JAMAR dynamometer  is a reliable and valid test to measure isometric grip strength in healthy subjects and PwMS , 24. TesThe Multiple Sclerosis Impact Scale 29 (MSIS-29) is a HrQoL questionnaire assessing the impact of MS on physical and psychological functions , 26. It Post-hoc Tukey test will be used to test for pairwise comparisons. The Benjamini–Hochberg procedure will be applied to control the false discovery rate .Descriptive statistics will be used to present baseline characteristics and results of outcome measurements. The main analysis will be an analysis of covariance (ANCOVA) with between-group factor Intervention (2 levels) and within group factor Time (3 levels). Baseline scores will be used as covariates. Two-sided 95% confidence intervals (CI) will also be calculated, as well as effect size (Cohen's d). ery rate . AccordiIn accordance with Good Clinical Practice Guidelines members of the ethics committees will be granted access to the original clinical data (coded) for audits or inspections, via the principal investigator. Throughout the entire study, strict confidentiality is ensured. All data will be coded and archived at the Luzerner Kantonsspital throughout the whole study period and archived for 15 years. All measurements , which are specifically related to the study design, will be entered directly into electronic Case Report Forms (eCRF).Impaired dexterity is a frequently reported problem in MS, leading to reduced HrQoL , 4, 7. HThe aim of the present proof-of-concept RCT is to investigate the effectiveness of a tablet app-based dexterity training at home, compared with a non-dexterity focused Thera-band® program. The exercises within the TAD-MS intervention focus on different components of dexterity such as pinch grip, coordinated finger movements, consequently being highly specific to improve dexterity. In addition, all exercises are game-based and designed to be challenging and to trigger motivation. During the performance of the dexterity exercises the app provides direct feedback of performance which can lead to immediate perception of error and correction of movement, increasing the effectiveness of progressive motor learning training , 29. InsThe total dosage of the TAD-MS intervention is 600 min of dexterity training , representing a trade-off between feasibility and adequate dosage. Although no studies have investigated tablet-app based dexterity training in MS, a previous home-based sensory re-education training  induced significant in manual dexterity . TherefoIn sum, we expect that the presented tablet app-based program, TAD-MS, through provision of challenging, stimulating dexterity training in the patients' home-environment will be effective in PwMS.When protocol amendments are needed , ethical approval will be obtained first. After having obtained this approval, relevant adaptations will be made in the relevant clinical trial registry databases.After completing recruitment, according to the inclusion and exclusion criteria, statistical analyses are planned. When completed, submission to a peer-reviewed journal is planned. In addition, results will be published in patient and healthcare professional magazines and will be presented at national and international congresses.JvB physical therapist, junior researcher and movement scientist, responsible for patient recruitment, provides data collection, manuscript writing. EvW senior researcher and movement scientist, gave critical review of concept and design of the study, and critically revised the manuscript. CB research assistant, responsible for patient recruitment, provides data collection, she critically revised the manuscript. MR senior researcher and movement scientist, gave critical review of concept and design of the study, and critically revised the manuscript. CK neurologist, provided concept and design of the study and critically revised the manuscript. TV is a senior researcher and principal investigator, obtained funding, conceived the idea for the present study, overall project coordination, manuscript writing. All authors contributed to the design of the interventions and outcome measures. All authors assisted in editing and reviewing the submitted manuscript. They all read and approved the final form.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.


Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) efficaciously reduce systolic blood pressure (BP), a well-established risk factor for myocardial infarction (MI). Both inhibit the renin-angiotensin system, albeit through different mechanisms, and produce similar reductions in BP. However, in parallel meta-analyses of ACEi and ARB trials, ACEis reduce risk of MI whereas ARBs do not—a phenomenon described as the ‘ARB-MI paradox’. In addition, ACEis reduce all-cause mortality, whereas ARBs do not, which appears to be independent of BP lowering. The divergent cardiovascular effects of ACE inhibitors and ARBs, despite similar BP reductions, are counter-intuitive. This systematic review aims to ascertain the extent to which clinical outcomes in randomised trials of ACEi and ARBs are attributable to reductions in systolic BP.p value < 0.05), relative risks, standardised per 10 mmHg difference in BP, will be reported for each study outcome. Publication bias will be examined using Funnel plots, and calculation of Egger’s statistic.A comprehensive search of bibliographic databases will be performed to identify all randomised studies of agents of the ACEi and ARB class. Placebo and active comparator-controlled studies that report clinical outcomes, with greater than 500 person-years of follow-up in each study arm, will be included. Two independent reviewers will screen study records against a priori-defined eligibility criteria and perform data extraction. The Cochrane Risk of Bias Tool will be applied to all included studies. Studies retracted subsequent to initial publication will be excluded. Primary outcomes of interest include MI and all-cause mortality; secondary outcomes include stroke, heart failure, revascularisation and cardiovascular mortality. Meta-regression will be performed, evaluating the relationship between attained reduction in systolic BP and relative risk of each outcome, stratified by drug class. Where a BP-dependent effect exists  contains supplementary material, which is available to authorized users. Elevated systolic blood pressure (BP) is a well-established risk factor for myocardial infarction (MI), stroke, heart failure, and death –4. This 1) receptor, reducing downstream aldosterone secretion, salt and water retention. However, AT1 inhibition uncouples the angiotensin II negative feedback loop, leading to marked counterregulatory upregulation; angiotensin II levels increase 2- to 3-fold from baseline [2) receptors, which are overexpressed in atheromatous plaques, and may promote plaque vulnerability [1 blockade include increases in plasminogen activator inhibitor-1 (PAI-1) and reductions in bradykinin. Conversely, ACEis suppress angiotensin II synthesis and inhibit the breakdown of bradykinin; yielding synergistic cardioprotective effects.Several putative biological hypotheses for this paradox have been advanced. Firstly, ARBs may have a pharmacological action that increases the risk of MI, independent of, and partially masked by their blood pressure-lowering effects . ARBs inbaseline . Putativrability . Other pSome authors have dismissed the validity of the ARB-MI paradox; attributing the lack of observed benefit to a ‘generation gap’ between trials of ACEis and ARBs . The priEvaluation of the association between treatment-associated BP reduction and incidence of clinical outcomes will provide greater insight into the mechanism of the ARB-MI paradox, and advance understanding of the comparative safety and efficacy of ACEis and ARBs.We aim to perform a systematic review and meta-analysis, of all available ACEi and ARB randomised controlled trial data. Analysis will be performed using summary-level data. Specifically, we will (i) investigate the extent to which the reported clinical outcomes in randomised trials of ACEis and ARBs are attributable to changes in systolic BP, using meta-regression, and (ii) ascertain if either class of drug has activity independent of BP reduction. We will calculate effect sizes, standardised per 10 mmHg difference in systolic BP, for each study outcome, where a BP-dependent effect is observed (see below).This protocol is in compliance with the relevant extension of the Prospective Reporting Instructions for Systematic Review and Meta-Analysis Statement; PRISMA-P  randomised, placebo or active comparator-controlled studies, (ii) use of a prospective, randomised, open, blinded end-point (PROBE) design , (iii) tThe study exclusion criteria are (i) studies that do not report relevant clinical endpoints , (ii) studies in which the control group received no treatment , (iii) studies retracted subsequent to initial publication and (iv) lack of sufficient data to calculate between-group differences in systolic BP.will be included in this meta-regression study. Previous meta-regression analyses have also pooled data from both hypertension and HF studies of renin-angiotensin inhibition [Trials that predominantly recruit participants with heart failure (HF) at baseline hibition . Given thibition . Furtherhibition . TherefoAll studies of the ACEi and ARB class, vs. placebo or active comparator, will be included in meta-regression analysis. Studies that report head-to-head comparison of ACEi and ARB will be excluded in sensitivity analysis, once in which the ACEi group is the control class, and once in which the ARB is the control class.ClinicalTrials.gov (from 1997). Literature that has not undergone formal publication  will be identified using The Conference Proceedings Citation Index and the OpenGrey website (via http://www.opengrey.eu/). This will be used to identify peer-reviewed publications based on these data. Where the grey literature source is the only record of the execution of a study, it will not be included in the synthesis. The expected impact of the non-publication of such data will be qualitatively discussed, and (if examples are present), will be included as a sensitivity analysis. The reference lists of previous meta-analyses and clinical trials of the ACEi and ARB class will be retrieved and scrutinised to identify studies that may otherwise be overlooked (backward citation searching). Citation lists of included studies will also be checked (forward citation searching).A pre-specified search strategy will be performed, querying the following bibliographic databases, from inception to the present date: (i) MEDLINE , (ii) ISI Web of Science , (iii) EMBASE  and (iv) the Cochrane Central Register of Controlled Trials . Unpublished trials will be identified using A broad and comprehensive search strategy was developed following a scoping review of the topic area. The search strategy will include both free-text (title and abstract keyword) searching and controlled vocabulary searching . Terms will be grouped by two concepts: (i) drug identifier terms, including the names of individual agents (e.g. perindopril) and relevant drug classes (e.g. angiotensin-converting enzyme inhibitors) and (ii) clinical trial identifier terms . The search strategy was adapted from the Cochrane Highly Sensitive Search Strategy (sensitivity-maximising version) . The priTwo independent reviewers will conduct a preliminary screen of all records identified by bibliographic searching; assessing each record for relevance according to pre-specified eligibility criteria. Studies that cannot be conclusively excluded by title and abstract screening will be advanced to full-text screening. Full-text articles will be retrieved in Portable Document Format (.pdf), and comprehensively reviewed using a 2-stage process. The first stage will assess the study with regard to design; the second stage will assess the study with regard to reporting of blood pressure differences and outcomes. Discrepancies between the two reviewers at any stage will be resolved through discussion, and if required, final arbitration will be performed by the senior authors (MHS and ASH). The flow of studies through the selection process, together with reasons for exclusion at the full-text stage, will be reported using a modified PRISMA diagram, as in Fig. Retrieval and storage of study records, abstracts and full-text articles will be performed using EndNote X8 . The primary database will be stored on a server-based platform to enable real-time synchronisation of data between investigators.Extraction of relevant data from included studies will be independently performed by JAB and MT. The concordance of each data point following extraction by both authors will be evaluated. Discrepancy will be resolved by discussion; final arbitration will be performed by MHS and ASH. A custom data extraction form will be piloted and optimised using a subset of five randomly selected studies satisfying the eligibility criteria. For those studies that satisfy the first stage of the eligibility screening process, but fail to report elements of necessary data  in the main study publication or supplementary appendices, the following steps will be taken: (i) searching for other peer-reviewed publications based on the primary study data, (ii) checking whether data are available in previous meta-analyses of this topic, (iii) searching for third-party sources of data, including US Food and Drug Administration (FDA) dockets, and, (iv) requesting data from the study author and/or sponsor. When data are not available from the primary study manuscript, a record of the data source will be made. If the minimum analytic dataset cannot be ascertained, such studies will be excluded. The expected effect of such exclusion  will be summarised qualitatively in the final report.When multiple publications arise from one study, relevant data will be extracted into a single form. Studies evaluating more than two groups, , are expected to occur infrequently in this context. For such studies, the group ‘shared’ in multiple comparisons  and corresponding number of events will be equally divided, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions . This paAll data items to be extracted are summarised in Table Pilot analysis has suggested that the expected range of between-group differences in systolic blood pressure lies between 5 and − 20 mmHg , with an expected standard deviation of approximately 5 mmHg. This degree of variability approximates well with that observed in a previous meta-analysis .The primary outcomes will be MI  and all-cause mortality (death from any cause). These outcomes were chosen as the focus of current inquiry as they represent the source of persisting controversy, and are measured most consistently across studies. Secondary outcomes were cardiovascular mortality , stroke , heart failure requiring hospitalisation, and unplanned revascularisation. The number of events occurring in the total at-risk population  will be extracted. This will be used to calculate a risk ratio for each study, which will be reported in addition to the raw data.When these endpoints are not reported verbatim in studies , this will be included, with appropriate acknowledgement in the final report. The hierarchy for reporting non-specific outcomes is presented in Table Where few outcomes are observed, resulting in a divide-by-zero error and unspecified risk ratio, one outcome will be added to each cell, in order to permit inclusion of the study. For example, in a hypothetical trial in which there were three deaths in the control arm and none in the active comparator arm, it would be impossible to calculate a risk ratio. The addition of one event to each cell of the contingency table would permit estimation of the relevant ratio measures.The risk of bias will be ascertained by two reviewers in parallel, using The Cochrane Risk of Bias Tool . AssessmStudies will be included in qualitative and quantitative synthesis if they fulfil all eligibility criteria. Notable records discarded during the screening procedure will be discussed, particularly if these required arbitration, or have been specifically included in or excluded from previous meta-analyses. Study characteristics will be summarised using means and standard deviations (or medians and interquartile ranges) for continuous variables, and numbers and percentages for categorical variables. A narrative report of study characteristics will also be provided.I2 statistic and quantified using Cochran’s Q statistic. Sources of heterogeneity, derived from the clinical characteristics of patients enrolled to each study  is the natural log-transformed relative risk for each outcome and Wi is the inverse variance, for each trial, i. Meta-regression will be performed to identify the impact of blood pressure reduction as a moderator of clinical outcome, and evaluate the assumption that reductions in RR will be proportional to the achieved reduction in BP. Meta-regression plots, with 95% confidence intervals, will be plotted by drug class and outcome. Relative risk will be plotted against between-group reduction in systolic BP. The x-axis intercept will be examined to assess the blood pressure-dependency of the effect of each agent . Subgroup analysis will be performed to address the presence of interaction with (i) overall duration of study follow-up, (ii) percentage usage of other agents , (iii) percentage of study participants revascularised, (iv) year of study publication and (v) enrolment period of patients; each categorised appropriately. p values for interaction will be presented for each case. The presence of meta-bias  will be examined by visual inspection of Funnel plots and calculation of Egger’s statistic, for both ACEi and ARB trials. All analyses will be performed using Stata  and R . Narrative evaluation of the risk of bias in individual studies will be undertaken to suggest the overall strength of the body of evidence.Where ∆SBPAll studies of the ACEi and ARB class, vs. placebo or active comparator, will be included in the primary meta-regression analysis. Multiple sensitivity analyses will be performed to evaluate restriction of analysis to exclude studies with (a) open-label (e.g. PROBE) design, (b) head-to-head comparison of ACEi and ARB only, (c) high-risk of bias, (d) greater than two randomisation arms and (e) principal recruitment of participants with HF. Both fixed effects (inverse variance-weighted) and random effects (DerSimonian and Laird-weighted) will be performed.The existence and mechanism of an ARB-MI paradox is controversial. We envisage that this systematic review will provide a detailed, state-of-the-art and unbiased synthesis of the evidence regarding the relationship between clinical outcomes and BP reduction as a result of treatment with ACE inhibitors and ARBs. To date, several methodologically similar meta-regression analyses have been performed. One such analysis included only those trials participating in the Blood Pressure Lowering Treatment Trialists’ Collaboration; lacking a systemic methodological rigour . A searcPrevious meta-regression analyses  estimatGreater characterisation of the relationship between drug-mediated BP reductions and clinical outcomes may better guide utilisation of ACE inhibitors and ARBs, and may highlight the need for further analysis, using individual participant-level randomised trial data.Additional file 1:PRISMA-P 2015 Checklist. (DOCX 30 kb)Additional file 2:Primary MEDLINE (PubMed) search strategy. (DOCX 14 kb)


Remote monitoring is an established, guideline-recommended technology with unequivocal clinical benefits; however, its ability to improve survival is contradictory.The aim of our study was to investigate the effects of remote monitoring on mortality in an optimally treated heart failure patient population undergoing cardiac resynchronization defibrillator therapy (CRT-D) implantation in a large-volume tertiary referral center.The population of this single-center, retrospective, observational study included 231 consecutive patients receiving CRT-D devices in the Medical Centre of the Hungarian Defence Forces  from January 2011 to June 2016. Clinical outcomes were compared between patients on remote monitoring and conventional follow-up.P=.004). The survival benefit remained statistically significant after adjustment for important baseline parameters .The mean follow-up time was 28.4 (SD 18.1) months. Patients on remote monitoring were more likely to have atrial fibrillation, received heart failure management at our dedicated heart failure outpatient clinic more often, and have a slightly lower functional capacity. Crude all-cause mortality of remote-monitored patients was significantly lower compared with patients followed conventionally (hazard ratio [HR] 0.368, 95% CI 0.186-0.727, In this single-center, retrospective study of optimally treated heart failure patients undergoing CRT-D implantation, the use of remote monitoring systems was associated with a significantly better survival rate. Remote monitoring of cardiac implantable electronic devices has proved to be beneficial on several clinical endpoints. The first studies confirmed the feasibility of early, automatic detection of technical issues , and recMoreover, registry data suggest a potential survival benefit in patients on remote monitoring ,11. The However, a recent randomized trial on remote monitoring (MORE-CARE) could not reduce mortality or risk of cardiovascular or device-related hospitalizations . FurtherConcerning these contradictory results, we aimed to investigate the effects of remote monitoring on mortality in an optimally treated heart failure patient population undergoing CRT-D implantation in a large-volume tertiary referral center.The population of this single-center, retrospective, observational study included consecutive patients receiving CRT-D devices in the Medical Centre of the Hungarian Defence Forces  from January 2011 to June 2016. Indication for implantation was established according to current guideline recommendations of the European Society of Cardiology . CRT-ICDThe possibility of remote monitoring was offered to every patient implanted with a wireless telemetry-capable CRT-D device. Patients who consented to remote monitoring formed the remote monitoring group. During the inclusion period, remote monitoring systems of two manufacturers  were available in our center. The control group consisted of CRT-D recipients, who were followed up in our outpatient device clinic without remote monitoring.The CareLink network operates with scheduled transmissions defined by the physician, and unscheduled transmissions, which can be triggered both by the patient  and by the device itself . Scheduled remote transmissions were set up every 3 months . It was Home Monitoring uses a mobile phone network to transmit device data automatically on a daily basis, as well as instantly on the occurrence of a potentially clinically relevant event . These pIn-office visits were recommended to patients on remote monitoring without symptoms at least once a year . Remote Patient demographics, comorbidities, pharmacotherapy, electrocardiogram characteristics, echocardiography, and laboratory data were collected at enrollment and during scheduled remote checks or in-office visits.All patients on remote monitoring signed a related informed consent form. The study complied with the Declaration of Helsinki, and the study protocol was approved by the Institutional Ethics Committee of Hungarian Defence Forces Medical Centre, Budapest, Hungary.The primary objective of this study was to compare the mortality of remote-monitored patients with patients on conventional follow-up. Survival was assessed as the time from CRT-D implantation to all-cause mortality. Mortality data were retrieved using the Hungarian National Health Fund Death Registry. The unique health insurance number of a patient is deactivated immediately after death. The secondary endpoint was the response to resynchronization therapy at the visit at 6 to 12 months, defined as 5% absolute increase in left ventricular ejection fraction. The number of all ambulant visits, device clinic visits, and heart failure outpatient clinic visits were also analyzed and compared between the two patient groups.t test or the Mann-Whitney U test was used for continuous variables among patient groups.Statistical analysis was performed using PASW Statistics software, version 18.0.0 . The Kolmogorov-Smirnov test was used to evaluate the normal distribution of continuous data. The chi-square test was applied to test for categorical variables; the two-sample P ≤.10 on univariate analysis were included in the multivariate Cox models. Two-sided P values <.05 were considered statistically significant. Survival curves were constructed according to the Kaplan-Meier method and compared with the Cox proportional hazard model. To check for interaction between survival and the specific remote monitoring system, all-cause mortality was also compared between the subgroups of patients on CareLink and on Home Monitoring systems.To assess the effects of remote monitoring on survival, the Cox proportional hazards regression model was used. Univariate analysis was performed for the following variables: age; gender; heart failure management; upgrade procedure; secondary prevention; ischemic etiology; atrial fibrillation; hypertension; hyperlipidemia; diabetes mellitus; stroke; peripheral artery disease; chronic obstructive pulmonary disease; New York Heart Association (NYHA) functional class; left ventricular ejection fraction; QRS duration; left bundle branch block; estimated glomerular filtration rate; hemoglobin; and therapy with platelet aggregation inhibitors, beta blockers, angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, mineralocorticoid antagonists, diuretics, digitalis, amiodarone, and statin. All variables with A total of 231 CRT-D recipients were included in this study. Of the 90 patients implanted with remote monitoring-capable devices, 62 consented to receive a remote monitor .During the average follow-up time of 28.4 (SD 18.1) months, 63 patients died, 2 underwent heart transplantation, 2 received a left ventricular assist device, and in 1 case device explantation was performed due to infection. Crude all-cause mortality of remote-monitored patients was significantly lower compared with patients followed conventionally ; however, this difference was statistically nonsignificant .P=.08). This was because patients on remote monitoring presented at our specialized heart failure outpatient clinic more often . Moreover, two patients reached an elective replacement indicator. In addition, 396 transmissions included OptiVol alerts. Telemonitoring observations in the 21 patients on the Biotronik Home Monitoring system were as follows: 3 red alerts  and 85 yellow alerts .In this single-center, retrospective, observational study of 231 CRT-D recipients, use of remote monitoring was associated with better survival compared with patients undergoing conventional follow-up. The total number of follow-up visits was not reduced with this technique in our cohort.Remote monitoring systems proved to be feasible, reliable, accessible, and were supported by the current guideline recommendations ,23. TheyThere are several proposed mechanisms contributing to the improved clinical outcome: early detection of clinically relevant arrhythmias  and early recognition of device malfunctions or suboptimal programming, which avoids unnecessary shocks and achieves proper percentage of biventricular pacing, respectively.Moreover, the number of OptiVol alerts and the related visits at the heart failure outpatient clinic suggest that the observed mortality benefit associated with remote monitoring was also driven by early response to cardiac decompensation in our study. OptiVol is a detection algorithm developed for early recognition of cardiac decompensation using changes of intrathoracic impedance as a marker of lung fluid status . This meOur analysis shows a survival benefit for patients on remote monitoring; therefore, we are convinced that remote monitoring should be part of the follow-up of patients with CRT-D devices. One possible reason for the conflicting results of previous studies is the wide variety of actions on remote monitoring findings. A recently published meta-analysis by Stockburger et al  showed tAdditional clinical factors can also modify the clinical benefit of remote monitoring, such as the time from implantation to initiation of remote monitoring , the adhThis research is a single-center, retrospective study with all the consequential limitations. Despite the adjustment for the most relevant baseline cofounders, a residual selection bias can not be completely excluded. Moreover, the choice of device was not randomized but was left to the implanting physician, which may have modified our results. The patient’s decision to consent to remote monitoring may also have modified the results. The potential sources of bias should also be addressed. The most important one is the patient’s decision to consent with a remote monitoring program. Patients with better adherence and motivation are more likely to participate in such programs, which might have improved the outcomes of patients in the remote monitoring group.In this single-center, retrospective study of optimally treated heart failure patients undergoing CRT-D implantation, the use of remote monitoring systems was associated with significantly better survival. However, a higher number of follow-up visits in the heart failure outpatient clinic was needed, which suggests that this survival benefit could be achieved by an increased and focused effort to follow and treat high-risk patients. Our results call for further randomized studies with a standardized action plan after certain telemonitoring observations to define the optimal role of this technology in the follow-up of heart failure patients.


For stable and effective control of the sensor system, analog sensor signals such as temperature, pressure, and electromagnetic fields should be accurately measured and converted to digital bits. However, radiation environments, such as space, flight, nuclear power plants, and nuclear fusion reactors, as well as high-reliability applications, such as automotive semiconductor systems, suffer from radiation effects that degrade the performance of the sensor readout system including analog-to-digital converters (ADCs) and cause system malfunctions. This paper investigates an optimal ADC structure in radiation environments and proposes a successive- approximation-register (SAR) ADC using delay-based double feedback flip-flops to enhance the system tolerance against radiation effects, including total ionizing dose (TID) and single event effects (SEE). The proposed flip-flop was fabricated using 130 nm complementary metal–oxide–semiconductor (CMOS) silicon-on-insulator (SOI) process, and its radiation tolerance was measured in actual radiation test facilities. Also, the proposed radiation-hardened SAR ADC with delay-based dual feedback flip-flops was designed and verified by utilizing compact transistor models, which reflect radiation effects to CMOS parameters, and radiation simulator computer aided design (CAD) tools. In order to control the sensor system stably and effectively, it is necessary to accurately diagnose and control the sensor environments by measuring signals such as temperature, pressure, and electromagnetic field. Various sensor signals are measured and converted from analog signals to digital bits in the sensor front-end readout system. Since the ADC consists of analog circuits that are sensitive to parameter variations, its performance can easily change due to external interferences such as temperature, process variations, and radiation effects. In particular, performance degradation of the ADC due to radiation effects leads to a major problem in system control. Typical radiation environments include flight, space, nuclear power plants, and nuclear fusion reactors . In receThe effects of high energy particles from radiation sources, such as neutrons and alpha particles, on CMOS integrated circuits, can be categorized into total ionizing dose (TID) and single event effect (SEE) ,4,5. TIDThe rest of this paper is organized as follows. ADCs have various structures, such as flash ADC, pipelined ADC, successive-approximation- register (SAR) ADC, and sigma-delta ADC, depending on the operation method and required performance. Flash ADCs have a high sampling rate but have limited resolution around 6–7 bit. Also, since a large number of comparators are used, ADC performance may be greatly degraded due to transistor variations caused by TID .SAR ADCs can realize the high resolution of 10 bit or above, while its sub-blocks can be mostly implemented with digital circuits, which is relatively robust to TID . The fliDigital-to-analog converter (DAC): A capacitor DAC commonly used in SAR ADCs can significantly reduce the accuracy due to voltage changes in capacitors caused by SEE. Therefore, this paper adopts a resistor-type DAC that can be robust to SEE.Sample-and-hold circuit (S/H): The sampling capacitor was set as large as possible within a given operation speed to minimize the voltage changes in capacitors due to SEE.thV variation in transistors and adjusts the gate voltage to compensate for TID on transistors [Comparator: A strong-arm digital comparator, which is robust against transistor variations by TID, is used . The inpnsistors .SAR logic: Conventional flip-flops used in the SAR logic circuit suffer from data flip due to SEE, which leads to soft errors . To reduIn this paper, the design target of the radiation-hardened ADC is to convert magnetic sensor signals in the nuclear fusion reactor into digital data. For this purpose, the ADC requires a high resolution of 10 bit and a sampling rate of 25 kS/s while consuming low power below 1 mW. Therefore, we selected the SAR ADC as a radiation-hardened ADC structure and proceeded with the following additional designs to enhance radiation-hardened performance. In order to solve the racing problem and enhance radiation tolerance, a latch with dual feedback structure has been proposed as shown in The proposed radiation-hardened latch adjusts the delay time of the feedback path by adding the delay cell to the 1st feedback inverter output as shown in In the extreme case when SEE occurs simultaneously at QB1 and QB2 in both conventional lath and proposed lath, the data values stored in Q can be flipped. However, since SEE is instantaneous radiation effects affecting in very short time periods, the probability of SEE occurrence at both QB1 and QB2, which leads to data flip in Q, is very small.flipQ, which means the data flipping errors can happen with smaller SEE charge. In addition, the flip-flop needs to operate within ADC operation speed, limiting the maximum feedback delay. In our design, we set the feedback delay as 0.4 ns considering those requirements.critQ), which represents the amount of externally injected charge when data is flipped, was compared. A double exponential current model was used for the critQ simulation [In order to compare the radiation-hardened performance of the proposed delay-based dual feedback latch  with themulation . A certacritQ value (based on the SS corner) more than 56% higher than critQ of conventional latches.The proposed radiation-hardened flip-flop test chip was fabricated with a 130 nm CMOS SOI process. To verify and compare the flip-flop performance in the radiation environment, the error rates of the flip-flop outputs were measured when the radiation time was 60 s, 90 s, 120 s, and 150 s. The experiment for each radiation time was repeated five times, and the number of measured errors was summed. Consequently, we could obtain the number of flipping errors for 50,000 flip-flops. For our radiation test, we use a 45 MeV proton beam gun, which has 22 mm diameter and a 1 nA flux. The distance between the proton beam gun and our test-chip is 2.5 m, and the effective energy of the proton becomes 41.16 MeV. At this time, each flip-flop operates with a supply voltage of 2.3 V.The chip verification results are shown in The proposed delay-based dual feedback flip-flop was applied to the radiation-hardened SAR ADC proposed in a and Qb, in In order to verify the SEE performance of the proposed radiation-hardened SAR ADC , a randoTo include the TID effects in circuit design, the Berkeley Short-channel IGFET Model (BSIM) 4 spice model was used to identify changes in CMOS transistors against TID. First, to create the BSIM4 spice model, we design the same NMOS and PMOS as a 65-nm CMOS process using 3D Technology Computer-Aided Design (TCAD) tool. Then, the radiation effect at each Gy level is reflected in the TCAD-designed NMOS and PMOS with the Victory Device Tool , and a graph of voltage and current characteristics are obtained. Finally, the BSIM4 spice model (compact transistor model) can be extracted by using the obtained I-V curves and applied to the radiation effect simulation as shown in flipQ), which leads to data flip, was checked.The TID effect was applied to the proposed flip-flop using the compact transistor model to verify the radiation tolerance against the TID. To consider both TID and SEE in model simulation, the SEE charge was also applied to the flip-flop using the radiation simulator CAD tool, in addition to the compact transistor models, and then the amount of flip charge  in addition to shielding and CMOS process techniques. In this paper, a radiation-hardened delay-based dual feedback flip-flop was designed, fabricated, and verified in actual radiation environments. In addition, a radiation-hardened SAR ADC with the proposed flip-flop was also designed, and its performance and radiation tolerance against TID and SEE were verified by using compact transistor models and radiation simulator CAD tools.