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March 2014 FAQs Heading link
Are there benefits to using genotype-guided warfarin dosing for INR control?
Warfarin is a vitamin K antagonist that interferes with the generation of clotting factors II, VII, IX, and X in addition to the anticoagulant proteins C and S.1 It is used as an anticoagulant for prophylaxis and treatment of venous thromboembolism associated with atrial fibrillation and mechanical heart valves and of deep vein thrombosis and pulmonary embolism. The dosing for warfarin is individualized for each patient to maintain an International Normalized Ratio (INR) of 2 to 3, or a higher goal of 2.5 to 3.5 in the setting of mechanical valves. Patients that have an INR that is subtherapeutic are at risk for clot development, while those with supratherapeutic INR values are at risk for minor and major bleeding events. Each patient requires different doses to achieve the target INR, and it has been discovered that there are a variety of genes, specifically VKORC1 and CYP2C9, that are involved in the dosing variations needed among patients. In addition to various genotypes that make it difficult to predict a patient's maintenance regimen, there are many foods and medications that interact with warfarin. Foods that contain high levels of vitamin K counteract the actions of warfarin and, therefore, patients are counseled to maintain a consistent amount in their diet to help keep their dose stable. Medications may interact with warfarin either to make the patient to be more prone to being supra- or subtherapeutic, depending on the interacting medication. Drug interactions are more easily manageable when involving a chronic medication; however, acute changes in the patient's medication regimen, such as a short course of antibiotics, can cause drastic changes in the patient's INR. In these cases, the warfarin dose may require adjusting in anticipation of the effects on the INR, or a different antibiotic may need to be selected to avoid this interaction. All of these factors require a patient to receive close follow-up every few days with a healthcare professional until their dose has been optimized to maintain a stable therapeutic INR. Once a stable dose of warfarin has been identified, the patient must be monitored every 4 to 6 weeks, with more frequent monitoring when outside factors are expected to lead to a change in INR.
Gene polymorphisms
As more pharmacogenomics services are being set up around the country, their use has been justified due to the narrow therapeutic index of warfarin and the inter-patient variability that occurs due to differences in genotypes.2 It has been hypothesized that choosing an initial warfarin dose based upon genotypes will lead to more time within the therapeutic INR range. This inter-patient variability has been linked to polymorphisms in the genes CYP2C9 and VKORC1.2,3,8 In a study designed specifically to look at variant alleles in the CYP2C9 genome, it was found that patients with CYP2C9*2 and CYP2C9*3 polymorphisms have an increased risk of being over-anticoagulated and thus are more likely to require lower doses of warfarin to maintain a therapeutic INR.4 Patients with VKORC1 AA genotypes also require a lower dose than patients with the GA or GG genotype.5 In 2007, the United States Food and Drug Administration (FDA) changed the labeling for warfarin, citing that up to one-third of patients metabolize warfarin differently depending upon their CYP2C9 and VKORC1 genotypes.3 At that time, the FDA stated additional studies were required to determine if pharmacogenomic testing should be required for patients being treated with warfarin. 6 In 2010, the FDA released a statement that encouraged practitioners to select a patient's starting warfarin dose based upon the genotype if available, but did not recommend genetic testing.7 At this time, the Centers for Medicare and Medicaid Services (CMS) do not cover genotyping as a service for its patients.8 As more pharmacogenomics services have come available, the utility of these services has been assessed with some conflicting results.
Pharmacogenomic-guided warfarin dosing
The technique of warfarin dosing could potentially change with the use of pharmacogenomics. In some institutions, clinical algorithms or clinical judgment are used for warfarin dosing. Clinical algorithms may include patient factors such as age, race, smoking history, anthropometrics, amiodarone use, target INR, and indication.1 However, in the advent of pharmacogenomics, algorithms are being developed to include a patient's CYP2C9 and VKORC1 genotypes in addition to other clinical variables. In 2009, an algorithm was developed by the International Warfarin Pharmacogenetics Consortium (IWPC) based on clinical and genetic data collected from 4043 patients and then validated in an additional 1009 patients.9 When the genotype-guided algorithm was compared with a clinical algorithm and a fixed-dose approach, it was significantly better at predicting more accurate initial doses, especially in those requiring weekly warfarin doses of 21 mg or less and 49 mg or more. While there are studies available that comment on the presence of the different genetics that affect warfarin dosing, there is one additional study that has evaluated the dosing of warfarin in the setting of known VKORC1 and CYP2C9 genotypes titled the CoumaGen-II trial.10 This study compared 2 pharmacogenomics-guided algorithms—a simple 1-step algorithm based loosely on the IWPC algorithm and a more complex 3-step algorithm with additional modifications to the IWPC algorithm—and found that the more complex protocol was noninferior but not superior to more simple protocol. The authors' conclusions were that these protocols would aid in determining stable maintenance doses of warfarin, but noted that limitations in study design and sample size need to be considered when interpreting the results. Since there is still somewhat conflicting and limited information regarding prospective genotype-guided protocols, 2 new studies—COAG and EU-PACT—allow the impact of genotype-guided protocols to be better assessed.
The COAG and EU-PACT studies
In a study performed by Kimmel et al, named the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, a dosing initiation algorithm, in addition to clinical factors was used for the first 5 days of warfarin therapy, followed by a standardized dosing-adjustment technique for the remaining 4 weeks.8 In another study, entitled the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT), patients that received genotype-guided therapy received loading doses days 1 through 3 based on their genotype, and then on days 4 and 5 the dose was determined based on a dose-revision algorithm that incorporated the clinical and genetic factors. From day 6 onwards, doses were then determined according to local clinical practices. 2
The COAG trial was a multicenter, double-blind, randomized, controlled trial with 1015 patients to determine if an initial dosing algorithm based on clinical variables and genotypes compared to clinical variables alone would increase the percentage of time in the INR therapeutic range of 2 to 3, with follow-up of up to 28 days of therapy.8 Patients included in the study were 18 years of age or older and being initiated on warfarin. Patients were randomized by study center and by self-reported race as black or non-black. Patients had their genotype determined immediately after blood-sample collection. In the genotype-guided group (n=514), a dosing initiation algorithm was used for the first 3 days followed by a dose-revision algorithm for the next 4 or 5 days. After 5 days of therapy, a standardized dosing-adjustment technique was used for the remaining 4 weeks. Patients in the control group (n=501) received dosing based on a clinically-guided algorithm. At the conclusion of the study, it was found that there was no statistical difference for the primary outcome, which was the amount of time spent in the therapeutic range from day 4 or 5 through day 28 (45.2% of the genotype-guided group vs 45.4% in the clinically-guided group; adjusted mean difference -0.2%, 95% confidence interval [CI], -3.4 to 3.1, p=0.91). A subgroup analysis determined that black patients spent less time in the therapeutic range when the genotype-guided protocol was compared to the clinically-guided group (35.2% vs 43.5%, respectively; adjusted mean difference -8.3%, p=0.01), showing a potential limitation of implementing the pharmacogenomics approach. There were no differences in percentage of time in the therapeutic range in the subgroup of nonblack patients, nor in terms of gender or number of genetic variants. This study was also unable to show a difference in the amount of time it took to achieve the first therapeutic INR. Additionally, this study failed to find a difference in the secondary outcomes such as rates of major bleeding, thromboembolism, or INR values of greater than 4. The authors' overall conclusions were that using a genotype-guided protocol did not aid in gaining anticoagulation control within the first 4 weeks of therapy.
The EU-PACT trial was a single-blind, randomized, controlled trial with 455 patients who were over the age of 18 years and were being initiated on warfarin for atrial fibrillation or venous thromboembolism with a target INR of 2 to 3.2 The same primary end point was used as the COAG study (percentage of time spent within the therapeutic range); however, these patients were followed for the first 12 weeks of warfarin therapy rather than the first 4 weeks. Patients were genotyped after randomization stratified by their study center and indication for treatment. Patients that received genotype-guided therapy (n=211) received loading doses days 1 through 3 based on their genotype, and then on days 4 and 5 the dose was determined based on a dose-revision algorithm that integrated the INR from day 4. Both algorithms incorporated clinical and genetic factors. From day 6 onwards, doses were determined according to the local clinical practices. Patients in the control group (n=216) received standard dosing of warfarin. At the conclusion of the study, it was found that more patients were therapeutic 4 weeks after the initiation of warfarin in the genotype-guided group versus the control group (67.4% vs 60.3%; difference 7.0%; 95% CI, 3.3 to 10.6, p<0.001). Unfortunately, these differences were no longer evident at the endpoint of 3 months, with 74.5% of the genotype-guided group versus 72.9% of the control group in therapeutic range (95% CI, -3.8 to 6.6, p=0.61). Of the secondary endpoints, there was a statistically significant difference in the median time to reach the therapeutic INR range, with 21 days being required in the genotype-guided group compared to 29 days in the control group (hazard ratio for time to therapeutic INR, 1.43; 95% CI, 1.17 to 1.76, p<0.001). In addition, this study did not find any difference in secondary outcomes such as INR values of greater than 4.0 or less than 2.0, major and minor bleeding events, thromboembolic events, or number of warfarin dose adjustments. The authors concluded that genotype-guided protocols were associated with reduced time to reach a therapeutic INR and more time in the therapeutic INR range initially, though this difference did not persist at 3 months.
The COAG and EU-PACT studies both compared a genotype-guided protocol to the normal clinically guided protocols. While similar dosing strategies were used to evaluate the same outcomes, there were differences in the populations studied and the length of follow-up between the 2 trials. The COAG study followed a large and diverse population in the United States and followed patients for a period of 28 days. Alternatively, the EU-PACT study was conducted in Europe with the majority of patients being white and followed for 12 weeks after warfarin initiation. Both studies were conducted largely at academic medical centers, which likely had clinical specialists and pharmacists aiding in the management of patients, making it difficult to evaluate the efficacy of the algorithms alone. Also, in the absence of a true control group in the EU-PACT study (the control group used a non-pharmacogenomic algorithm rather than usual standard of care), it is difficult to truly evaluate the efficacy of the algorithm used compared to what occurs in general practice. At this time, these studies indicate that there may not be additional benefits to using genotype dosing for better therapeutic INR control; however, these dosing protocols may aid in better predicting maintenance doses and may help with getting to a therapeutic INR faster, and may have larger implications in certain subpopulations, such as African American patients. The addition of pharmacogenetic factors in the approach to warfarin dosing may not be as significant when clinical factors are already being taken into consideration.
1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S-88S.
2. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013:12;369(24):2294-2303.
3. Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and Coumarin Dosing – Recalibrating Expectations. N Engl J Med. 2013:12;369(24):2273-2275.
4. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcome during warfarin therapy. JAMA. 2002;287(13):1690-1698.
5. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329-2333.
6. FDA Approves Updated Warfarin (Coumadin) Prescribing Information. FDA website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm . Accessed January 29, 2014.
7. Coumadin (warfarin sodium) tablet and injection. FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm201100.htm. Accessed January 29, 2014.
8. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013: 12;369(24):2283-2293.
9. International warfarin pharmacogenetics consortium, Klein TE, Altman RB, et al. N Engl J Med. 209;360(8):753-764.
10. Anderson JL, Horne BD, Steves SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation. 2012;125(16):1997-2005.
Written by: Laura Means, PharmD
PGY1 Pharmacy Resident
Does perioperative use of selective serotonin reuptake inhibitors increase the risk of adverse outcomes?
Mental illness can be defined as an alteration in an individual's cognitive ability, mood, or behavior that impairs their daily life. Some of these mental illnesses include depression, anxiety, bipolar disorder, and post-traumatic stress disorder. Depression alone affects 26% of the US adult population. By the year 2020, depression will be second only to ischemic heart disease as a cause of disability throughout the world.1
One drug class that is used as a first-line treatment for mental illnesses such as depression and anxiety are the selective serotonin reuptake inhibitors (SSRIs).2 The SSRIs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. These agents work by inhibiting the reuptake of serotonin in the central nervous system. Although SSRIs are a good treatment option for depression and related conditions, they do have risks associated with their use. The labeling for these drugs currently carry a Food and Drug Administration (FDA) box warning for increased risk of suicide in children and young adults. Other concerning side effects with SSRIs are serotonin syndrome, QT prolongation, and increased risk of bleeding.
In recent years, there have been growing concerns with the perioperative use of SSRIs. The concern revolves around the issue of whether SSRIs are more helpful or harmful when used perioperatively. These concerns have arisen because studies have shown that SSRIs increased the risk for bleeding when taken alone or with aspirin, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDs), or other anticoagulants.3-5 One study from 1999 showed that SSRIs used alone increased the risk of upper gastrointestinal (GI) bleeding.3 This study also showed that when SSRIs were combined with aspirin or NSAIDs, the risk of upper GI bleeding was greatly increased. A case control study showed that patients who were on SSRIs and a vitamin K antagonist had a higher risk of hospitalization from non-GI bleeding.4 A third study illustrated that SSRIs alone increased the risk of bleeding but did not have a much greater risk when SSRIs were combined with NSAIDs.5
Despite these reports of a potentially higher risk of bleeding, currently there are no formal guidelines on how to manage SSRIs perioperatively. It has been suggested to continue SSRI use throughout the perioperative period for most patients, with discontinuation only in patients at high risk for bleeding. 6 The available literature on the bleeding risks with perioperative SSRI is discussed below.
Several studies have been performed over the past decade evaluating SSRI use perioperatively and their impact on adverse bleeding outcomes in different types of surgeries, most commonly orthopedic and coronary artery bypass graft surgery. Studies evaluating outcomes in these 2 types of surgeries are summarized in Table 1.
Table 1. Outcomes following perioperative use of SSRIs.7-15
Study Design and Study Population Results Conclusions/Comments
Dall 20147
Retrospective study of patients who underwent hip arthroplasty from 2007 to 2012
Primary outcome: intraoperative blood loss
Secondary outcome: need for transfusion
1318 patients enrolled (83 on SSRIa, 33 on non-SSRI, 1202 non-antidepressant users)
Difference in intraoperative blood loss in SSRI users vs. nonusers: 93 mL (95% CI 38 to 147)
Difference in intraoperative blood loss in non-SSRI users vs. nonusers: -50 mL (95% CI -125 to -25)
No differences between groups was observed in need for transfusion
Higher blood loss was observed in SSRI users compared to nonusers without a greater number of transfusions
No change in guidelines with respect to SSRIs are needed
Users and nonusers may have been misclassified if surgeons directed patients to discontinue SSRI even though prescription record was active
Retrospective design, potentially affected by confounding or bias (e.g., the effect of depression on bleeding risks).
Seitz 20138
Retrospective cohort study of patients > 66 years old who underwent hip fracture surgery from 2003 to 2009
Primary outcome: need for transfusion
Secondary outcomes: use of additional blood products, diagnoses of hemorrhage or hematoma, ICU admission after surgery, and 30 day mortality
11,384 patients enrolled (6668 current SSRI usersa, 2816 current non-SSRI users, 1900 former SSRI users)
The need for transfusion was more frequent in current users of SSRIs (adjusted OR 1.28, 95% CI 1.14 to 1.43, p < 0.001) and non-SSRIs (adjusted OR 1.17, 95% CI 1.03 to 1.33, p < 0.01) compared to former users.
SSRI users compared to non-SSRI users had an increased risk of transfusion (adjusted OR 1.10, 95% CI 1.01 to 1.21, p=0.04)
There were no significant differences between groups in the secondary outcomes.
The subgroup of patients receiving concomitant antiplatelet agents and SSRIs or non-SSRIS had a higher risk of transfusion
SSRIs use is associated with a higher risk of transfusion in older patients undergoing hip surgery; however, morbidity and mortality is not increased
Concomitant use of antiplatelet agents increases the risk of transfusion
Potential unaccounted confounders are possible with the observational study design (e.g., the effect of depression on bleeding risks).
Medication documentation from inpatient database may not have been complete
Sample size was large
Tavakoli 20129
Retrospective case-control study of patients who underwent hip or knee replacement from 2005 to 2011
Secondary outcome: hematologic laboratory parameters, need for transfusion
194 patients enrolled (71 serotonergic agentsb, 123 nonusers)
No significant difference in blood loss was observed between the 2 groups (p=0.436)
No differences in hematologic laboratory parameters were observed and no transfusions were required in either group
Serotonergic agents are not associated with a higher risk of bleeding
Amount of blood loss is an estimate made by the surgeon
Potential unaccounted confounders are possible with the retrospective study design (e.g., the effect of depression on bleeding risks).
van Haelst 201010
Retrospective cohort study of patients who underwent elective total hip arthroplasty from 2004 to 2008
Secondary outcome: need for blood transfusion
380 patients enrolled (66 on an SSRIa and 29 on non-SSRI antidepressant at time of admission and for at least 2 weeks prior; 285 nonusers as a reference group)
Difference in intraoperative mean blood loss in SSRI group (661 mL) vs. nonusers (566 mL): 95 mL, 95% CI 9 to 181)
Difference in intraoperative mean blood loss in non-SSRI group (470 mL) vs. nonusers (566 mL): -96 mL, 95% CI -209 to 17)
No difference in blood transfusions between SSRI, non-SSRI, and non-antidepressant users
Higher blood loss was seen with SSRI use, but was considered clinically unimportant
Volume of blood loss estimated by anesthesiologist may be inaccurate
Retrospective design, potentially affected by confounding or bias (e.g., the effect of depression on bleeding risks)
Movig 200311
Retrospective study of orthopedic patients from 1999 to 2000
Primary outcome: need for blood transfusion during surgery
520 patients enrolled (480 on no antidepressants, 26 on a serotonergic antidepressant [24 on an SSRI], and 14 on non-serotonergic antidepressants)
Need for blood transfusion in serotonergic antidepressant group vs. nonusers: adjustedOR 3.71 (95% CI 1.35 to 10.18)
Need for blood transfusion in non-serotonergic antidepressant group vs. nonusers: OR 0.74 (95% CI 0.10 to 5.95)
Increased blood loss during surgery: 1019 mL for serotonergic antidepressant users vs. 582 mL in nonusers (p=0.001)
Greater blood loss and need for blood transfusion among patients given serotonergic antidepressants (primarily SSRIs) prior to orthopedic surgery
Tully 201212
Prospective observational study of patients undergoing CABG from 1996 to 2008
Primary outcome: postoperative bleeding events including transfusion of platelets, packed RBCs, fresh frozen plasma, reoperation for bleeding and GI bleeding
Secondary outcome: postoperative morbidity and 30 day mortality
4136 patients enrolled (105 on SSRIa , 4031 on no antidepressants)
No significant difference in any bleeding outcome was observed between the 2 groups including in patients taking concomitant antiplatelet agents
Of the postoperative morbidity measures, renal dysfunction and prolonged ventilation were significantly higher in the SSRI group compared to nonusers
No effect on all-cause mortality was observed
SSRIs do not pose a higher risk of postoperative bleeding events or mortality in patients undergoing CABG
Study design dependent on information entered into an electronic database
Compliance to use of antidepressants cannot be confirmed
Wide confidence intervals reflect large variability of results
Observational design potentially affected by confounders (e.g., duration and dose of SSRI, effect of depression on bleeding risk)
Xiong 201013
Retrospective observational study on CABG performed from 1999 to 2003
Primary outcome: reoperation due to bleeding
Secondary outcomes: need for postoperative RBC transfusion and a composite of postoperative hematocrit drop ≥15%, reoperation for bleeding, and postoperative RBC transfusion
4794 were enrolled (246 on an SSRIc, 4548 not on an SSRI)
Reoperation for bleeding: SSRI group 3.3% vs. nonusers 2.6% (p=0.56); OR 1.14 (95% CI 0.52 to 2.47)
No significant difference in RBC transfusion: OR 1.04 (95% CI 0.75 to 1.44)
No significant difference in composite endpoint: OR 1.21 (95% CI 0.67 to 2.19)
Use of SSRIs was not associated with increased bleeding or related outcomes following CABG surgery
Larger sample size when compare to previous trials
Kim 200914
Retrospective analysis of patients undergoing CABG at an academic medical center from 2003 to 2006
Primary outcome: composite of in-hospital mortality or any bleeding events
Secondary outcome: 30-day readmission rate.
1380 patients enrolled (1076 on an SSRIa and 304 on a non-SSRI antidepressant from admission to time of surgery)
Composite (mortality and bleeding): SSRI group 9.4% vs. non-SSRI group 8.2%, OR 1.03 (95% CI 0.60 to 1.78)
30-day readmission rate: OR 0.93 (95% CI, 0.53 to 1.61)
No increase risk in SSRI users vs. non-SSRI users undergoing CABG
Reason for antidepressant use not included
Retrospective design, author noted possibility of incomplete data capture and lack of detailed clinical information
Patients who were discontinued from antidepressants at admission were not included
Andreasen 200615
Population-based cohort study of patients living in Denmark who underwent CABG from 2003 to 2008
Outcomes: need for transfusion, reoperation for bleeding, 30-day mortality
3454 patients enrolled (124 on SSRIs, 40 on non-selective SRIs d, 37 on other antidepressants, 228 with former use of antidepressants, 3025 on no antidepressants)
Compared to patients on no antidepressants, the RR of blood transfusion for current SSRI users was 1.1 (95% CI 0.9 to 1.4), for current SRI users was 0.9 (95% CI 0.6 to 1.3), and for current users of other antidepressants was 1.1 (95% CI 0.7 to 1.6)
The adjusted RR for re-operation for bleeding with current SSRI use was 1.0 (95% CI 0.5 to 2)
No difference in 30-day mortality was observed
Current SSRI use was found not to be associated with a higher frequency of blood transfusions following CABG
Data on medication use, blood transfusion and other covariates was obtained from national databases; compliance to medications and accuracy of documentation cannot be ensured
a SSRI group included venlafaxine, duloxetine, and clomipramine. b Serotonergic agents included SSRIs, duloxetine, venlafaxine, trazodone, and mirtazapine. c SSRI group included venlafaxine. d non-selective SRIs included amitriptyline, imipramine, lofepramine, venlafaxine, and clomipramine. CABG=coronary artery bypass grafting; CI=confidence interval; GI=gastrointestinal; OR=odds ratio; RBC=red blood cell; RR=relative risk; SRI=serotonin reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor.
Similar to results described in Table 1, studies of other surgical procedures including breast cancer, breast augmentation, spinal fusion, cosmetic face-lift, and percutaneous endoscopic gastrostomy (PEG) placement have demonstrated conflicting effects of SSRIs on bleeding outcomes.16-20
The latest study, by Auerbach et al, also a retrospective study, had a large diverse population and included data from January 2006 to December 2008 from 375 hospitals.21 The study enrolled 530,419 patients who underwent elective major surgery. The primary outcomes were in-hospital mortality, length of stay, readmission at 30 days, bleeding events, transfusions, and incidence of ventricular arrhythmias. Target SSRI antidepressants included citalopram (14.2%), escitalopram (25.3%), fluoxetine (with [0.02%] and without olanzapine [17.8%]), paroxetine (16.3%), sertraline (26.5%), and fluvoxamine (0.3%). To distinguish between uninterrupted and interrupted SSRI use, administration of an SSRI was classified as the day before or the day of surgery and onward or as the day after (or later) surgery, respectively.
The SSRI user cohort consisted of 72,540 patients; there were 457,876 non-SSRI users.21 The study found that patients on SSRIs had a higher overall mortality (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.07 to 1.36) versus non-SSRI users, for a number needed to harm (NNH) of 839. Patients on SSRIs were also found to have higher rates of bleeding (OR 1.09, 95% CI 1.04 to 1.15; NNH 424), 30-day readmission (OR 1.22, 95% CI 1.18 to 1.26; NNH 75), transfusion counts (OR 1.10, 95% CI 1.08 to 1.13), and length of stay (OR 1.02, 95% CI 1.02 to 1.03). With the exception of mortality, the outcomes remained significant among patients given an SSRI after surgery (interrupted use) or before surgery (uninterrupted use) compared to no use. For mortality, uninterrupted SSRI use was associated with worse outcomes (OR 1.25, 95% CI 1.11 to 1.41) compared with nonusers. The study also found that when SSRI use was stratified by depression or no depression, there was no increase in mortality, but the increased risk of bleeding and transfusion count compared to no SSRI use remained.
Although the study by Auerbach is the largest study to date, is it an observational trial, with weaknesses inherent to that design. The authors noted that it could not be determined how long prior to surgery an SSRI may have been held among those patients considered to have interrupted therapy, or if therapy was discontinued just prior to admission and restarted after discharge. The study also used data from an electronic billing system and not directly from medical records. The authors concluded that SSRI exposure resulted in poorer outcomes after major surgery. However, it remains unclear as to what timeframe to withhold therapy (e.g., early discontinuation or close to surgery) is needed.
A recent review conducted by Jeong and colleagues aimed to provide a summary of the current literature evaluating various bleeding outcomes in surgical patients taking serotonergic antidepressants and recommendations for SSRI management in surgical patients; however, the Auerbach study was not included in this review.22 Due to the inconsistent results of these studies, as demonstrated above, the authors do not recommend the routine practice of discontinuing SSRIs before surgery. However, based on the results of certain studies, discontinuation of SSRIs before breast and orthopedic surgery may be considered for patients with stable depression. Based on the pharmacokinetics of SSRIs and the life span of platelets, a general timeframe for SSRI discontinuation recommended by the authors is 2 weeks prior to surgery. However, a longer timeframe may be needed for patients receiving high doses or SSRIs associated with severe withdrawal. Evaluation of individual patient factors such as depression severity, suicide risk, type of surgery, concomitant medications, other risk factors for bleeding, type and dose of antidepressant, and health status must be undertaken when creating a plan for managing SSRI use prior to a surgical procedure.
Although many studies have been performed over the past decade on the potential risk of using SSRIs perioperatively, the results do not present a clear picture of how SSRIs should be managed in these situations. The latest study by Auerbach, with its large, diverse patient population, resolved some of the problems of earlier, smaller trials but some questions still remain. Ideally, large, prospective randomized clinical trials need to be completed in order to obtain a definitive answer as to whether SSRIs should be used perioperatively. Additionally, in an editorial accompanying the Auerbach study and a recent literature review, it was noted that the adverse consequences of stopping SSRI therapy, such as discontinuation syndrome, worsening depression, or increased postoperative pain, need to be considered.22,23 Based on the available evidence, the authors do not support the routine tapering and discontinuation of SSRI therapy prior to surgery. Tapering an SSRI over a 2-week (or longer) period preceding orthopedic and certain breast surgeries or in patients at high risk of bleeding can be considered according to the review by Jeong et al.22 Ultimately, however, it is up to the practitioner to weigh the risks and benefits of SSRI therapy to make the best decision for the patient before each surgery.
1. Center for Disease Control and Prevention. Mental health basics. http://www.cdc.gov/mentalhealth/basics.htm . Accessed August 1, 2013.
2. Hirsch M, Birnbaum RJ. Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): pharmacology, administration, and side effects. In: Roy-Byrne PP, Solomon D, eds. UpToDate.Waltham, MA: UpToDate; 2014 http://www.uptodate.com/contents/unipolar-depression-in-adults-and-selective-serotonin-reuptake-inhibitors-ssris-pharmacology-administration-and-side-effects?detectedLanguage=en&source=search_result&search=ssri&selectedTitle=1~150&provider=noProvider . Accessed February 26, 2014.
3. de Abajo FJ, Rodrıguez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case control study. BMJ. 1999;319(7217):1106-1109.
4. Schalekamp T, Klungel OH, Souverein PC, de Boer A. Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Arch Intern Med. 2008;168(2):180-185.
5. Tata LJ, Fortun PJ, Hubbard RB, et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Aliment Pharmacol Ther. 2005;22(3):175-181.
6. Muluk V, Macpherson DS. Perioperative medication management. In: Basow D, ed. UpToDate.Waltham, MA: UpToDate; 2014. http://www.uptodate.com/contents/perioperative-medication-management. Accessed January 27, 2014.
7. Dall M, Primdahl A, Damborg F, Nymark T, Hallas J. The association between use of serotonergic antidepressants and perioperative bleeding during total hip arthroplasty-cohort study. Basic Clin Pharmacol Toxicol . 2014 Feb 18. [Epub ahead of print].
8. Seitz DP, Bell CM, Gill SS, et al. Risk of perioperative blood transfusions and postoperative complications associated with serotonergic antidepressants in older adults undergoing hip fracture surgery. J Clin Psychopharmacol . 2013;33(6):790-798.
9. Tavakoli HR, DeMaio M, Wingert NC, et al.Serotonin reuptake inhibitors and bleeding risks in major orthopedic procedures. Psychosomatics. 2012;53(6):559-565.
10. Van Haelst IM, Egberts TC, Doodeman HJ, et al. Use of serotonergic antidepressants and bleeding risk in orthopedic patients. Anesthesiology. 2010;112(3):631-636.
11. Movig KL, Janssen MW, de Waal Malefijt J, Kabel PJ, Leufkens HG, Egberts AC. Relationship of serotonergic antidepressants and need for blood transfusion in orthopedic surgical patients. Arch Intern Med. 2003;163(19):2354-2358.
12. Tully PJ, Cardinal T, Bennetts JS, Baker RA. Selective serotonin reuptake inhibitors, venlafaxine and duloxetine are associated with in hospital morbidity but not bleeding or late mortality after coronary artery bypass graft surgery. Heart Lung Circ . 2012;21(4):206-214.
13. Xiong GL, Jiang W, Clare RM, et al. Safety of selective serotonin reuptake inhibitor use prior to coronary artery bypass grafting. Clin Cardiol. 2010;33(6): e94-e98.
14. Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol. 2009; 103(10):1391-1395.
15. Andreasen JJ, Riis A, Hjortdal VE, Jørgensen J, Sørensen HT, Johnsen SP. Effect of selective serotonin reuptake inhibitors on requirement for allogeneic red blood cell transfusion following coronary artery bypass surgery. Am J Cardiovasc Drugs . 2006;6(4):243-250.
16. Gartner R, Cronin-Fenton D, Hundborg, HH, et al. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study.BMC Surg. 2010;10:3.
17. Basile FV,Basile AR, Basile VV. Use of selective serotonin reuptake inhibitors antidepressants and bleeding risk in breast cosmetic surgery. Aesthetic Plast Surg. 2013;37(3):561-566.
18. Harirchian S,Zoumalan RA, Rosenberg DB. Antidepressants and bleeding risk after face-lift surgery. Arch Facial Plast Surg. 2012;14(4):248-52.
19. Sayadipour A,Mago R, Kepler CK, et al. Antidepressants and the risk of abnormal bleeding during spinal surgery: a case–control study. Eur Spine J . 2012;21(10):2070-2078.
20. Richter JA,Patrie JT, Richter RP, et al. Bleeding after percutaneous endoscopic gastrostomy is linked to serotonin reuptake inhibitors, not aspirin or clopidogrel. Gastrointest Endosc. 2011;74(1):22-34.
21. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173(12):1075-1081.
22. Jeong BO, Kim SW, Kim SY, Kim JM, Shin IS, Yoon JS.Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics. 2013 Dec 4. [Epub ahead of print].
23. Mrkobrada M, Hackam DG. Selective serotonin reuptake inhibitors and surgery: to hold or not to hold, that is the question. JAMA Intern Med. 2013;173(12):1082-1083.
Written by: Tuan Vu, PharmD candidate
What is the evidence for the use of albumin for treatment of intradialytic hypotension?
Currently in the United States, about 530,000 individuals have end-stage renal disease (ESRD), and the majority of that population requires dialysis. 1 Although there are 2 different types of dialysis, hemodialysis and peritoneal, the majority of patients receive hemodialysis. Hemodialysis involves the removal of metabolic waste products from the circulation into the dialysate. For most dialysis patients, 9 to 12 hours of hemodialysis each week is necessary. A patient's dialysis dose is determined by the following: patient size, residual kidney function, dietary protein intake, degree of anabolism or catabolism, comorbid conditions, urea nitrogen, and electrolytes. Patient criteria for receiving maintenance dialysis include the following: a creatinine clearance (CrCl) or glomerular filtration rate (GFR) < 10 mL/min per 1.73m2, refractory hyperkalemia, refractory expansion of extracellular volume, refractory acidosis, or a bleeding diathesis.
Intradialytic Hypotension
There are many complications associated with dialysis including hypotension, muscle cramps, and dialyzer-related anaphylactoid reactions. Intradialytic hypotension is the most predominant of these dialysis-related adverse effects. The 3 main criteria for intradialytic hypotension are a sudden fall in blood pressure, the need for an intervention, and symptoms such as headache, leg cramps, and nausea and vomiting.2 Potential interventions for this hypotension are a reduction in the ultrafiltration rate, placing the patient in the Trendelenburg position, and intravenous saline. The National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) guideline defines intradialytic hypotension as a drop in systolic blood pressure by ≥ 20 mmHg or a decrease in mean arterial pressure by 10 mmHg with the following accompanying symptoms: abdominal discomfort, yawning, sighing, nausea, vomiting, muscle cramps, restlessness, dizziness, fainting, and anxiety.3 Another similar definition that has been used for this condition is a drop in blood pressure of at least 20 mmHg systolic or 10 mmHg diastolic, symptoms of end organ ischemia, and the need for intervention by the dialysis staff. 4
Previous studies have reported various incidence rates of intradialytic hypotension. K/DOQI estimates the incidence rate as being about 25% of all hemodialysis sessions.3 One study by Sands et al looked at a total of 44,801 hemodialysis treatments in 1,137 patients that took place at 13 outpatient hemodialysis centers.5 The defining criterion for intradialytic hypotension in this study was a greater than 30 mmHg drop in systolic blood pressure to less than 90 mmHg. The mean age of patients in this study was 62 years; 51% were black, 44% white, and 11% Hispanic. The mean body mass index (BMI) was 29 kg/m2. The overall incidence rate of intradialytic hypotension was 17.2%. However, the incidence rate was highly variable among both the patients and the centers. For example, 25.1% of patients never experienced an episode of intradialytic hemodialysis while 16.2% experienced it in more than 35% of their treatments. A moderate frequency rate (1% to 35% of treatments with a hypotensive episode) was experienced by 58.8% of patients.
Numerous risk factors were identified for intradialytic hypotension in this study by Sands et al.5 Risk factors found to be significant for intradialytic hypotension included age, female gender, diabetes, Hispanic ethnicity, longer duration of ESRD, a higher BMI, a higher ultrafiltration volume, the second and third weekly treatments of dialysis, a lower pre-hemodialysis systolic blood pressure, a higher difference between prescribed and achieved post-hemodialysis weight, and a higher dialysate temperature. This study also found that there was a statistically significant higher rate of mortality (22.4/100 patient-years; p=0.036), hospital admissions (1.5/patient-year; p=0.04), and hospital days (10.84/patient-year; p=0.0002) in patients who experienced intradialytic hypotensive episodes in > 35% of their treatments compared with patients with a low incidence of hypotensive episodes (<1% of treatments).
Treatment for Intradialytic Hypotension
Different treatments exist for the treatment and prevention of intradialytic hypotension. One nonpharmacologic method that can be tried in these patients is sodium restriction in order to reduce interdialytic weight gain and decrease the need for high ultrafiltration rates.4 In addition, increasing the dialysis time can reduce the need for high ultrafiltration rates. High ultrafiltration rates can not only cause problems in regards to intradialytic hypotension, but may also contribute to an increased risk of cardiovascular complications. It is thought that the mechanism behind this is similar to the reason why fluid overload exacerbates patients in heart failure.6 Some other nonpharmacologic treatment methods include not allowing patients to eat during dialysis and cooling the patient during the treatment, because an elevated body temperature may lead to peripheral vasodilation. The patient can be cooled during the treatment by cooling the dialysate (usually to between 35 and 35.5ºC, just below the patient's core temperature).4 Some physicians hold blood pressure medications prior to hemodialysis in order to decrease the risk of intradialytic hypotension, but there is not much data to support this. It has been recommended to avoid short-acting antihypertensive medications just prior to dialysis. 4,7 The K/DOQI guideline recommendations for nonpharmacologic treatments are similar to these recommendations from published literature and include dialysate temperature modeling and isothermic dialysis, both of which involve keeping the dialysate temperature down, ultrafiltration modeling, dialysate calcium modeling, and dialysate sodium modeling.3 The evidence does not seem strong in support of calcium modeling, and there are many limitations with sodium modeling, especially in regards to postdialysis hypernatremia.
There are several different pharmacologic agents that have been used for intradialytic hypotension, including carnitine and midodrine.3 Carnitine has been used to decrease the incidence of muscle cramps and intradialytic hypotension in dialysis patients. However, evidence for its use is limited. A meta-analysis that looked at this intervention did not see a reduction in these complications with carnitine, in part due to the small number of studies available.8 Midodrine, in doses of 2.5 to 10 mg given 15 to 30 minutes prior to dialysis, has been suggested to prevent intradialytic hypotension.5,7 A meta-analysis reported midodrine to be effective in preventing hypotension during dialysis, although studies were small and of lesser quality.9 However, one individual study found that there was no benefit to adding midodrine (10 mg predialysis) if a patient was already receiving cool dialysate (at 35.5ºC) during dialysis.10
For acute treatment of intradialytic hypotension, intravenous administration of fluids for volume expansion is frequently done, often with normal saline. 11,12 Albumin has also been used as a pharmacologic intervention for intradialytic hypotension. Albumin works by increasing intravascular oncotic pressure, which can lead to a movement of fluids from the interstitial into the intravascular space.13 This fluid expansion may lead to an improvement in blood pressure. A 2010 Cochrane review by Fortin et al looked at the use of human albumin alone or in combination with crystalloid or nonprotein colloids for the treatment of intradialytic hypotension through volume expansion.14 The review specifically looked at the harms and benefits of these treatment methods. The criteria for symptomatic intradialytic hypotension in this study was a drop in systolic blood pressure by at least 10 mmHg or a systolic blood pressure of less than 100 mmHg in addition to symptoms associated with intradialytic hypotension. The selection criteria for this review were that the studies had to be randomized controlled trials, quasi-randomized controlled trials, or randomized crossover trials. The investigators only found one study that compared albumin with normal saline. No controlled trials were found comparing albumin versus hypertonic saline, nonprotein colloids, or a combination of nonprotein colloids and saline. The authors concluded that since no randomized or controlled studies were found that compared albumin to these other interventions, there is currently not enough data to support the use of albumin for the treatment of symptomatic intradialytic hypotension over crystalloids or nonprotein colloids. Based on a lack of evidence in support of albumin and the cost difference between albumin and saline, the authors believe that saline should be the first-line therapy for this condition.
The one study that was identified in the Cochrane review is a study by Knolls et al that compared albumin with 0.9% normal saline for the treatment of intradialytic hypotension.12 The study was a randomized, double-blind, crossover trial that studied 72 dialysis patients. The mean age of patients in the study was 65 years. Patients in the study were randomized to treatment with either sequence 1 or sequence 2. Sequence 1 consisted of 12.5 g of 5% albumin (250 mL) for their first episode of hypotension during the first dialysis sessions; normal saline (250 mL) was used for hypotension during the second dialysis session and during the third dialysis session. Sequence 2 consisted of normal saline, 5% albumin, and normal saline for hypotension during the first, second, and third dialysis sessions, respectively. Up to 750 mL of study solution could be given for each episode of intradialytic hypotension. Per the protocol if the patient experienced an episode of symptomatic hypotension then the dialysis session would be stopped, the patient would be placed in the Trendelenburg position, and study solution administered. If after the third infusion of study solution (the third round) the patient still did not recover, then the episode was considered a treatment failure and treatment was given at the discretion of the attending physician. If the symptomatic hypotension recurred during the same dialysis session after the blood pressure had become normotensive then the patient was not treated with another round of the study drug and the patient was treated at the discretion of the attending physician.
The primary outcome for the study was percentage of target ultrafiltration achieved.12 The secondary outcomes were postdialysis systolic blood pressure, postdialysis diastolic blood pressure, the volume of study fluid used, the time it took to restore blood pressure, the nursing time it took to treat the episode, treatment failures, recurrent hypotension, and the use of other interventions. The authors did not find any statistically significant differences between albumin and normal saline except for the need for additional saline to treat hypotension (16% with albumin versus 36% with normal saline, p=0.04); however, no difference was seen in the volume of additional normal saline fluid needed for albumin versus normal saline (231 mL versus 260 mL, p=0.74). The normal saline intervention took 9.9 minutes for the restoration of blood pressure versus 7.9 minutes in the albumin group (p=0.09). The authors concluded that for the treatment of intradialytic hypotension, albumin is not superior to normal saline.
In a another study by Emili et al, the authors investigated the use of human serum albumin for the treatment of intradialytic hypotension under a specific protocol.15 The protocol consisted of giving patients 200 mL of 0.9% normal saline (or 10 mL of 23% saline) over 2 to 3 minutes first to see if that would restore the patient's blood pressure. If no response in blood pressure was seen, saline (0.9% and/or 23%) could be repeated at 5-minute intervals up to a preset fluid maximum. If normal saline did not work, 100 mL (25 g) of mannitol was given as a one-time dose to the patient, but not during the last 30 minutes of hemodialysis. Lastly, if the other interventions did not work, the patient was given 100 mL (25 g) of human serum albumin, which could be repeated once after 10 minutes. During 2559 dialysis sessions, 608 episodes of intradialytic hypotension occurred. Among 433 dialysis sessions where the protocol was used, the success rate (defined as reversal of hypotension with completion of dialysis and use of prescribed ultrafiltration) was 93%. Albumin was used in a total of 105 dialysis sessions (17%) with hypotension. Among 414 sessions where the protocol was completed, hypotension was successfully resolved with saline alone in 92%. Mannitol was needed in 3% and albumin in 3%; protocol failures occurred in 2% of patient. After the initiation of this protocol, the rate of albumin use at the hospital decreased from 22% of dialysis sessions with hypotension (prior to implementation of the protocol) to 6% with the protocol for 2559 dialysis sessions. This study found that almost all episodes of intradialytic hypotension were resolved by normal saline and that albumin was reserved for refractory cases and was effective in those cases that were resistant to normal saline and mannitol.
Currently there is a lack of studies looking at albumin versus saline or intravenous fluids. What little information there is from the study by Knoll et al was not able to show albumin as being superior to normal saline for the treatment of symptomatic intradialytic hypotension. Even though there was a statistically significant difference between albumin and normal saline for the percentage of patients needing additional normal saline, the volume of saline used in either group was not significantly different. Also, even if the study by Knoll had shown albumin to be superior, it has limited generalizability since the population studied was older and the study size was small, at only 72 participants.
Based on the limited data that is currently available and the lack of mention of albumin in the K/DOQI guidelines, the evidence does not seem strong to support that treatment protocols be switched from normal saline to albumin for the treatment of symptomatic intradialytic hypotension. Further studies need to be done to compare the efficacy of albumin against normal saline, especially since it is a more expensive product. However, based on the study by Emili et al, albumin may still work as a treatment for refractory intradialytic hypotension.
1. Liu KD, Chertow GM. Chapter 281. Dialysis in the Treatment of Renal Failure. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York: McGraw-Hill; 2012. http://accessmedicine.mhmedical.com/content.aspx?bookid=331&Sectionid=40727070. Accessed February 12, 2014.
2. Henderson LW. Symptomatic intradialytic hypotension and mortality: an opinionated review. Semin Dial. 2012 May;25(3):320-325.
3. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis. 2005;45(4Suppl3):S1-153.
4. Reilly RF. Attending Rounds: A Patient with Intradialytic Hypotension. Clin J Am Soc Nephrol. 2014 Jan 2. [Epub ahead of print].
5. Sands JJ, Usvyat LA, Sullivan T, et al. Intradialytic hypotension: Frequency, sources of variation and correlation with clinical outcome. Hemodial Int. 2014 Jan 27. doi: 10.1111/hdi.12138.
6. Kalantar-Zadeh K, Regidor DL, Kovesdy CP, et al. Fluid retention is associated with cardiovascular mortality in patients undergoing long-term hemodialysis. Circulation. 2009;119(5): 671-679.
7. Agarwal R. How can we prevent intradialytic hypotension? Curr Opin Nephrol Hypertens. 2012 Nov;21(6):593-599.
8. Lynch KE, Feldman HI, Berlin JA, Flory J, Rowan CG, Brunelli SM. Effects of L-carnitine on dialysis-related hypotension and muscle cramps: a meta-analysis. Am J Kidney Dis. 2008;52(5):962-971.
9. Prakash S, Garg AX, Heidenheim AP, House AA. Midodrine appears to be safe and effective for dialysis-induced hypotension: a systematic review. Nephrol Dial Transplant. 2004;19(10):2553-2558.
10. Cruz DN, Mahnensmith RL, Brickel HM, Perazella MA. Midodrine and cool dialysate are effective therapies for symptomatic intradialytic hypotension. Am J Kidney Dis. 1999;33(5):920-926.
11. van Der Sande FM, Kooman JP, Leunissen KM. Strategies for improving hemodynamic stability in cardiac-compromised dialysis patients. Am J Kidney Dis. 2000;35(5):E19
12. Knoll GA, Grabowski JA, Dervin GF, O'Rourke K. A randomized, controlled trial of albumin versus saline for the treatment of intradialytic hypotension. J Am Soc Nephrol. 2004 Feb;15(2):487-492.
13. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc.; February 20, 2014.
14. Fortin PM, Bassett K, Musini VM. Human albumin for intradialytic hypotension in haemodialysis patients. Cochrane Database Syst Rev. 2010 Nov 10;(11): CD006758. doi: 10.1002/14651858.CD006758.pub2.
15. Emili S, Black NA, Paul RV, Rexing CJ, Ullian ME. A protocol-based treatment for intradialytic hypotension in hospitalized hemodialysis patients. Am J Kidney Dis. 1999 Jun;33(6):1107-1114.
Written by: Andrea Derlet, PharmD
PGY-1 Pharmacy Resident


Modern spread spectrum modulation enables HopeRF LoRa modules to communicate on a long distance or in severe environment.
This time we come with a novelty – module RFM95SW with a "LoRa" suffix, indicating membership with a "Long Range" family of modules. Long range of HopeRF LoRa modules is reached by usage of a modern efficient modulation with a spread spectrum, able to transmit data even on a noise floor level.RFM95W solves a traditional compromise among range, immunity (selectivity) and a power consumption while conforming to limits for usage in free bands.
LoRa modulation is quite complex and a user has a possibility to adjust all three main modulation parameters in order to fully meet requirements of a given application. These parameters are spreading factor, modulation bandwidth and error coding rate. For example if don´t need maximum transmission speed, You can set parameters so as to gain the highest possible quality and reliability of connection. By setting these three parameters you can choose an optimal combination for a given application.
RFM95SW is ideal for OEM products with higher production series, where development costs usually get quickly refund also thanks to a very affordable price of these modules.


text:
522 F. 2d 1034 - Cullinan v. Burlington Northern Inc
522 F2d 1034 Cullinan v. Burlington Northern Inc
522 F.2d 1034
William T. CULLINAN, Plaintiff-Appellee,
BURLINGTON NORTHERN, INC., a Delaware Corporation,
Defendant-Appellant.
No. 74-1285.
United States Court of Appeals,
Ninth Circuit.
Sept. 10, 1975.
Stephen H. Foster (argued), Billings, Mont., for defendant-appellant.
Patrick J. Foley (argued), Minneapolis, Minn., for plaintiff-appellee.
Before WRIGHT and CHOY, Circuit Judges, and PLUMMER,* Senior District Judge.
EUGENE A. WRIGHT, Circuit Judge:
This is an appeal from a directed verdict for the plaintiff on the issue of liability and a refused instruction on damages in an F.E.L.A. case. We affirm.
The plaintiff, William Cullinan, was an experienced member of a Burlington Northern wrecker crew which was sent in August of 1971 to clean up a railroad derailment site in Montana. The operation was under the control of a master mechanic who supervised the wrecker foreman. The wrecker crew consisted of four groundsmen, a large bulldozer and a crane mounted on a railway car, each with its own operator.
A major task of the crew was to return to the tracks a number of derailed gondola cars loaded with coal by overturning them with a cable pulled by the wrecker crane, righting them by the same method, and then by placing them back on their trucks and the track.
Two of the gondola cars lay to the east of the tracks, parallel to one another and several yards apart. The master mechanic, in accord with company rules, consulted with the foreman about a general plan of operation. They agreed to roll the gondola nearest the tracks eastward toward the second car in order to empty it. No agreement was made to place the cars in contact.
The car was rolled eastward. However, it came into contact with the second car and did not turn completely over. Wedged against the second car, the gondola canted at a thirty degree angle with its bottom upward. The wrecker foreman and plaintiff climbed onto the car to fix the cable for the roll in the opposite direction. They found that the cable from the wrecker had so much slack that the hook at its end would not remain in place in the eyelet used for rolling the car. The foreman signalled to have the cable lifted, then to stop, signalled again for the slack to be taken out and again to stop. Either when he signalled for the last stop or immediately thereafter the car began to rock and then rolled back on its side. Plaintiff was thrown off and injured. Although the parties disputed whether the crane operator stopped when told to do so, the witnesses agreed that the gondola car would not have moved without a taut cable and pressure from the crane.I. DIRECTED VERDICT
The court directed the jury to find that the railroad had been negligent in failing to provide a safe place for the plaintiff to work and that the negligence had been the proximate cause of the injury, but the question of contributory negligence was allowed to go to the jury.
We have held that only in an "exceptional case will the plaintiff in an accident case be entitled to a directed verdict on his behalf." Juhnke v. EIG Corp., 444 F.2d 1323, 1325 (9th Cir. 1971). A verdict can be directed where "without weighing the credibility of the witnesses there can be but one reasonable conclusion as to the verdict." Brady v. Southern Railway, 320 U.S. 476, 479-480, 64 S.Ct. 232, 234, 88 L.Ed. 239 (1943). The trial judge is obliged to view the evidence in the light most favorable to the party moved against, even though contrary inferences might reasonably be drawn. Case-Swayne Co. v. Sunkist Growers, Inc., 369 F.2d 449, 452 (9th Cir. 1966); Moore, Federal Practice, P 50.02(1) at p. 2325.
Here the experienced trial judge found that there was uncontradicted evidence from defendant's witnesses that the railroad had been negligent in not providing plaintiff a safe place to work and that this had caused his injury. An examination of the record of trial supports his conclusion.
There was uncontradicted testimony from the master mechanic that a dangerous condition is created when a railroad car is rolled into contact with another. Testimony indicated that a car could be rolled any distance desired, yet the gondola in question was rolled into contact with a second. No special precautions were then taken to assure the safety of the plaintiff when he was ordered to climb onto the canted car. Although the master mechanic admitted that he was responsible for safety on the job site and that safety of the workmen was the paramount concern, he testified that he was too busy supervising other activities at the site to see if the foreman was acting in a safe manner. After the cars had been rolled into contact, he admitted that he walked by without examining the cars.
Thus there was uncontradicted evidence that the supervising employees created a dangerous condition by rolling the cars into contact and by failing to take steps to protect the plaintiff when he was ordered to perform work on top of the canted gondola.1
II. JURY INSTRUCTION
The appellant also argues that the court erred in refusing to give its proffered instruction on damages:
Any award made to the plaintiff in this case, if any is made, is not income to the plaintiff within the meaning of the federal income tax law. Should you find that plaintiff is entitled to an award of damages, then you are to follow the other instructions the court gives you in measuring those damages, and in no event should you either add or subtract from that award on account of federal income tax.
Appellant does not argue that the award given by the jury in the absence of this instruction was in fact excessive, but only that the failure to give such an instruction raised the possibility that the jury would compensate for the supposed taxable nature of the award and increase it accordingly by several fold. In other circumstances we have declined to reverse because of erroneous instructions on damages where the award actually granted was not "grossly excessive" or "monstrous", Vannoy v. Chicago, Burlington & Quincy R.R. Co., 462 F.2d 186 (9th Cir. 1972). Here the award given was admittedly not excessive and there is no indication that the jury mistakenly raised its verdict to compensate for income tax liability. Absent a claim that the verdict granted was excessive, it would be improper to overturn the jury's verdict on the mere speculation of prejudice.
Senior District Judge of Alaska
It seems clear that the immediate cause of the accident was either the failure of the foreman timely to order the crane operator to stop tightening the line or the latter's tardiness in stopping the crane once he had been ordered to do so
In either event the railroad is responsible for the plaintiff's resulting injuries.

redpajama_set_name: RedPajamaCommonCrawl


It gave one last opportunity to Amrapali Group and its directors and promoters to comply with each and every direction passed by the court since May last year.
New Delhi: "Writing is very clear on the wall", the Supreme Court warned the embattled real estate firm Amrapali Group on Tuesday over its repeated non-compliance and "hood-winking" of the court's order.
The top court asked the realty firm to reveal by December 3 the details of all its properties in the name of directors, their family members, relatives, Chief Financial Officers and statutory auditors in India and abroad.
A bench of Justices Arun Mishra and U U Lalit said that Amrapali Group will have to disclose each and every detail and activity including financial transactions by which home-buyers' money was transferred.
"We make it very clear that Amrapali Group should disclose each and every activity in clear terms it took since 2008 onwards related to the construction of residential, commercial, personal, official and financial where the money was transferred. If all the disclosures are not made by Amrapali Group and its directors then the writing is very clear on the wall," the bench said.
It said the company has to disclose details of assets of all the directors since 2008, assets created in the name of their family members, relatives, Chief Financial Officer and statutory auditors.
The company is responsible for diversion of home-buyers' money, it said.
The court asked the embattled group to furnish details of all the land which has been sub-leased, structures raised on it and the financial benefits to the company.
It directed the banks, Noida and Greater Noida authorities and other bodies concerned to cooperate with the forensic auditors saying that they have been acting on the direction of the court and any non-compliance will be treated as contempt of the court.
It directed the registry of the court to accept Rs 1 crore demand draft given by Amrapali's CFO Chander Wadhwa and asked the group to depute four persons for assisting the forensic auditors in their investigation of company's affair.
The bench posted the matter for further hearing on December 5 and asked the company to file its reply by December 3.
On November 13, in a massive crackdown on Amrapali Group for "wilful disobedience" of its orders, the apex court had attached the company's 100-bed multi-speciality hospital, bank accounts, the building which houses its office, certain firms and a "benami" Villa in Goa.
The top court has also restrained Amrapali Group from creating any third party rights for 86 luxury cars and SUVs purchased from the company's funds.
It had sought the presence of CMD Anil Sharma and two directors Shiv Priya and Ajay Kumar on November 19 and said that Amrapali Group had deliberately not complied with its earlier order and committed a "serious fraud" by diverting home-buyers' money from one company to other.
It has ordered the attachment of the group's state-of-the-art, multi-speciality, 100-bed hospital situated at Greater Noida for which funds from sister company Ultra Home Construction Pvt Ltd were utilised.
The court has also attached the bank accounts of GauriSuta Infrastructures Pvt Ltd, its director Sunil Kumar and its assets after forensic auditors disclosed that Amrapali transferred home-buyers' money from one firm to sister companies using it as conduit.
Besides, it has ordered attachment of towers which housed the company's office and 'Aqua Fortis' villa in Goa for no one came forward to claim ownership.
On October 31, the apex court had directed the Amrapali Group to disclose the names of all the companies with which it had any kind of transactions after forensic auditors pointed out that there may be a web of more than 200-250 such firms where home-buyers' money was transferred.
The two forensic auditors, appointed by the court to look into the affairs of Amrapali Group had said besides 47 sister companies, they stumbled upon 31 companies whose names were never disclosed by the embattled real estate firm.
It had also initiated contempt proceedings against Sharma and its directors for prima facie violating court's order and thwarting the course of justice. The matter is listed on November 20.


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The Young Pope: First-look official teaser trailer from Paolo Sorrentino's TV series unveiled
This is a discussion on The Young Pope: First-look official teaser trailer from Paolo Sorrentino's TV series unveiled within the Sky TV Channels forums, part of the Other Sky help and support category; The Young Pope: First-look official teaser trailer from Paolo Sorrentino's TV series unveiled today https://corporate.sky.com/media-cent...unveiled-today The first official teaser trailer ...
The Young Pope: First-look official teaser trailer from Paolo Sorrentino's TV series unveiled today
https://corporate.sky.com/media-cent...unveiled-today
The first official teaser trailer from the Sky, HBO and Canal+ original joint production, The Young Pope, has been revealed, featuring Jude Law as Lenny Belardo, Pope Pius XIII.
Please find the YouTube link and embed code for the first look teaser trailer below:
Lenny Belardo, aka Pius XIII, is the first American Pope in history. Young and charming, his election might seem the result of a simple and effective media strategy by the College of Cardinals. But, as we know, appearances can be deceptive. Especially in the place and among the people who have chosen the great mystery of God as the guiding light of their existence. That place is the Vatican and those people are the leaders of the Catholic Church. And the most mysterious and contradictory figure of all turns out to be Pius XIII himself. Shrewd and naïve, old-fashioned and very modern, doubtful and resolute, ironic, pedantic, hurt and ruthless, Pius XIII tries to walk the long path of human loneliness to find a God for mankind. And for himself.
The first official teaser trailer from The Young Pope was unveiled today. The TV series directed by Academy Award-winning filmmaker Paolo Sorrentino, is a joint production of Sky, HBO and Canal+ to air on Sky Atlantic from October in the five countries in which the media company operates (Italy, UK, Germany, Ireland and Austria) and in France on Canal+.
An international cast joins the two-time Academy Award nominee Jude Law starring as Pius XIII: award-winning actress Diane Keaton (Sister Mary), Silvio Orlando (Cardinal Voiello), Scott Shepherd (Cardinal Dussolier), Cécile de France (Sofia), Javier Cámara (Cardinal Gutierrez), Ludivine Sagnier (Esther), Tony Bertorelli (Cardinal Caltanissetta) and James Cromwell (Cardinal Michael Spencer).
The Young Pope is produced by Wildside and co-produced by Haut et Court TV and MEDIAPRO. Executive Producers for Wildside are Lorenzo Mieli and Mario Gianani together with John Lyons.
Executive Producers for Haut et Court TV are Caroline Benjo, Carole Scotta and Simon Arnal. Executive Producers for MEDIAPRO are Jaume Roures and Javier Mendez. Executive Producers for Sky Italia are Nils Hartmann, Roberto Amoroso and Sonia Rovai.
International distributor is FremantleMedia International.
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If you don't understand that I have a mental illness, and respect that aspect of me, then we can't be friends. Or family.
My spiritual belief is to practice love and tolerance, though I sometimes fall woefully short. Nevertheless, I keep striving. But a corollary to that tenet is to detach with love. Detaching with love is distancing oneself from a person who is detrimental to one's spiritual, emotional, and mental well-being.
Such people certainly have no place in my life. And while it's still my job to love them, and ultimately help them if they get into dire straits, I can and will do so from a healthy distance.
I have had friends and family members from whom I have had to detach with love because they didn't acknowledge or respect my Bipolar Disorder and the things I need to do consistently to remain stable.
Imagine if you had cancer and a friend or loved one denied that cancer was real. Or quipped that it was all in your head. Or tried to persuade you to stop your treatment. How much room would you make for them in your life? How close would you remain with them?
Emotional support is critical for those of us with a mental illness. If a "friend" or "family member" isn't willing to give it, it's time to bid them adieu.


After you have identified where your money is actually going, and how much actual income you have, identify your spending priorities, and cut out all unnecessary purchases.
You should immediately contact your creditors if you are having trouble making payments.
In Massachusetts, credit counselors must be nonprofit organizations. Shop around and avoid credit counselors who charge large up-front fees or large monthly fees.
Two other methods of dealing with debt problems are consolidating debt through a single loan, and filing for bankruptcy.
The Personal Financial Workbook is a tool that you can use to organize your finances and gain an understanding of how you are spending your money.
By using the worksheets, you'll be able to paint a clear picture of your financial situation and make better decisions for the future.
We're ready to do a complete analysis of your financial situation and formulate a strategy that best suits your needs.
A plan to manage your debt is any strategy that helps consumers repay debt obligations or otherwise handle debt payments through a plan of action that is mutually beneficial to both debtor and creditors.
Plans may involve working with creditors to restructure debt payments or negotiate better terms, consumer rights to legal protection and fair debt collection, strategies to accelerate debt repayment or elimination, loan products, or consolidating to better manage monthly payments.
You will receive periodic updates from our Free Credit Counseling Blog in Newsletter format.
The blog provides unbiased relevant information from the best credit counselors in the country, including a link to Financial Talkcast Radio, devoted to debt solutions.
Anime dating sim games Play as Kuroki Tomoko and try to find a date! Virtual Date Ariane Walkthrough Full; hacked sim girls version 5.1? "Sim Girls" is a dating game where players meet a wide variety of girls..
Tinder claims it has seen a 400% jump in its downloads in India in the last one year..


Let Marco and Amelia, our Lonely Planet Kids explorers, take you off the tourist trail and guide you on a journey through New York you?ll never forget. This book is perfect for any kids who have been to New York, plans to go there or is just interested in finding out more about this amazing city!Discover New York?s best?kept secrets, amazing stories and loads of other cool stuff from the comfort of your own home or while visiting the city! But, you don?t have to be a visitor or armchair traveller to enjoy this New Yorkers are sure to learn new things about their very own city too!Find out what's lurking in the pumpkin garden, why you might find cows underground, how eating hotdogs could make you rich and lots more! For readers ages 8 and up.
Vas a comprar el ebook "NEW YORK CITY TRAILS"


Care Packages are often the easiest way of letting a friend/family member know you care without the interruptions. This is especially helpful during an illness, accident or death in the family. Choose from the drop down selection to send your love and we will deliver the meals no later than the next business day. Be sure to provide an email address so we can send the menu for your meal options.


text:
<?xml version="1.0" encoding="utf-8"?>
<!--
     Copyright (C) 2016 The Android Open Source Project

     Licensed under the Apache License, Version 2.0 (the "License");
     you may not use this file except in compliance with the License.
     You may obtain a copy of the License at

          http://www.apache.org/licenses/LICENSE-2.0

     Unless required by applicable law or agreed to in writing, software
     distributed under the License is distributed on an "AS IS" BASIS,
     WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.
     See the License for the specific language governing permissions and
     limitations under the License.
-->
<FrameLayout xmlns:android="http://schemas.android.com/apk/res/android"
    android:layout_width="match_parent"
    android:layout_height="match_parent">

    <android.support.v7.widget.RecyclerView
        android:id="@+id/recyclerview_forecast"
        android:layout_width="match_parent"
        android:layout_height="match_parent"/>

    <TextView
        android:id="@+id/tv_error_message_display"
        android:layout_width="wrap_content"
        android:layout_height="wrap_content"
        android:padding="16dp"
        android:text="@string/error_message"
        android:textSize="20sp"
        android:visibility="invisible" />

    <ProgressBar
        android:id="@+id/pb_loading_indicator"
        android:layout_height="42dp"
        android:layout_width="42dp"
        android:layout_gravity="center"
        android:visibility="invisible" />

</FrameLayout>

redpajama_set_name: RedPajamaGithub


There is hardly any scope to doubt how the Best Local Locksmiths in Oceanside New York is one of the best locksmith service providers in the state New York. We are fortunate to possess a team of sincere and dedicated workers who are always ready to respond to any call for emergency along with their experience and performance are usually certain to manage any crucial circumstance with such ease that can hardly be matched by another related supplier in Oceanside NY.
With The most effective Local Locksmiths, you are sure to have complete satisfaction regarding the safety of one's household along with your commercial establishment.


text:
Ashoka tree is a common name for two plants which are frequently confused with each other:

Saraca asoca, native to South Asia and western Myanmar
Saraca indica, native to eastern Myanmar and Southeast Asia
Monoon longifolium is sometimes called the "false ashoka"

Holy tree of the ancient Jains as well as Hindus.

redpajama_set_name: RedPajamaWikipedia


This is identical to the Fists stunt: Brawling, but for Weapons.
Your peripheral vision and situational awareness during combat is highly developed. If you are ambushed during a fight (or otherwise tricked, backstabbed by an ally, or whatever), you may use Weapons in place of Alertness to defend. If you would roll Weapons anyway, you recieve a +2 bonus to your defence.
Option: Since this isn't going to happen in every fight, the GM might allow the following to give it a bit more teeth: If you gain spin on this defence roll, you may spend a fate point to make an immediate free attack against the surprise attacker. This is only useful if it's a melee attack, of course.


text:
Q: How can I make react router redirect to root after signup? I have crated a signup method that is creating a user and saves it on MongoDb. The backend is working fine, all good there. The user gets created but on the frontend it stays on the same signup page instead of redirecting to root.
async function authFunction (evt) {

    const response = await fetch('http://localhost:5000/api/users/signup', {
        method: 'POST',
        headers: { 'Content-Type': 'application/json' },
        body: JSON.stringify({
            username: nameValue,
            email: emailValue,
            password: passwordValue
        }),
    });

    const data = await response.json();
    if (!response.ok) throw new Error(data.text);
    console.log({ user: data });

}

In App.js I have created the routes I needed and added  but nothing happens.
<div className='App'>
    <Switch>
        <Route exact path='/' component={Landing} />
        <Route path='/tasks' component={TasksInitial} />
        <Route path='/auth' component={AuthPanel} />
        <Route path='/api/logout' component={Landing} />

        <Redirect to='/' />
    </Switch>
</div>

I want to make it redirect to root after signup.

A: From the component where the authFunction function is called, you should pass a redirecting function and use it inside as a callback.
authFunction(evt, this.props.history.push);

and inside your function:
async function authFunction (evt, changeRoute) {
   ...
   if (response.ok) {
      changeRoute('/');
   }
}

Remember to wrap your component with withRouter hoc to have access to the history object.

redpajama_set_name: RedPajamaStackExchange


I get a lot of questions about the resources mentioned in the blog and those we use to manage, market and operate our vacation rental businesses. Everything mentioned on this page has been personally tested or highly recommended by our guest posters and expert partners.
Please note: Some of the links on this page are affiliate links, meaning that I receive a referral fee if you decide to purchase after using the link. This referral fee does not mean any increase in the price of the product or service; in fact some of the links include special discounts we have been able to negotiate for our community. In addition, we only recommend sites and products/services we have found to be particularly helpful, and not because of the commissions we may earn from you using them.
We'd always recommend listing on one of the major sites as well as some that are focused on your area. These are the biggies and are probably worth the money. Just make sure you monitor the enquiries you get from each one so you can assess which ones are working the best for you.
: The behemoth of listing sites, Homeaway delivers the punch that comes with the money it spends on marketing. If you are in an area that has a lot of similar properties you might want to explore some of the premium options to get your place higher in the list that comes up when vacationers are looking.
: Of course I have a bias here because I'm involved with VHR as Director of their Owner Community. That aside I would recommend it anyway because they have been in the market for a long time and consistently achieve good rankings in the search engines.
Flipkey: This is Trip Advisor's vacation rental arm so if you list here you'll show up on the world's largest review site as well. Personally, Trip Advisor is my go-to site when I'm looking for my next holiday destination because I like to read live reviews and not the owner-posted ones.
International Vacation Home Exchange: My family participated in a home exchange back in the late 90's and had a wonderful time doing a simultaneous exchange with a family in San Francisco. What if you could exchange vacant weeks in your vacation rental property with another around the world. Enter ivhe.com! Listen to Episode 009 of the Vacation Rental Success podcast for more information from ivhe.com founder Larry Klimczyk and check out his Free Home Exchange Guidebook.
Larry has also added some discounts for the Cottageblogger.com audience. Check out the Show Notes for VRS009 for more information.
Please, please don't use a free website creation option. They are free for a reason and although they can do the job of getting your presence on the web, you may be the only one to see it. Although you can link to the site from your other listings, there is usually minimal or non-existent search engine optimisation, so you'll be unlikely to show up on a Google search. There are some other options that do cost you some money, but will make your times and effort working on it, much more worth-while.
Webchalet: These guys are doing a great job providing an easy and convenient way to develope a web presence outside of your standard listings. Their templates give you a lot of freedom to create the style and look you are looking for to suit your ideal guests.
I interviewed Sarah Brubaker of Webchalt in Episode VRS026 of the Podcast. Sarah is passionate about the connection between good design and a solid marketing strategy to create a full functional website that can equally serve an individual owner or a rental management company with multiple properties.
They were also kind enough to offer 50% OFF to all the listeners of the podcast and visitors to the website.
By far the best way of building and managing your own web site and blog is to use WordPress. The blogging platform has come a long way in the past few years and it's so easy to create and set up a simple site to host a blog, and you can develop a full-scale web site as you become more familiar with it.
WordPress.org: This is the self-hosted option of the two WP offers (the other is WordPress.com) and is the one I recommend. The other is free but like anything at no, or low costs, you will sacrifice a lot to save a few bucks. Pay the reasonable amount for hosting and a fully supported theme and you will have a lot more options and control over your site or blog.
: Blue Host is very easy to use. There is a 1-click automatic WordPress installation and they have very responsive customer service if you have any problems with setting up your first blog or site. We highly recommend using Bluehost for your first site.
: Whether you're running a business website or a personal blog, Thesis is a perfect choice because it enables you to do what other WordPress themes can't. Cottageblogger.com used to use the Twenty Eleven theme from DIY Themes and its really easy to use but now we have moved to a Genesis based theme. Support for Thesis is friendly, prompt and informed.
: We've used Genesis before and like Thesis it's very user-friendly with a lot of options. Cottageblooger.com is currently using the Genesis Theme with the Child Enterprise child theme.
WP Security Lock: Back in 2011, Cottage Blogger was hacked and it was very costly and time consuming to get it fixed and back to some normality. Regina Smola at WP Security Lock was amazingly responsive and got me back to an operational level quickly – she also pointed out many areas of my blog that had security holes. I recommend her fully.
Back up Buddy: Regina recommended several plugins to make my site more secure and one in particular has proved very useful. Sites get hacked every day. Our passwords are rarely as strong as we think. And sometimes it doesn't matter. Sometimes we delete the wrong file or make a change that breaks something. Ever trigger a fatal error from a bad plugin? Crashes happen. But with BackupBuddy, recovering from a problem is quick and easy.
Ever since I started my podcast (Vacation Rental Success Podcast) in 2013 I have seen Cottage Blogger grow dramatically. With tens of thousands of downloads in iTunes and an ever growing listener base I realized how this medium can be used to market your Vacation Rental business. Whether you are an individual owner, agency, real estate agent or VR software developer the podcast medium is a way to develop a very person and lasting relationship with your audience. Your potential, present and past guests/clients get to listen to your voice, your passion and your personality which helps you develop these relationships on a wide shale without having to do one-to-one marketing.
Pat Flynn is one of my go-to people for anything to do with internet marketing; delivering information and more recently, podcasting. The great thing about Pat is that once he has mastered something, he is out there giving away all he has learned, and that information is absolutely free.
In six videos, this step-by-step tutorial covers every aspect of podcast production from the 5 things you need to do before you start, to the equipment you will need; where to host your podcasts and how to publish them and get them seen by your audience.
There's a lot of links to resources, equipment and more advanced tutorials, and this is a great tutorial giving basic instruction for getting started. Best of all, this tutorial is FREE.
If you get serious about podcasting and want the gold standard in training I highly recommend Cliff Ravenscraft's A – Z Podcasting course. I did this when I started my podcast and it was my launchpad for Vacation Rental Success.
I've done a bunch of online courses in the past, and this one went a long way beyond expectations. After 18 months, I still go back to the videos occasionally for a refresher. This course has a fairly hefty price-tag at $1999 but is well worth the time and money if you really want to move into podcasting in a serious way. The A-Z courses start periodically, and if you decide this could be a great investment for you, use the code 'cottage' to get a $500 discount.
John Lee Dumas took the whole industry to the next level since he started his podcast with his 7-day a week show interviewing successful people from all walks of life, and then launching Podcasters Paradise.
PP is a training programme, forum, commuunity of poodcasters, and a resource-loaded site of video instruction, webinars with successful podcasters, documentation…in fact as the tag-line says – it has everything you need to Create, Grow and Monetize your podcast.
Along with the site, there is a private Facebook group with, at the last check, 859 members. Posting a question usually gets a response in minutes – it is an extremely supportive group. It is worth watching a Podcasters Paradise webinar to get a flavour of the programme and the community.
Problogger: If you want to start writing a blog then Darren Rowse is the one to follow. There are some great ebooks on his site that I have personally used and learned a lot from. The best one is 31 Days to build a better blog – it's easy to follow with great suggestions. This ebook does not cover how to set up a blog but will help you improve your blogging skills once you are up and running.


text:
Q: How to transmit the image information back to the template and display in the browser I am sending a get request from my template to views.py to get an image file from the database back to the template and display in my browser.
However I am unable to display the image at all.
Here is the relevant parts of my codes:
$.ajax({
    url: '{% url 'get_images' %}',
    data: {"getInit[]": initData,
    ...,
    ...,
        },
    dataType: 'json',
    cache: false,
    success: function(data) {
        if (data.get_image_entity_str) {
          console.log('RESPONSE FROM AJAX CALL BACK: ' + data.get_image_entity_str);
          //$("#id_initImgIdx22").attr('src', 'data:image/png;base64,' + data.get_image_entity_str); // Has no effect, ref the html portion of the code

          $('#id_initImgIdx22').append('');  // Displays only the "broken" image icon
          $('#id_initImgIdx22').append(data.get_image_entity_str);  // Only shows the image path (url)
        }
    }
});

The relevant part of my view:
var_image_type = "R"
try:
    get_image_entity = ArchiveImg.objects.get(image_type=var_image_type).image_blob
    get_image_entity_str = json.dumps(str(get_image_entity)) # Converting it into string
except ArchiveImage.DoesNotExist:
    pass

data = {
    #'get_image_entity': get_image_entity,      # Trying to use this results in error: TypeError: Object of type 'ImageFieldFile' is not JSON serializable
    'get_image_entity_str': get_image_entity_str,   # Using this does not display the image (only broken image shows), but the image path is being sent back to template
    }
return JsonResponse(data)

The relevant area from the template:

     #
    ...

How may I successfully transmit the image information back to the template and display in the browser?
Edit 9th July 2022
I am now able to display the image successfully. What I did was to :

*

*Encloded the image file to BASE64

*Then decoded the encoded file

And using my earlier code in the success segment viz.
$('#id_initImgIdx22').append('');
the image gets displayed in the browser (in the designated cell of the table).
Edit 2
I am now faced with another whammy. Not able to set the image size (and other related properties).
I tried to incorporate the styles in the .append code in the success callback, but then the image stops getting displayed at all.
How do I set the styles of the image under the circumstances?


Now that you have a very basic understanding of how the conscious and subconscious mind work, your first step is to learn how to put your mind in an Alpha state yourself in order to facilitate the changes that need to be made. Since self-hypnosis is simple to learn we will begin with that modality and give you several examples that you can use for self-hypnosis.
The first thing you need to do is learn how to hypnotize yourself. There are three tools that you will be using: suggestion, concentration and imagination. If you have a good imagination you will have no trouble mastering these techniques very quickly. It is important not to try too hard. The whole concept is to just relax and let yourself go. If you try too hard you will become tense and this is exactly what you don�t want. Also ignore any analytical attitude. If you don�t, you will keep the conscious mind awake and the whole object of hypnotizing yourself is to relax.
Lie down on your back, arms parallel to your body, fingers loosely outstretched and palms downward. Separate the feet by eight or ten inches so that no part of your thighs are touching. Use a pillow if you wish, and make yourself as comfortable as possible. Remove or loosen clothing that binds you in any way and remove your shoes if they are tight. The idea is to get comfortable and relaxed. If you are recording this procedure, use the second person throughout, but if you intend to use it without a recording, memorize it in the first person. It is given here in the second person so it may be read directly from the book into the microphone. Start reading in a soft voice, rather slowly, and gradually slow down more and more, drawing out your words and pausing often between sentences. Your voice and the pace of your speech must suggest drowsiness and relaxation. Speak in a very slow monotone.
Now, I want you to concentrate all of your attention on your right foot. Relax the toes of your right foot. Imagine they are like loose rubber bands dangling from your foot. (pause) Let this loose feeling spread back through the ball of the foot, and then all the way back to the heel. (pause) (Drag out the word all and speak very slowly fro this point on, pausing between ALL sentences.) Now, let this relaxed feeling go up into the calf of the leg. Let the calf muscles go loose-and-limp and LA-A-A-ZY. (long pause) And now, while your muscles and nerves are relaxing, let your mind relax also. Let it drift away to pleasant scenes in your imagination. Let your mind wander where it will, as you go deeper � deeper into drowsy relaxation. You are breathing easily; all of your cares and tensions are fading away, as you go deeper � d-e-e-p-e-r into drowsy slumber. Every breath that you take � every noise that you hear makes you go deeper, deeper, into pleasant, comfortable relaxation.
Relax the muscles in your neck. Let your jaws separate and let the chin and cheek muscles go loose and rubbery. (pause) Now let your eyes go. Let them go completely � relax and feel comfortable and good. Relax the eyebrows too and the forehead. Let the muscles rest. Back across the scalp � let the entire scalp relax � from the forehead all the way back to the back of the neck � all relaxed � all resting � all loose. You are now completely relaxed.
Your body feels boneless. You are going deeper and deeper into restful hypnosis. Your mind is experiencing a wonderful feeling of tranquility. Your subconscious is now receptive to the helpful suggestions I am now going to give it.
1.	Make yourself as comfortable as you can on a mat, a couch or a chair.
2.	Inhale deeply and exhale, releasing all muscular tensions everywhere in the body. Continue to breathe naturally, easily and gently.
b.	Let go and let down. Feel your mind, your emotions and your physical body sink quickly and deeply into relaxation, drifting ever deeper and deeper until you reach a plateau of relaxation.
d.	Feel yourself plunging deeper into relaxation, going down further and deeper until you reach another plateau of relaxation.
g.	At this time you should reach a very effective level of deep relaxation when you can give yourself very effective suggestions toward achieving your desired goals.
Visualizing your ideal configuration and weight.
Replacing any fears, anxieties, depressions or other negative feelings by a sense of self confidence, optimism, pride or other positive emotion through verbal suggestions and suggested feelings.
Permitting a feeling of deep pervasive peace to envelop you.
Suggesting to your subconscious mind � time contractions � for example, that the next hour will seem like only ten minutes have passed.
Any other suggestions consistent with your selected goals.
4.	With daily practice for about two weeks, using this Rapid Self Induction Technique, you should be able to put yourself into an effective level of deep relaxation, within 30 seconds whether lying down, sitting or standing up.
5.	After you have mastered the Rapid Self Induction Technique, with an additional 1 to 3 weeks of daily practice to achieve a state of deep, effective relaxation within 1 to 5 seconds merely by closing your eyes and silently saying to yourself, �RELAX.� This almost instant self induction should be practiced consistently in all positions (lying, sitting and standing) to maintain proficiency.
Now that you have learned how to induce an advanced state of relaxation, you must learn how to structure the suggestion you would like to teach to your subconscious mind. The subconscious mind must obey suggestions as though they were orders. While in hypnosis, with the conscious mind somewhat inhibited, it is possible to reach the subconscious mind directly with the suggestions that you want it to program.
There are examples of two complete auto suggestions. A couple of factors are important. You must always phrase the suggestion in the present tense as if the action has already occurred. You must never mention the negative behavior you wish to eliminate.
Suggest action, not the ability to act. In other words, don�t say, I have the ability to live stress free. . . .and so on. You must be specific.
Use repetition when writing your suggestion. Repeat it, enlarge upon it and repeat it again in different words. Embellish it with convincing adjectives. Repeat your suggestion daily until it becomes entrenched in your subconscious.


The 5th edition of the Latin American Congress of Telecommunications will be held on 20-23 June, in Cartagena de Indias, Colombia.
The event will bring together ICT ministers, regulatory authorities, representatives of the ICT industry, and organisations of the digital ecosystem in Latin America, for four days of discussions on how to possibly shape a common agenda that would allow stakeholders in the region to face the challenges and take advantage of the opportunities brought by the digital economy. Debates will revolve around public policies for developing the digital ecosystem in Latin America, particularly with regard to the role of states in the promotion of investment and innovation, as well as the development of appropriate regulatory frameworks for he convergence era. There will also be discussions about the contribution of the mobile industry to the achievement of the United Nations sustainable development goals (SDGs).
A plenary session addressing issues such as the role of the state in the digital economy, regulatory models for convergence, effective implementation of SDGs, and public policies for developing telecommunications.
A workshop on the Strategy for promoting the digital economy in Colombia.
A workshop on education for the 21st century.
A workshop on redefining the regulatory frameworks for digital inclusion.
A communication policy research conference, focused on policies in telecommunications and information technology for economic and social development.