In recent years, the progress of science and medicine greatly has influenced human life span and health. However, lifestyle habits, like physical activity, smoking cessation, moderate alcohol consumption, diet, and maintaining a normal body weight represent measures that greatly reduce the risk of various diseases. The type of diet is very important for disease development. Numerous epidemiological clinical data confirm that longevity is linked to predominantly plant-based diets and it is related to a long life; whereas the western diet, rich in red meat and fats, increases the risk of oxidative stress and thus the risk of developing various diseases and pre-aging. This review is focused on the bioavailability of polyphenols and the use of polyphenols for the prevention of prostate diseases. Special focus in this paper is placed on the isoflavonoids and flavan-3-ols, subgroups of polyphenols, and their protective effects against the development of prostate diseases. Homo sapiens have not yet fully adapted to the meat diet. Namely, millions of years ago all human ancestors were herbivores. It is evidenced by anatomical features and evolutionary evidence, as well as by the diet of the closest human relatives, hominids [It seems that hominids .Only some 15,000 years ago, man began to build settlements, raise livestock, and eat the meat of domestic animals. The transition to meat foods was probably related to a sharp increase in the number of free radicals in the cells and oxidative stress occurrence. At the same time, man reduced plant intake, from some 3000 species to only 20–30 species; the number of plant foods rich in antioxidants, vitamins, and polyphenols also reduced. Coffey believes that this change in diet brought an explosive jump in the occurrence of prostate cancer and breast cancer [How is the protective effect of plant foods on the human body explained? The basis of plant and animal cell functioning are similar biochemical processes, and are understandable, given the common origin of plants and animals. Namely, life on Earth existed for 3.5 billion years, and animals separated from plants about 670 million years ago . The firOxygen is an element without which life on Earth as we know it today would be impossible. Oxygen is the driver of an incalculable number of oxidative chemical reactions that occur in the entire living and non-living world. The first amounts of oxygen in the ocean began to produce cyanobacteria through photosynthesis, about 2.7 billion years ago, while significant oxygen production began 2.5 billion years ago, when oxygen was released from the sea and entered the atmosphere. The large amount of oxygen enormously increased the energy sources necessary for living beings, which led to the expansion of evolution [The first terrestrial plants appeared 410 million years ago, some 100 million years before the appearance of the first terrestrial herbivores ,7. These2O2), hypochlorous acid (HClO), and the free radicals: hydroxyl radical (OH−) and superoxide anion (O2−). The largest producers of ROS are NADPH oxidase enzymes, which are found on the cell membrane, mitochondria, and endoplasmic reticulum.In all aerobic organisms, the energy for biological functions is generated in the mitochondria. As byproducts, ROS are also produced on a daily basis; the most important ROS are hydrogen peroxide (H+) through the inner membranes of the mitochondria, by the electron transport chain process. During this chain of reactions, electrons undergo a series of proteins via oxidative-reduction reactions; each protein in the series that receives an electron has a greater reduction potential than the previous one. The ultimate destination of the electrons in this chain is the oxygen molecule, O2. Under normal circumstances, O2 is reduced and produces water, H2O. However, in 0.1–2% of electrons passing through the chain, O2 is reduced prematurely and incompletely into radical superoxide, O2. Hydrogen peroxide, H2O2, is formed from superoxide, which leaks from the mitochondria. The enzymes catalase and superoxide dismutase convert H2O2 to oxygen and superoxide to H2O2, from which H2O is formed. However, this conversion is not 100% efficient and a certain amount of H2O2 lags in the cell. If too much damage occurs in the mitochondria, programmed death, apoptosis, occurs in the cell. The Bcl-2 protein, located on the surface of the mitochondria, detects damage and activates a class of protein called Bax, which drill holes in the mitochondrial membrane and leads to the leakage of the protein of the electron transport chain, called cytochrome C. After that, the released cytochrome C begins a series of reactions leading to the cleavage of proteins in the mitochondrial membrane and its disintegration [Mitochondria convert the energy into a usable form, adenosine triphosphate (ATP). The process of ATP formation involves the transport of hydrogen ions ; OS is associated with the aging and development of various diseases. There is evidence that animals that have been genetically engineered to remove antioxidant enzymes have a shorter life span .One of the main causes of mutations is DNA oxidation. It is estimated that the normal daily endogenous production of ROS in a single cell modifies about 20,000 DNA bases . HoweverAntioxidants react with ROS by self-oxidizing and thus reducing the possibility of oxidative damage to cellular organelles. The function of the antioxidant system is not to completely remove the oxidants, but to maintain them at the optimal level. Antioxidants are generally reducing agents, such as thiols, ascorbic acid or polyphenols. Human cells can produce some antioxidants on their own, like superoxide dismutase, catalase, and glutathione peroxidase, while some have to be ingested through food, like vitamin E, vitamin C, polyphenols, carotenoids, etc. . When viThe prostate is an organ that belongs to the accessory of the male reproductive organs. In all mammals, the prostate is involved in the production of seminal plasma, which serves as a medium for the transport and nourishment of sperms. The prostate function is controlled by steroid hormones and its structure is basically similar in all mammals. In most primates, the prostate is composed of two parts, the cranial and caudal prostate; in humans, these two parts are located in one compact organ and correspond to the central zone (CZ) i.e., peripheral zone (PZ) .The diseases of the prostate are rare in mammals. Benign prostatic hyperplasia (BPH) occurs in humans, chimpanzees, and dogs. Prostate cancer (PCa) is extremely rare in all mammals, including chimpanzees and apes. The low incidence of PCa in hominids is primarily explained by the fact that they are obligate herbivores .The prostate structure is made up of connective stroma and epithelial cells. The stroma consists of the basic substance, axons of nerve cells and stromal cells, fibroblasts, endothelial cells, and smooth muscle cells. The prostate epithelium is composed of secretory, neuroendocrine, basal, and intermediate cells.The most important physiological functions of the prostate are secretory and hormonal. The prostate synthesizes and secretes numerous non-peptide substances, such as polyamines, cholesterol, lipids, citrates, and zinc. Citrates and zinc are found in the prostate at a much higher concentration than in other organs and tissues . The mosThe hormonal function of the prostate is related to the intracrine and paracrine activity. Paracrine factors, acting from neighboring cells, are tissue growth factors (GFs), small peptide molecules that stimulate and/or inhibit cell division and differentiation. The balance between proliferation and cell death is dictated by the complex interactions between GFs and steroid hormones. Fibroblast GF (FGF), vascular endothelial GF (VEGF) and insulin-like GF (IGF) are thought to promote cell proliferation in BPH, and DHT enhances their action . TransfoThe most important serum androgen, testosterone (T), acts as a prohormone: In prostate cells, most of T is converted to potent DHT by the action of enzyme 5-alpha reductase (5-αR); a number of T molecules are converted to estradiol (E2) by the action of enzyme aromatase. Estrogens act on the human prostate via interaction with two receptor subtypes, ERα and ERβ. The dominant estrogen receptor in the prostate is ERβ, which is found both in the stroma and in the epithelium , whereasGrowth factors (GF) are small peptide molecules that stimulate, and sometimes, inhibit the division process and cell differentiation, by activating cell receptors for GF. The balance between proliferation and cell death dictate the complex interactions between GF and steroid hormones. It is considered that FGF (fibroblast GF), VEGF (vascular endotel GF) and IGF (insulin-similar GF) stimulate cell proliferation with BHP, and DHT increases their effect. The most important factor is the interaction of stroma and epithelium is FGF-7 . The facThere are numerous reciprocal reactions between the stroma and the epithelium, called the stroma–epithelial interaction; this process begins during embryonic development, continues during prostate development, and lasts throughout adulthood and old age .Prostate diseases are of great importance in modern men: BPH is ranked fourth in the most common chronic diseases and eighth in the cost of their treatment. Prostate cancer (PCa) is the fourth most common cancer in the world and the second most common cancer in men. In the USA, PCa is the most common malignancy in men and accounts for 27% of all cancers ,24. ProsBy definition, BPH is a histologic diagnosis, which involves the uncontrolled proliferation of the prostatic stroma and epithelium and enlargement of the prostate gland. Lower urinary tract symptoms (LUTS) very often accompany BPH and enlargement of the prostate and they gradually worsen over time. The most frequent LUTS are very difficult urination and the feeling of incomplete bladder vacating, frequent urination, night urination, etc. A complete discontinuation of an urination process and a bladder stone are indications to have BPH surgery.Global BPH prevalence is 26%. The prevalence increases with aging: After 50 years of age, it is 50%, and at the age of 60, 60% of men have BPH with LUTS. The prevalence of BPH is higher in Chinese people living in the USA than in Chinese people in China ,26,27. TRisk factors for BPH development are low physical activity, obesity and metabolic syndrome. The familial form of BPH is present in 50% of patients under 60 years of age who underwent simple prostatectomy . The preHowever, the role of androgens in the onset of BPH is not entirely clear, as BPH develops in elderly people with normal or low serum androgen levels. However, DHT levels in prostate tissue remain high ,30. PejčProstate cancer (PCa) is generally diagnosed in men over 65, and very rarely in the ones under 50. Today, PCa is the most commonly diagnosed cancer in men in America, Europe, Australia, and Sub-Saharan Africa ,35. In tPursuant to the data of the CDC-National Program of Cancer Registries and National Cancer Institute Surveillance, Epidemiology and End Result Program in the USA, the incidence of PCa in 2014 was around 100 for all races, 50 for the Asians living in the USA, 90 for white-Americans and 150 for Afro-Americans.PCa incidence in Asia is 50–100 times lower than in western countries. Pursuant to the data of WHO from 2012, PCa incidence in Asia was 10.5% . The lowGenetic factors are very important in PCa development: if the father had PCa, the son’s risk is 2× higher; if both father and brother had PCa, the risk is even 5 times higher . A signiAndrogens are essential for the development, growth, and survival of PCa. Castration is known to lead to apoptosis of malignant cells and the decrease of PCa bone metastases. Like in normal prostatic tissue, in PCa cells estrogens play an important role: activation of ERα stimulates proliferation, and activation of ERβ leads to an antiproliferative and pro-apoptotic effect. Over time, loss of ERβ occurs in PCa, leading to disease progression. Animal experiments show that PCa occurs in mouse strains lacking the ERβ receptor (betaERKO), but does not occur in mice lacking the ERα receptor . Also, mice strains lacking the enzyme aromatase (ArKO) have a lower PCa incidence ,44. TherVitamin D has a protective effect on the development of PCa, and men with vitamin D deficiency are known to have a higher PCa incidence. This category includes the elderly, people from the north and African-Americans; in the latter, a large amount of melanin in the skin reduces the production of active vitamin D. The vitamin D receptor, to which serum vitamin D binds, is present in the normal and malignant prostate epithelium . Normal Disorders at the level of cellular molecular signaling pathways play a key role in the development of malignant tumors. In PCa, disturbances of the PI3K/Akt/mTOR signaling pathway are of great importance . The majPI3K/Akt activity is enhanced by EGF, IGF-1, and insulin. On the other hand, the natural inhibitor of PI3K/Akt, the enzyme PTEN (tumor suppressor phosphatase and tensin homolog), reduces the activity of this pathway by interfering with PI3K and negatively affecting mTOR signals. One of the most common reasons for mTOR activation is mutations or deletions in PTEN, which are present in over 80% of PCa .There are two complexes created by mTOR: mTOR complex 1 (MTORC1) and mTOR complex 2 (MTORC2). The MTORC1 is the most important regulator of cell growth, responding to and integrating different signals from food and the environment; this complex is inhibited by rapamycin. The MTORC2 stimulates cell survival via Akt activation . AberranThe key genetic events in PCa progression are loss of functional androgen receptor (AR) and increased expression of epidermal growth factor receptor, erbB. Genetic alterations lead to feedback between the membrane receptor (erbB1) and the associated ligand . The result is the enhanced activation of the most important component for uncontrolled PCa growth, namely ERK1/2  .PCa resistance to therapy is associated with abnormally increased expression of AR, Bcl-2, erbB, HER2 , cyclin D1, and cyclooxygenase (COX-2), all of which are associated with the activation of transcription nuclear factor NF-κB. The NF-κB is a protein complex that controls DNA transcription, cytokine production, and cell survival. NF-κB is found in the cells of almost all animals and is involved in the cellular response to stress, cytokines, free radicals, heavy metals, ultraviolet radiation, oxidized LDL, as well as bacterial and viral agents .Human prostate adenocarcinoma cell lines, such as LNCaP, DU-145, and PC-3, are most commonly used in in vitro experiments. Androgen-dependent lines are LNCaP, obtained from PCa metastases to lymph nodes and 22Rv1. Androgen-independent lines are DU-145 and PC-3, which have no AR and have ER. Animal experiments are most commonly performed on specific strains of mice and rats, such as TRAMP (transgenic adenocarcinoma of the mouse prostate), betaERKO (mice lacking the ERβ receptor), alphaERKO (mice lacking the ERα receptor), and ArKO (mice lacking aromatase). A nude mouse is a laboratory mouse of the thymus-free variety that has an inhibited immune system due to reduced T-cells. He got his nickname because he has no hair. This variety of mice can receive different tissues and tumor grafts, without rejection .Prostatitis is the most common urological diagnosis in people under 50 and the third most common urological diagnosis in people over 50 years, after BHP and PCa. The overall prevalence of chronic prostatitis and chronic pelvic pain syndrome is 7.1%. However, the prostate inflammation is seen in as many as 44% of the prostate tissue samples at autopsy, and even in individuals who have not had prostate disease. Acute bacterial prostatitis is a prostate infection, most commonly caused by gastrointestinal gram-negative bacteria. The risk factors for prostatitis are intraprostatic ductal reflux, phimosis, indwelling urethral catheter, transurethral surgery, and secretory prostate dysfunction. Secretory dysfunction is accompanied by decreased levels of fructose, citric acid, acid phosphatases, Zn, Mg, and Ca and an increase in pH, levels of inflammatory proteins and LDH-5 / LDH-1 ratio .Polyphenols are the most abundant and most examined secondary metabolites in the plant kingdom, with over 8000 species known, but are still an area of research that claims many scientists . PolypheThe average daily intake of polyphenols in the European countries differs a lot: it is the highest in Denmark (1700 mg) and the lowest in Greece (660 mg). The majority of ingested polyphenols are phenolic acids (~55%), and in some regions, flavonoids (50–60%). The most important sources of polyphenols in foods are coffee, tea, and fruits .All plant phenol compounds originate from amino acids phenylalanine, i.e., silimatic acid. Silimatic pathway is a metabolic pathway, one of seven steps used by bacteria, fungus, algae, and the bio-synthesis of plants for flavonoids and aromatic amino acids, while animals and people must intake them through food. Polyphenols are classified in a number of ways, usually based on the number of phenolic rings and they also contain the elements binding these rings to each other. The major classes of polyphenols are flavonoids, phenolic acids, stilbenes, and lignans. Polyphenols can also be divided into flavonoids and non-flavonoids ,61.The antioxidant properties of polyphenols have been demonstrated in vitro, in numerous experiments on isolated cell cultures; on the other hand, but a much larger problem is to prove these properties in vivo. In addition to its direct antioxidant effect, polyphenols also act indirectly in humans by increasing the level of uric acid. However, the “antioxidant hypothesis” does not offer precise answers to understand the molecular mechanisms behind the beneficial effects of polyphenols from food. Yet, the signaling effects of polyphenols are thought to occur at much lower concentrations than those required for antioxidant activity ,63.The second effect of polyphenols is the modification of cellular signals and the regulation of the action of various enzymes, such as PI3K, Akt/protein kinase B, tyrosine kinase, protein kinase C, mitogen-activated protein kinase, etc. Signal effects of polyphenols probably appear with a lot lower concentrations from the ones needed for antioxidant activity. In accordance with this, the “antioxidant hypothesis” does not offer true answers for the understanding of molecular mechanisms that are in the background of favorable polyphenol effects from foods. Also, another important effect of polyphenols is to increase the secretion of paraoxonase, an enzyme that prevents low-density lipoprotein (LDL) oxidation ,65.The debate regarding the absorption of polyphenols from food is still ongoing. On the one hand, epidemiological studies agree that there are positive health effects of taking polyphenols; on the other hand, there is a low bioavailability of polyphenols in the body, due to low resorption and rapid transformation and excretion. The absorption of polyphenols via the stomach and small intestine is only 5–10% of the total intake. To be absorbed, polyphenols must be chemically transformed by the intestinal microflora (“microbiota”) and enzymes from the intestinal epithelium. The absorption of polyphenols depends on the amount and size of the phenolic compound, previous diet, nutrient matrix, sex, and gut microflora ,67.The accurate assessment of the physiological effects of polyphenols from foods is very complicated because single foods often contain a lot of different polyphenols, whose outcome is impossible to track and measure. For example, there are about 60 different flavonoids in red wine. On the other hand, mixtures of different polyphenols can have a synergistic and antagonistic effect. Also, polyphenols effect antagonistically in the presence of vitamin C. The more powerful a polyphenol is, an antioxidant regenerates faster, while the weaker antioxidants are spent ,69.flavus, which means yellow. Flavonoids are found in large quantities in fruits and vegetables and drinks such as tea, cocoa, and wine. Today, there are about 6000 flavonoids, which are mostly found as multicolored pigments of fruits, vegetables, and medicinal plants [Flavonoids belong to the class of low molecular weight phenolic compounds and are widespread in the flora world. They got their name from the Latin word l plants .The antioxidant activity of free flavonoids depends on the number and position of their hydroxyl groups. The basic structure of flavonoid compounds is the flavone nucleus, which consists of two benzene rings (A and B) that are linked via a heterocyclic pyran C ring. The position of the benzenoid B ring is the basis for dividing the class of flavonoids into flavonoids (2-position) and isoflavonoids (3-position) .The average intake of flavonoids in the USA adults is about 250 mg per day, with flavan-3-ols accounting for 80% of total intake. Tea is the main primary source of flavonoids and accounts for 80% of the intake of all flavonoids. In Korea, the average daily intake of flavonoids is about 110 mg ,73. The The medical use of flavonoids is based on their antioxidant, anti-inflammatory, and anticarcinogenic properties and their capacity to modulate key enzymatic functions in the cell. They are strong inhibitors of enzymes such as xanthine oxidase, cyclooxygenase, lipoxygenase, and PI3-K. The primary role of flavonoids in plants is to protect them from UV radiation, living or inorganic stress, etc. In the food industry, flavonoids are added to foods to prevent fat oxidation.There are numerous classifications of flavonoids. According to the degree of oxidation of the central piran ring, flavonoids can be divided into six classes: 1. flavones, 2. flavonols, 3. flavanones, 4. isoflavonoids, 5. flavan-3-ols (monomers and oligomers), and 6. anthocyanins.Flavones are widely represented in leaves and flowers. The most important sources of flavones are celery, parsley, red pepper, chamomile, mint, and ginkgo biloba. Their well-known representatives are luteolin, apigenin, and tangeretin .Han (2018) found that luteolin inhibited PC-3 cell proliferation, migration, and cell renewal . ApigeniThe best-known flavonols are quercetin, fisetin, myricetin, and kaempferol . FlavonoQuercetin is largely found in red grapes, red wine, apples, tea, and berries. The highest concentration of quercetin is found in canned capers (~170 mg/100 g) and red onions (33 mg/100 g). Quercetin acts as an antioxidant, as a protein kinase inhibitor and activator of ERα and ERβ. The action of quercetin is three times weaker than E2; however, it is nine times more selective for ERβ, than for ERα . The FDAFisetin is found in apples, grapes, kiwi, strawberries, onions, and cucumber. On the PCa cell lines, fisetin has been shown to act as a dual inhibitor of PI3K/Akt and mTOR metabolic pathways. This is an important finding, as mTOR activation is a lot more common in tumors with high PI3K/Akt expression. It is believed that fisetin could be probably used in the treatment of PCa, alone or in combination with chemotherapeutic drugs .Kaempferol showed cytotoxicity across different cancer cell lines including Du145; it is offered as a potential anticancer agent .Flavanones are present in citrus fruits, oranges, lemons, and grapes. The most well-known are hesperetin, naringenin, and eriodictyol .Hesperetin inhibits proliferation and induces cell cycle arrest in PC-3 cells, in the G1 phase. Similarly, naringenin, natural flavonoid from grapefruit, and fruit, inhibits proliferation and migration and induces ROS production and apoptosis on PC3 and LNCaP cells. Naringenin has been shown to enhance the effect of paclitaxel on reducing progression in PCa lines ,82.Isoflavonoids are a large and inhomogeneous group of flavonoids. Isoflavonoids are derived from the flavonoid biosynthesis pathway, via liquiritigenin or naringenin. In plants, they play a role in the formation of phytoalexins during defense against germs. The most important isoflavonoids belong to the subgroup of isoflavones and these are genistein, daidzein, and glycitein  and theiThe largest source of isoflavones in nature is soya, which contains about 200 mg of isoflavones per 100 g of fresh product. Genistein and genistin make 30–60% of total soya isoflavones, daidzein, and daidzin 40–60%, while glycitein and glycitin make 1–13% of total soya isoflavones. Genistin and daidzin in soya are in conjugated form with sugars, as glycosides. Glycosides are converted into active forms, genistein, and daidzein, by fermentation, which is the traditional way of preparing soya in Asia . Except In soybean flour, the level of genistein is lower than genistin about 50 times, but only two times in fermented soya products. Specifically, during microbial fermentation, the beta-glycosyl bond of genistin is cleaved and genistein is formed . A fermeThe average daily isoflavonoid intake ranges 0.3–0.8 mg in Europe and the USA and 50–100 mg in Asia. Vegetarians and vegans in Europe consume an average of 22 mg of food isoflavones and 50 mg of supplements. In some epidemiological studies, it was determined that an average daily intake of isoflavones in Japan and China is up to 75 mg and even 150–200 mg in the traditional Japanese diet ,88,89. IThe average plasma isoflavones concentration in Europeans is 0.01 μmol/L and around 0.6 μmol/L in Japan ,88. IsofGenistein, like all other bioactive phytochemicals, has two major disadvantages: low bioavailability and high pleiotropy. The oral bioavailability of genistein is lower than that of genistin, due to its poor solubility in water. The plasma concentration of genistein from food is much lower than the concentration required for initiating an anticancer response in an experimental model. A significant clinical effects of genistein can be expected when given at pharmacological doses of >100 μM/L and weak effects when it is given at chemopreventive doses <1 μM/L. Pleiotropy is a phenomenon when a compound acts at several levels in a cell and at the same time initiates several biochemical reactions; the anticancer effects of genistein are probably the result of numerous synergistic mechanisms .Isoflavones are called plant estrogens because of their structural similarity to human estrogens and their mild estrogenic activity. Compared to physiological estrogens, isoflavones have only between 0.01% and 0.1% of E2 activity on the molar base. However, isoflavones exert physiological effects in high serum concentrations. Studies have shown that the concentration of isoflavones in people who eat soya is at the micromole level and in people who do not eat soya, at the nanomole level .A very important characteristic of isoflavones is that they do not have the same binding affinity for both estrogen receptors. Specifically, isoflavones have a much higher binding affinity for ERβ than for ERα; the relative binding affinity of genistein for ERβ is 36% and for ERα, 5% . In variKostelac and co-authors found that half-maximal effective concentration, EC (50) for ERα activation, for E2, genistein, and daidzein, were 0.03 μM, 15 μM, and 300 μM, respectively. On the other hand, the EC (50) for ERβ activation, for E2, genistein and daidzein, were 0.01 μM, 0.03 μM and 0.35 μM, respectively . ReceptoIsoflavones act on the enzymes 5-alpha reductase (5αR) and aromatase. Genistein inhibits 5αR activity in prostate fibroblasts, at a high dose, with an IC (50) of 710 μM .At high doses genistein also inhibits some of the enzymes involved in T synthesis, so it can act as an antiandrogen. In the fetal murine testis, at a dose of 10 nM (corresponding to a dose of 100 mg/kg in humans), genistein reduces the early synthesis of T, via an ERα-dependent mechanism ,102.Isoflavones also act on the enzyme aromatase, or estrogen synthetase, which converts T to estradiol (E2) and androsterone to estrone (E1) . GenisteGenistein and D vitamin synergistically inhibit prostate epithelial cell growth. The flow cytometry showed that genistein induces arrest in the G (2) M phase, and vitamin D induces arrest in the G (1/0) phase of the cell cycle .Genistein has been previously known to block cell cycle progression in the G1 phase and inhibit PSA expression in PCa cell lines. At a dose of 1.25–10 μg / mL, genistein reduced the growth of BPH and PCa in histoculture. Physiological concentrations of genistein can reduce the expression of AR, mRNA, and protein levels in androgen-sensitive LNCaP cells ,107.PART-1 gene in LNCaP cells [A large number of in vitro studies have proven that genistein inhibits the growth and metastatic activity of hormone-dependent and hormone-independent PCa, with an IC50 of 5–40 nM (2–10 mg/mL). At doses ≤20 mM, genistein inhibits growth and induces apoptosis in LNCaP, DU-145, and PC3 lines. At 50 mM/L, genistein completely inhibits the expression of the androgen-responsive aP cells ,109,110.Chiyomaru found that genistein inhibits cell growth on PC3 and DU145 by down-regulating the oncogenic HOTAIR (human gene located on chromosome 12) molecule and altering the expression of several micro-RNAs .More recent studies show that phytoestrogens do not act on AR but reactivate ERβ, which is otherwise “dormant” during carcinogenesis; so, reduced expression of ERβ leads to the same effect as androgen stimulation . ERβ reaSpagnuolo summarized the molecular mechanisms of genistein action: action on caspases, Bax (B cell lymphoma 2 (Bcl-2) -associated X protein), KIF20A , ERK1/2 , NF-κB (nuclear transcription factor κB), MAPK (mitogen-activated protein kinase), IκB (inhibitor of NF-κB), Wnt/β-catenin (Wingless and integration 1 β-catenin), and PI3K/Akt (phosphoinositide 3 kinase/Akt) signaling pathways. Genistein works synergistically with adriamycin, docetaxel, and tamoxifen .At a dose of 1 mg/g, genistein reduces prostate weight in rats and inhibits the expression of key cellular pathways. Kim believes that genistein at higher doses acts more as a tyrosine kinase receptor inhibitor than via the ERβ receptor . Yang haHealthy men consumed portions of 400 mL of soy milk, with 54 mg of genistein and 34 mg of daidzein. After eight weeks, no differences in E2, T, free T and SHBG (sex hormone-binding globulin) concentrations were observed between the persons and the control group. The only difference was the decrease in estrone concentration, in the milk-drinking group . Busby sNumerous epidemiological studies have shown a lower incidence of PCa in Asia, where soya-based foods make up a large proportion of the diet ,126. BasIn 1998, the results of a multinational study from 42 countries showed that the use of soya products significantly reduced the mortality of PCa . HoweverA meta-analysis of 11 different studies (2015) showed that high levels of genistein and daidzein and elevated serum enterolactone concentrations were associated with a significantly reduced risk of developing PCa . Russo  . FischerVan Veldhuizen administered isoflavones, at a dose of 112 to 224 mg daily, to patients prior to RP. After surgery, the values of serum T, E2, and expression of ERα receptors were compared in preoperative biopsied tissue and definitive histopathological findings. A mild decrease in serum T level was observed in most patients. There was also a decrease in serum E2 as well as decreased expression of ERα in tissue .Jarrard gave patients before RP genistein, 600 mg daily. The patients also received a single dose of 200,000 IU of vitamin D3, at the beginning of the research. The increased AR expression was demonstrated relative to the placebo group. It was shown that vitamin D inhibited the proliferation of the prostate epithelium, and genistein enhanced this effect by inhibiting the CYP24 enzyme, which is responsible for the intracellular metabolism of vitamin D. Both genistein and vitamin D inhibited the synthesis of important mediator of the inflammation in prostate, prostaglandin E2 .Flavan-3-ols are found in large quantities in tea, wine, bananas, apples, blueberries, peaches, and pears. These compounds include catechin, epicatechin, epicatechin-3-gallate, epigallocatechin and epigallocatechin-3-gallate, proanthocyanidins, theaflavins, and thearubigins . ChemicaThe flavan-3-ol monomers are catechin, epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG). All listed catechins are present in a high concentration in green tea (30–42%) and less, in black tea (3–10%) . The posAfter digestion in the human digestive tract, the fate of the complex of low-molecular-weight phenolic compounds and proteins is not entirely clear. In an in vitro digestion model, Laurent found that about 44% of catechins and 85% of epicatechins disappear after two hours of intestinal incubation, probably due to their interaction with pancreatic enzymes .In Vitro StudiesCatechins from green tea cause cell cycle arrest and apoptosis in malignant cells; EGCG is the most potent catechin that inhibits cell growth and causes apoptosis in human PCa lines. In addition, EGCG was proven to inhibit the activity of the enzyme NO synthase ,147,148.p53 and the reduction of MDM2 protein expression; the second pathway is the negative regulation of NF-jB activity, which leads to a decrease in the expression of the anti-apoptotic protein Bcl-2. The p53 gene is the most commonly mutated gene in PCa and other human cancers. NF-jB is a nuclear transcription factor that controls various immune responses, such as inflammation and apoptosis [Agarwal found that in DU145 cells genistein and EGCG caused inhibition of erbB1 membrane receptor activation caused by TGFα. Silymarin, genistein, and EGCG caused inhibition of cell growth at lower doses and complete growth inhibition at high doses . Gupta hpoptosis ,150.p16, p18, p21, and the expression of p53 gene. In addition, EGCG has been shown to stabilize the p53 gene and thus induce apoptosis in LNCaP cells [SHP-1) and the prostatic acid phosphatase-producing genes [In PCa cells, EGCG increases the expression of CDK inhibitors, such as aP cells ,151. Morng genes .On DU145 and LNCaP cell lines, Siddiqui has demonstrated that EGCG causes induction of apoptosis as well as cell cycle arrest in the G0/G1 phase . On LNCaAnimal StudiesLiao inoculated cells from PC-3 and LNCaP 104-R (androgen-repressed) lines into nude mice. Intraperitoneal injection of EGCG inhibited growth and rapidly reduced the size of human PCa in nude mice . Kao repHuman StudiesTea polyphenols are partially resorbed from the intestinal tract so that they can exert effects not only in the gut but throughout the body . NumerouHowever, in a major European study (2018), involving 140000 subjects over a 14 year period, no relationship was found between coffee and/or tea consumption and the risk of PCa .Proanthocyanidins are blue and purple pigments found in numerous plants. A large number of these compounds are dimers of epicatechin  and oligomers of catechins and epicatechins and their esters with gallic acid. Proanthocyanidins are found in a large number of plants, such as apple, cinnamon, aronia, coconut, grapes and grape products, blueberries, cranberries, black currants, and green and black tea. The highest amount of proanthocyanidins is found in chocolate and apple , significantly higher than in red wine and cranberry juice (22 mg and 32 mg per serving) .Since the discovery of “French Paradox”, polyphenols from grapes and wine have attracted the attention of scientists. The average concentration of polyphenols in certain parts of the grapes, expressed as gallic acid equivalent (GAE) is: in seeds 2180 mg/g, in skin 375 mg/g, in leaf 350 mg/g and in “meat”, i.e., the juicy part, only 24 mg/g .Some phenolic compounds in grapes are bioavailable, while compounds composed of large molecules are not, because they cannot be absorbed . Of the In Vivo StudiesKaur found that grape seed extract (GSE) had a higher antioxidant capacity than vitamins C and E. At a concentration of 100 mg/L, GSE inhibited superoxide anion and hydroxyl radical by about 80%, which was significantly higher than with vitamin C (~15%) and vitamin E (~40%) . In DU14After two hours of incubation in vitro, the monomers and dimers were stable in the intestinal medium at pH 7; dimer degradation began at pH 7.4 and all dimers disappeared at pH 8.5. At pH 7.5, after two hours of incubation, 15–34% of epicatechins underwent degradation while catechin was stable . In an iAnimal StudiesChokkalingam has demonstrated that GSE increases the level of insulin-like growth factor binding protein-3 (IGFBP-3), which can influence the suppression of PCa growth. DU145 cells were implanted to nude mice; after seven weeks of feeding with GSE, there was a decrease in the proliferation index and an increase in the apoptosis index, as well as a decrease in tumor size. GSE strongly inhibited the secretion of vascular endothelial growth factor (VEGF) and strongly increased IGFBP-3 production in the tumor .Human StudiesGrape polyphenols are rapidly absorbed into the plasma, reaching a maximum concentration 2–3 h after ingestion . After tPolyphenols from red wine and grape juice inhibit LDL oxidation and increase HDL concentration, which reduces the risk of atherosclerosis and coronary heart disease. Grape polyphenols also have a beneficial effect on diabetes by improving insulin resistance. Moderate and regular consumption of red wine reduces the risk of type 2 diabetes by 30% ,184,185.Anthocyanins  are water soluble pigments that, can be red, blue, or purple, depending on pH. About 2% of all hydrocarbons generated during photosynthesis are converted to flavonoids and their derivatives, such as anthocyanins, which have antioxidant properties and provide protection against ultraviolet radiation and cold .Anthocyanin analogs without sugar are called anthocyanidins. Anthocyanins are found in all tissues of higher plants, especially in fruits, flowers, and leaves. They are mainly found in fruits such as cranberries, black currants, red and merlot grapes, strawberries, blackberries, blueberries, raspberries, cherries, red apples, red peaches and vegetables, like eggplant, black rice, and red cabbage .The highest concentrations of anthocyanins per 100 g of fruits are found in the shell of black soybean (2000 mg), aronia (1480 mg), red grapes (888 mg), and blue eggplant (750 mg) ,190. TodO-β-glucopyranoside (C3G), especially abundant in red orange juice. The anti-proliferative effect of C3G via activation of caspase-3 and induction of p21 protein expression in two different lines, LNCaP and DU145, has been demonstrated [In the wine, malvidin-3-glucoside has the highest antioxidant capacity . The mosnstrated . In anotnstrated .O-methyl-gallic , gallic , syringic, vanillic, and protocatechuic acid. The digestion of anthocyanins into the colon is completed six hours after their administration. Megal and Gal are effective in reducing the vitality of colon cancer cells. Anthocyanins from wine and grapes inhibit phosphodiesterase-5 activity, lead to vasorelaxation and thus reduce the risk of cardiovascular diseases [Anthocyanins are poorly absorbed in the human gastrointestinal tract, and massively metabolized by the intestinal microflora into several metabolites, such as phenolic acids 3-diseases ,195,196.Although the effects of anthocyanins have been demonstrated in vitro, there is no reliable evidence that anthocyanins act as antioxidants after consuming these plants. The fate of anthocyanins in vivo shows that they are poorly conserved and that most of the chemically modified metabolites are rapidly excreted. However, a 2019 study proved that the administration of anthocyanins caused an increase in organ antioxidant capacity in animal models .The results of a 20 year study (2012) showed that high anthocyanin intake reduced the risk of T2D ,199.Gallic acid (GA) is naturally found in grapes, tea, hops, and oak bark. In nature, GA is free or as a part of soluble tannins. Gallic acid produces dimers, such as ellagic acid (EA) . During Mcl-1.The inhibition of Mcl-1 and caspase activation are the key moments in PCa cell apoptosis, induced by gallotannin [Kaur demonstrated that GA leads to apoptosis in DU145 and 22Rv1 cell lines. In nude mice fed with GA, tumor growth inhibition occurs . It has lotannin .Epilobium angustifolium), which is used in traditional medicine to treat BPH and prostate inflammation [Dimeric ellagitannin, Enotein B, causes a decrease in LNCaP cell proliferation and reduction of BPH in rats. Enotein B is found in the willowherb (ammation . In humaammation .Punica granatum). There is evidence that pomegranate has a positive effect on the treatment and prevention of diabetes, atherosclerosis, PCa, breast, colon, lung, and skin cancers [A significant amount of ET is found in pomegranate  caused induction of apoptosis in PC-3 and LNCaP cells . In addiUrolithins A and B are metabolites of the microflora of the colon produced by the intake of EC derivatives. Sánchez-González (2014) has shown that foods rich in ET, such as nuts, can contribute to the prevention of PCa. In the study, urolithins induced apoptosis in LNCaP cells and this effect was correlated with a decrease in Bcl-2 protein levels. Urolithins most likely block the expression of the androgen receptor (AR), and thus, leads to the induction of apoptosis and decreased PSA synthesis .Echinacea, strawberries, pineapple, coffee, sunflower, and blueberries. In the animal model, chlorogenic acid inhibits BPH growth, probably via inhibition of 5αR [Chemical structures of the most important hydroxycinnamic acids are presented in n of 5αR . Ferulicn of 5αR .Resveratrol  is a powSaralkar (2017) believes that resveratrol will be able to be used in nanoparticles in the future. In fact, hydrophobic medicines can be “trapped” in nanoparticles, such as Ca-alginate. Nanoparticles filled with medicines have had a cytotoxic effect on the cells of DU-145. It is believed that the nanoparticles with Ca-alginate could probably be given intravenously .The highest concentration of lignans is found in oilseed rape (20 µg/100 g) . The mosThe flax extract has been shown to prevent the induced BPH in rats . Ren  is a consistent part of turmeric, a spice to give it the yellow powder color of curry .PCa resistance to a therapy is associated with the abnormally increased expression of Bcl-2, and androgens receptor (AR), epidermal growth factor receptor (EGF), HER2 , cyclic D1, and cyclone-oxygenize (COX-2), and all of them are connected to the activation of the transcription factor NF-kB. Nuclear factor-kB (NF-κB) is a protein complex and it controls DNA transcription, cytokine production, and cell survival. NF-κB is placed in cells of almost all animals and it is included into the cell answer to stress, cytokines, free radicals, heavy metals, ultraviolet sunrays, oxidized LDL, and also to bacterial and virus agents .trans-activation and the expression of AR and it acts as its antagonist. Thus, curcumin reduces the expression of receptors of EGF and induces the degradation of HER2. Curcumin reduces angiogenesis in vivo and the expression of VEGF. The pathway of t PI-3K/AKT plays a critical role in the cell activation of CaP. The phosphatase regulating this pathway, PTEN, is mutated with PCa and it leads to AKT activation studies on the ability of curcumin to inhibit AKT activation AKT [The agent that can slow down these mechanisms would be good both for the prevention and the treatment of PCa. Curcumin can modulate several of these ways. It has been shown that curcumin to sublimates the proliferation of androgen-dependent lines, such as LNCaP, but also of androgen-independent lines, such as DU145. Besides this, it has been shown for curcumin to increase the sensitivity of cell cultures of PCa onto gamma-radiation. Curcumin reduces the tion AKT .Mohebbati et al. have come to the facts by researching the data banks for curcumin as an inhibitor of the tumor necrosis factor production (TNF-α) and prostaglandin E2 (PGE2), but it increases the caspase activity  in HL-60 prostate carcinoma. Besides this, we have found for curcumin to sublimate vascular and endothelial growth factor (VEGF) in the line of carcinoma ovarium .In a study in 2018, Chen examined the anti-carcinoma potential of curcumin analogs of the second generation. The cells of PC3 and DU145 were treated in series of curcumin analogs, in concentrations of 0–10 μM. It was found for curcumin to inhibit the expression of the nuclear factor (NF)-kB, mTOR , AKT and p-AKT. For curcumin, it was found to have anti-carcinoma effect against CRPC cells .The aim of the investigation of Morabito and co-workers was to verify whether the different concentrations of curcumin, conducted on human erythrocytes, may counteract Band 3-mediated anion transport alterations due to oxidative stress. This study demonstrated that curcumin at a concentration of 10 uM was very effective in protecting red cells from oxidative stress. .In the paper in 2018, Ide et al. examined the effect of curcumin on the intracranial synthesis of androgen in the cells of CaP, in the lines of LNCaP and 22Rv1. The tissue from the trans-gene adenocarcinoma of the mouse prostate (TRAMP) was taken after one month of oral intake of 200 mg/kg/curcumin per day. Curcumin reduced the expression of steroid acute regulatory proteins CYP11A1 and HSD3B2, and it confirmed a reduction of testosterone production. At the same time, it confirmed the testosterone reduction in the prostate tissue of TRAMP mice. Simultaneously, curcumin brought to the increased level of Aldo–Keto reduction 1C2 (AKR1C2), and it confirms reduced level of dihydrotestosterone .It is fascinating how much biochemical processes in plants are incorporated into the metabolism of animal cells. However, this fact is logical, when we know how many billion years a common microcosmos has existed in plant and animal cells. Herbivores have used plant nutrients in their diets for eons. However, in addition to sugars, proteins, and fats, animals also ingest thousands of secondary plant metabolites, such as polyphenols. Polyphenols in plants play important roles such as protection against herbivores, oxidative stress, UV radiation, etc. However, their roles in animal and human organisms are much too complicated and plentiful to be completely understood.There are a very large number of investigations on human cell cultures and animal models to confirm the antioxidant and antitumor effects of polyphenols. In addition, extensive epidemiological studies and centuries-old traditional folk experiences confirm the positive effects of polyphenols on human health. However, the pathways of polyphenols in the human body are difficult to follow, due to their relatively low resorption, the production of a large number of metabolites and relatively rapid excretion from the body.The future researches on the vast range of polyphenolic compounds in nature and their effects on the human body will probably evolve towards increasing resorption and bioavailability, through nanotechnology or other technologies. In the future, major randomized epidemiological studies will provide more comprehensive answers to the questions of the role of polyphenols in human health.


To compare the effect and safety of intravitreal conbercept (IVC), intravitreal ranibizumab (IVR), or intravitreal triamcinolone acetonide (IVTA) injection on 23-gauge (23-G) pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). n = 20 in each group). The 23-G PPV was performed with intravitreal conbercept or ranibizumab injection 3–7 days before surgery or intravitreal TA injection during surgery. The experiment was randomized controlled, with a noninferiority limit of five letters. Main outcome measures included BCVA, operation time, incidence of iatrogenic retinal breaks, endodiathermy rate, and silicone oil tamponade.  Fifty patients (60 eyes) of varying degrees of PDR were randomly grouped into 3 groups (1 : 1 : 1) , but they were significantly different from the IVTA group . IOP increases did not show significant differences between the IVC and IVR groups, but both were significantly different with the IVTA group. More patients had higher postoperative IOP in the IVTA group.  At 6 months after surgery, there were no significant differences of BCVA improvements, operation time, incidence of iatrogenic retinal breaks, endodiathermy rate, silicone oil tamponade, vitreous clear-up time, and the incidence of intraoperative bleeding between the IVC and IVR groups (all  The intravitreal injection of conbercept, ranibizumab, or TA for PDR had a significant different effect on outcomes of 23-G PPV surgery. Conbercept and ranibizumab can reduce difficulty of the operation, improve the success rate of PPV surgery, and decrease the incidence of postoperative complications. Proliferative diabetic retinopathy (PDR) is the leading cause of blindness among DR in diabetic patients –6. PDR cIn order to reduce the chance of complications, a variety of drugs have been utilized in PPV for PDR. TA   is a water-insoluble steroid that inhibits various inflammatory reactions. It has been confirmed that it can aid visualization of transparent vitreous, reduce the degree of postoperative inflammation, and decrease the incidence of reoperation owing to epiretinal membrane formation in TA-assisted PPV for PDR –12. In rThis study adheres to the guidelines of the Declaration of Helsinki. The study was approved by the Institutional Review Board of the First Hospital of Qiqihar City. The protocol number is 2006-04. Patients' consents were given to all participants, and all patients signed the consents before participating the study. Between Jan 2015 and Dec 2015, 60 eyes from 53 patients were collected of varying degrees of PDR in the First Hospital of Qiqihar. There were 33 (55%) male and 27 (45%) female. The age was between 29 and 78 years old, with the average age of 58.83 (±3.62). Mean duration of DM was 26.57 ± 5.82 years. All patients had a history of DM, with 14 (23.3%) cases of type 1 DM and 46 (76.7%) cases of type 2 DM. Visual acuity was tested using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at 4 m . The BCVn = 20 eyes in each group). Mean BCVA was 27.83 ± 6.78, 25.31 ± 4.23, and 28.46 ± 7.55 (ETDRS letters) in the IVC, IVR, and IVTA groups, respectively. The IVC group were 20 eyes in 17 patients, including 11 eyes  of male and 9 eyes  of female. Patients received 0.5 mg  intravitreal injections of conbercept [Patients were randomly divided into IVC, IVR, and IVTA groups (1 : 1 : 1) (nbercept . PPV in nbercept . The TA nbercept . IntraopThe primary outcomes were mean BCVA (ETDRS chart) monthly, operation time, incidence of iatrogenic retinal breaks, endodiathermy rate, and silicone oil tamponade. Secondary outcomes included average vitreous clearing time and the frequency of intraoperative and postoperative bleeding, PRP completion rate, reoperation probability, and intraocular pressure (IOP) in each group. Vitreous clearing time was defined as the interval between the end of surgery and the time at which the vitreous cleared up completely. Increased IOP was defined as an intraocular pressure > 21, which occurred within 24 hours after injections. To prevent effect of silicone oil on postoperative visual acuity, the final results of BCVA were determined after silicone oil removal. For patients with cataract after surgery, BCVA was measured after cataract extraction combined with intraocular lens implantation. Complications of cataract surgery were not included in this study.t-test. The same statistical procedure was applied when analyzing the data according to the intent-to-treat principle, using multiple imputing to replace missing observations at 6 m follow-up.The margin of clinical noninferiority was defined as five letters on the ETDRS visual acuity chart. Statistical analysis of the primary outcome variable, the mean change in BCVA from baseline to 6 m follow-up, was performed on data from the per protocol population (patients attending the 6 m visits). The mean scores of the primary outcome variables in three treatment groups were compared to each other using the independent samples t-test; if p < 0.05, the difference was considered statistically significant.Statistical analysis of secondary outcomes was performed only on data from the per protocol population, the operation time by independent samples 60 patients were included in the treatment and safety analysis. The 6-month visits were completed by 58 (96.7%) patients . However, each of these two groups showed significant difference with the IVTA group   .The average vitreous clear-up time was 6.10 ± 1.52, 6.32 ± 1.57, and 11.11 ± 2.38 in the IVC, IVR, and IVTA groups, respectively ; the incIOP increase is defined as an intraocular pressure > 25 mmHg, which appeared within 24 hours after injections. If IOP increased, subjects were monitored until intraocular pressure at 25 mmHg or less. The cases with increased IOP were 3 (15.0%), 2 (10.5%), and 9 (47.4%) in the IVC, IVR, and IVTA groups, respectively . There wPDR usually is extremely complicated with intraocular hemorrhage and TRD. Because of the existence of hemorrhage, exudation, and proliferation membrane during surgery in severe PDR, structures of retina are not easily identified and surgical difficulty and complexity are increased. Several studies have confirmed that VEGF plays a very important role in complex PDR , 26. DueIn addition, postoperative inflammation is also one of the major causes of postoperative complications, such as proliferative vitreoretinopathy (PVR). The postoperative inflammatory cells can secrete varieties of chemical mediators and cytokines, which stimulate the invasion of secondary inflammatory cells into the vitreoretinal tissue and activate the retinal glial cells and retinal pigment epithelium cells. These activated cells cause the proliferation of themselves, produce extracellular matrix, and contract the epiretinal membrane, thus leading to a secondary retinal detachment , 38. TheIVC, IVR, and IVTA are three commonly used procedures to improve the PDR operation in China. Only a single injection of TA was used early. Currently, anti-VEGF drugs in this study have been used in conjunction with PPV for PDR in China. Early studies showed that intravitreal injection of TA successfully inhibited experimental PVR in the rabbit and optic disk neovascularization in the pig , 40. In In our study, 60 eyes of PDR which combined with vitreous hemorrhage in different degrees and TRD were selected. Patients were randomly divided into three groups, ignoring the severity of the disease. The results showed that the preoperative application of intravitreal injections of conbercept and ranibizumab had equal effect in improvement of visual acuity, operation time, incidence of iatrogenic retinal breaks, endodiathermy rate, frequency of silicone oil tamponade, vitreous clearing time, and the incidence of intraoperative bleeding. Compared with the IVTA group, the IVC and IVR groups had more visual acuity gains after surgeries and increased operation safeties. In PPV surgery of the IVC and IVR groups, the fibrous proliferative membranes were easily separated from the retina with a few individual of bleeding. The advantages of the IVC and IVR groups are time saving for operations and reduced risks of surgical complications.However, the posterior hyaloid can be clearly seen after the injection of TA suspension that enhanced visualization of vitreous in the IVTA group. Nevertheless, considering the potential increased risk of glaucoma and cataract associated with the use of intravitreal corticosteroids, the use of intravitreal corticosteroid preparations to reduce the likelihood of retinopathy worsening does not seem warranted .Our data indicated that there were no significant differences among the three groups in the incidence of postoperative bleeding, PRP completion rate, and reoperation probability. Thus, although IVC, IVR, and IVTA may function in variable degrees, they all improved postoperative conditions and reduced complication occurrence of PPV. Conbercept, ranibizumab, and TA also improved the completion rate of postoperative PRP, prevented the development of DR, and greatly improved the patient's prognosis. The number of eyes with IOP increase was more in the IVTA group than the other two groups, suggesting that although TA was believed able to be removed from vitreous after PPV , its effIt has been controversial on the optimal timing of preoperative injection of anti-VEGF drugs before vitrectomy. In our study, PPV was completed during 3–7 days after intravitreal injection. Data indicated that drugs were effective and patient postoperative conditions were significantly improved. Furthermore, no significant development of proliferative lesions was observed in 6 m. Since the blood glucose level is one of the important factors that affect the development of PDR , in our In conclusion, this study suggested that in a developing country such as China, PDR patients living in rural areas usually could not receive early and effective treatment due to inconvenient transportation and inadequate community health care services; therefore, it is essential to reduce the cost of surgical complications, reoperation, and long-term treatment. 23-G PPV surgery assisted by intravitreal injection of conbercept, ranibizumab, or TA for PDR had a significant impact on patient health condition and economic burden. The application of these drugs can reduce difficulty of the operation, improve the success rate of PPV surgery, and decrease the incidence of postoperative complications, therefore reducing the patient's economic burden in China. Conbercept and ranibizumab have equal effectiveness and achieved better results than TA. The safety and efficacy of the anti-VEGF drugs were confirmed in the treatment of complex PDR. However, our research is limited, as the observation time is short, the long-term effects and complications of drugs had not been well reflected. Function mechanism of these drugs is also not completely understood. In addition, the number of cases in this study is inadequate for a definitive conclusion. Therefore, these results also need to be proved by clinical trials of large sample sizes and extended follow-up period.


Medicaid expansion’s impact has been studied on national and statewide levels with respect to the patient outcomes, access to health services and uncompensated care. The objective of this study was to examine the effect of the Medicaid expansion on an emergency department (ED) at a large, academic center by evaluating changes in total charges, services rendered, types of providers, number of visits, and length of stay. Findings from this study include more males frequenting the ED for health services and a bottleneck in operations with an average waiting time in the ED increasing by 17%. Additionally, Medicaid recipients required non-emergent services that could be delivered by primary care providers, albeit at the ED, with average total charges for Emergency Medicine services seeing a statistically significant reduction with increases in average total charges for Family Medicine. While Medicaid expansion provided more individuals with coverage, a large academic medical center adapted in concordance. One of the tenets of the Patient Protection and Affordable Care Act  was to eResearch on increasing access to health insurance has addressed the scope and depth. A 6.1% reduction in adjusted all-cause mortality was found in states that expanded Medicaid coverages relative to non-expansion states . States While a subset of the population gained insurance coverage, the benefits of this expansion were also experienced by hospitals. Analysis of public and private hospitals in Connecticut demonstrated a 7% - 9% increase in Medicaid discharges, a 7% - 8% boost in Medicaid’s share of revenue, and a 33% decrease in uncompensated care . EstimatOne objective of this government-funded expansion of insurance coverage was to encourage utilization of health services in a non-emergent setting, preferably at a primary care facility, rather than visiting the emergency department (ED) for these healthcare needs -14. The While these analyses utilized data from statewide, publicly available databases, there is sparse literature that empirically evaluates the effect of the Medicaid expansion on ED visits using data held by individual hospitals. Access to proprietary data can shed light on the delivery of care with an influx of patients. The objective of this study was to understand the changes in (1) total charges, (2) services rendered, (3) types of providers, (4) number of visits, and (5) length of stay from prior to and after Medicaid expansion in Medicaid recipients visiting the ED at a large academic medical center.From January 1, 2011, to December 31, 2016, the ED at a large Midwestern academic medical center (AMC) saw patients from all financial classes , out of which 257,252 (39.8%) were inpatients with Medicaid coverage. Using business intelligence tools and electronic medical record administrative tables and data sources, 31,310 (12.2%) unique Medicaid billings were randomly extracted. This extraction yielded 98,244 total patient encounter billings. Patient billings were then split by year: 2011 , 2012 , 2013 , 2014 , 2015 , and 2016 . The years 2011 to 2013 were categorized as the pre-expansion group , while 2014 to 2016 were aggregated as the post-expansion group .Data on patient visits included categories, such as patient identifier, unique encounter code, age, gender, race, arrival time, admit time, discharge time, length of stay, primary diagnosis, problem list, specialty utilized, total charges, ED readmission, and in-patient readmission. With admission encounters as a base, readmissions were counted as the number of times a patient was readmitted to the ED or the hospital within three days of a previous discharge. All patient lists were programmatically de-identified to preserve patient privacy and this de-identified dataset was achieved through the honest broker system. Due to the nature of this research project , institutional review board (IRB) approval was not required; however, IRB exemption was received through the Data Quality Request process.Using de-identified abstraction identifiers, 6,675 (21.3%) patients were found to have utilized Medicaid in both the pre- and post-expansion eras and, therefore, were not considered as new enrollees from the Medicaid expansion. Aggregation of these patients was used to approximate readmission rates.To appreciate the changes in the cost of services rendered by the ED, total charges were normalized to account for the compounding effect of inflation. Using the consumer inflation rates from the Bureau of Labor Statistics from 2011-2016, the total charges subsequent from 2011 were normalized to the value of the dollar in 2017. Year-to-year inflation rates from 2011 to 2016 were noted to be 1.7%, 2.1%, 1.8%, 1.8%, 1.8%, and 2.2%, respectively [Inferential statistical analysis of the database was conducted using the Statistical Package for Social Sciences (SPSS) Statistics, version 25.0 . The analysis of variance (ANOVA) was employed to determine the statistical significance between the means of two or more groups. The Scheffé test was used to explore post hoc multiple comparisons for ordinal independent variables. Statistical significance was determined by using the p = 0.05 cutoff.This study found that the mean cost of care for Medicaid recipients steadily increased from 2011 to 2016, with a slight decrease in 2012. Figure Aggregating total charges by specialties and comparing pre- and post-expansion groups provided insight as to the utilization of ED services and the types of providers needed to render these services. Total charges increased in Family Medicine, Internal Medicine, Nurse Practitioners, Hospitalists, Pulmonary Disease, and Cardiovascular Disease, with a reduction in charges seen in Hematology, Pediatrics, and Emergency Medicine. Statistically significant changes between the average total charges from pre and post-expansion groups were found in Family Medicine , Hospitalists , and Emergency Medicine . Specialty categories with an aggregation greater than $5 million were plotted in Figure Family Medicine, Internal Medicine, and Nurse Practitioners were the three largest specialties by total charges combined. Separating each specialty by gender utilization found that prior to Medicaid expansion, females’ utilization of each specialty, except Hospitalists, was greater than 50%. However, post-expansion, male utilization greater than 5% was seen in Nurse Practitioners, Hospitalists, Emergency Medicine, and Pulmonary Disease Figure . RelativSeparating total charges by gender found that the average cost accrued by females increased from approximately $9,583 to $10,163 from pre- to post-expansion era, with males increasing from $16,409 to $17,782 Figure . This diUsing unique patient identification, 6,675 individuals utilized Medicaid services in both pre- and post-expansion groups. This group served as a proxy to appreciate changes in the total charges, visitation frequency, and length of stay (in hours). The post-expansion group saw increases in the number of visits, total charges, and length of stay with statistically significant differences found in the latter two Figure . AnalyziHealthcare delivery was measured by the average waiting time in the ED, which increased by 17% (0.82 hours to 0.96 hours) or 10.24 minutes from 2013 to 2014 at the approximate time Medicaid expansion went into effect  of the total possible Medicaid billings from 2011 to 2016 were studied. It should be noted that the inclusion of the other 87.8% of billings could potentially affect some of our findings and unveil new findings, currently undetected or underappreciated. However, random extraction of billing data can help reduce biases in the evaluation of data while providing an adequate sample size to parse out differences between genders and services utilized from the pre and post-Medicaid expansion groups in a statistically significant manner.The third limitation of this study includes the impact of variables that were outside the control of this study. For example, demographic changes in the patient population could possibly affect the utilization of Medicaid services. These changes could potentially impact the perception of Medicaid, willingness to seek out care, and follow-up with a provider . FurtherUsing hospital-specific data for Medicaid patient encounters between 2011 to 2016, while analyzing trends for a pre- and post-expansion state, provided actionable insights on Medicaid expansion’s impact on an ED at a single, large academic medical center. No statistically significant changes were found in the mean total charges from 2013 to 2015 (representing the post-expansion time period). A plateau in the median costs from 2013 to 2015 was detected Figure , suggestFindings from this case analysis suggest that coverage via Medicaid expansion potentially decreased a barrier to care for males, with more males seeking healthcare services at the ED post-expansion. This finding is consistent with the analysis of the National Health Interview Survey (NHIS) which found expansion states to cover 1.8% more males than non-expansion states (p = 0.01) . ConsideFindings from this study indicate that, upon expansion, more individuals frequented the ED, less for the actual ED service but rather more for primary care services. The existence of this pattern prior to Medicaid expansion  allowed It should be noted that increased ED utilization is associated with a higher number of barriers to primary care services, such as a lack of transportation, the timing of the provider’s office, length of time spent waiting at provider’s office, and the next available appointment . AdditioMedicaid expansion also created bottlenecks in operational management. While proper types of providers were hired, operational processes did not seamlessly handle the influx of patients as an increased average waiting time in the ED was seen Figure . This fiAs Medicaid expansion went into effect and provided more individuals with coverage, a large academic medical center adapted accordingly. This study found five important and actionable insights. First, insurance coverage encouraged more males to frequent the ED for health services. Second, the influx of newly eligible Medicaid patients caused a bottleneck in ED operations with average waiting time increasing by 17%. Third, many of the newly eligible Medicaid recipients required non-emergent services that could be delivered by primary care providers, albeit at the ED. The average total charges for Emergency Medicine saw a statistically significant reduction balanced with an increase in average total charges in Family Medicine. Fourth, the addition of more advanced practice providers, such as nurse practitioners, potentially stemmed the costs of services provided. Fifth and last, while the mean cost of care for Medicaid recipients did not exhibit a clear trend, a plateau in median costs from 2013 to 2015 potentially hints at the impact of Medicaid expansion on curbing the rising costs of healthcare services rendered to Medicaid patients.


Proton pump inhibitors (PPIs) are commonly used in the treatment of acid-related diseases; however, the association between the use of PPIs and potential risk of hypomagnesemia is controversial.In the present study, databases including PubMed, EMBASE, MEDLINE, PsycINFO, CINAHL, the Cochrane Library, and 4 Chinese databases were searched since the inception until April 2018. Previous observational studies on the incidence of hypomagnesemia in individuals exposed to PPIs were included.2, 85.2%]. Subgroup analysis revealed that the use of PPI was not associated with the incidence of hypomagnesemia in outpatients  and hospitalized patients , respectively. The use of PPIs was not related to the risk of hypomagnesemia based on the cut-off values of 1.8 mg/dL , 1.7 mg/dL , and 1.6 mg/dL .This systematic review involved 15 studies including 129,347 participants, and the sample size varied from 52 to 95,205. Meta-analysis of 14 studies indicated that the use of PPIs increased the risk of hypomagnesemia [RR, 1.44, 95% CI, 1.13–1.76; IThe association between the exposure to PPI and the incidence of hypomagnesemia remained unclear. Due to the remarkable heterogeneity in previous studies, a definitive conclusion could not be drawn. Further research should be conducted to investigate the relationship between the use of individual PPI and potential risk of hypomagnesemia, and a dose-response analysis may be required. Two systematic reviews have revealed the association between the use of PPIs and potential risk of hypomagnesemia, suggesting that PPIs treatment may increase the incidence of hypomagnesemia;,9 however, due to the notable heterogeneity among the studies, no definitive conclusion could be drawn.Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases including gastroesophageal reflux, functional dyspepsia, and peptic ulcer. investigated the clinically significant alteration of serum magnesium levels in 2400 patients treated with various PPIs at different dosages, with or without diuretics. The results revealed that mean magnesium levels remained unchanged in patients treated with PPIs (P=.40), and there was no statistical difference in the prevalence of hypomagnesemia . Thus, a systematic review of previous observational studies was conducted by analyzing the available data on the association between the use of PPIs and potential risk of hypomagnesemia.In addition, previous observational studies have indicated that the risk of hypomagnesemia is associated with the use of PPIs, but the results were controversial. For example, Chowdhry et al22.12.1.1Previous observational research such as cohort studies and case-control or cross-sectional studies which evaluate the risk of hypomagnesemia in patients treated with PPIs were included. Odds ratios, relative risks (RR), or hazard ratios (HR) with 95% confidence intervals (CIs) were presented. Ethical approval was not required considering the nature of the study. Studies were excluded if the outcomes of interest were not reported; the effect sizes were not provided or could not be calculated using the data provided.2.1.2Patients exposed to PPIs were included. There was no restriction with respect to indications for the use of PPIs.2.1.3The exposure of interest was the use of PPIs. Participants without PPIs treatment were used as control.2.1.4The outcomes of interest were the potential risk of hypomagnesemia.2.2Previous studies were searched on the databases including PubMed, EMBASE, and the Cochrane Library by 2 independent reviewers since inception until April 2018. Additional studies in the reference lists of all the identified publications were referred, such as relevant meta-analyses and systematic reviews. The terms “proton pump,” “dexlansoprazole,” “esomeprazole,” “ilaprazole,” “lansoprazole,” “omeprazole,” “pantoprazole,” “rabeprazole,” “hypomagnesemia,” “hypomagnesaemia,” and “magnesium” were used in the searches.2.3Two reviewers screened the titles and abstracts of each search record independently. Entire articles were obtained when either the information provided in the title or abstract matches the aforementioned selection criteria, or the inclusion eligibility could not be ascertained due to the limited information provided. For the studies included, relevant data were extracted by each reviewer and entered into a standardized form. Following information were included in the data extraction form: general study characteristics; general patient characteristics; study design; sample size; exposures and comparisons; and outcomes of interest with effect size and 95% CI. Discrepancies were resolved by consensus.2.4http://www.ohri.ca/programs/clinical epidemiology/oxford.asp) as recommended by the Cochrane Collaboration. The maximum score on the Newcastle–Ottawa quality assessment scale is 9. In the present review, a score of 7 to 9 was considered as high, 4 to 6 as moderate, and 0 to 3 as low quality, respectively. Disagreements were discussed and agreed upon consensus.Two reviewers assessed the methodological quality of identified studies independently. The quality of observational studies was evaluated using the Newcastle–Ottawa quality assessment scale . The subgroup analysis was performed using various settings, cut-off values, and study types. The sensitivity analysis was conducted by excluding the trials with low quality.Meta-analyses were performed by calculating the pooled RRs with 95% CIs. By performing a conservative approach, random effect model that produces wider CIs compared with fixed effect model was used. The 33.1In the present review, 912 search results were initially identified. Then duplicates were removed, the titles and abstracts were screened and subsequently the entire articles were reviewed. A total of 15 observational studies  met the inclusion criteria, including 10 cross-sectional, 1 case-control, and 4 cohort studies , the Netherland , Switzerland , Japan , Korea , Belgium , Brazil , Croatia , and Israe . The age of participants ranged from 18 to 94 years old. Seven studies recruited participants with numerous diseases, including renal transplant recipients (2/15), hematopoietic cell transplant recipients (1/15), patients with late-stage renal diseases on hemodialysis, and acute or chronic kidney disorders treated with hemodialysis (4/15). Ten studies enrolled participants with various settings, such as hospitalized patients in 7 studies, outpatients in 2 studies and inpatient or patients from emergency department in 1 study. Additionally, 12 studies investigated the effects of confounding factors, including age, sex, race, and comorbidities.The characteristics of identified studies were presented in Table 3.3A total of 13 studies (86.7%) were rated as high quality (scoring 7.54 ± 0.66), 2 (2.9%) were rated as moderate (scoring 6), and no study with low quality was included  was 0.4% (3/834) and 0.4% (1/242) in the patients treated with PPIs and the control group, respectively (P = .904).A large cohort study was performed by Park et al reported that the levels of serum magnesium remain unchanged in 250 participants after 12 months of PPIs treatment, and no association between the use of PPIs and potential risk of hypomagnesemia was found in healthy donors. Therefore, these findings are also important and should be further reviewed.In addition, Bahtiri et al revealed that the concentration of [H+] could affect the binding of magnesium to TRPM6/TRPM7 during magnesium transport. Thus, the change of pH in intestinal lumen could influence the activity of TRPM6/TRPM7 channels where the binding and absorption of magnesium take place. Therefore, the use of PPIs should be avoided in the treatment of patients with TRPM6/TRPM7 mutation to reduce the incidence of hypermagnesemia.Furthermore, variant alleles of transient receptor potential membrane melastatin 6 and 7 (TRPM6/TRPM7) are associated with subtle malabsorption and/or persistent urinary leakage that may be aggravated by PPIs, consequently leading to hypomagnesemia in susceptible individuals. Bai et alHowever, there are some limitations in the present study: previous studies published in English were reviewed, thus some research published in other languages may not be included; certain information such as the type of PPIs and duration of PPIs treatment were not clarified in some studies, thus the effects of individual PPIs could not be investigated and dose-response analysis was not performed to evaluate the influences of different PPIs and treatment duration on hypomagnesemia; this is a meta-analysis of previous observational studies with its inherent limitations. Therefore, further studies need to be designed and conducted to minimize these limitations.In the present study, remarkable heterogeneity was found when the data from previous studies were pooled. Although potential confounding factors had been adjusted in most studies, some clinical variations in patients such as age, the type of PPIs, the type of diseases, the settings of participants, and comorbidities could still lead to the heterogeneity. Therefore, future research should focus on the influences of PPIs on patients with specific diseases and in certain age group to minimize the clinical heterogeneity. In addition, to evaluate the severity of PPIs-induced hypomagnesemia and identify the high-risk groups, it is necessary to establish a global multicenter registration platform.,31 Therefore, PPIs derived drugs could be used in the treatment of patients with cardiovascular diseases and hypomagnesemia in clinical practice.The present review revealed that exposure to PPIs may increase the risk of hypomagnesemia. Additionally, some epidemiological studies have indicated the association between hypomagnesemia and the risk of recurrent coronary heart disease and serious arrhythmias.6The association between the exposure to PPIs and potential risk of hypomagnesemia remained unclear. Due to the remarkable heterogeneity in the studies, a definitive conclusion could not be drawn. Further research should be conducted to investigate the relationship between the use of individual PPI and potential risk of hypomagnesemia, and a dose-response analysis may be required.ZM and SL designed this research. SL and LG performed the study. SL analyzed the data. All authors have read and approved the final manuscript.Conceptualization: Zhechuan Mei.Data curation: Shengtao Liao, Li Gan, Zhechuan Mei.Formal analysis: Shengtao Liao, Li Gan, Zhechuan Mei.Investigation: Shengtao Liao, Zhechuan Mei.Methodology: Shengtao Liao, Zhechuan Mei.Project administration: Li Gan, Zhechuan Mei.Resources: Li Gan, Zhechuan Mei.Software: Li Gan.Validation: Li Gan.Visualization: Li Gan.Writing – Original Draft: Shengtao Liao, Li Gan, Zhechuan Mei.Writing – Review & Editing: Zhechuan Mei.


Tick-borne relapsing fever (TBRF) is a bacterial infection transmitted by tick bites that occurs in several different parts of the world, including the western United States. We describe 6 cases of TBRF acquired in the White Mountains of Arizona, USA, and diagnosed during 2013–2018. All but 1 case-patient had recurrent fever, and some had marked laboratory abnormalities, including leukopenia, thrombocytopenia, hyperbilirubinemia, and elevated aminotransaminases. One patient had uveitis. Diagnosis was delayed in 5 of the cases; all case-patients responded to therapy with doxycycline. Two patients had Jarisch-Herxheimer reactions. The White Mountains of Arizona have not been previously considered a region of high incidence for TBRF. These 6 cases likely represent a larger number of cases that might have been undiagnosed. Clinicians should be aware of TBRF in patients who reside, recreate, or travel to this area and especially for those who sleep overnight in cabins there. The White Mountains comprise a relatively dry, high-elevation region in the eastern part of Arizona that is in close proximity to Phoenix and Tucson, the 2 major metropolitan areas of Arizona, both of which are in lower-elevation deserts. Ranging from 6,000 feet  to >11,000 feet  in elevation, the White Mountains are a place for recreation and respite for urban dwellers, particularly during the hot summer months, and many cabins and summer homes are located throughout the region. Persons who acquire illnesses in the White Mountains often seek medical care in the desert metropolitan communities, and physicians there might not be aware of the differences in the diseases or their host habitats in these mountains compared with the lower-elevation deserts.Ornithodoros spp. ticks; Borrelia hermsii is thought to be the most common cause. We describe 6 cases of TBRF occurring over a 6-year period in persons who visited the White Mountains. Although infection probably was acquired in these mountains, given the timeframe of exposure to illness onset , all cases were diagnosed in either Phoenix or Tucson. We suspect that these cases represent a small proportion of the total number of cases and would alert both clinicians and public health officials to the presence of TBRF in this area.Tick-borne relapsing fever (TBRF) is a bacterial infection transmitted by tick bites. In the United States, TBRF most often occurs in western states and is usually transmitted by bites of B. hermsii conducted 9 weeks after symptom onset demonstrated an IgM titer of 1:64 and an IgG titer of 1:512.A 34-year-old man with no prior medical history had fevers in early July 2013. One week before fever onset, he had spent time with his family in a privately owned cabin in Alpine, Arizona, in the White Mountains. Mice and ticks had been seen in the cabin, but the patient was not aware of any bites. Fevers reaching 39.9°C with chills, headache, arthralgias, and myalgias were reported. These symptoms persisted for ≈3 days, remitted for 3 days, and then recurred for the next 3.5 weeks. Laboratory evaluation of the patient 2 weeks after symptom onset was notable for mild anemia and markedly elevated C-reactive protein but normal leukocyte and platelet counts and aminotransaminases. After ≈25 days, the fevers stopped, but the patient noticed floaters and blurry vision in his right eye. In August, he was seen by a retinal expert in Phoenix, and anterior and posterior uveitis with optic nerve inflammation were noted. A Lyme ELISA serologic screening test result was positive, and Western blot revealed IgM bands of 23 and 41 kDa and negative IgG. A Lyme-specific rapid plasma reagin test was negative. An infectious diseases consultant recommended treatment for possible TBRF, and oral doxycycline (100 mg 2×/d) for 14 days was prescribed. The patient had complete resolution of his visual symptoms 2 months after completing antimicrobial therapy. Immunofluorescent serologic tests for B. hermsii showed strongly positive results for both IgM and IgG.A 64-year-old woman with a medical history of hypothyroidism and hypertension sought care at an emergency department in Tucson in late October 2016 because of a 10-day history of fevers with rigors, fatigue, body aches, and generalized malaise. The symptoms began on October 24, one day after she returned from her cabin in the White Mountains, where she had spent 10 days with her husband doing various recreational activities. The patient denied insect bites or stings. Physical examination revealed a well-appearing female in no acute distress with mild resting tachycardia, normal temperature, and right upper quadrant tenderness to palpation. Laboratory values were remarkable for a total leukocyte count of 2,900 cells/µL with normal differential, platelet count of 32,000/µL, total bilirubin of 2.3 mg/dL, alkaline phosphatase of 483 IU/L, alanine aminotransferase of 78 IU/L, and aspartate aminotransferase of 137 IU/L. The patient was admitted to the hospital, and a subsequent Wright-stain peripheral blood smear demonstrated numerous spirochete-like organisms on light microscopic examination . A Lyme B. miyamotoi on whole blood yielded an indeterminate result. Doxycycline was restarted without further adverse effects, and the patient completed a 2-week course. Immunofluorescent serologic testing for B. hermsii demonstrated an IgG titer of 1:128. Serum sent to CDC for tickborne diseases was found to be positive by Western blot assay for B. hermsii IgM and IgG. The patient later recalled a possible insect or tick bite on his forearm during his stay at his cabin.A 72-year-old man with a medical history of hyperlipidemia and complete heart block requiring a permanent pacemaker spent ≈3 weeks at his cabin in the White Mountains near Greer, Arizona, doing outdoor cleaning in early June 2017. On June 22, he had onset of shaking chills and sought evaluation at a local emergency department, where sinusitis was diagnosed and amoxicillin prescribed. A temperature of 38.1°C was recorded. Several hours after taking a single dose of amoxicillin, he experienced severe rigors, prompting him to return to the emergency department. He was admitted to the hospital, where peripheral leukocyte count was 1,800 cells/µL, platelet count was 44,000/µL, total bilirubin was 2.3 mg/dL, and alanine aminotransferase was 78 IU/L. A peripheral blood smear demonstrated toxic granules in the neutrophils but no organisms. The patient improved without further antimicrobial therapy and was discharged home. One week later, he presented to an emergency department in Phoenix with recurrent fevers, fatigue, and rigors. A peripheral blood leukocytosis with lymphopenia was observed over several days. Because of positive coccidioidal serologic results, fluconazole was started; the patient was discharged home after his fevers resolved during hospital observation. He was seen 2 weeks later after a third episode of fever with rigors and was prescribed oral doxycycline (100 mg 2×/d). Within hours of the first doxycycline dose, he developed rigors, dizziness, and tachycardia and discontinued treatment. Subsequently, a PCR test for B. hermsii IgM and IgG by Western blot assay. The patient completed a course of doxycycline and completely recovered. During the investigation, local and state public health authorities learned of >6 other family members who visited the same cabin over a 2-year period, and all reported febrile illnesses. Only 1, case-patient 5, was tested for and diagnosed with TBRF.A previously healthy 4-year-old boy stayed in a cabin near Greer during the last week of May and the first week of June 2017 and experienced 1 month of recurring fever, chills, sweats, body aches, and headaches beginning on June 5. Blood samples sent to CDC at 28 and 43 days after symptoms started demonstrated B. hermsii IgM and IgG. The patient was treated with doxycycline (100 mg 2×/d), and his symptoms resolved.A 41-year-old man stayed in the same cabin as case-patient 4 from late May through early June 2017. On June 2, the man had onset of fever reaching 39.4°C with sweats, chills, headaches, fatigue, and dizziness. He visited healthcare providers multiple times during the month of June for evaluation of these symptoms. ELISA and Western blot tests for Lyme disease and coccidioidomycosis were positive. Finally, on August 30, ≈12 weeks after symptoms began, a serum sample sent to CDC was positive by Western blot assay for A 71-year-old woman with a medical history of hypertension, hypothyroidism, and past splenectomy for idiopathic thrombocytopenic purpura had sudden onset of fever, chills, generalized weakness, and myalgias in late July 2018, four days after visiting her family-owned cabin in Alpine. She subsequently sought care at an emergency department in Tucson. She had a temperature of 38.9°C and was found to be tachypneic, hypotensive, and hypoxemic. She was admitted to the intensive care unit, where it was noted that her initial peripheral leukocyte count was 11,400 cells/µL, platelet count was 39,000/µL, and serum creatinine was 2.7 mg/dL. Spirochetes were identified on peripheral blood smear by using light microscopic examination. During her hospital stay, the patient experienced acute respiratory failure and septic shock and required mechanical ventilation. A diagnosis of TBRF was made, and doxycycline (100 mg 2×/d) was initiated for a total of 10 days. The patient improved and was discharged home. She recalled substantial rodent activity in the area of the cabin. No other persons staying at the cabin reported illness.Vector-associated illnesses are increasing in frequency across the United States . All case-patients responded promptly to doxycycline therapy; 2 had Jarisch-Herxheimer reactions in association with antimicrobial therapy, a phenomenon previously described . Because of frequent travel by US residents, healthcare providers should report cases to the appropriate state or local health department; prompt reporting by clinicians has been critical to the identification and control of several outbreaks. For example, in 2014, a local Arizona hospital notified the Coconino County Public Health Services District (Flagstaff) of a cluster of 5 students with fever, headache, and myalgia who had attended the same camp; the ensuing investigation led to identification of an outbreak of 10 cases of TBRF among a high school football team who had attended an outdoor education camping trip in northern Arizona . Although TBRF is not a nationally notifiable condition, prompt reporting of TBRF cases was required in The first case of TBRF in Arizona was reported in 1930, involving an exposure near Greer, similar to the 6 cases we have described. In that instance, after staying in the area for 18 days during the summer, a 37-year-old man had repeated bouts of fever with interval periods of well-being lasting several days. During 1 febrile attack, which occurred >1 month after symptoms began, a blood smear demonstrated spirochetes. The patient received an arsenial injection, and his fevers resolved (Far more cases of TBRF probably have occurred recently in the White Mountains than the 6 reported here. Unlike previous recent reports from other parts of Arizona (