text:
By Tarek Souaid, MD; Jonathan Taliercio, DO; James F. Simon, MD, MBA; Ali Mehdi, MD, MEd; and Georges N. Nakhoul, MD, MEd
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy
Editor’s note: This article was originally published in the Cleveland Clinic Journal of Medicine and was reproduced with permission from the journal. Access the original article here.
Anemia is a common complication of chronic kidney disease. Its prevalence increases as the glomerular filtration rate decreases,1 and most patients with a rate lower than 30 mL/min/1.72 m2 develop anemia.2 Older studies linked anemia of kidney disease to numerous complications, including the onset and progression of left ventricular hypertrophy, heart failure, decreased quality of life, faster progression of chronic kidney disease, and death.3–6
Subsequently, several randomized controlled trials shed light on the benefits and limitations of iron supplements and erythropoiesis-stimulating agents (ESAs). This allowed the development of iron supplementation and hemoglobin targets. In addition to traditional ESAs, newer therapies have been developed and are now being used in clinical practice.
In this article, we discuss the pathophysiology of anemia of chronic kidney disease, the major clinical trials, and novel therapies.
How chronic kidney disease leads to anemia
Anemia of chronic kidney disease is multi-factorial and can be caused by decreased erythropoietin production by the peritubular interstitial cells of the kidney, higher circulating levels of uremia-induced inhibitors of erythropoietin, shorter red blood cell life span, and relative iron deficiency.7 However, measuring serum levels of erythropoietin is of no diagnostic utility in patients with anemia of chronic kidney disease, as there is no clear threshold defining a low value, especially in uremia, which can induce resistance to erythropoietin.8,9
Absolute iron deficiency results from decreased iron stores, whereas functional iron deficiency is characterized by sufficient iron stores but inadequate incorporation of iron into erythroid precursors.10 Hepcidin, a liver peptide and crucial regulator of iron homeostasis, is thought to play a key role in this process. Mobilization of iron into the circulation from enterocytes, iron-recycling macrophages, and hepatocytes requires transport across the cellular membrane by a transporter called ferroportin.11 Binding of hepcidin to ferroportin degrades the channel and inhibits iron mobilization out of the cell.
Normally, hepcidin levels decrease in conditions such as anemia, absolute iron deficiency, and hypoxia, in which more iron is needed for erythropoiesis. Conditions of systemic inflammation, such as chronic kidney disease, result in elevated hepcidin levels, diminished iron mobilization, and relative iron deficiency.12,13 The result is less iron available for erythropoiesis, with resistance to the action of ESAs (Figure 1).14–16
Figure 1. Hepcidin limits erythropoiesis. (A) Hepcidin plays a key role in iron homeostasis. It is produced by the liver and acts to degrade the iron transporter ferroportin, thus preventing release of iron (Fe2) from enterocytes, hepatocytes, and macrophages into the circulation. (B) In chronic kidney disease, hepcidin levels are elevated as a result of the underlying occult inflammatory state and as a result of decreased renal clearance of hepcidin. This makes less iron available for erythropoiesis and can lead to resistance to erythropoiesis-stimulating agents. Prolyl hydroxylase inhibitors (PHIs) decrease liver production of hepcidin, which may improve iron metabolism and lead to efficient management of anemia of chronic kidney disease. (RBC = red blood cell.)
ESAs are the mainstay, but have limited benefit
Before erythropoietin was discovered, anemia of chronic kidney disease was treated with red blood cell transfusions and androgens. Frequent red blood cell transfusions led to iron overload, transmission of viral infections, and allosensitization to human lymphocyte antigens, with potential adverse effects on transfusion responsiveness and importantly, transplant candidacy and outcomes. Androgen therapy was the only potentially transfusion-sparing option, and it was used in the 1970s.17
After approval of the first of the ESAs by the US Food and Drug Administration (FDA) in 1989, studies continued to demonstrate benefits of the drugs. In a study published in 1990, the ESA recombinant human erythropoietin showed promising results, raising hemoglobin levels by more than 5 g/dL and keeping them there after 2 months of therapy in 10 patients on hemodialysis whose mean baseline hemoglobin level was 6.3 g/dL.18 A year later, a double-blind, randomized placebo-controlled trial in 118 patients on hemodialysis with hemoglobin levels less than 9 g/dL found improvements in quality of life and exercise capacity.19
By 2006, ESAs had become the treatment of choice of renal anemia, along with oral and intravenous iron supplementation, and were being given to most patients on dialysis in the United States.20
Clinical trials dampen enthusiasm for normalizing hemoglobin levels with ESAs
However, then came four randomized controlled trials21–24 using ESAs to raise hemoglobin levels to higher vs lower target levels in patients with chronic kidney disease, some of whom were on dialysis and some not. Except for reducing the number of transfusions needed and perhaps improving quality of life (the results differed), the trials found no benefits of treating to higher targets, and indeed highlighted higher risks of cardiovascular and cerebrovascular events and worsening of cancer outcomes (Table 1).21–25
Table 1. Clinical trials of erythropoiesis-stimulating agents to increase hemoglobin to different targets in chronic kidney disease
In view of these results, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines26 strongly advised against trying to raise hemoglobin to normal levels (eg, higher than 13.5 g/dL in men, 12 g/dL in women), instead recommending a target of 10 to 11.5 g/dL in patients with end-stage kidney disease. The guidelines also advised that the decision to start ESAs should be individualized for patients with chronic kidney disease with a hemoglobin level less than 10 g/dL.26
In addition, a closer look at the data identified a “hyporesponsive” group in whom ESAs failed to achieve a higher hemoglobin target despite increasing doses. Interestingly, patients who received higher doses of ESAs had a higher rate of adverse events.27,28 Therefore, the KDIGO guidelines recommend using the lowest ESA doses needed to achieve the hemoglobin goal, realizing the only proven benefit is avoiding transfusions.29 Other possible benefits (again, the data conflict) include lessening of anemia-related symptoms, higher quality of life,30–32 and reduction in left ventricular hypertrophy.33 Table 2 summarizes the potential risks and benefits of ESA therapy.18,21–24,29–33
Table 2. Potential benefits and risks of erythropoiesis-stimulating agents
Commonly used ESAs are recombinant human erythropoietin (epoetin alfa), darbepoetin alfa (which has a longer half-life),34,35 and a recently approved form of pegylated recombinant human erythropoietin (Table 3).36–39
Table 3. The most widely used erythropoiesis-stimulating agents in the United States
ESAs continue to be the mainstay in managing anemia of chronic kidney disease. The newer ESAs were developed by increasing the glycosylation or pegylation of recombinant human erythropoietin to prolong its half-life and affinity for the erythropoietin receptor. However, their mechanism of action is essentially the same, and they carry the same potential risks, ie, adverse cardiovascular events, thrombosis, stroke, and poor cancer outcomes.
A new class of drugs: prolyl hydroxylase inhibitors
The hypoxia-inducible factor (HIF) pathway was a revolutionary discovery, and drugs that target it promise to improve outcomes in diseases that include anemia of chronic kidney disease.
HIF is a heterodimer consisting of an alpha and a beta subunit. Heterodimerization of the two subunits activates transcription of numerous genes and regulates a multitude of biologic and metabolic processes such as angiogenesis, cell growth and differentiation, and erythropoiesis.40,41 The transcriptional activity of HIF is controlled primarily by its degradation rate.42
Stable HIF leads to more erythropoietin
While the beta subunit of HIF is constitutively expressed (ie, it is present all the time), the alpha subunit is regulated by oxygen tension. At normal oxygen levels, the proline residue of HIF alpha is hydroxylated (ie, receives a hydroxyl [OH–] group) by the enzyme prolyl hydroxylase, leading to ubiquitylation (inactivation by binding to ubiquitin) and proteasomal degradation.43 This impedes formation of alpha-beta heterodimers, preventing erythropoietin transcription. The opposite happens in hypoxic states, in which HIF alpha is no longer degraded, and HIF heterodimers bind to the hypoxia-response elements, increasing erythropoietin transcription.
Prolyl hydroxylase inhibitors (PHIs), also known as HIF stabilizers, prevent hydroxylation of HIF alpha and its subsequent degradation. Thus, they stabilize the HIF alpha-beta heterodimer and enhance downstream expression of the erythropoietin gene EPO, leading to increased endogenous erythropoietin production (Figure 2).
Figure 2. Prolyl hydroxylase (PH) inhibitors increase erythropoiesis. Hypoxia-inducible factor (HIF) is a heterodimer consisting of 2 subunits, alpha and beta (HIF-α, HIF-β). Undernormal oxygen tension, the proline residue of HIF-α is hydroxylated and subsequently degraded. This prevents the formation of the heterodimer and stops subsequent erythropoietin transcription. When oxygen tension is low, HIF-α is not degraded, thus allowing HIF heterodimers to form. This leads to an increase in erythropoietin transcription. By preventing hydroxylation of HIF-α, PHIs prevent its degradation and stabilize the HIF-α/HIF-β heterodimer. This leads to increased downstream gene expression with increased production of endogenous erythropoietin.
Trials of the new agents in patients not on dialysis
In 2015, a phase 2 randomized clinical trial compared an oral PHI (roxadustat) with placebo in patients with anemia of chronic kidney disease not on dialysis who had never received an ESA.44 An effective hemoglobin increase from baseline (arbitrarily defined as ≥ 1 g/dL) occurred in all 20 of the 20 patients receiving roxadustat 2 mg/kg 2 to 3 times per week compared with 3 (13%) of the 23 patients receiving placebo. Notably, roxadustat raised endogenous erythropoietin and lowered hepcidin levels.
In 2019, in an 18-week, double-blind, randomized, open-label, phase 3 trial in China in 154 patients with anemia of chronic kidney disease who were not on dialysis, those receiving roxadustat had a higher mean hemoglobin level than those receiving placebo after 8 weeks, with maintained efficacy afterwards.45 In this study, roxadustat reduced cholesterol levels.
In 2020, in the ANDES study,46 a phase 3 global randomized clinical trial in 916 anemic patients with nondialysis-dependent chronic kidney disease (analyzed by an intention-to-treat model), oral roxadustat given 3 times per week was superior to placebo in hemoglobin correction and maintenance, with the same overall tolerability.
In OLYMPUS,47 another recent phase 3 randomized clinical trial, in 2,781 patients, roxadustat significantly raised hemoglobin levels and decreased the need for blood transfusions, with a side-effect profile similar to that of placebo.
Additionally, the ALPS study,48 a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 594 patients, found that roxadustat was superior to placebo with regard to hemoglobin response rate and change in hemoglobin level from baseline, with a comparable adverse-event profile.
A pooled analysis of the ANDES, OLYM-PUS, and ALPS trials concluded that roxadustat was effective at increasing hemoglobin levels in anemic patients with chronic kidney disease not on dialysis, reduced the need for blood transfusions, and did not demonstrably increase the risk of major adverse cardiac events.49,50
Trials in patients on dialysis
The first phase 2 clinical trial of oral PHI therapy to report hemoglobin correction in patients on dialysis who had never received ESAs, published in 2016, was an open-label study of roxadustat (with no placebo group).51 The mean hemoglobin level increased by at least 2.0 g/dL within 7 weeks, independent of initial hemoglobin level, iron-repletion state, iron supplementation, C-reactive protein level, and dialysis type (hemodialysis or peritoneal), and hepcidin concentrations decreased. This was the first study to challenge the historical notion that anemia in dialysis-dependent chronic kidney disease was a result of loss of the cells that produce endogenous erythropoietin. Instead, it showed that the mechanism remains intact but was suppressed in the uremic milieu.
In 2019, a randomized phase 3 study of 305 patients in China with dialysis-dependent chronic kidney disease on ESAs found that oral roxadustat was noninferior to intravenous epoetin alfa.52 A notable result also seen in the 2016 phase 2 trial 51 was that inflammation (assessed by C-reactive protein levels) did not affect the hemoglobin-correcting effect of roxadustat, whereas ESAs produce less of a response in inflammatory states.53
In 2021, the HIMALAYAS study 54 explored the efficacy and safety of roxadustat in a phase 3 open-label trial using epoetin alfa as the control treatment in 1,043 patients with anemia who had never received an ESA before and who had recently started on dialysis (from 2 weeks up to 4 months before randomization). Roxadustat was noninferior to epoetin alfa in correcting and maintaining hemoglobin levels, with comparable adverse-event rates with either treatment.54
Benefits and side effects of PHIs
PHIs are promising drugs, as they are at least as effective as ESAs in raising hemoglobin levels in patients with chronic kidney disease either on or off dialysis. They increase iron availability by decreasing hepcidin levels, thus potentially reducing the need for intravenous iron. Most importantly, they seem to remain effective in inflammatory states. This is a striking difference from ESAs, which require higher doses in inflammatory states and often fail to achieve target hemoglobin values.21,22,24 This ESA resistance and the higher required doses are likely responsible for the negative cardiovascular outcomes in hyporesponsive patients.27,28
Additional advantages of PHIs include ease of administration (oral dosing, especially advantageous in patients not on dialysis or who are on home hemodialysis), cheaper manufacturing with less stringent transportation logistics (ESAs need to be kept refrigerated),55 and less immunogenicity (a concern with ESAs), given that they are not protein-based. Also, roxadustat seemed to lower cholesterol levels, though the mechanism remains to be understood.45
Adverse effects of PHIs
So far, no major serious adverse effects have been found in clinical trials. The serious adverse events that happened in phase 2 trials were not considered drug-related or were deemed “within expected range,” as they happened at comparable rates in comparable patients who were not on these drugs.56 However, studies of the PHI FG-2216 were suspended after a patient died of hepatic necrosis, making it the only drug of this class for which a study was halted due to safety concerns.57
Hyperkalemia. The two Chinese phase 3 trials45,52 showed an increased risk of hyperkalemia with roxadustat. Hyperkalemia has also been reported in trials of daprodustat in patients on hemodialysis.58 Thus, use of PHIs in patients predisposed to hyperkalemia should be approached with caution.
Upper respiratory tract infections and metabolic acidosis have also been reported. More side effects may emerge with larger and longer studies.
Cardiovascular safety. A pooled post hoc analysis compared roxadustat with epoetin alfa in 1,530 patients newly started on dialysis.49 Although the results suggested a lower risk of death, myocardial infarction, and stroke in the roxadustat group, an analysis with prespecified stratification factors had shown attenuated benefits and wider confidence intervals,59 leading to the results of this study being called into question.60 Thus, the cardiovascular superiority of PHIs is yet to be fully established.
Theoretical risk of malignancy. To date, no animal or human study has shown PHIs to increase the risk of kidney cancer or other malignancies. However, HIF activation may enhance the proliferation, invasion, and metastatic potential of cells, as HIFs appear to be linked to metastasis in several malignancies (breast, prostate, lung, bone, and colorectal cancer).61
Diabetic retinopathy (either its induction or progression) is another potential adverse effect. HIF-1 alpha can induce vascular endothelial growth factor, which is involved in the progression of this disease. No such cases have been reported, but because many trials excluded patients at high risk of retinal hemorrhage, PHIs should be used with caution in this population.42
Progression of autosomal dominant polycystic kidney disease. In theory, PHIs could raise the risk of cyst growth, since HIF expression levels have been correlated in human and rat models with increased cyst burden.62 Until better evidence is available, some experts suggest limiting PHI use in patients with this disease who are not on dialysis.63
PHI drugs: Current status
Roxadustat is currently approved for use in anemia of chronic kidney disease in nondialysis-dependent and dialysis-dependent patients in China, Japan, and Chile, and recently received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency.64
However, concerns about its cardiovascular safety prompted the FDA Cardiovascular and Renal Drugs Advisory Committee to vote against the approval of roxadustat in July 2021. In August 2021, the FDA responded to roxadustat’s New Drug Application by asking for a new clinical trial to assess the safety of this drug in both nondialysis-and dialysis-dependent chronic kidney disease.64 Therefore, it seems unlikely that roxadustat will be available in the United States in the immediate future.
Although other PHIs have been approved for clinical use in Japan,65 roxadustat is the most studied to date. The 14 published phase 2 and 3 trials of roxadustat44–48,51,52,54,66–71 are summarized in Table 4.
Table 4. Published phase 2 and 3 trials of roxadustat
Key questions remain
More research is needed to answer the following important questions about PHIs:
Given their ability to achieve hemoglobin targets at physiologic plasma erythropoietin levels, could they be used to treat hyporesponsive patients more effectively and safely?
Given their effects on iron mobilization, can they reduce the need for intravenous iron in patients with anemia of chronic kidney disease?
Will their cholesterol-lowering properties prove clinically relevant?
What is the future of roxadustat in light of the recent FDA decision?
However, regardless of the lingering questions, the exploration and exploitation of the HIF pathway opens the door to multiple possibilities. Will PHIs deliver on the promises? We certainly hope so. It would be great to have one more tool at our disposal to treat anemia in patients with kidney disease.
- Hsu C-Y, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13(2):504–510. doi:10.1681/ASN.V132504Abstract/FREE Full TextGoogle Scholar
- Kazmi WH, Kausz AT, Khan S, et al. Anemia: an early complication of chronic renal insufficiency. Am J Kidney Dis 2001; 38:(4)803–812. doi:10.1053/ajkd.2001.27699CrossRefPubMedGoogle Scholar
- Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis 1996; 28(1):53–61. doi:10.1016/s0272-6386(96)90130-4CrossRefPubMedGoogle Scholar
- Moreno F, López Gomez JM, Sanz-Guajardo D, Jofre R, Valderrábano F. Quality of life in dialysis patients. A Spanish multicentre study. Spanish Cooperative Renal Patients Quality of Life Study Group. Nephrol Dial Transplant 1996; 11(suppl 2):125–129. doi:10.1093/ndt/11.supp2.125CrossRefPubMedGoogle Scholar
- Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999; 10(7):1606–1615. doi:10.1681/ASN.V1071606FREE Full TextGoogle Scholar
- McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13(7):1928–1936. doi:10.1097/01.asn.0000018409.45834.faAbstract/FREE Full TextGoogle Scholar
- Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012; 23(10):1631–1634. doi:10.1681/ASN.2011111078Abstract/FREE Full TextGoogle Scholar
- Colbert GB, Lerma EV, Stein R. Anemia of chronic disease and kidney failure. Medscape. Updated December 16, 2021. https://emedicine.medscape.com/article/1389854-overview#a6. Accessed March 17, 2022.Google Scholar
- Nangaku M, Mimura I, Yamaguchi J, Higashijima Y, Wada T, Tanaka T. Role of uremic toxins in erythropoiesis-stimulating agent resistance in chronic kidney disease and dialysis patients. J Ren Nutr 2015; 25(2):160–163. doi:10.1053/j.jrn.2014.10.011CrossRefPubMedGoogle Scholar
- Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2013; 161:(5)639–648. doi:10.1111/bjh.12311CrossRefPubMedGoogle Scholar
- Frazer DM, Anderson GJ. The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis 2003; 30(3):288–297. doi:10.1016/s1079-9796(03)00039-1CrossRefPubMedGoogle Scholar
- Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102(3):783–788. doi:10.1182/blood-2003-03-0672Abstract/FREE Full TextGoogle Scholar
- Ganz T, Nemeth E. Iron balance and the role of hepcidin in chronic kidney disease. Semin Nephrol 2016; 36(2):87–93. doi:10.1016/j.semnephrol.2016.02.001CrossRefPubMedGoogle Scholar
- Macdougall IC, Hutton RD, Cavill I, Coles GA, Williams JD. Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously. BMJ 1989; 299(6692):157–158. doi:10.1136/bmj.299.6692.157FREE Full TextGoogle Scholar
- Troutt JS, Butterfield AM, Konrad RJ. Hepcidin-25 concentrations are markedly increased in patients with chronic kidney disease and are inversely correlated with estimated glomerular filtration rates. J Clin Lab Anal 2013; 27(6):504–510. doi:10.1002/jcla.21634CrossRefPubMedGoogle Scholar
- Hirota K. An intimate crosstalk between iron homeostasis and oxygen metabolism regulated by the hypoxia-inducible factors (HIFs). Free Radic Biol Med 2019; 133:118–129. doi:10.1016/j.freeradbiomed.2018.07.018CrossRefGoogle Scholar
- Richardson JR, Weinstein MB. Erythropoietic response of dialyzed patients to testosterone administration. Ann Intern Med 1970; 73(3):403–407. doi:10.7326/0003-4819-73-3-403CrossRefPubMedGoogle Scholar
- Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335:(8688)489–493. doi:10.1016/0140-6736(90)90733-lCrossRefPubMedGoogle Scholar
- Keown PA. Quality of life in end-stage renal disease patients during recombinant human erythropoietin therapy. The Canadian Erythropoietin Study Group. Contrib Nephrol 1991; 88:81–86; discussion 87–89. pmid:2040199PubMedGoogle Scholar
- Centers for Medicare and Medicaid Services; Kinney R. 2005 Annual report: ESRD Clinical Performance Measures Project. Am J Kidney Dis 2006; 48(4 suppl 2):S1–106. doi:10.1053/j.ajkd.2006.07.015CrossRefPubMedGoogle Scholar
- Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:(9)584–590. doi:10.1056/NEJM199808273390903CrossRefPubMedGoogle Scholar
- Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355: (20)2085–2098. doi:10.1056/NEJMoa065485CrossRefPubMedGoogle Scholar
- Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:(20)2071–2084. doi:10.1056/NEJMoa062276CrossRefPubMedGoogle Scholar
- Pfeffer MA, Burdmann EA, Chen C-Y, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:(21)2019–2032. doi:10.1056/NEJMoa0907845CrossRefPubMedGoogle Scholar
- Nakhoul G, Simon JF. Anemia of chronic kidney disease: treat it, but not too aggressively [published correction appears in Cleve Clin J Med 2016; 83(10):739]. Cleve Clin J Med 2016; 83(8):613–624. doi:10.3949/ccjm.83a.15065Abstract/FREE Full TextGoogle Scholar
- Drüeke TB, Parfrey PS. Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s). Kidney Int 2012; 82(9):952–960. doi:10.1038/ki.2012.270CrossRefPubMedGoogle Scholar
- Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int 2008; 74:(6)791–798. doi:10.1038/ki.2008.295CrossRefPubMedGoogle Scholar
- Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363:(12)1146–1155. doi:10.1056/NEJMoa1005109CrossRefPubMedGoogle Scholar
- Popovsky MA, Ransil BJ. Long-term impact of recombinant human erythropoietin on transfusion support in patients with chronic renal failure. Immunohematology 1996; 12(1):1–3. pmid:15387752PubMedGoogle Scholar
- Beusterien KM, Nissenson AR, Port FK, Kelly M, Steinwald B, Ware JE. The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients. J Am Soc Nephrol 1996; 7(5):763–773. doi:10.1681/ASN.V75763Abstract/FREE Full TextGoogle Scholar
- Evans RW, Rader B, Manninen DL. The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. Cooperative Multicenter EPO Clinical Trial Group. JAMA 1990; 263(6):825–830. pmid:2404150CrossRefPubMedGoogle Scholar
- Collister D, Komenda P, Hiebert B, et al. The effect of erythropoietin-stimulating agents on health-related quality of life in anemia of chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2016; 164:(7)472–478. doi:10.7326/M15-1839CrossRefPubMedGoogle Scholar
- Parfrey PS, Lauve M, Latremouille-Viau D, Lefebvre P. Erythropoietin therapy and left ventricular mass index in CKD and ESRD patients: a meta-analysis. Clin J Am Soc Nephrol 2009; 4(4):755–762. doi:10.2215/CJN.02730608Abstract/FREE Full TextGoogle Scholar
- Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus 2009; 2(suppl 1):i9–i17. doi:10.1093/ndtplus/sfn175CrossRefPubMedGoogle Scholar
- Locatelli F, Olivares J, Walker R, et al. Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency. Kidney Int 2001; 60:(2)741–747. doi:10.1046/j.1523-1755.2001.060002741.xCrossRefPubMedGoogle Scholar
- Amgen. Highlights of prescribing information. Epogen (epoetin alfa) injection for intravenous or subcutaneous use. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/epo-gen/epogen_pi_hcp_english.pdf. Accessed March 17, 2022Google Scholar
- Amgen. Highlights of prescribing information. Aranesp (darbepoetin alfa) injection for intravenous or subcutaneous use. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aranesp/ckd/aranesp_pi_hcp_english.pdf. Accessed March 17, 2022Google Scholar
- Vifor Pharma. What is Mircera? https://mircera.com. Accessed March 17, 2022Google Scholar
- Pfizer Laboratories. Retacrit prescribing information. http://labeling.pfizer.com/ShowLabeling.aspx?id=10738. Accessed March 17, 2022Google Scholar
- Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005; 2005(306):re12. doi:10.1126/stke.3062005re12Abstract/FREE Full TextGoogle Scholar
- Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999; 15(1):551–578. doi:10.1146/annurev.cellbio.15.1.551CrossRefPubMedGoogle Scholar
- Hirota K. HIF-alpha prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review. Biomedicines 2021; 9(5):468. doi:10.3390/biomedicines9050468CrossRefGoogle Scholar
- Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 1997; 272(36):22642–22647. doi:10.1074/jbc.272.36.22642Abstract/FREE Full TextGoogle Scholar
- Besarab A, Provenzano R, Hertel J, et al. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant 2015; 30:(10)1665–1673. doi:10.1093/ndt/gfv302CrossRefPubMedGoogle Scholar
- Chen N, Hao C, Peng X, et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 2019; 381:(11)1001–1010. doi:10.1056/NEJMoa1813599CrossRefPubMedGoogle Scholar
- Coyne DW, Roger SD, Shin SK, et al. Roxadustat for CKD-related anemia in non-dialysis patients. Kidney Int Rep 2020; 6(3):624–635. doi:10.1016/j.ekir.2020.11.034CrossRefGoogle Scholar
- Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with ckd not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol 2021; 32(3):737–755. doi:10.1681/ASN.2020081150Abstract/FREE Full TextGoogle Scholar
- Shutov E, Sułowicz W, Esposito C, et al. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant 2021; 36(9):1629–1639. doi:10.1093/ndt/gfab057CrossRefGoogle Scholar
- Provenzano R, Fishbane S, Szczech L, et al. Pooled analysis of roxadustat for anemia in patients with kidney failure incident to dialysis. Kidney Int Rep 2021; 6(3):613–623. doi:10.1016/j.ekir.2020.12.018CrossRefGoogle Scholar
- Provenzano R, Szczech L, Leong R, et al. Efficacy and cardiovascular safety of roxadustat for treatment of anemia in patients with non-dialysis-dependent CKD: pooled results of three randomized clinical trials. Clin J Am Soc Nephrol 2021; 16(8):1190–1200. doi:10.2215/CJN.16191020Abstract/FREE Full TextGoogle Scholar
- Besarab A, Chernyavskaya E, Motylev I, et al. Roxadustat (FG-4592): correction of anemia in incident dialysis patients. J Am Soc Nephrol 2016; 27:(4)1225–1233. doi:10.1681/ASN.2015030241Abstract/FREE Full TextGoogle Scholar
- Chen N, Hao C, Liu B-C, et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 2019; 381:(11)1011–1022. doi:10.1056/NEJMoa1901713CrossRefPubMedGoogle Scholar
- Bradbury BD, Critchlow CW, Weir MR, Stewart R, Krishnan M, Hakim RH. Impact of elevated C-reactive protein levels on erythropoiesis-stimulating agent (ESA) dose and responsiveness in hemodialysis patients. Nephrol Dial Transplant 2009; 24(3):919–925. doi:10.1093/ndt/gfn543CrossRefPubMedGoogle Scholar
- Provenzano R, Shutov E, Eremeeva L, et al. Roxadustat for anemia in patients with end-stage renal disease incident to dialysis. Nephrol Dial Transplant 2021; 36(9):1717–1730. doi:10.1093/ndt/gfab051CrossRefGoogle Scholar
- Hu Z, Tao H, Shi A, Pan J. The efficacy and economic evaluation of roxadustat treatment for anemia in patients with kidney disease not receiving dialysis. Expert Rev Pharmacoecon Outcomes Res 2020; 20(4):411–418. doi:10.1080/14737167.2020.1747436CrossRefGoogle Scholar
- Sanghani NS, Haase VH. Hypoxia-inducible factor activators in renal anemia: current clinical experience. Adv Chronic Kidney Dis 2019; 26(4):253–266. doi:10.1053/j.ackd.2019.04.004CrossRefPubMedGoogle Scholar
- Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int 2017; 21(suppl 1): S110–S124. doi:10.1111/hdi.12567CrossRefPubMedGoogle Scholar
- Meadowcroft AM, Cizman B, Holdstock L, et al. Daprodustat for anemia: a 24-week, open-label, randomized controlled trial in participants on hemodialysis. Clin Kidney J 2019; 12:(1)139–148. doi:10.1093/ckj/sfy014CrossRefPubMedGoogle Scholar
- FribroGen. FibroGen provides additional information on roxadustat. Press release. https://investor.fibrogen.com/news-releases/news-release-details/fibrogen-provides-additional-information-roxadustat. Accessed March 17, 2022Google Scholar
- McCarty AN. Clinical trial paper that made anemia drug look safer than it is will be retracted. Retraction Watch 2021. https://retractionwatch.com/2021/05/11/clinical-trial-paper-that-made-anemia-drug-look-safer-than-it-is-will-be-retracted. Accessed March 17, 2022Google Scholar
- Pezzuto A, Carico E. Role of HIF-1 in cancer progression: novel insights. A review. Curr Mol Med 2018; 18(6):343–351. doi:10.2174/1566524018666181109121849CrossRefGoogle Scholar
- Buchholz B, Eckardt K-U. Role of oxygen and the HIF-pathway in polycystic kidney disease. Cell Signal 2020; 69:109524. doi:10.1016/j.cellsig.2020.109524CrossRefPubMedGoogle Scholar
- Patel DM, Dahl NK. Examining the role of novel CKD therapies for the ADPKD patient. Kidney 360 2021; 2(6):1036–1041. doi:10.34067/KID.0007422020FREE Full TextGoogle Scholar
- AstraZeneca. Update on US regulatory review of roxadustat in anaemia of chronic kidney disease. August 11, 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-us-review-of-roxadustat.html. Accessed March 17, 2022.Google Scholar
- Yap DYH, McMahon LP, Hao C-M, et al. Recommendations by the Asian Pacific Society of Nephrology (APSN) on the appropriate use of HIF-PH inhibitors. Nephrology (Carlton) 2021; 26(2):105–118. doi:10.1111/nep.13835CrossRefGoogle Scholar
- Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, randomized, double-blind, active-comparator (darbepoetin alfa) study of oral roxadustat in CKD patients with anemia on hemodialysis in Japan. J Am Soc Nephrol 2020; 31(7):1628–1639. doi:10.1681/ASN.2019060623Abstract/FREE Full TextGoogle Scholar
- Akizawa T, Otsuka T, Reusch M, Ueno M. Intermittent oral dosing of roxadustat in peritoneal dialysis chronic kidney disease patients with anemia: a randomized, phase 3, multicenter, open-label study. Ther Apher Dial 2020; 24(2):115–125. doi:10.1111/1744-9987.12888CrossRefPubMedGoogle Scholar
- Akizawa T, Ueno M, Shiga T, Reusch M. Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies. Ther Apher Dial 2020; 24(6):628–641. doi:10.1111/1744-9987.13468CrossRefGoogle Scholar
- Akizawa T, Yamaguchi Y, Otsuka T, Reusch M. A phase 3, multicenter, randomized, two-arm, open-label study of intermittent oral dosing of roxadustat for the treatment of anemia in japanese erythropoiesis-stimulating agent-naïve chronic kidney disease patients not on dialysis. Nephron 2020; 144(8):372–382. doi:10.1159/000508100CrossRefPubMedGoogle Scholar
- Provenzano R, Besarab A, Sun CH, et al. Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) for the treatment of anemia in patients with CKD. Clin J Am Soc Nephrol 2016; 11:(6)982–991. doi:10.2215/CJN.06890615Abstract/FREE Full TextGoogle Scholar
- Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: a phase 2, randomized, 6-to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis 2016; 67:(6)912–924. doi:10.1053/j.ajkd.2015.12.020CrossRefPubMedGoogle Scholar


Adam Rudolph is percussion master, composer, arranger, and producer. His Moving Pictures group has been one of his three mainstays (along with HU Vibrational and Go: Organic Orchestra) since he founded the group in 1992 (despite having literally dozens of other projects including the Mandingo Griot Society and collaborating with Dr. Yusef Lateef on some 20 albums in as many years). Its members have shifted continuously, but jazz drummer Hamid Drake has been a member almost since the beginning; Ned Rothenberg has also been a contributing member in the past. On Dream Garden, however, his debut for Justin Time Records, Rudolph moves his group into an entirely new sphere, one in which the culminations of his hundreds of collaborations and his multi-disciplinary approach to composition and improvisation all come to bear on a single recording. That doesn't mean hodgepodge, either. This version of Moving Pictures contains perhaps its most talented lineup yet. Rothenberg is here on everything from shakuhachi, C-and bass flutes, to bass clarinet and alto saxophone; Drake, with his drum kit, gourds, and frame drums, is present. Trumpeter Graham Haynes has put his experimental electronic and club explorations on hold for the time being to bring his trumpet and flugelhorn to this mix, while Shanir Blumenkranz is here on bass and the three-stringed sintir (a bass-like lute). As if this weren't an already impressive ensemble, guitarist Kenny Wessel and multi-instrumentalist Brahim Fribgane (who plays not only his trademark oud, but also cajon, bendir, and tarija) are here as well. Finally, rounding all of this out is the great bansuri flutist Steve Gorn, who also plays a Pakistani oboe, clarinet, and various Indian penny whistles.
What's it sound like? It sounds like the center of a universe where the cyclical rhythmic pulses are those of the world's various traditions -- many of which Rudolph himself is has studied as both musician, and ethno-musicologist -- and he plays seven instruments including thumb pianos, naqqara, tarija, caxcixi, gourds, hand drum sets (djembes, tablas, congas, timbales, and talking drums), with a boatload of other percussion items; all of which meet in the great vanguard tradition of spiritual jazz structured elements of world folks and classical musics. While it would be simple to call this "world fusion," it would be inaccurate. The aesthetics that create Dream Garden are quite specific and disciplined. Rudolph's hand drums open the album for "Oshogbo." Drake fills the backdrop almost immediately and then Haynes comes in on trumpet with flutes, saxophone, and whistles entering with a stretched, loping, unhurried melody that is underscored and colored by electric guitar chords and the exploration of intervallic mediums. The bassline rambles and rumbles not as a pulse but as an accent; it moves between the percussionists on a steady, ever intensifying drive. Haynes takes his solo and is answered by the chorus of instruments as he splays and splatters notes, never moving too far outside the melody. He is in turn answered by Rothenberg, who smatters and moans into the very heart of the rhythm, only to be rejoined by Haynes in a series of pulses that bring us to an abrupt stop. The short interlude that is "The Violet Hour" with its gorgeous shakuhachi, painterly electric guitar splashes, with clarinet and trumpet caresses, is a whisper of the wide open, slowly evolving collective improvisation that introduces "Twilight Lake." While there is space and room to breathe, there is never a stop in the action, and this beautifully Eastern-tinged melody begins to articulate itself in shades of color, the dialogue between muted trumpet, bass clarinet, an upright bass, and the guitar is pensive at first as scales are being formed right from the ground up. Notes are held as others slip through and pull them off their moorings to travel. By the time Rudolph and Drake enter, the shakuhachi is moving into another lyrical idea. Nothing is hurried, it's all paced but it's humid, nocturnal, like purple night. The shakuhachi is the sound of a singer, and of Rudolph, who is conducting this ensemble, just as Fribgane's oud slides into the front. The sense of voice is an important one in articulating music this full, rich, and texturally adventurous. Indeed, one can hear traces of the intense lyricism of everything from the great Japanese and Eastern layers to Lateef's mode and tuning exploration on Eastern sounds, to the more restrained feel of Djivan Gasparayan's duduk improvisations, to the African ecstasies of the griots as they enter the long passages in the middle of their stories.
What is so remarkable is the seamless way that all of this seemingly disparate music is brought together in the ear of the listener. It is an uncompromising music that is full of spaces, strange dimensions, and alien phrasing, as well as what may appear, on first listen, to be simply dissonance. But there isn't any really. The harmonic structure of this music and the improvisational acumen of the players is all guided by Rudolph's elegance of approach, his keen investigation of the interval, which is graceful even in the urgency of fresh expression, and his method of revealing this to both musicians and listener alike is spiritually grounded; he's always watching with the inner ear and moving the process an inch further, a level deeper, as a conductor. Because of this, freedom follows through the various channels of his players in a series of seemingly loose trails that come together in unexpected ways. It results in sense of restless but attentive adventure; it's expressed as a desire for communication between disparate sources toward the whole. We encounter his music as such. Check the way the killer polyrhythms utter their incantations on "Happiness Road." When the whistles offer a lyric line, it is because of the percussive interplay, not on top of it. It seeks its proper place in this rich and earthy mix. The kalimbas and frame drums echo their calls and responses across time, and not just across musical architecture. Some of these rhythms are ancient, some of them are variations on relatively current world traditions, and still others bring with them the keen sense of syncopation and interruption that come from jazz and the field chants of the blues, while still others carry a striated sense of New Orleans street marching. This track is answered by the sparse, indeed almost skeletal, high lonesome flute, bass, and bluesy guitar which introduce "Cousin of the Moon." When Haynes and Rothenberg enter, and lines are twinned in octave, one can feel the tension rise, but as it does, and Rudolph and Drake fold their way in, it opens wide, allowing for many different timbral expressions from the brass, winds, and reeds. Wessel and Blumenkrantz are on fire, albeit at a slow burn because Rudolph is taking off as Drake and he play tag along the broken heartbeats of the world creating a new one from the pieces.
What's utterly confounding is that this is only half of the album.
The second half doesn't ever revisit the territories created here, but builds on them with pieces like "Spectral," and "Helix." The latter track begins in the bottom, the steamy, humus-like undercover which is roiling with life. The fat double bassline, Drake's and Rudolph's popping, break and continue as talking drums, and the angular lines of Wessel's guitar offers an enormous gap for the horn lines to speak through. And they do, but sparingly at first, almost haltingly. There is so much going on rhythmically, that as these other voices emerge, they have to have footing, to see that it is all the same ground and it's solid. Rudolph allows for long notes but short phrases. They answer Wessel who is playing around and through the entire mix. Meanwhile, the drumming gets louder, more insistent; it's almost demanding in its call to the horns. It is a pair of songs joined together as inseparable. Fascinating colors emerge from this density without ever sounding dense or self-indulgent. The Latin tinge from Haynes' solo enables a new song to emerge and the drums respond with Yoruba traces confirming origin and utterance, and Haynes goes for it! The forest-like melody of the title track is brief at only a shade over two minutes; but with its clarinet lines, rounded bottom pitch drums, flutes, and a children's singsong quality, it is taken out with the notes of the sintir. This serves to enter the primal in "The Sphinx," which is beyond description except to say that it is the place where Machito, Miles Davis, and Mulatu all meet as folk musicians. The set ends with "Walking the Curve," where Fribgane's oud, Rudolph's hand drums, and a droning but punchy bassline offer an intro that is answered by tough, bluesy brass and reeds in a post-bop head, only to be turned in on themselves with the beautiful bamboo flute and acoustic guitar. It's all funky, but otherworldly; and it swings like mad. This is one of Graham Haynes finest solos on record-and indeed this album may be his very best recorded performance ever -- and it shows his full maturity as a player who can make his instrument sing and cry within a narrow channel that brings out not only his, but the entire ensemble's voices. The way Wessel, Blumenkrantz, and Fribgane interplay with one another is literally amazing. When Rothenberg's bass clarinet moans its blues holler, which shape shifts into a snake charm then a harvest song, it seems natural, effortless. Rudolph guides elements of shape, color, and an investigative approach to group music-making, that pushes the entire record so far, it has met itself back at the beginning in a perfect circle. It's so large, poetic, and wide, it carries within it all the emotions, mornings, and stories of the world. This is, thus far, a career achievement for Rudolph, one that should finally make the jazz world sit up and take notice of this man as a front line composer and bandleader, as an arranger, mentor, and improviser who doesn't acknowledge boundaries between different musical traditions, but knows and respects their lineages enough to understand how they connect and speak to one another endlessly.


text:
Farmland loss is alarming
I was wondering, do you know how scarce farmland is? Only four percent of the world is arable — that means farmable — and Iowa has 10 percent of that. It’s kind of crazy, but it’s all true. Also, it takes 500 years to grow one inch of farmland back, and Iowa loses 26,000 acres of farmland every year. After doing all the math, that means Iowa loses 100 farms every month.
We can control land use. Iowa does have the ability to feed billions of people, but because of all the stuff we build in Iowa, we lose so many farms. We can’t feed as many people.
Do you know how almost all the meat in Iowa is raised? Most people think of it as the animal at the farm, like in “Charlotte’s Web,” but the sad truth is that it is not how we get our meat in America. Normally, animals are shoved into tight quarters, not ever being able to move in their whole life. In order to keep the animals living, they give them lots and lots of drugs and growth hormones. Some of these animals never see daylight. This is animal abuse, and the complete opposite of local food.
Shipping food from one place to another uses a lot of excess packaging, which lands in landfills and pollutes the earth. The chemicals that are on the food we eat from other countries usually are not tested as much as food in Iowa, so it’s not very healthy for us. That’s why it’s a lot better to get food from your local farmers’ market instead of the grocery store. Also, farmland has more value when we buy food that’s from Iowa.

domain: geography


text:
Resort Ba Na - Nui Chua
Tourist area Ba Na - Nui Chua is located in Hoa Vang district, Da Nang city, the center of the city about 50 kilometers to the west. Located at an altitude of 1.487m above sea level, year-round cool climate, the average temperature in Da Nang, Vung Thung bay with arc-shaped contour from Vanden Deo Hai Son Tra Peninsula, My Khe beach , Non Nuoc, Ngu Hanh Son, Thu Bon river winding fertile fields, Cham Island between undulating waves ... Nature as rare picture wearing a place to be.
In the early 20th century, to cater to the needs of people resting in central France, many guesthouses, villas, hotels have sprouted up along the mountain side, top and top of Ba Na Nui Chua. Later ravaged by war, it became abandoned and forgotten by time. In recent years, Da Nang has gradually restored and embellished some old French villas, the Buddhist culture, wineries and numerous hotels such as Morin Hotel Ba Na, Ba Na By Night Hotel , villas, bars, tennis courts, badminton, billiards ... here also regularly organize bonfire night, the promotion of specialty mountains and facilitating tourists to visit the picnic. From Vong Nguyet hill, visitors will be modern cable car system brought to the center. The system has 16 cabins can accommodate about 320 passengers / hour.
To reach the top of Ba Na, visitors must pass 15km winding road, winding. Flat topography like a miniature plateau. Visitors to tourist Ba Na not only enjoy the fresh air, green, clean and beautiful, but also admire the beautiful landscape that rarely get the public holiday. On days when the weather is clear, visitors can collapse in sight a vast region of space
Maybe you are interested
Roll pork coated cakes are people of Danang are increasingly favored by the great mix between taste, color, aroma
Every tourist visiting Quang Nam - Da Nang are more or less listen to advice visit Ngu Hanh Son - Non Nuoc. This is one of the attractions most tourists of...
At the press conference, the organizers said that from the fireworks competition in Da Nang international cycle takes place with 2 years / 1 times, the name has...
Samuel Pan (Mr)
Bích Ngọc (Ms)
Tour Operator (Book phòng Khách sạn)
Tường Vũ (Mr)
Sales Domestic & Outbound
- DA NANG - HOI AN - BANA HILLS - CAM THANH ISLAND Price: Call
- HO CHI MINH CITY – MEKONG DELTA – HANOI CITY – NINH BINH PROVINCE – HALONG BAY Price: 501USD
- [4D3N] EXCURSION TO ISLAND - DISCOVER CULTURE AND CUISINE OF NHA TRANG (HOTELS INCLUDED) Price: 192USD
- 4D3N NORTHWEST ROUTE TOUR: HANOI - MOC CHAU - DIEN BIEN - SAPA Price: 194USD
- [2D2N] HA NOI - HA GIANG - YEN MINH - DONG VAN Price: 92USD


text:
Vietnam had been on my list of places to visit for a long time. When we moved to Korea I knew that I would get to Vietnam at some point during our time here. I mean it’s so close! So off we went in August for 8 days of exploring Hanoi and Halong Bay.
I knew that Vietnam was going to be cheap. I read a lot. I planned. I saw budget breakdowns from travelers all over the world. And yet, I was still shocked by the low cost of everything! Even in tourist hot spots like the old quarter of Hanoi and Cat Ba Island; the prices were so low!
This trip to Vietnam was vacation. So we were not terribly concerned with the price of things, as we did not need to ration our savings over a long term trip. We stayed in hotels, did any activity that piqued our interest, and bought a lot of things. Even though we didn’t pay close attention to money, we still spent very little!
This budget breakdown is for you if…
- You are traveling to Vietnam on a short trip.
- You like to travel in comfort
- You love to be active and experience the culture
- You really love to eat
*All of the expenses are for 2 people
*In August 2015 $1 USD = 22,000 Vietnamese dong
Accommodation – $194
We stayed at three hotels during our eight days/seven nights in Vietnam. The two hotels in Hanoi were immaculate; Clean, beautiful and convenient, plus the hotel staff went above and beyond to make sure we were comfortable. The hotel in Cat Ba Island was a little bit run down, but it was very clean and comfortable and in a quiet part of town.
I would recommend staying in all of these hotels while traveling through Vietnam. We stayed at the Hanoi Gem Hotel and Hanoi Central Park Hotel. In Cat Ba we stayed at the Cat Ba Palace Hotel. If you are looking for places to stay, I use Agoda for all of my hotel bookings in Asia!
How to do it cheaper: There are many hostels that have beds in a dorm room for $5-$10.
Spend more: Plenty of luxury hotel options in Vietnam like the Sofitel and Intercontinental.
Food – 2,565,000 dong = $114
This is not a joke. Two people, who love to eat, went on vacation to Vietnam and spent $114 on food in 8 days. Never in all my life has a food bill been that low for a trip. Typically, food is the number one expense, so this goes to show how inexpensive Vietnam is. AND since it was raining for a good portion of our trip, we did a lot more eating than we would have if it was sunny and nice.
The majority of the food we ate was street food. We actually found ourselves bargaining on food, this was a first. A big bowl of flavorful, filling pho will set you back a whopping 30,000 dong.
One night, we bought fried donuts from a roving street food vendor and she quoted us 30,000 dong for 6 mini-donuts. We had no problem spending $1.50 on this treat. A Vietnamese man nearby heard her, came over and said something in Vietnamese, then suddenly the price dropped to 15,000 dong. Even though everything was so cheap, many places obviously charged tourists more than the locals.
How to do it Cheaper: Eat only street food, and eat less! You could easily eat three filling meals a day for less than 100,000 ($4.45).
Spend more: Skip the street food and only eat at restaurants, though that would be criminal!
Drinks – 1,670,000 dong = $74
Beer is always our next biggest expense. This was not the case in Vietnam because beer is so, so, so, so, so cheap! Bia Hoi is fresh beer served at many street food joints. A glass of Bia Hoi runs between 5,000-10,000 dong depending on where you get it. Plus typical snacks that go with beer are just as cheap; a bowl of boiled peanuts is about 8,000 dong.
After full nights of drinking, it never failed to shock us how much we drank and how low the bill was. We also ended up buying many rounds for new friends, which added to the price.
How to do it Cheaper: Only drink Bia Hoi; don’t buy rounds for other people.
Spend More: Go to more upscale bars and restaurants with views.
Coffee – 635,000 dong = $28
Vietnam does coffee right. The coffee is strong and flavorful and served in many different ways. In most places, 15,000 dong gets you black coffee with sweet condensed milk. Coffee with coconut milk, yogurt, an egg, or alcohol just adds a little bit more to the price. We drank a lot of coffee (rainy days are perfect for coffee shop sitting) and never spent more than 30,000 dong on a cup.
How to do it Cheaper: Drink less coffee; only have the basic black coffee with condensed milk.
Spend More: I’m not sure how you could spend more on coffee. I suppose if you went to Starbucks and didn’t try the local specialties, you would spend a lot more, but that would be shameful!
Transportation – 1,842,282 dong = $82
This transportation budget includes pickup and drop off at the airport at both ends of our trip, taxi rides, and buses.
The most expensive trip was a bus-boat-bus combination to get from Hanoi to Cat Ba Island and cost 250,000 dong ($12.50) per person. Taxi rides were cheap; from one side of the city to the other it cost just 20,000 dong. When getting into a taxi, be sure to ask the price ahead of time as I read that some taxis meters run fast or they will try and get you for a higher price because you are a tourist.
How to do it Cheaper: Skip the pickup from the airport and take the local bus
Spend More: Get private transportation to Cat Ba Island
Activities – 2,336,553= $104
The activities included some low cost excursions like temple visits, a prison, and a water puppet show all under 100,000 dong. We also took a street food tour through the Old Quarter which cost 500,000 each, and I went to a cooking class which was $59. The other activity expense was some pampering. I got a few massages, a manicure and pedicure. Very hard to pass up a full body massage when it costs 150,000 dong!
It’s important to note that we would have spent more on activities if it weren’t for all the rain! We had planned on going kayaking through Lan Ha Bay, rock climbing in Halong Bay and other outdoor adventure activities!
How to do it Cheaper: Go on your own food tour of Hanoi, skip anything that adds too much to your total.
Spend More: Do more!
Souvenirs – 760,000= $34
When traveling, we don’t typically load up on souvenirs. The case was different in Hanoi. Stuff was so cheap, we couldn’t help but buy it all. North Face backpacks (fake? probably, but they are fantastic quality), shoes, shirts and some knickknacks for our co-workers. Shopping was plentiful and inexpensive, so leave little extra room in your luggage!
Miscellaneous – $111
This included the visas on arrival once we got to Vietnam ($90) plus a few tips. Tipping is not expected in Vietnam, but our street food tour guide did a great job, as did the people who ran our hotels, so we slipped them a few extra bucks.
How to do it Cheaper: I think if you get your visa ahead of time through the embassy in your country, it is cheaper.
The grand total for 8 days/seven nights in northern Vietnam for two people was $741. That breaks down $92 a day for two people.
Have you been to Vietnam? Did your budget look similar?

domain: travel


Here’s a friendly place to connect with other AgFuse community members regarding topics outside of ag. Do you want to post a fun snapshot from your latest vacation, share a random meme, brag about your family, or so on? This is the perfect spot to do so.
Interest: Fishing, Hunting
Nut Garden is a company specializing in providing nutritious nuts and a variety of imported high-quality dried fruits and grains with quality and origin certificates. Address: A75/18 Bach Dang, Ward 2, Tan Binh, HCMC Tel: 0901862795 - 0901862796 https://www.vuonhat.com/
Interest: Canola, Corn, Cotton
Natures Enzymes sells 100% natural enzyme based products for Agriculture, Poultry, Cattle, Goats, Wild Birding and more. We are about to combat Zika Virus with Mosquito Free Water Tension Eliminator.
Interest: Beef, Dairy, Poultry, Swine, Organic Row Crops, Marketing, Agribusiness
We are a family ran farm that believes in raising livestock in a caring and natural way, Our livestock is raised on pasture with many animals free ranging. We currently raise Scottish Highland Cattle, multiple species of hogs, goats, sheep, chickens, ducks, and turkeys.
Interest: Beef, Grass-Fed Livestock, Poultry, Specialty Livestock, Swine
Looking to transition to more sustainable practices? Wanting to get out of your current industry and into a new one? Experiencing a generational management shift? This group is intended to be a supportive and informational hub for ag folks that want to diversify or change their current systems.
Interest: Organic Row Crops, Beef, Dairy
Soil and everything in it is the focus here. Crop Nutritionists and CCAs know that growing a crop is more than planting, watering and applying fertilizer. It requires testing, planning, monitoring and adjusting the plan as needed.
Interest: Corn, Wheat, Vegetables, Cover Crops, Ag Policy, Precision Agriculture, Organic Row Crops, Irrigation, Agribusiness
By Kathy Humate
Published Feb 28
water soluble shiny flake potassium humate from high leonardite source,it contained high fulvic acid,humic acid,and organic matter,good solubility with high purity. Name of Product: Humic and Fulvic acidFormulation Type: Percentage of raw materialsl Humic acid (dry basis): 60% l Potassium oxide(k2o): 10%~12%l Fulvic acid : 10%~15%,25~50%l Source Leonardite Appearance Black brown powder or flakeUsage Rate: Soil application: 8~12kg/ha/time,or 5% of total blend. I. e... Anyway make a miscibility test before first application...
By David Berg
Published Jul 4, 2019
Use this checklist to ask the right questions to avoid buying a medical plan your employees can't afford. Are the services I need most covered? Why this is important: Primary care, labs, generic Rx, chiropractors, annual exams, immunizations and routine xrays are the routine services over 90% of people need over 90% of the time. These services should be easy and have very few rules and costs associated with them. Are the copays reasonable? Why this is important: The system has many ways to nickel and dime you. $0 copays for routine services are smart...
By Darren Chan
Published Sep 3, 2019
Importance of healthy rootsFirst, they anchor the plant in place, resisting the forces of wind and running water or mudflow. Secondly, the root system takes in oxygen, water and nutrients from the soil, to move them up through the plant to the stems, leaves, and blooms... Top 4 ways to promote root growth1... Potassium can thicker plants' cell walls... Appropriate ManagementApply root promoting fertilizer under regular schedule contain a high content of phosphorousEnsure the appropriate growth temperatureProvide adequate lightDo not overwaterMore info how to prevent root growth...
Updated Dec 30, 2019
And Accompanying Crop Rotations What Is Equipment Efficiency? What Scale-Related Questions Do You Need to Ask Yourself? When Does It Make Sense to Add Equipment? Part 1: Know Your True Cost of Production Want to make more money farming this year? Step one is to know your true cost of production (TCOP)... Before you begin calculating your TCOP, you’re going to want to do a few things... If not, you’ll want to begin categorizing your input purchases for each crop and, ideally, each practice for that crop (for example, Corn > Fertilizer > Nitrogen)... You’ll want to take a pen and mark up the budgets, adjusting things to make them reflect your operation... Are your interest costs way out of line compared to the university’s budgets? That may be a red flag...
By Darren Chan
Published Oct 22, 2018
If you grow grapes,you may reaching to see a white powdery substance on the grape leaves. It’s the grape powdery mildew... Prune grapevines once hard frosts are over, cutting away all canes except one or two young, unfruited canes eight to ten buds long on either side of the grape trunk... Repeat the spraying every ten days if last season’s disease was severe... Some interesting solutionThis solution was developed specifically for zucchini by a Brazilian person...
By Jenny Hoo
Published Sep 30, 2019
There seems to be growing demand for housing development but state government would also want to expand agricultural area to fit the food demand and other agricultural produce... One positive note about planting MD2 pineapple is that it needs no artificial water irrigation system. MD2 pineapple grows naturally with sunlight and water resources...  Mukhriz: Look for ways to balance agricultural and development land in Kedah | Malay Mail JERLUN, Aug 29 — Kedah government is looking for ways to balance agricultural land and development to ensure food security as its role as the rice bowl of Malaysia while also ensuring the needs of its growing population is met...  Mukhriz: Look for ways to balance agricultural and development land in Kedah | Malay Mail JERLUN, Aug 29 — Kedah government is looking for ways to balance agricultural land and development to ensure food security as its role as the rice bowl of Malaysia while also ensuring the needs of its growing population is met...
Published Mar 7, 2019
”While soil health may be harder to quantify than benefits like biomass production or input savings, there are ways of measuring how cover crops are making a difference in your soil... Reduced ErosionProtecting soil from wind and water erosion is a common reason growers begin using cover crops. The easiest way to monitor this benefit is simply by looking for signs that less erosion is occuring... If you’re looking for more precise measurements of your soil compaction, you’ll want to use a penetrometer, which measures the soil’s compaction in pounds per square inch (psi)... Push it in the soil and watch the gauge to see how much pressure is required to get through...
Categories: Cover Crops
Published Jan 22, 2020
One way to help manage these high rainfall events is to improve soil water infiltration — the faster it can enter the soil, the less likely it will pond or run off the farm, taking valuable soil and nutrients with it. But what are the best practices for increasing water infiltration rates?University of Nebraska-Lincoln (UNL) assistant professor of agronomy and horticulture Andrea Basche set out to find just that... Top Practices: Perennials & Cover CropsBasche and DeLonge’s research discovered the practice that improved water infiltration rates the most was having perennial crops, such as grasses or trees, incorporated into the cropland... ”The second most influential practice was cover crops, which the meta-analysis found improved soil water infiltration by an average 35%... Basche and DeLonge also noted there was evidence that cover crops had a greater impact on water infiltration rates in coarsely textured soils with higher sand content and less clay...
Categories: Cover Crops
By Sam Davinci
Updated May 25, 2020
Tractor of the Year 2020Winner of the Tractor of the Year 2020 award was the Fendt 942 Vario. The new 942 series for the first time reaches more than 400 hp (298. 3 kW)... In this way the engine smoothly works at a specific max torque level at a minimum consumption level... Tractor manufacturers are increasingly challenged to deliver vehicles that provide superior productivity and operator comfort while minimizing the environmental impact through high fuel efficiency and reduced soil compaction, says Aziz Aghili, President of Dana Off-Highway Drive and Motion Technologies...
Published Feb 10, 2018
With the average age of todays farmer at 60, and rural America losing population as the cost of land and equipment soars, this film reveals the people waiting to take their place, the practices theyre championing and the obstacles they must overcome... Meriwethers goal is to bring these two perspectives together and forge a shared path towards our next agriculture... JFAN (@JFANIowa) | Twitter The latest Tweets from JFAN (@JFANIowa)... , a SE Iowa educational foundation protecting Jefferson County from industrial hog confinements... Jefferson County, Iowa Jefferson County Farmers & Neighbors JFAN is a nonprofit educational foundation composed of rural and town residents, & traditional family farmers...
By Zubair Ahmad
Published Mar 18, 2020
Hello everyone I'm Zubair here from mountainous region of Pakistan. Im trying to increase my yields, what is the best way.
By Anonymous Member
Published Dec 1, 2020
Published Oct 18, 2020
Looking at planting triticale with hairy vetch and cow peas for a cover crop next year for a cash crop or corn to be planted late May 2021 using a roller crimper to terminate the cover crop before plant. It’s October 18th, I won’t be able to plant until the 22nd. Night time temps have fluctuated from mid 30s to high 20s no consistency yet. Some nights stay closer to 40. Highs are in the 70s and 80s. Am I too late for any of my covers? Any suggestions on planting rates? Will triticale terminate properly if I follow the method used for Rye, waiting until the entire field is dropping pollen?
By Anonymous Member
Published Jan 12
Currently, Facebook is highest social media platform among the Agriculture industry, due to the recent fallout, do you for see the Agriculture industry moving to another platform? If so, which one and why?


34CrMo4,35CrMo,SCM435 Alloy Steel Bar, US $ 680 - 850 / Ton, ASTM 4135 SCM435 34CrMo4, AiSi, ASTM, bs, DIN, GB, JIS, Dia 12-160mm.Source from Ningbo Chenglong Special AISI 4135/JIS SCM435/DIN 34CrMo4 Alloy Structural Steel Name:AISI 4135/JIS SCM435/DIN 34CrMo4 Alloy Structural Steel Round Bar. Place of Origin:Liaoning,China Brand Name:Dongbei Tegang. Shape:Round Bar Material:Alloy Structural Steel. Steel Grade:AISI 413/JIS SCM435/DIN 34CrMo4. Size:Diameter:10mm~100mm. Application:used in making pressure vessel, like gas cylinder. Chemical composition
35CrMo(A30352)/4135/SCM435/34CrMo4(1.7220) alloy structural steel. 35CrMo(A30352)/4135/SCM435/34CrMo4(1.7220) alloy structural steel is used to be manufactured all kinds of important parts which can bear impact, crankle, high heavy load, such as the herringbone gear of the rolling machine, bent roller, plumbing bar, connecting rod, fasteners, spindle of the steamer China Alloy Steel Scm435 Alloy Steel Round Bar Material 72283090. alloy steel scm435 alloy steel round bar material price. scm435 steel material is Japan standard which is widely used in Asia countries. It's equivalent material such as:sae4135, astm4135 in German Standard. scm435 in Japan JIS standard. 34CrMo4 steel in German DIN standard and. 35CrMo steel in Chinese GB standard. SCM435 datasheet,SCM435 chemical,SCM435 heat treatmentSteel SCM435 Ex-stock Suppliers,JIS SCM435 Chemical,SCM435 Properties from Steelmaking, ESR melted, Blooming, Hot forging,Hot rolling, Heat treatment, Straightening, 100% Ultrasonic test, Cold working, Peeled or rough turned machining. Technical specification JIS G4053 -2003.
SCM435H (Japan, JIS ) - European (EU, EN) and wordwide Steel equivalent grades. These comparison table is only intended as an indication of the closest khown equivalent grades. The source standarts should always be checked for the specific purpose for each material, in case of doubt. Buy, sell, suppliers search product SCM435H on-line. Scm415 Scm420 Scm435 Scm440 42CrMo4 Alloy Steel Scm415 Scm420 Scm435 Scm440 42CrMo4 Alloy Steel Round Bars, Find Details about Quenched & Tempered Steel Round Steel Bar, Scm415 Steel Bar from Scm415 Scm420 Scm435 Scm440 42CrMo4 Alloy Steel Round Bars - Laiwu Xincheng Metal Co., Ltd. Scm435 Steel Price, 2021 Scm435 Steel Price Manufacturers Scm435 Steel Price - Select 2021 high quality Scm435 Steel Price products in best price from certified Chinese Scm435 Steel Plate manufacturers, Scm435 H13 Alloy Steel Bar suppliers, wholesalers and factory on Made-in-China
Easy-to-Weld A572 AlloySteel Sheets and Bars. Combining strength with weldability and formability, A572 alloy steel is an economical choice for structural components, such as channels, beams, and framing. It has a low carbon content, making it easy to weld with a variety of welding methods. scm435 steel price, scm435 steel price Suppliers and SCM435 /34CrMo4/ 1.7220/ 4135 alloy steel hollow bar with good price/pipe/tube Jiangsu Xihao International Trade Co., Ltd.scm435 alloy steel bar, scm435 alloy steel bar Suppliers offers 918 scm435 alloy steel bar products. About 10% of these are Steel Round Bars. A wide variety of scm435 alloy steel bar options are available to


text:
If you lose a tiny possession on a vacation across the world, chances are, it's gone forever. But a New Jersey couple just beat the odds by recovering an engagement ring they lost in Italy nine years prior, USA Today reports. Justin and Margaret Mussel lost her 1.1 karat, diamond engagement ring while they were on vacation in Italy soon after their wedding. "My wife’s ring was loose, but she didn’t realize it was gone until later," Justin told USA Today. "She took a nap [after], and woke...READ FULL ARTICLE »
Become a member to take advantage of more features, like commenting and voting.
Register or sign in today!

domain: news


text:
The legacy of Toni Morrison, who died this week at the age of 88, seems nearly impossible to summarize. The 1993 Nobel laureate for literature, she was the author of 11 novels, one of which won a Pulitzer Prize, as well as numerous works of nonfiction. As an editor, she published and promoted the work of a generation of black writers—which is to say nothing of the artists she continues to inspire, including other cultural giants such as Oprah and Beyoncé.
For all this legendary status, however, a recent documentary captures Morrison’s life in intimate, personal terms. And the strength of her work is deeply rooted in its humanity—in black characters whose internal struggles and strengths are fully realized and compassionately written. Her first novel, The Bluest Eye, challenged the oppression of white beauty standards. And her last, God Help the Child, celebrated how people can overcome painful histories to find fulfillment.
Each week in the Books Briefing, we thread together Atlantic stories on books that share similar ideas. Check out past issues here.
Know other book lovers who might like this guide? Forward them this email.
What We’re Reading
A writer of rare compassion and kaleidoscopic vision
“Both despite and because of the specificity of their settings, her characters evince fears and desires and pain that then consume the reader. Morrison’s world extends far beyond her pages; it embeds itself in those who witness it.”
📚 The Source of Self-Regard, by Toni Morrison
📚 “On Black Difficulty,” by Namwali Serpell
📚 Nobel lecture, by Toni Morrison
📚 “No Place for Self-Pity, No Room for Fear,” by Toni Morrison
I’m writing my memoir for Toni Morrison
“I survived the white gaze for Pecola [the heroine of The Bluest Eye], and it was Morrison who taught me how.”
📚 Surviving the White Gaze, by Rebecca Carroll (forthcoming)
Mining lyrical power and human strength from childhood suffering
“Morrison’s greatness—the beauty of her prose, her formal and imaginative risk-taking, her intellectual prowess—is founded on fiction about human devilishness and weakness, bodies crippled and in crisis, and the impact of our histories on our emotional faculties.”
📚 Jazz, by Toni Morrison
📚 Love, by Toni Morrison
📚Song of Solomon, by Toni Morrison
A documentary that shows another side of Toni Morrison
“In spite of her larger-than-life status, Morrison is captured [on-screen] in exceedingly human terms.”
📚 Beloved, by Toni Morrison
The Reference Desk
After Sarah requested some titles for her upcoming trip to Hawaii, a reader named Grant proposed making a similar list for future travelers to Australia, as “sort of homework before [they] go.” His choice to start that list is Bruce Chatwin’s book The Songlines, which is named for—and traverses—the paths that, according to Aboriginal mythology, were traveled by spirits in the Dreamtime and have been recorded in traditional songs. Murray Bail’s novel Eucalyptus tells the fablelike story of a young woman, her suitors, her father, and his hundreds of eucalyptus trees in a similarly inventive, meandering narrative (as the writer Jane Alison notes in her own recent book). The Guardian lists some of the best recent books from Australia here, and the magazine Australian Geographic selects 12 of the country’s must-reads here.
Write to the Books Briefing team at email@example.com or reply directly to this email with any of your reading-related dilemmas. We might feature one of your questions in a future edition of the Books Briefing and offer a few books or related Atlantic pieces that might help you out.

domain: library


text:
San Diego Personal Injury Attorneys
Personal Injury is an area of law that is comprised of tort claims in which one person has been injured by the actions of another.
Examples of Personal Injury Cases Include:
The personal injury attorneys of Hiden, Rott & Oertle, LLP, (HR&O) handle a variety of tort claims from a simple car accidents to more complex cases such as professional malpractice. Since its inception in 1993, the personal injury department of HR&O has carved as a reputation throughout California as a firm well-known for taking on the tough cases, which other attorneys decline. With millions of dollars obtained on behalf of our clients, HR&O is the first choice for injured parties.
At HR&O, we represent plaintiffs throughout California and other states, in all stages of personal injury cases, from date of injury through trial. Unlike other law firms that will only represent a client up to the point of litigation, your attorneys at HR&O will file lawsuits to protect your rights and take other steps to ensure you receive aggressive and competent legal representation.
While always ready to file a lawsuit to protect your case, HR&O also recognizes the usefulness in utilizing prelitigation settlement tactics such as mediation, arbitration and settlement discussions in an effort to settle your case quickly, efficiently and in a manner most effective for the needs of any individual case.
Concentrate on Your Recovery, Not Your Medical Bills — We Have You Covered
Many clients of HR&O have suffered catastrophic injuries but have no medical insurance or financial means to pay their bills. If this is the case, HR&O can assist in helping you locate competent medical care and assistance without the burden of immediate payments for care. Based on the reputation of all HR&O attorneys, medical providers, in fields as diverse as acupuncture or chiropractic care to surgical intervention, will provide treatment, without an upfront payment from the patient. Freed from the unnecessary stress of medical payments, you are then able to concentrate on your recovery rather than finances. Medical bills will then be paid when your case settles rather than you worrying about payment immediately when hurt. HR&O will also help you to obtain a rental vehicle, alternate housing, coordinate with your employer for time off or assist in other areas, depending on your individual needs. If your medical condition is such that you cannot come to our office, our attorneys will make arrangements to visit you at the hospital, your home or another location which best suits your needs.
Our legal assistance in personal injury cases also involves the coordination and/or payment of medical care, protecting your credit rating (in the event you already received care which you cannot pay for) and ensuring that your insurance rates will not increase if you are involved in a car accident. HR&O can even assist you when the person who hurt you has no or little insurance, or if you were involved in a car accident but do not have insurance yourself.
Our Personal Injury Attorneys Can Help You
At HR&O, we pride ourselves in offering the highest caliber of assistance and representation to our clients. We will provide you not only with the cellphone numbers of all our paralegals, but also all attorneys, including partners, within the firm, giving you easy, and immediate, access to our firm.
If you or anyone you know has been injured, please contact Hiden, Rott & Oertle, LLP, at: 619-369-3323 to speak with an attorney at one of our California offices.
Hiden, Rott & Oertle, LLP’s front lobby

domain: law


text:
March 20, 2014
The development of sustainability is an ongoing platform under review. Despite its critical need the understanding and disconnect from its overall good and application is under utilized. Sustainability resides within a window where education and promotion are vital.
The Guardian post “Every quarter, US lobbyists report their activities. But how valuable are these reports? In a close look at environmental disclosures from 27 companies that talk about – and promote – sustainability, we found a lot of vague language, as well as widespread failure to disclose company positions. This was the case even when companies were lobbying in favor of climate-change regulation.
It’s becoming a key issue for investors, as well as for NGOs and consumers. But raising transparency might be more difficult than it seems. As Anne Kelly, director of public policy at Ceres, said at the GreenBiz Forum last month, talking with companies about lobbying is a bit like speaking with her son about the reproductive system. “It’s not always comfortable,” she said.
It is a mind shift to incorporate sustainable thinking that leads to implementation among companies. In the U.S. with short-term thinking the swaying effect is cost determinant versus a long-term solution that lives beyond the tenure of the current CEO and Board.
This sustainable shift is economic, environmental and a dynamic shift in operating procedures that lead to cost benefit, valuation and growth. The opportunity is to educate the leadership on the importance of sustainability to achieve change is evolutionary corporate step.


text:
I've been very busy since last month. So could not work on any saree, all the colors were sitting idle :-). For Dasara I had 2 days holidays. So screen printed on two sarees, one of them is Kerala Cotton saree.
On the border printed with Ambari designs and and on the body also printed small motifs of the same designs.
Closer view of the motif:
Another one is Black color South cotton, with Orange border, printed with two colors:
Here is the motif:
And for the pleats, flower motifs:
Still orders from my friends are pending. Hope to complete those soon. Once completed definitely share those designs with you.
Love , laugh and live the life to the fullest,

domain: artistic


(dpa) - German Chancellor Angela Merkel will become the first foreign head of government to address the Israeli Knesset on Tuesday afternoon.
Her speech became possible after the Knesset changed its regulations which stipulate that only a head of state, and not a head of government, may be invited to address the legislature.
And, in another indication of how the two countries are drawing closer together, on Monday morning 17 German and Israeli ministers, including Prime Minister Ehud Olmert and Merkel, held a joint cabinet session, to discuss projects in such fields as defence, education ad the environment.
Germany currently holds similar joint cabinet consultations with other countries, but Israel is the only one outside of Europe, indicating, as Merkel said on her arrival, that her visit has opened a "new chapter" in the relationship between the sides.
But the "old chapter", the other aspect of the Israeli-German relationship, is never far away, and it was highlighted when right- wing lawmakers objected to Merkel addressing the Knesset in her native tongue, arguing that it was inappropriate for German to be heard in the parliament of the Jewish state, only 63 years after the Holocaust.
The Holocaust, the Nazi genocide of 6 million Jews during World War II, and the years of persecution which preceded it, was once the dominant factor in Israeli-German relations - for example in the frosty, often downright acrimonious, relationship between former Israeli premier Menahem Begin, whose parents were murdered by the Nazis, and former German chancellor Helmut Schmidt, who served as an artillery officer in the German army during the war.
The argument could be, and in fact is, made that the subject still dominates the relations between the two countries, in that it leads Israel to expect preferential treatment from Germany, and causes Germany to avoid criticising Israel harshly, or even - say critics - at all.
But during the Merkel's visit, both sides, while not neglecting to mention the impact of the Holocaust, seemed determined to emphasize other aspects of their ties.
Israel regards Germany as its closest ally in Europe, and Ambassador to Berlin Yoram Ben-Zeev described the Merkel visit as "one of the most important by a head of government in many years."
Jerusalem, said Ben-Zeev, had high expectations from the trip, regarding both Germany's role in mediating Israel's ties with the European Union, and its efforts to promote the creation of "viable and democratic state structures in the Palestinian territories."
"The two sides seek to strengthen and intensify their political, cultural, economic and social relations as a partnership of democratic and pluralistic nations," a joint statement issued after the special cabinet session said.
Whether or not the Merkel visit does indicate a "new chapter" or is merely a logical progression of the ties which, apart from one of two blips, have become steadily closer over the years, is debateable.
What is beyond argument, however, is that the relationship has moved on from the suspicion of the early years, and from the angry protests which greeted the arrival of the first German ambassador to Israel, Rolf Pauls, in 1965.


The technological development of central heating systems has become prominent recently as the need for more energy efficient homes has been realised by politicians and homeowners.
Not only is a more energy efficient new boiler beneficial to the environment, which in turn helps the Government meet its energy targets, it is more cost effective; simply put, upgrading from an old E-rated boiler to a new A-rated boiler can shave around £200-£250 off the average household energy bill, which is significant in this age of continued economic uncertainty. Naturally, an upgraded gas boiler will only make a difference so far as gas bills are concerned, which is why Baxi, one of the UK’s leading manufacturers of heating systems, has devised a new concept in home heating: the Baxi Ecogen.
The Baxi Ecogen is unlike any other gas boiler on the market because it is not just a gas boiler. The Baxi Ecogen is a wall-hung gas boiler that also generates electricity for use in the home, thereby making it a dual energy heating and power system. The process of generating both electricity and heat from the same source within close proximity to where such energy is to be consumed is known as micro-combined heat and power or micro-CHP. The Baxi Ecogen employs state-of-the-art micro-CHP technology to provide efficient heating and hot water in addition to cost effective, low carbon electricity.
Combined heat and power (CHP) systems have been used for many years on a larger scale, such as in hospitals and schools. Baxi has taken CHP technology to develop micro-CHP systems for use in domestic environments, which could mark something of a revolution in environmentally friendly home heating and energy generation. Households using the Baxi Ecogen will require less electricity from the national grid, not only saving money but also reduces their carbon footprint; standard electrical consumption can also be reduced by using the Baxi Ecogen alongside solar hot water heating installations. Crucially, the Baxi Ecogen is estimated to reduce average annual bills by up to £600 and the dual system can generate 1kW of electricity, which is enough to power various appliances, including washing machines, computers and televisions.


text:
August 4, 2022 -- Drought conditions throughout Texas continue with little relief. The Brazos River Authority has issued a Stage 2 Drought Warning declaration for Lake Proctor. The reservoir is the surface water supply for Upper Leon River Municipal Water District, which is a wholesale water provider, and several other agricultural users.
The BRA has notified each organization with water supply agreements from Lake Proctor that Stage 2 conservation efforts are now in effect. At the Drought Warning stage, the BRA requestsa10 percent reduction in water use from amounts that would have occurred in the absence of any drought contingency measures.
The Stage 2 Drought Warning is part of the Brazos River Authority's Drought Contingency Plan (DCP). This DCP, which is required by the state, is intended to help preserve and extend water supplies during drought conditions and includes recommended actions to achieve the water use reduction goal requested by the BRA.
The DCP has four conditions, or stages, ranging from 1-4 in level of severity. Each stage is tied to corresponding drought severity triggers.
When a reservoir drops below its Stage 1 trigger level, the BRA implements a Stage 1 Drought Watch Condition where customers and the public are made aware of potential drought problems. During Stage 1, there is a recommended 5 percent reduction in water use than would have occurred under normal conditions.
A Stage 1 – Drought Watch was established for Lake Proctor on March 17, 2022. Since that time, Lake Proctor has dropped below its Stage 2 Drought Warning trigger of 1156.1 feet mean sea level. At this level, the reservoir is about 63 percent full.


text:
ACLU Statement on the 2022 Midterm Election Results
NEW YORK — Below is a statement from Anthony D. Romero, executive director of the American Civil Liberties Union, on the results so far of the 2022 midterm elections.
“Last night represents a historic victory for reproductive freedom. Voters in Michigan, Kentucky, Vermont, California, and across the country demonstrated they will protect reproductive freedom and stand up for the ability to access essential abortion care in overwhelming numbers. We are especially proud of last night’s citizen-initiated victory in Michigan where voters passed one of the most comprehensive constitutional amendments that will preserve the right to reproductive freedom for generations to come.
“Well before Roe v. Wade was overturned, the ACLU and our affiliates played a role in supporting historic ballot measure campaigns this cycle, investing millions during this record-breaking year for abortion measures on the ballot. While we celebrate last night’s ballot measure results, our work is far from finished on the federal level or in states across the country. Every person deserves the power to make personal medical decisions during pregnancy, and we won’t stop fighting until that vision is a reality across the country. The ACLU promises to hold those in power accountable to ensure that we expand access to abortion in every way we can.”
Every month, you'll receive regular roundups of the most important civil rights and civil liberties developments. Remember: a well-informed citizenry is the best defense against tyranny.
The Latest in Voting Rights
Civil Rights Groups Seek to Lift Stay in Federal Lawsuit Challenging Louisiana’s Discriminatory State Legislative Maps on Heels of U.S. Supreme Court Alabama Decision
Historic Win: U.S. Supreme Court Rules Alabama’s Congressional Map Violates the Voting Rights Act by Diluting Black Political Power
Utah State Legislature v. League of Women Voters
New Motions Filed in Lawsuit Challenging Georgia’s Omnibus Anti-Voter Law Seek to Defend Against Racial Discrimination and Remove Barriers to Absentee Voting
The American Civil Liberties Union is a nonprofit organization whose mission is to defend and preserve the individual rights and liberties guaranteed to every person in this country by the Constitution and laws of the United States of America.
Learn More About Voting Rights
Voting is the cornerstone of our democracy and the fundamental right upon which all our civil liberties rest. The ACLU works to protect and expand Americansʼ freedom to vote.

domain: sociology


text:
By Joe Satriani. Guitar Educational. Softcover Audio Online. With guitar tablature. Published by Cherry Lane Music (HL.2501684).
Item Number: HL.2501684
ISBN 160378358X. 9x12 inches.
Now available with online audio featuring PLAYBACK+, a multi-functional audio player that allows you to slow down audio without changing pitch, set loop points, change keys, pan left or right – exclusively available from Hal Leonard!
Learn guitar tips, tricks and secrets with this collection of 41 private lessons from Satriani's famous columns from Guitar for the Practicing Musician magazine. Host Dave Celentano covers: chords, scales & modes, tunings, theory, technique, harmonics, soloing, and much more!


text:
Earnings season is getting started, providing plenty of potential opportunities for options traders.
Unlike buying or selling stocks outright, trading options allows investors to express much more specific viewpoints. In the context of earnings, that means that traders can bet a stock will rise or fall specifically on the news event, or that it will make either a larger or a smaller move than the market is expecting.
For this earnings season, Goldman's options research team suggested four trades in a Wednesday note to clients: Buying bullish call options on PepsiCo, buying bullish call options on Dow Chemical, and buying "straddles" on semiconductor stock Sanmina and on networking company JDS Uniphase.
A straddle is a trade composed of buying both a put option and a call option, and it is designed to profit if a stock moves more than implied by options prices.
So far, the trades have gotten off to a rough start. Pepsi shares fell Thursday after the company reported earnings, which has led the July 96.50-call that Goldman suggested buying for $1.18 to lose three quarters its value.
With Dow, Sanmini and JDS Uniphase yet to report, the wisdom of the remaining trade ideas remains to be seen.
More generally, one might notice that each trade idea proposed by Katherine Fogertey and John Marshall of Goldman involves buying options, not selling them. That's because they claim to spot a trend that the market is missing.
"Since 2011, we have noticed that preannouncement activity has picked up in July, but we think that the options market is missing this historical pattern," the options experts wrote. That should increase the prices of some options covering the July period, since "Investors that buy these options could benefit if a company preannounces results, but likely does not suffer significant decline in implied volatility if this does not occur since the options still capture earnings."
In other words, the now-increased chance of seeing a company provide news regarding its earnings before the actual event should boost the value of options, since it adds an additional potential catalyst, but the options market isn't accurately increasing the value of options to adjust for this opportunity, according to Goldman.
Want to be part of the Trading Nation? If you'd like to call into our live Monday show, email your name, number, and question to email@example.com.


Get the Best Priced Porsche 911 Ignition Lock Cylinder
- Fast Shipping
- 30-Day Money-Back Guarantee
- Lowest Prices
Porsche 911 Replacement Ignition Lock Cylinder Information
Search our online ignition lock cylinder catalog and find the lowest priced discount auto parts on the web. We sell wholesale to the public. We offer high quality new, OEM, aftermarket and remanufactured Porsche 911 Ignition Lock Cylinder parts. We specialize in a wide-variety of high-quality car parts and accessories for your car, truck or SUV. Call toll free to order or place your order online via our secure checkout system. Our online parts catalog uses real-time inventory, so you can be assured the parts you buy are in stock at the time of ordering. Most orders are shipped the same day. They are available for the following Porsche 911 years: 2005, 2004, 2003, 2002, 2001, 2000, 1999, 05, 04, 03, 02, 01, 00, 99. This part is also sometimes called Porsche 911 Ignition Switch Lock Cylinder. We stock ignition lock cylinder parts for most Porsche models including 914, 944, Boxster, 924 and Carrera GT.
We stock these Ignition Lock Cylinder brands for the Porsche 911: Genuine.
Ignition Lock Cylinder
Sale Price: $276.33
Product SKU: W0133-1599965
Inventory: In Stock
Made By: OEM
(Original Equipment Manufacturer) - a replacement part made by the manufacturer of the original part.
Free Ground Shipping or (Overnight and 2-Day Shipping)
- 79 1979 Porsche 911 Ignition Lock Assembly Genuine
- 03 2003 Porsche 911 Ignition Switch Meyle
- 90 1990 Porsche 911 Power Steering Hose Genuine
- 99 1999 Porsche 911 Power Steering Pump LUK
- 91 1991 Porsche 911 Steering Rack ZF - w/o Tie Rods
- 96 1996 Porsche 911 Tie Rod Sebro w/Rack Boot & Lock Nut
hard to find parts, great prices, and fast shipping
Partsgeek.com is the real deal. I had searched everywhere and the part i needed was costing me triple, i found it on partsgeek for more than half the price and in same condition and it was here in ...


text:
Are you tired of dealing with warts either personally or with your children? If so, I have put together some basic information and treatment strategies to keep in mind.
Common skin warts are raised round or oval growths. Some warts may have tiny dots in them called seeds which are clotted blood vessels.
Warts are caused by skin that is infected with HPV (Human Papillomavirus) through direct contact. HPV more commonly infects injured skin. It can take up to six months after exposure to HPV to develop a wart. Warts are commonly seen on fingers, hands, knees, and elbows. They can also be found in the feet or genital area.
Should you seek treatment?
That depends on how much they bother you. About two-thirds of skin warts will resolve on their own in two years.
What are some common treatments?
1. Salicylic Acid - Is a type of acid that is directly applied to the wart. First soak the area for 10 - 20 minutes to soften the skin. Apply the acid at bedtime and leave in place overnight. You should continue treatment for one to two weeks after the wart is gone to make sure that the virus is eradicated.
2. Duct Tape - It is unclear if it works or why. Cover the skin and leave in place for six days. Then remove the tape, soak the skin in warm water for 10 to 20 minutes and use emery board or pumice stone to gently slough off dead skin. Then reapply the tape. Most people who find duct tape useful have resolution in four weeks.
3. Liquid Nitrogen - Destroys warts by freezing the skin. Multiple treatments are often necessary. After treatment most people heal in 4 - 7 days.
4. Cantharidin - Liquid applied to wart that is applied by the healthcare provider. May be useful for children as it causes no pain initially.
5. Shave Excision - Involves removing the skin with a blade after injecting local anesthesia.
6. 5-Fluorouracil - Cream used to treat wars. Applied twice daily for three to fine weeks.
7. Imiquimod - Cream that stimulates the immune system to eliminate the wart. Applied at bedtime several times per week.
When should you seek help?
Consult a healthcare provider if:
Let me know what you think or if you have found any other treatments to be useful in the comments below.
Of course, each individual case is different and the advice in this post should not substitute for getting a consultation with your doctor.
Visit the home page for more information on Murdock Health and our services or call 214-929-2411 to schedule an appointment today.
Doctor/Telemed/Sick Visit $60
WEIGHT LOSS $60
HCG DIET $399
HORMONE VISIT $60
BLOOD WORK $60
STEM CELL $999
Testosterone Visit $69
Vitamin B12 $25

domain: health