This activity is supported by educational grants from AbbVie Inc., Acerta Pharma, a member of the AstraZeneca Group, and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC.
Discover the latest pharmacology and indication approvals for the management of patients with hematologic malignancies, including pivotal clinical trial data, associated signs and symptoms of serious or life-threatening adverse effects, and the impact of these agents in advanced practice.
DR. NELSON: [Audio begins in middle of sentence] – talking about any of their medications throughout this presentation.
So before I actually go into this previous year's new updates, I can't proceed any further without talking about the past year. So, we had a fundamental new landscape of new drugs that came out in 2016 and 2017, that I just want to really quickly highlight.
So for AML, we had four big drugs. We had our daunorubicin, gemtuzumab in our CD33, specifically favorable risk, in AML. We had midostaurin and alecitinib as well for our oral agents. In ALL, we had our big CAR T approval, tisagenlecleucel, as well as inotuzumab and ozogamicin in our ALL relapsed/refractory indication.
We had two formulary differences. We had copanlisib that came out with our PI3K inhibitor, as well as rituximab/hyaluronidase human. So rituximab/hyaluronidase human actually gave another alternative formulation to give rituximab to a subset of our patients. And then lastly, ibrutinib. So ibrutinib also gave an extended indication – a couple extended indications.
So, all of those actually paved the way to a new landscape, but they left a few holes. And some of those holes were actually taken care of this year with some recent approvals. I'm going to first go over the monoclonal antibodies and some of our new CAR T cells. The new approvals that we have is the moxetumomab pasudotox, which is our CD22 inhibitor; mogamulizumab; axicabtagene; and then I'll go through some of the expanded indications for drugs that we already have out on the market. Pembrolizumab, tisagenlecleucel, blinatumomab. Brentuximab actually had two expanded indications, as well as obinutuzumab.
So, first let's get started with moxetumomab pasudotox. So, moxetumomab's mechanism of action is as a CD22-directed antibody fused to a truncated bacterial or pseudomonal toxin. This inhibits protein synthesis and triggers apoptotic cell death. It's indicated for adult patients with relapsed/refractory hairy cell leukemia who have received two systemic therapies, including treatment with a purine nucleotide. So this is likely going to be cladribine in most of our patients.
So the dose is 0.04 mg/kg IV over 30 minutes on days 1, 3, and 5 every 4 weeks for up to six cycles disease progression or unacceptable toxicity.
Now, the study, the 1053 trial that actually got this approval, was a phase 3 single-arm, open-label trial. They actually showed an overall response rate of 75%, a complete response of 41%, and hematologic remission of 80%. Now, the hematologic remission was defined as an ANC greater than 1,500, platelet count greater than 100,000, hemoglobin greater than 11, and no growth factor and no blood transfusions for up to 4 weeks. So 80% of patients actually met this criteria. For the durable complete response, they actually took that criteria and those patients that actually met that criteria for 180 days. That was about 30% of patients. So they definitely showed improvement with the addition of moxetumomab.
Now, this is what I want to focus on, and actually, at my institution now, we've been highlighting this drug. Moxetumomab pasudotox in this phase 3 trial did have some interesting adverse events that I want to focus on.
So hypertension febrile neutropenia was over grade 3 or grade 4, over 5% incidence. However, capillary leak and hemolytic uremic syndrome were also seen with these patients. Why is this important to know? We know in hematology, a lot of patients actually have both of these, or they can have both of these indications or side effects. But a lot of the patients will actually be receiving this medication out in the clinics and the infusion center versus inpatient. So it is very, very important that a lot of you know some of these toxicities, as well as educate our nursing staff about some of these toxicities.
So, grade 3/grade 4 capillary leak and HUS was seen in about 2 to 3% of these patients. So because of that, it's important to know, are they hypertensive? Look at their albumin, look at their bilirubin. What are their platelets doing? So, looking at these labs.
The other thing is the adverse – or other adverse reactions, the infusion-related reactions. This occurred in up to 50% of these patients. What's important to note is, a lot of monoclonal antibodies do have those reactions in the first couple of cycles, but with this drug specifically, you can see this throughout any treatment phase. So, you could see this eight lines down, you could see it in the first. So it is important to keep in mind that infusion reactions can be seen throughout treatment of this drug.
The other thing, and because I created the order sets and did a lot of the education at my institution, the fluids are vitally important to these patients. So these patients actually required 2 to 3 liters of fluids with each dose of drug. They also require the fluid intermittently between those days of treatment.
The other thing to keep note is the CLS and HUS does actually occur typically within the first 8 days of treatment. In the study, they did resolve within 2 weeks. There was death associated with HUS, and a lot of those patients didn't receive enough fluids. And so I just want to press the importance here about making sure that we're monitoring these patients, that we're looking at their weights. We're looking to see if they're febrile. And we're making sure that we give them a lot of fluids. We are going to be doing this outpatient, and so patients who are not receiving the treatment that day, we will require them to drink fluids when they're at home, and so that's very, very important that you educate patients about that as well.
Mogamulizumab is the next drug that I'm going to talk about, and this is indicated for relapsed/refractory mycosis fungoides and Sezary syndrome. It's mechanism of action – it's a humanized IgG kappa monoclonal antibody that binds to CCR4, and CCR4 is on our T cells. This hones in the trafficking to different lymphocytes, brings in those cytokines, which then ultimately kills the cell.
It is indicated for adult patients with relapsed/refractory mycosis fungoides or Sezary syndrome after at least one systemic therapy. It's dosed at 1 mg/kg over an hour weekly for 4 weeks, and then every subsequent cycle every 2 weeks. It's recommended that we do premedicate these patients for infusion-related reactions. It's recommended only the first cycle, although most of us use monoclonal antibodies all the time, and we do premedicate most of our monoclonal antibodies. So I would probably recommend giving everybody Tylenol/Benadryl that receives this infusion.
Dose modifications – I'll try to highlight dose modifications throughout this presentation, because it is important to know whether we need to make a call to the physician or the pharmacist, or you need to be aware of the different side effects or things that are occurring so that we need to make a judgment call and whether we need to make that dose adjustment.
So mogamulizumab – it is recommended that we do dose adjustments for dermatologic toxicity. SGAF and TEN were actually seen in the clinical trial. There was actually associated mortality with this. So because it was seen in the clinical trial, it's definitely a possibility. So it is really, really important that we keep this in mind. If this does occur, we obviously want to discontinue the drug and we don't want to give it again.
Grade 2 and grade 3 rash, it's recommended that you interrupt the treatment for about 2 weeks and apply topical steroids. And then a grade 1 rash, you could continue treatment but also the need for applying topical steroids.
Infusion reactions – with any monoclonal antibody, infusion reactions can occur. So it is important to assess this. Obviously, if it's an anaphylactic-type reaction, we probably don't want to continue the drug. So we would discontinue and not recontinue. However, if it's a temporary – and we see this all the time in the infusion center – temporary reaction, we would treat it, treat that reaction. Symptomatic care. And as long the patient goes down to baseline, we generally can restart that medication, normally at 50% of the rate and then titrate as they tolerate it.
Other common adverse reactions – so I mentioned rash. So, a lot of these patients obviously are going to have dermatologic effects. You're going to see rash. So how are you going to know? How are you going to know the difference between the drug rash versus the disease? Well, there's a couple ways. Obviously, you can look at timing. So, when did we see the rash? When did the rash appear? Maybe it's associated with the actual infusion of the drug. But the other thing, the only way to ever really know, is to biopsy. So biopsy would be the only way to know the difference between whether it was from the drug or whether it's the disease.
Infusion-related reactions – with any monoclonal antibody, you're going to see this. What I wanted to note here is that in the studies, it was 90% incidence. Actually over 90% incidence. So it's very common. However, you generally see this within the first couple of cycles. So daratumumab is very similar to this, where it's more common in the first few cycles, whereas moxetumomab, the last drug I talked about, you could actually see that in any cycle.
So, other adverse events, musculoskeletal pain, upper respiratory tract infections, grade 3 and grade 4 adverse reactions, edema, constipation, thrombocytopenia, hypertension, and cough.
The other thing that I don't have on this slide that I want to note is autoimmune toxicity. So, there was an association with an increased mortality in patients who had graft-versus-host disease that went on to allogeneic stem cell transplant. So, keeping that in mind, not that you shouldn't give this drug in the patient population, but depending on the timing – so, because this drug does affect your T cells, we know that that's really important for allogeneic stem cell transplant patients. And so, looking at the patient population and seeing if that patient does need to proceed on to transplant, and then maybe looking at that time frame in which you give this drug and starting the actual transplant itself. And so that's something that I've talked to some of our physicians at my institution about, and that's something that they have brought up that they are considering, and something that does factor in when they're considering treating with this agent.
So, the MAVERICK trial. The MAVERICK trial, which got the approval for mogamulizumab looked at vorinostat versus mogamulizumab, and they actually showed a statistically significant, actually 4-month improvement, in progressive-free survival. They actually also focused on the fact that even though there is an approval for mycosis fungoides and Sezary syndrome, it tended to favor Sezary syndrome over, a little bit over, mycosis fungoides. The other part is that it tended to favor stage III and stage IV disease, although you will look and see that in the indication, they only required to see one prior line.
So, the other thing is that a lot of these patients are presented with skin lesions. They have some kind of skin involvement, and so they actually looked at this, and they looked to see if there was any complete response or partial response in their skin involvement. Because you can have involvement in the blood and in the skin and in the viscera. So specifically, skin involvement – you can see there in green, complete response and partial response was pretty significant over vorinostat.
And then overall, to kind of summarize these results, is that it was – it did show improvement in mycosis fungoides and Sezary syndrome, mostly grade 2 and grade 3, but you can see that it definitely favored Sezary syndrome. Also, the duration of response was a little bit longer in Sezary syndrome versus mycosis fungoides.
And then lastly, looking at all the different compartments that you can see that there could be involvement – the skin, the blood, the lymph nodes – the blood is where they seem to have the best efficacy. So, I think looking at our current treatments and where you would see this fit in, is mostly patients with Sezary syndrome over maybe mycosis fungoides, and then maybe patients that have more blood involvement versus skin. Although, that being said, you can see that it's definitely effective and is FDA indicated for all of those indications.
Okay. So, expanded indications. So, these are all drugs that are already currently approved, but now we've expanded them into different indications. Pembrolizumab was indicated for adult and pediatric patients with refractory primary mediastinal B-cell lymphoma, or who have had relapsed after two or more prior lines of therapy. The approval was based off a study of 53 patients with relapsed or refractory primary mediastinal disease. This was a multicenter, open-label, single trial. The pembrolizumab was given at 200 mg IV every 3 weeks until unacceptable toxicity, disease progression, for up to 2 years. Common adverse events that were seen were musculoskeletal pain, upper respiratory tract infections, cough, dyspnea, diarrhea, and even arrhythmias.
So, the KEYNOTE-170 trial showed an overall response of 45%, 11% complete response, about 34% partial response. Now, the median duration was actually not met at the end of that trial of 10 months, but the onset of that first objective response was about 3 months. So, why is that important for us to know? It is recommended that patients that need immediate treatment and need cytoreductive treatment probably shouldn't get and start with pembrolizumab. They probably should be getting cytoreductive chemotherapy first. And then pembrolizumab would be an option later. And mostly this is because of that onset of action, you don't see response for about 2 to 3 months.
All right, blinatumomab. Blinatumomab. So, blinatumomab now has an expanded indication for treatment of adult patients and pediatric patients with B-cell ALL in their first or second complete remission with MRD greater than 0.1%. The BLAST trial looked at this. It was an open-label, multicenter, single-arm trial of patients that had received three chemotherapy lines prior to this of standard ALL therapy. All of these patients were in complete hematologic remission. They only had MRD-positive disease. So, why do we care about this patient population? Well, we care because there is definitely an association of patients that have MRD-positive disease and higher risk of relapse, and so that's what this study was tackling.
So, in the study, the patients received blinatumomab 28 mcg per day for all treatment cycles. And this is also important to note. So, right now, relapsed/refractory ALL, we know that we start our patients typically in the hospital at 9 mcg per day for about a week, and then we increase them to 28 mcg a day. They do that in the hospital, and then they're discharged. This is different. So, these are patients who do not have hematologic-positive disease. They only are MRD-positive. So, you can actually start these patients at 28 mcg a day. That's important to know. So, the dosing is different.
The other thing that's important to note is the duration of hospital stay. So, normally we would give them about a week of hospital, and then we would discharge them to receive subsequent treatments outpatient. In this case, you only have to keep them in the hospital for 3 days. All subsequent cycles, it's only required to keep them in the hospital for 2 days.
So, in the BLAST trial, they actually took these patients and they had four cycles of therapy. The first cycle would be induction, the three subsequent cycles would be consolidation. The frequency is very similar to how we give ALL and relapsed/refractory, where we would do four continuous weeks of the 28 mcg a day, followed by a 2-week break. So it would be 6-week cycles for up to four cycles.
The BLAST trial had a total of 116 patients. They actually showed, after patients received their first cycle of blinatumomab, about 80% of those patients actually became MRD-negative, which is great. So, these would be the MRD responders versus the other percentage of patients that were nonresponders. The trial actually showed that that was a statistically significant difference in these patients that had MRD-negative after that first cycle. Overall survival benefit, hematologic relapse-free survival benefit and duration of hematologic remission.
As far as the toxicity profile, it was pretty similar, and it would be pretty similar, to what we would normally see now with blinatumomab. So, obviously, fevers, neutropenia, can be seen. We do see that now in practice with either indication of blinatumomab. Tremors, aphasia can also be seen. We had a case recently in the hospital where they did start with the 28 mcg, and a lot of people actually thought that these patients wouldn't have as much toxicity, maybe because they didn't have as much active disease and not as much disease in the bloodstream. However, we – all three patients – we actually saw all of them had neurotoxicity. Which is not what we would have thought. So, kind of to go with what the study is saying here with safety, you can actually still see the same amount of neurotoxicity and fevers with patients that only have MRD-positive disease.
Okay. So, brentuximab. Brentuximab actually expanded to two different indications. I'm going to talk about the first one now, which is the ECHELON-1 trial. So, brentuximab is now indicated for treatment of adult patients with previously untreated stage III/IV classical Hodgkin's lymphoma. And this is in combination with chemotherapy. So, this approval was based off the ECHELON-1 randomized, open-label, two-arm trial that compared standard ABVD to ABD with brentuximab. This brentuximab dose was a smaller dose of 1.2 mg/kg with a max of 120 mg. So really, all we're doing here is getting our standard ABVD and substituting it with brentuximab with the bleomycin.
These patients were randomized for up to six cycles on day 1 and day 15 of a 28-day cycle, which is similar to how we do our standard ABVD.
So they actually showed progressive-free survival that was statistically significantly better in the brentuximab arm versus standard ABVD, which is important to note. They actually noted this not only in the investigator-initiated committee, but also the independent review committee.
But what about toxicities? We definitely saw, and what we would probably see, is that there was an increase in elevated toxicity level in patients that received brentuximab. So you can see across the board that there were toxicities, more toxicities, but most notably, neutropenia, and neuropathy. And so there's a couple things I want to talk about. One is that the patients in the brentuximab arm did receive growth factor. We don't standardly give growth factor for ABVD patients. The other part is that the brentuximab patients also had more hospitalization, which is also important to note.
So, where does this fit into therapy, and how do we know where they're going to give the brentuximab ABD versus ABVD? It is now in NCCN guidelines for stage III or stage IV. They do recommend patients that aren't able to receive bleomycin that you would switch them over to this. Also, we need to keep in mind, because of the increases in neuropathy that these patients obviously shouldn't have pre-existing neuropathy prior to starting this regimen.
The other thing, and I don't really want to talk about cost, but the cost of this medication, giving brentuximab and the additional growth factor, is about $100,000 more than the treatment of ABVD. And that's not an exaggeration. So, I think it's important to keep this in mind, and if you actually look this up, you'll see a lot of dialogue about this, about, is it worth it? And I'm not saying – there's clearly progression-free survival difference, it clearly benefits a subset of patients. So I think in a subset of patients, it certainly is worth it. But I think all of these factors need to come into play when you're looking at your patient, and even the cost of the treatment.
So, the other trial, the ALCANZA trial, is brentuximab's other indication. So this is treatment of adult patients with primary cutaneous anaplastic large cell and CD30-expressing mycosis fungoides who have received prior systemic therapy. This was a phase 3 randomized, open-label, multicenter clinical trial of brentuximab patients, over 100 patients, who actually received this therapy compared to physician's choice. The physician's choice was either methotrexate or bexarotene.
Adverse reactions were very similar to the study I just presented, because we're talking about brentuximab, so you saw very similar adverse reactions, most notably primary – or peripheral central neuropathy, diarrhea, fatigue, and again, neutropenia. Most common cause of discontinuation was going to be the peripheral neuropathy.
This dose, it is single agent, so it's the larger dose of the 1.8 mg/kg every 3 weeks up to 16 cycles disease progression or unacceptable toxicity.
So, you can see here that there was actually another statistically significant, greater-than-10-month progressive-free survival with giving brentuximab over its counterparts, methotrexate and bexarotene. The other part to note is that it was more favored in patients with an ECOG of 0, and patients less than 65.
Now, the next one is the obinutuzumab, and this is kind of similar to the study I talked about, the ECHELON-1 trial, but a different disease state. So, obinutuzumab in this GALLIUM-1 trial. So, the indication and what it expanded is the treatment of adult patients with previously untreated stage II, III, or IV follicular lymphoma. This was based off a multicenter, open-label, randomized phase III trial of patients who had previously untreated non-Hodgkin's lymphoma, including 1,200 patients with follicular lymphoma.
So, what were the randomization of the arms? What we're really doing here is we're comparing obinutuzumab to rituximab. They're both CD20-targeted. They looked at CVP, CHOP, in combination of bendamustine. And so, they compared obinutuzumab to rituximab in those three different arms of treatment.
So, what they actually saw was progressive-free survival in the arm with the bendamustine versus rituximab. However, they did not see a difference in overall survival.
This is important to keep in mind, and I'll talk about the toxicities first, and then we'll talk about when we kind of maybe use this in practice. So, in the GALLIUM trial, even though obinutuzumab did show progressive-free survival, they did see a higher incidence of toxicity. Most notably, serious adverse events, especially more than rituximab, 50% versus 43%, grade 3 reactions 79% versus 72%, and fatal infections. I think the take-home point here too to keep in mind is the bendamustine combination.
So, they did see a higher incidence of serious infections with obinutuzumab in combination with bendamustine versus the CHOP and the CVP. These patients previously received untreated – that were untreated follicular lymphoma – were recommended to get a dose of 1,000 mg days 1, 8, and 15, followed by 1,000 mg on day 1 for each subsequent cycle.
So, this is another question that we pose, of when do we substitute with obinutuzumab versus rituximab? And I think a lot of that depends on the patient characteristics, their ECOG status, and their current comorbidities. And I think, as I talk to different physicians about when they use obinutuzumab, I'm getting all kinds of answers. I have some that think it's great, there's progressive-free survival, Rebecca, why would we not use this? And he only uses it in a subset of patients, where I have other doctors that absolutely think that this is bogus, and they don't want to use this in any other patients, because they see the increase in toxicities, and they're concerned about the cost.
I think it will be interesting at this year's ASH, because they may talk about maybe where this may be more applicable in some patient populations over others.
Okay, now I'm switching gears completely, to talk about chimeric antigen receptor T cells, or our CAR T cells. So, we know that these are T cells that are genetically modified to target the patient's own tumor cells. And specifically, in the two that I'll talk about today, and the only two that are FDA approved, is CD19.
So, axicabtagene is the first one I'll talk about. It's mechanism of action, it's modified CD19, which I just mentioned that it targets. It's reprogrammed to identify and eliminate CD19-expressing malignant and normal cells. It's made from a murine single-chain antibody fused to a CD28 and CD3 zeta. The CD3 zeta is what's critical for initiating that T-cell activation in secretion of those inflammatory cytokines and chemokines, which leads to cell death.
It's currently indicated for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two more lines of systemic therapy, including diffuse large B cell not otherwise specified, and I won't read off all of those. But pretty much every formulation of diffuse large B cell, and if they have had two prior lines, are able to get this. There's a lot of other factors that come into play as far as toxicities, and we'll get there.
So the ZUMA-1 study – so the ZUMA-1 study is actually what got their approval. What they showed is sustained response – about 30 to 40% of patients had sustained progressive-free and overall survival. The ratio of response was also sustained in patients that actually had complete response, but you'll notice that patients who had partial response, it was only about 4 months.
What about the toxicity profile? And this is what we hear about all the time in our hospital is CRS, so common grade 3 or higher adverse events – febrile neutropenia, cytokine release syndrome, encephalopathy, infections, hypoxia, hypotension. The most common things that we obviously see are going to be our CRS effects. Also infections. Infections is something else that we have seen in practice.
Because of the fatal CRS and the concern for that, it is recommended that these patients undergo a REMS program after the FDA mandated a REMS program for these patients.
As far as the dose, it is a single IV infusion of these cells. All of these patients will have had lymphodepleting chemotherapy prior to receiving their CAR T cells, and because of the CNS effects and the encephalopathy, it is not recommended that these patients be treated with, or any patient with primary central nervous system lymphoma, be treated at this time with CAR T cells.
Now following right behind this is tisagenlecleucel, which had already been out there in the market for relapsed ALL. So the JULIET trial. So this is again targeting CD19, and I'm saying that because a lot of our new CAR T-cell agents coming out are not targeting CD19 anymore, but these two still are.
So, CD19-directed genetically modified autologous T-cell immunotherapy. Again, relapsed/refractory diffuse large B cell – I won't read off all of those indications, but they're exactly the same as the last drug. This was actually based, the JULIET trial, was based off a multicenter phase 2 of 46 patients that had diffuse large B cell. These patients did receive the drug and had received lymphodepleting chemotherapy prior to the infusion of their CAR T cells.
Overall response for these 68 patients was 50%. You can see complete response is about 32%, median follow-up time was 9.4 months, but most notably in the slide is looking at the duration of response. These are almost identical to what we saw in axicabtagene. So, duration of response was not met in those patients that actually had complete response. And then duration of response for patients that had a partial response was only about 3 to 4 months.
Again, common adverse events almost identical – CRS, infection risk, nausea, fatigue, hypotension. And because of all of this, they do recommend a REMS program.
So, the big question I had after learning about all of this is, how do you know which one to use? They're both indicated for the exact same thing. They both cost just about the exact same amount of money, for the most part. And so I asked a lot of questions about this to a lot of the providers I work with, and their general consensus is that, no one knows. We don't know. Maybe in ASH they'll probably tell us. Maybe not. But two of the things that they do look at is, tisagenlecleucel apparently is associated with less CRS effects. This could be argued probably, but if you ask a bunch of doctors that treat – that do this, a lot of them will say that. They've seen less CRS effects with tisagenlecleucel.
But the other thing to keep in mind is that a lot of these patients that get tisagenlecleucel, the turnaround time of those cells is actually about a week to a week and a half longer than axicabtagene. And so, that can play a point. If the patient has aggressive disease or they're very concerned that the patient's going to relapse, they might not have a week and a half to wait.
So, these are – they're typically the things that they do consider in their patients, whether they have pre-existing issues, but at the end of the day, these are all hypothetical things, and we don't really know.
Okay. So we're going to switch gears and talk about small molecular inhibitors. The two that I'm going to start with is ivosidenib and acalabrutinib, and then I'll go into expansion of some indications for nilotinib. It actually is not an expansion of an indication. We're actually going to be talking about when we can discontinue nilotinib. Now it's okay to do that. And then venetoclax. And then we'll talk about two indications of expansion in CML for bosutinib and dasatinib.
So, ivosidenib, IDH1 inhibitor – we already have an IDH2 inhibitor out there in AML now. So now we have an IDH1 inhibitor. It's indicated for treatment of adult patients with relapsed or refractory AML with susceptible IDH1 mutation as detected by the FDA-approved test. So, of course I asked this. I'm like, so, do all the hospitals have this test? I don't know if all the hospitals have this test, and that's important to know.
The other thing is that, just because the patient has a mutation on primary diagnosis doesn't mean they're going have the mutation during relapse. So it is important to make sure that we are checking this, and we're definitely checking this prior to starting the drug, in that relapsed/refractory setting.
The mechanism of action, which I've kind of already stated, but it's a molecular inhibitor that targets the mutant isocitrate dehydrogenase 1, IDH1 enzyme, and reduces the 2-hydroxyglutarate, the blast cells, and induces differentiation.
The dose is 500 mg once a day, with or without food, up until disease progression or unacceptable toxicities. It is recommended to avoid high-fat meals. If they take a high-fat meal, it will increase the concentrations of the drug. And it is supplied at 250 mg, which I don't always put in these slides, but this is important to note, because it means that you can actually adjust the drug if you need to for dose adjustments.
Drug interaction – I feel like every oral chemo has drug interactions, especially with a lot of our anti-infectives. So, this is no different. So, strong 3A4 inhibitor and inducer, and it also is sensitive to a 3A4 substrate. So, those patients who have fungal infections, who are on voriconazole, fluconazole, isavuconazonium – these will be things that we need to consider when starting this drug or starting an antifungal.
Also QTc. QTc is also an issue, so patients who are on other QT-prolonging drugs, we need to monitor. And I'll talk about that.
So, black box warning is differentiation syndrome. I've seen this several times already. This can be fatal. This is very important, and I actually know a lot of providers that I practice with, physicians, that are not aware of this. They are not aware that it causes this, they don't know what the symptoms are, they don't know what it looks like, which surprised me. So I think it's important if you are aware that you do educate and let them know that it can cause differentiation syndrome.
The other thing to keep in mind is that you can actually treat this with corticosteroids. It's recommended – dexamethasone 10 mg twice a day for 3 days, is the recommended treatment. You can extend that, but generally, you don't need to.
Also important to note is to monitor for hemodynamic monitoring for symptom resolution.
The other warnings, and I talked about QTc prolongation. And so it is recommended when you start patients that you get an initial EKG, and then you get one every week for 3 weeks, and then subsequently every month. That is the recommendation. A lot of these patients may be on QT-prolonging drugs, so it is important to monitor that.
Ondansetron, if this causes nausea. Some patients might be on ondansetron. So all of this is important to note.
I get this question a lot in clinic about looking at this, and as long as you're routinely monitoring these patients, and there are no QT prolongations happening, then it is okay to continue these drugs.
Guillain-Barre syndrome, monitoring patients for signs and symptoms of new or central findings, permanently discontinuing if patients are found to actually have this diagnosis.
And then the most common adverse events, I've already kind of honed in on some of these – fatigue, leukocytosis. So patients who have leukocytosis, you actually can start hydroxyurea. White blood cell count greater than 25,000 is generally recommended. We start hydroxyurea, and you can give it concurrently, which is a question I have been asked. It is – and they actually recommend doing that. Obviously making sure that you monitor, because we'll want to stop it at some point.
Diarrhea, dyspnea, edema, nausea, mucositis. EKG, I mentioned this. Monitoring those EKGs. Rash, pyrexia, cough, and constipation.
Okay. So looking at the trial, you can see here that complete response or hematologic complete response was seen in about 30 to 40% of patients, and this was sustained. The other thing in this trial that noted is all the things that I've already mentioned that I will mention again, is the QT prolongation that we need to monitor for, the differentiation syndrome that we can give dex 10 mg twice a day for 3 subsequent days, as well as leukocytosis, which we can use hydroxyurea in combination with ivosidenib.
How about acalabrutinib? So this is our Bruton tyrosine kinase inhibitor for mantle cell lymphoma. It's mechanism, it's a selective irreversible second-generation BTK inhibitor that decreases malignant B-cell proliferation and survival. It's treatment is for mantle cell lymphoma, those patients who have received at least one prior therapy. It is dosed at 100 mg twice a day until disease progression or unacceptable toxicity.
Drug interactions – again, oral chemo, lots of drug interactions. Strong 3A4 inhibitor, moderate 3A4 inhibitor, and strong 3A4 inhibitor. So, all of these have dose recommendations. If patients are going to be started on voriconazole, and I'm going to use that, because a lot of our patients are on that drug and it is a strong inhibitor, it is recommended that you don't even start acalabrutinib in those patients, unless you're only going to give vori for maybe 5 days.
If it's a moderate inhibitor, so let's say fluconazole, we may recommend that you can actually start fluconazole with acalabrutinib, but maybe lower it to 100 mg once a day.
And then for any strong 3A4 inducers, it actually says to avoid this. So what is this going to do? It's actually going to decrease the concentration of acalabrutinib.
The other recommendation is to give a higher dose, which I don't know if I would recommend that. But it says to give a higher dose of 200 mg every 12 hours, so both possibilities. So you can either avoid and wait until they're ending their fluconazole, or you can give a higher dose of the acalabrutinib, depending on how much treatment they need and the duration of treatment that they needed.
The other recommendation, kind of similar to ibrutinib, due to potential risk of bleeding, consider interrupting treatment for 3 to 7 days prior to and after surgery.
Other dose adjustments – so this is unique to acalabrutinib, is occurrences of hematologic and nonhematologic toxicities. If it's the first or second occurrence of one of the two of these, then you would actually hold treatment until it's a grade 1, and then resume at that standard 100 mg twice a day dosing. If it's the third occurrence of this actually occurring, you would still want to hold the drug, wait until you're down to a grade 1, and then maybe restart at half the dose, the 100 mg once a day. If it's the first occurrence of this, then you would recommend, or we recommend, or the package insert recommends, that you would discontinue the medication.
Other adverse effects seen – headaches, skin rashes, diarrhea, nausea, anemia, and myalgias. So the acalabrutinib study was a phase 2, open-label, single-arm clinical trial of 124 patients. These were adult patients with relapsed or refractory mantle cell lymphoma. Overall response rate was about 80%. Complete response was about 40% with 40% partial response. Acalabrutinib actually in practice seems to be doing really well. A lot of our providers are actually using this in place of ibrutinib. They're also seeing slightly less toxicities with acalabrutinib versus ibrutinib. So, I think it will be interesting, especially at this year's ASH, to see what else is coming out there. I think we can probably foresee that acalabrutinib is going to be indicated and used in multiple other settings. I can tell you in my institution, it is being used in other settings, but right now, the mantle cell approval, it seems to be working very well.
Okay. So, this is actually looking at nilotinib. In patients that receive nilotinib, in – looking at discontinuations. So this is two different trials – the ENESTfreedom and the ENESTop trial. Both of them have a similar number of patients, very similar results, which is why I have them paired up next to each other.
So, all of these patients actually received 3 years of nilotinib. After 3 years of nilotinib, they're in sustainable molecular response. These patients were actually able to discontinue their nilotinib after that 3-year period, and then they took a look at these patients. And they showed, not only after the first year, but the second year, they were in treatment-free remission. At the 96-week cutoff in both of these trials, those patients that actually lost their molecular response, so they got their disease back, and they started back on their treatment, nearly 100% of those patients were able to regain molecular remission, which is very important to know.
And this also is interesting because it will – after the study and after the FDA approval of this, it kind of makes you wonder if they're going to start extrapolating this into other TKIs, and maybe even other disease states.
So in these two trials, they showed that none of these patients progressed to accelerated or blast phase in CML during this treatment-free remission. So while these patients were not receiving nilotinib, none of them progressed to accelerated or blast phase.
Common adverse effects – and these are not common adverse events of nilotinib but not taking nilotinib. So these patients have been on nilotinib for 3 years, at least 3 years, and then they just all of a sudden stopped it. And so that's what we're talking about. What are those side effects? So these patients had musculoskeletal symptoms, body aches, bone pain, extremity pain. But overall, there's been no long-term outcomes looking at discontinuing versus continuing treatments. And so we don't really know what this is going to look like in the long term. However, this was enough information for the FDA to actually expand the labeling and what's on the package insert, saying that it is okay. It's okay to discontinue nilotinib in your patients, as long as they've met certain criteria. And a lot of that is the duration – it's been at least 3 years and they had sustained molecular response.
If the patient were to have – and obviously, after you stop it, you would still want to bring the patient back to monitor these patients – if the patient's disease does start to come back, you would obviously want to continue nilotinib within 4 weeks at this previously started – the previous dose that they were on.
Now, the BFORE trial – so this is bosutinib in the BFORE trial. So this is the indication for treatment of patients with newly diagnosed chronic-phase Ph-positive CML. The approval was based on data from an open-label, randomized, multicenter trial of 487 patients with Ph-positive newly diagnosed CML who were randomized to receive bosutinib or imatinib at 400 mg once a day. And so what we're looking at is bosutinib in the front-line setting.
The efficacy outcomes of major molecular response at 12 months is what was measured. And so you can see here, the major molecular response at 12 months was statistically significantly in favor of bosutinib at 47% versus imatinib, around 37%. Common adverse events were diarrhea, nausea, thrombocytopenia, rash, increased LFTs, abdominal pain. So obviously this now says to us that we can start bosutinib as front line in CML. There are some other options, so a lot of this is based off of what are the current side effects of the patient, what's going on with the patient, and is this a valuable option for the patient to start bosutinib front line?
Now dasatinib, again we're talking about CML patients. This is looking at pediatric patients. So, this is dasatinib in a phase 1 or phase 2 clinical trial, approved for treatment of pediatric patient with Ph-positive CML. This was 97 pediatric patients with chronic-phase CML in two different studies. The first one was a phase 1 open-label, non-randomized, dose ranging trial, and a phase 2 open-label, nonrandomized trial. This was 51 patients exclusively who were newly diagnosed, and 46 patients who were resistant or intolerant to imatinib. In these patients, after those 24 months, you could see that 96% of those patients had complete cytogenetic response, whereas 82% of the resistant or intolerant to imatinib patients also had complete cytogenetic response.
They also looked at medium duration of cytogenetic response, as well as major outcomes in response and major molecular response overall, and they actually show that they couldn't estimate this because half of the responding patients had not progressed after that 5-year mark. So this actually expanded the indication to dasatinib in that pediatric population.
Adverse effects – a lot of us use dasatinib, so it's very similar to what we would see in dasatinib – headache, nausea, skin rash, pain in extremities, fatigue, arthralgias.
Now we'll talk about venetoclax. So this is the MURANO trial. I'm going to talk about venetoclax in a couple different settings. So this is expanding venetoclax in its indication for CLL or SLL with our without 17p deletion who have received at least one prior line of therapy. So, this is comparing venetoclax with rituximab to bendamustine and rituximab. And what they did is, they took venetoclax and did the ramp up over 5 weeks, staring at 20 mg and ending at 400 mg, and then followed by rituximab. So rituximab was given after the venetoclax. And this was compared to bendamustine/rituximab that was standard dosing for up to six cycles.
The venetoclax/rituximab arm was statistically significantly improved with progressive-free survival over the bendamustine arm, which you can also see relayed over to overall survival as well. So it was very effective.
The MURANO trial also looked at MRD-negative patients. So they looked at MRD-negative in these patients of venetoclax versus bendamustine, and you can see there in the green, and that's the most important thing to see, is in the green you can see it was pretty substantial for patients that were able to achieve MRD-negative status.
The other thing is the side effect profile. We know that venetoclax has concerns for tumor lysis, specifically in our CLL population. We also know that there's a concern for neutropenia. So you can see here, a lot of these patients actually didn't come in with high counts, and so tumor lysis wasn't a huge issue. However, they did see a higher incidence of neutropenia.
The other thing is with the bendamustine arm, even though they saw higher neutropenia in venetoclax, the bendamustine arm had higher febrile neutropenia, and also had higher incidence of infections.
And so the other indication that I want to talk about is actually not FDA indicated, but we are using this all the time, and I'm sure that a lot of you are probably seeing this in your practices, is the addition of decitabine and azacitidine with venetoclax in AML.
So we know that BCL2 is a poor-risk predictor in our AML population, which is sort of where this idea came from. And so, this is actually a study, a multicenter, open-label, phase 1, dose-escalation study that looked at venetoclax at different dosing schemes. You have here in this chart, you can see, 400 and 700 mg, but some of these patients also receive the 1,200-mg dose. They looked at patients that received azacitidine versus decitabine, as well as if they're in complete response or CRi, and then looked at the risk stratification. And I can summarize that in the next slide.
So, multicenter, open-label, phase I study – so venetoclax plus decitabine and azacitidine was well-tolerated with deep, durable responses in elderly patients with previously untreated AML. You can see the CR and the CRi rate was about almost 70% of these patients. The overall response rate was about 80% in this trial. So, when the actually split it up and they looked at poor risk disease, secondary AML, and greater than 75 years of age, it was almost 70% of patients.
The median overall survival was about 17.5 months in all of the patients, so about 50% 1-year overall survival. And MRD-negative was observed in 45% of these patients. Overall, the study actually supported the use of venetoclax 400 mg every day, or daily, in combination with decitabine and azacitidine.
What I do want to say is that, when they looked at the different dosing schemes, obviously 1,200 had higher toxicities, and I don't have this on here, but the 800 actually showed very similar efficacy to the 400. However, a lot of people thought, well, why would we give a higher dose if there's no benefit to it? And all now you have is an increased risk of toxicities. So the 400-mg dose has been the recommended dose in combination with azacitidine and decitabine.
Okay. So, this is my last slide. This is the pipeline drugs. So, these are drugs that are going to be coming out, and some of these actually have – duvelisib, our PI3K inhibitor, already has come out, and I didn't talk about that today. But I think the important things that I want to note here, is what are we going to do with this information?
So we have all these new drugs coming out, and what do we do with that? We have these biosimilars coming out, and a lot of the biosimilars are very similar to these drugs. And so, I think that poses a lot of questions of what we're going to do. Some of these are Me Too drugs. And so, what we say in pharmacy as Me Too drugs, it's like having 50 ACE inhibitors, is that we're not going to have all of them on formulary. And so, now we really need to start looking at these, and which ones are actually beneficial to the patients.
Looking at the toxicity profile of these agents, some of them claim that they have less toxicities than the other, and all of that needs to be compared. But the biosimilars that are coming out as well are just as great as these ones. And so, you'll probably see at ASH that we're going to be looking at a lot of this in a more big picture.
So I think the whole idea, in my take-home message, was – this whole presentation, is to keep an open mind and know your drugs. Know your targets. If you know what those targets are – because a lot of these FDA approvals are going to continuously be expanding to all of these different targets – so if you know the drug and you know the target, you can probably start to foresee where we might start using some of these agents in the future.
The other thing in your practice settings is keeping in mind supportive care. So the doctor may decide to start one of these agents, but the supportive care is almost the more important part in some cases. So, antifungals, antivirals. Do we know if it's going to deplete their lymphocytes? Do we know if they're going to be neutropenic for more than 2 weeks? Are they going to need growth factor support? Were there growth factors used in those trials? All of these things are so pivotal and important to a lot of these drugs, and the lifeline of these patients.
And I think I'm running out of time, so I'm going to go ahead and answer any questions anybody has.


According to a recent study from The Economist, greenhouse gas emissions could be greatly reduced by 2050 with one annual change: The Purge.
Many of us are aware of the challenges facing Earth and its inhabitants. Overpopulation, global warming, the melting of ice caps, and the extinction of wildlife—mass changes must be made to preserve life as we know it.
The motion was brought up at a United Nations meeting, to mixed reviews. Gillian Frances, part of the Security Council, took issue with the idea.
The two debated movie franchises for a half hour, while many reporters took to the streets to speak to local citizens.
"If my kill count is higher than 50, do I have to recycle for the rest of the year?" asked Jennifer Egret, BC Hydro employee.


• Following up on a spring delivery of the black colorway, Nike is gearing up to release its latest "Swarovski" Air Max 97 in a familiar scheme. Again, the iconic sneaker here boasts shimmering Swarovski Crystal Fabric swatches throughout the upper.
Details: Dubbed Air Max 97 LX "Swarovski", these sneakers are laced with Swarovski Crystal Fabric swatches, tonal laces, Max Air tooling. The Air Max 97 LX with Swarovski crystals then accounts for first time that Nike Women has used Swarovski crystals on a shoe.
Purchase Info: Expect a price tag of $400 USD; Available online via Nike.
…. More Views Of The Swarovski Air Max 97's Below, ENJOY ….


On a recent return trip from Milwaukee, I took a detour along the shores of Lake Erie in Northern Ohio making quick stops at Ottawa National Wildlife Refuge and Magee Marsh. As mentioned last week, Magee Marsh is a top spot for spring migration and a must for those undertaking a 'big year'.
As birds migrate north and hit Lake Erie, Magee Marsh becomes a staging area as they rest up to cross the lake (or continue their journey around the lake) to reach northern breeding grounds. Point Pelee, across the lake in Ontario, is another spring migration hot spot and can be filled with exhausted birds resting after making it across the lake.
The Ottawa refuge is adjacent to Magee Marsh and may also have high quantities of migrants in the spring. There are some hiking trails and an auto tour though a large part of the refuge is not open to the public.
I got some photos of a few shorebirds while visiting these spots (and nearby Sandusky) that I'll post next week.
This entry was posted on 6 September 2012 by patacoate. It was filed under iPhone and was tagged with Magee Marsh, Ottawa National Wildlife Refuge.
Thanks for the pictures and orientation of this fabulous place!


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Q: ASP.NET MVC IIS Deployment I have following 2 ASP.NET MVC Web Application under 1 VS Solution

*

*Public Site

*Admin Site

I don't want to deploy this as two separate IIS instance, my aim is to achieve the following

*

*When user navigate to www.mysite.com it should go to the public site

*When user navigate to www.mysite.com/admin it should go to the admin site.

How can this be achived

A: You could use Area's for separation and deploy it as one app.

redpajama_set_name: RedPajamaStackExchange


Our school cooperates with Fu-Lin (´IªL), Pei-Hu (¥_´ò) and Ben-Gang (²Â´ä) elementary schools and Datan (¤j¼æ) Power Plant (Taiwan Power Company) to propose a sustainable campus project aiming to build up a green and sustainable study environment. Ke-Jian and the other three elementary schools sit on the same coastal highway and share the same resources: strong wind and sunlight. Therefore, we decide to take the advantage and turn them into green energy. We installed wind and solar power systems and put them into our eco education. With the assistance from Datan¡¦s professionals, professors of <?xml:namespace prefix = st1 ns = "urn:schemas-microsoft-com:office:smarttags" />Chung Yuan Christian University and local communities, we combined the specialized knowledge and our green courses and proposed this sustainable campus project.
The coastal plants and birds near Ke-Jian are actually a free teaching aid of our eco education. Students can approach nature and appreciate its beauty. As for the strong wind and sunlight in our daily life, after smart use, they are converted into green energy used to cut our electricity bills. The solar power system provides electricity for our toilet lighting. Such smart reuse of natural resources is green and economical.


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What is Pod May Never Die: Two Targaryens
By Jon Block, Caitlin Mannering and Daniel Varghese
In this episode of What is Pod May Never Die, Jon Block and Caitlin Mannering are joined by Voice legend Daniel Varghese to discuss the legendary meeting of Jon and Daenerys, Cersei's power play, and the demise of the Queen of Thorns.
http://media.blubrry.com/voicepodcastnetwork/georgetownvoice.com/wp-content/uploads/2017/07/What-is-Pod-May-Never-Die-Ep-4-73117-11.01-PM.mp3
Jon Block
Jon was podcast editor, Halftime leisure editor, and Halftime sports editor for the Voice. You can follow him on Twitter @jon_block_ but not on Instagram because he doesn't have one.
Caitlin Mannering
Caitlin studied Biology of Global Health and minored in English in the College. She is a former washed-up Leisure editor. It's unfortunate that her biology major will in no way relate to her dream job of working on Game of Thrones.
Daniel Varghese
Daniel was an editor at the Voice from December 2013 to November 2016. He loved it. Follow him on Twitter @drvarg01 for his thoughts on Global Health and Kanye West.
More: Game of Thrones, What is Pod May Never Die
Netflix's The Witcher Takes HBO's Fantasy Throne
By Lindsey Powell
Marco Polo Is A Guilty Pleasure
By Sabrina Kayser
Halftime's Game Of Thrones Recap: Season 4
By Dajour Evans

redpajama_set_name: RedPajamaCommonCrawl


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The Smederevo Fortress
District: Podunavlje
Municipality: Smederevo
The "Jugovo" excursion site
The "Golden Hill" villa
The 15th century Church of the Dormition of the Holy Mother of God
Smederevo' s Autumn
Smederevo – Town on the Danube river
By order of Despot Ðurad Branković began in 1428, at the mouth of the rivers Jezava and Danube, at the very north of the country, the building of the Smederevo fortress, which became the seat of Serbian secular and clerical authorities of the time.
Enormous quantities of stone necessary for the construction were dragged from ancient sites: Viminacium, Margum and Kulič, and Serbian medieval burial grounds were also sacrified. The Small Town The Court – was built within two years, triangular of shape, with six towers, the strongest of which is the Donjon tower.
A red brick inscription on the Despot's tower that tells of the building of the town is preserved, inside the Court, facing the Danube, there was a reception hall – MAGNA SALA AUDIENTIAS, that is – with three Gothic bifores where medieaval court life took place. Along with it there was a room with a Romanic bifore designated for the ruling family. In the Small Town there was a famous centre for goldsmiths and transcription work, as well as a coin mint.
In the period from 1430 – 1439, THE LARGE TOWN – The Fortified Town – was erected in accordance with the triangular shape, taking up almost 11 hectares which puts the Smederevo Fortress among the largest European plain fortifications. Originally, the fortress was made for defence against cold steel weapons, but it was soon adapted for fire – arms warfare. In a longer, peaceful period from 1444 – 1453, the Large Town was raised with 19 towers, whose height was more than 20 meters. In this space there were The Court Church and The Church of the Annunciation with the holy remains of St Luke, who is also today the patron saint of the town. The Large Town became known as craft and trade centre in which also a colony from Dubrovnik did their trade. After the Turkish conquest of Smederevo in 1459, the Serbian mediaeval state ceased to exist.
In 1480 the Turks raised an outer defence wall around the fortress, and at the corners and at the entry into the Town four polygonal towers with gun openings.
The outer wall facing the town and the Turkish polygonal tower at the entry to the Town were pulled down when railway tracks were built in
In World War One, the Fortress was badly damaged. The last, largest destruction happened in an explosion of ammunition, on the 5th of June,1941.
The fortress is currently used as a city park, and occasionally hosts festivals, concerts, fairs, and other cultural events. A stage has been built in the small town. To the southeast, the previously open space along the Jezava now boasts a harbor and a marina. There are also discussions underway to determine compatible future, modernized uses, and to develop projects to restore and rehabilitate the fortress.
Sports and recreations complex "The Sunny River" is located in …
Sports and rekreations complex "The sunny river"
From the travels of Evlija Celebija we can learn that …
Hisardzik Mosque
Kriva Reka is a cultivated village that is located 17 …
Trajans bridge
A rich historical and cultural heritage of the municipality of …


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Leopold Jaroslav Pospíšil (26. dubna 1923 Olomouc – 25. října 2021 New Haven, USA) byl americký právník a právní antropolog českého původu, emeritní profesor Yaleovy univerzity a v letech 1980–1984 předseda exilové Společnosti pro vědy a umění.

Leopold Pospíšil vystudoval Slovanské gymnázium v Olomouci (maturoval v roce 1942) a práva na Univerzitě Karlově v Praze. V roce 1948 emigroval přes uprchlický tábor a stal se starostou exilové Sokolské župy Dr. Edvarda Beneše v uprchlických táborech v Německu a v Itálii. Následně emigroval do USA, kde pracoval na statku, pak studoval sociologii a filosofii na univerzitě v Oregonu a konečně antropologii na Yale university v New Haven, Connecticut. Přednášel na různých univerzitách, v letech 1956–1983 byl profesorem na univerzitě Yale a kurátorem antropologického oddělení Peabodyho muzea. Roku 1984 byl jmenován členem americké National academy of sciences.

Po roce 1989 často navštěvoval Československo, přednášel v Olomouci a na Filosofické a Přírodovědecké fakultě UK v Praze.

Pospíšilovy dlouholeté výzkumy, zejména mezi inuity Nunamiut na Aljašce, indiány Hopi v USA, Kapauky na Nové Guineji a mezi tyrolskými sedláky v rakouském Obernbergu patří k zakladatelským pracím v oboru antropologie práva. Významný je zejména jeho objev "právního pluralismu", stavu, kdy se lidé v různých oblastech svého života řídí různými právními systémy, i jeho výzkumy o povaze vlastnictví a vůbec zájem o domorodé ekonomiky.

Zemřel v americkém městě New Haven ve věku 98 let.

Odkazy

Reference

Literatura

 L. Pospíšil, Etnologie práva. Praha 1997
 L. Pospisil, The Kapauku Papuans of west New Guinea. New York 1963
 L. Pospisil, Anthropology of law. New Haven 1971

Související články
 Antropologie práva
 Vznik práva

Externí odkazy
 L. Pospíšil, Matematika papuánců kmene Kapauku (Vesmír 2002)
 L. Pospíšil, Antropologie a věda. Olomouc: Univerzita Palackého, 1992

Američtí antropologové
Čeští antropologové
Američtí právníci
Čeští právníci
Členové České strany národně sociální
Členové Sokola
Absolventi Právnické fakulty Univerzity Karlovy
Nositelé Ceny Neuron
Nositelé Stříbrné medaile předsedy Senátu
Narození v roce 1923
Narození 26. dubna
Narození v Olomouci
Úmrtí v roce 2021
Úmrtí 25. října
Muži

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President Biden Will Extend Student Loan Payment Freeze Through Sept. 30
SAT Discontinues Subject Tests And Optional Essay
Didn't Get Enough Financial Aid For College? You Can Ask For More Money
What's behind all the big spending on the LA school board primary
Hundreds of students, parents, teachers, staffers and supporters of Magnolia charter schools circled the downtown headquarters of the Los Angeles Unified School District on Tues., Oct. 18, ahead of a school board vote to deny three Magnolia schools' charter renewal requests.
Kyle Stokes/KPCC
Kyle Stokes | March 8, 2017
Outside political groups have already spent more on this year's Los Angeles Unified School District board campaign than has ever been spent on a board election before.
Independent expenditure groups — most with ties to either L.A.'s teachers union, United Teachers Los Angeles, or the political arm of the California Charter Schools Association — spent a primary-record $5.5 million on ads, staffing phone-banks and canvassers in hopes of swaying the races for three seats.
And Tuesday's results mean the campaign isn't even over yet. In two of the three races, no candidate won a majority of votes, meaning the top two vote-getters will face off in a May 16 runoff — an election that's likely to push the spending from charter school groups and labor unions even higher.
"I think this is going to be a dog fight," said Raphael Sonenshein, executive director of the Pat Brown Institute for Public Affairs at California State University, Los Angeles. "I'm getting out of the prediction business ever since election day in November, but I would say more money is going to come in, I would imagine."
The narrative of charter groups and teachers unions battling over school board seats has gotten so familiar in L.A. — Sonenshein likens the decades-long, protracted back-and-forth to the medieval War of the Roses — that it's easy to forget why the battle exists, and why it matters to families.
The total of "independent expenditures" outside political groups have poured into this year's Los Angeles School Board campaign has already set a record for outside money in an L.A. Unified primary election. Candidates have also raised more for their own campaigns ahead of the primary in 2017 than was collected during the primary and general elections in every year since 2007.
KPCC
For the uninitiated in this debate, let's back up: Charter schools receive public funding like any other public schools. They're unlike traditional district-run schools in that they are run by an outside group — most often, a nonprofit organization — which hires teachers and recruits students. There are more than 220 independent charter schools operating in L.A. Unified.
To open, charter schools need the permission of an "authorizer," which holds the school accountable for its academic performance and monitors its finances. In Los Angeles, most often, that authorizer is the L.A. Unified board. To remain open, charters must go before the board every few years for renewals.
And here's where the importance of the school board's makeup becomes critical.
L.A. Unified board members have approved most charter school applications and renewals with few public questions in recent years. But the board's infrequent decisions to deny a bid for a new charter or to reject an existing charter's renewal request have caused friction.
As Joshua Pechthalt, president of the state's second-largest teachers union, the California Federation of Teachers, put it, the state's charter school advocates "don't want any constraints placed on the opening of charter schools."
This chart compares the pace at which outside groups made independent expenditures in 2017 and 2013 — the year that previously held the record for outside spending in an L.A. Unified School Board primary election campaign.
But skeptical board members can serve as a check on charter school growth.
Here's an example: In late 2015, a document leaked from the Eli and Edythe Broad Foundation outlined plans for a massive expansion of L.A. Unified's charter school sector.
But, in January 2016 the school board passed a resolution denouncing the plan. In February, current board President Steve Zimmer told KPCC he was scrutinizing charter applications more than he was before. (The foundation downplayed the leaked document's importance, and it has since shifted its strategy.)
That extra scrutiny hasn't necessarily resulted in an uptick in denials for charter petitions.
Zimmer — who has the endorsement of United Teachers Los Angeles, which spent more than $1 million on his behalf — has said that he supports expanding school choice and that his voting record shows he's supported many charter schools over his eight-year tenure.
Compare Zimmer's stance, though, to that of Nick Melvoin, his challenger in the May 16 runoff for the board's District 4 seat.
Melvoin, who has the endorsement of the California Charter Schools Association's political affiliate, points out there are, according to the association's estimates, roughly 40,000 students on charter school waitlists.
"That shows an indictment of the status quo that the district is not meeting the needs of kids and families," Melvoin said at a recent candidate forum.
"I don't think we should be saying, 'More charter schools, less charter schools,'" Melvoin said. "We should be saying, 'Let's make sure we're meeting the needs of every kid.' The reason I'm running for the LAUSD board is to help improve the district so we are meeting their needs, and charters are one part of that solution. Until we have no families on waitlists, I support that option."
Melvoin is not only speaking of expanding charter options, but of expanding in-district choice programs like magnet and pilot schools as well.
Still, it's easy to see charter advocates' attraction to Melvoin's position. Pro-charter groups spent $556,000 in outside money to support him and another $1.5 million to oppose Zimmer in the primary.
But remember, the board's job isn't just to decide which charter schools get to open — it decides which ones remain open.
During a contentious, raucous meeting last October, the board denied renewals to five charter schools — including two campuses from the Celerity Educational Group, the charter school network whose offices were raided by the FBI last month. While the reason for the raid is still unclear, board members denied the renewal based on concerns that district staff raised about the charter's governance.
"The real issue we should be raising is oversight of charter schools and making sure that there's good accountability on charter schools," said Pedro Noguera, a professor at UCLA's Graduate School of Education and Information Sciences. "I don't know if that issue has gotten the attention that it needs and deserves."
Zimmer has said he opposes what he sees as charter school advocates' push for "deregulation" of L.A. Unified's charter school sector.
Sympathetic board members could help charter schools in ways that go beyond charter petitions, renewals and oversight.
For instance, L.A. Unified officials are currently creating a "unified enrollment system" — that is, a "one-stop shop" that takes the balkanized and scattershot systems for applying to the district's many school choice programs and consolidates it into a single online application.
As of the latest update to the board, the one-stop shop would include every choice option — from magnets to open enrollment to gifted education — except for charter schools.
"And yet we have, what, 16 percent [of L.A. Unified students] in charter schools? To pretend they aren't part of the program is ludicrous," said Katie Braude, the executive director of SpeakUp, an advocacy group that's backing Melvoin. (The organization doesn't advocate solely for charter schools, she said; many of the group's parent members send their kids to non-charter schools as well.)
Would a board made up of more charter association-endorsed members be more likely to push for charters' inclusion in the system?
Also, charter school operators often find themselves in desperate need for facilities — they don't receive the same public funding sources as districts do to build or buy school buildings — and so they often rely on a state law entitling them to operate in school district-owned buildings for modest fees.
The process of determining which campuses should host these "co-locations" is often contentious. While the final co-location decisions are technically out of board members' hands, the board may eventually have to act to changes to a process that's prompted litigation and sowed confusion.
By the same token, teachers unions have a lot at stake in the election outcome beyond charter schools.
"It might be, given how much the union invested" in the race, UCLA's Noguera said, "that there's a concern some candidates who are running would be less pro-union and what that would mean for the future of the district."
After all, the teachers union, UTLA, has been a fierce critic of charter school expansion.
The union represents more than 35,000 teachers and health workers in a district that has faced criticism for, detractors say, failing to cut staff at the same pace enrollment has declined in recent years.
"Once you're in the position of serving on the board," Noguera said, "it becomes more difficult to focus on a single issue like charter schools."
Candidates have expressed frustration at the dominance of the charter-versus-union narrative in the election.
In the race for the board's District 6 seat, Kelly Gonez, who has the charter school association's endorsement, has said she hopes to be able to work with union leaders if elected to the board.
She advanced to a May 16 runoff against Imelda Padilla, who has UTLA's endorsement. Padilla has criticized the charter association for being reflexively opposed to union rights, but said charter schools in her district show that coexistence and cooperation with L.A. Unified is possible.
Yet the campaign finance numbers show the dominance of two political titans in the race: UTLA's political affiliates spent at least $1.6 million in outside money on the race; pro-charter groups spent nearly $3.4 million.
And about two-fifths of that money went to oppose candidates the other side had endorsed.
2 Celerity charter schools shut down by state education board
Human Voter Guide: Get ready for May 16 election
What to do about the ballooning cost of LAUSD's benefits
KPCC's Education coverage is a Southern California resource provided by member-supported public radio. We can't do it without you.


Angela Strickland has over 20 years of leadership experience in the energy industry. During her tenure with a major U.S. electric utility she held numerous leadership roles and has expertise in corporate innovation, strategy development, electric transportation, energy storage, regulatory policy and customer experience. Strickland received an MBA from Georgia State University and a bachelor's degree in Industrial Engineering from the University of Tennessee. She is a licensed Professional Engineer.


text:
\section{Introduction}

Recent progress on superconducting qubits suggested that superconducting
Josephson circuits are promising candidates for practical quantum
computating \cite{Makhlin01,Clarke08,Neeley10,DiCarlo10,Sun10a}. However,
extensive works are needed to understand the decoherence mechanism hence
increase the decoherence time of these macroscopic quantum systems. For
instance, microscopic defects are ubiquitous in solid state devices. Each of
these defects may behavior empirically as a quantum two-level-system (TLS)
with characteristic frequency ranging about several gigahertz. The
anticrossings resulting from the resonance between the TLSs and qubit were
observed in the spectra of phase qubit \cite{Simmonds04,Sun10b}, flux qubit
\cite{Plourde05}, and charge qubit \cite{Schreier08}. Experiments have shown
that TLSs not only shorten the decoherence time \cite{Cooper04}, but also
reduce the visibility of Rabi oscillation of the qubit, limiting the
fedelity of the quantum gate. Moreover, an ensemble of TLSs with various
characteristic frequencies may produce low frequency $1/f$ noise \cit
{Shnirman05}. Therefore, it is imperative to understand the microscopic
coupling mechanism between TLS and superconducting qubits.

Unfortunately, it is nearly unattainable to directly probe a single TLS's
microscopic mechanism due to its microscopic nature. Nevertheless, utilizing
qubit as a detector of TLS supplied an alternative method to extract useful
information \cite{Cooper04,Martinis05,Yu08}. Based on the experimental
results, three coupling models between TLS and superconducting qubit were
suggested: critical current fluctuator \cite{Simmonds04}, electric dipole
\cite{Martinis05}, and flux fluctuator \cite{Cole10}. Great effort has been
put to determine which is the exact coupling mechanism \cit
{Martinis05,Tian07,Kim08,Lupascedilcu09,Cole10}. Recently, it is suggested
that one may clarify the coupling mechanism by investigating the
longitudinal component of the interaction Hamiltonian \cit
{Lupascedilcu09,Cole10}. Lupa\c{s}cu \emph{et al}. have measured the flux
qubit at symmetric double-well potential and only found transverse term \cit
{Lupascedilcu09}. Furthermore, Cole \emph{et al}. have theoretically shown
that for different models, the coupling form between qubit and TLS changes
remarkably. For the electric dipole model the coupling type is totally
transverse, while for the other two models, besides the transverse, a weak
longitudinal coupling exists \cite{Cole10}. However, their experiments in a
flux-biased phase qubit is unable to determine the coupling type, because
the observed longitudinal coupling strength is too small to discriminate it
from the experimental uncertainty. Therefore, two questions come out from
their works. One is whether we have to consider both transverse and
longitudinal terms simultaneously for all superconducting qubits coupled
with TLS. The other is whether the magnitude of the two terms depends on the
coupling model thereby we can determine the exact coupling model by
measuring the two terms. In this work, we have analyzed the interaction
Hamiltonian of the three models. We found that the transverse and
longitudinal terms vary for different types of superconducting qubits. For
phase qubits the longitudinal coupling is always small thereby it is not a
good system to probe the coupling form. However, the longitudinal term for
flux qubits is comparable to the transverse term. In addition, for different
coupling models the longitudinal term exhibits distinct flux bias
dependencies, supplying a hopeful scheme to clarify the microscopic model of
the TLS.\newline
\indent We start from a short review of the three models which are used to
describe the microscopic nature of the coupling between TLS and qubits.
Although they are also valid for flux qubits, we at first discuss them in a
flux biased phase qubit for simplicity. The first model is critical current
fluctuator. In this model, the microscopic TLS was assumed as a critical
current fluctuator whose two states respond to two different critical
currents of the Josephson junction \cite{Simmonds04}. The fluctuator could
be considered as a ion moving between the left and right well in a double
well potential. If $\hbar \varepsilon $ is the energy difference between the
two position states, $\Delta $ is the tunneling matrix element, the
interaction Hamiltonian can be written as \cite{Cole10}
\begin{equation*}
H_{I}=\upsilon _{i}\cos \hat{\phi}(\cos \theta \sigma _{T}^{x}+\sin \theta
\sigma _{T}^{z})
\end{equation*
with $\sigma _{T}^{x,z}$ being Pauli operators of TLS in its eigenenergy
space. $\upsilon _{i}=-\frac{\delta I_{0}\phi _{0}}{2\pi },$ where $\delta
I_{0}$ represents the difference of the critical currents for the ion
populating the right and left well, $\phi_0$ is flux quantization. $\hat{\phi}$ is phase difference across
the Josephson junction. $\theta $ denotes the relative orientation of the
TLS's configuration basis and eigenbasis, $\tan \theta =\varepsilon /\Delta
. Although in many literatures it is assumed $\theta =0$ \cit
{Simmonds04,Ku05}, we would like to keeping the above formula which is more
accurate and general.\newline
\indent The second model is the interaction of an electrical dipole with
field \cite{Martinis05}. TLS has been modeled as an electric charge
distribution that changed between the two states. In Ref. \cite{Martinis05},
each TLS was assumed as an electron of charge e at position R or L separated
by a distance $d,$ resulting a dipole moment $\mu =ed$. The interaction
Hamiltonian is given by
\begin{equation*}
H_{I}=\overrightarrow{\mu }\cdot \overrightarrow{E}=\upsilon _{q}\hat{q
(\cos \theta \sigma _{T}^{x}+\sin \theta \sigma _{T}^{z})\cos \eta
\end{equation*
where $\upsilon _{q}=\frac{2e^{2}d}{Cx}$. $x$ is the thickness of the
junction. $\hat{q}$ represent the number of Cooper-pairs tunneled across the
junction. $\eta $ denote the relative angle between electric dipole
\overrightarrow{\mu }$ and the electric field $\overrightarrow{E}$. The
defination of $\theta $ is terminologically the same as that in the last
model. However, $\varepsilon $ and $\Delta $ may depend on different
physical variables. It is worth to note that the coupling term in this model
is purely transverse no matter whether the double well of the TLS is
symmetric \cite{Martinis05,Lupascedilcu09,Cole10}. This is a useful
characteristic which offers a possibility to discriminate this coupling
mechanism from others.\newline
\indent Another reasonable model for TLS is magnetic flux fluctuator. It has
been found nearly three decades ago that the flux embraced by a rf-SQUID
fluctuates with frequency lying in low frequency regime. The flux
fluctuation is responsible for the dephasing of superconducting qubits.
Recently, several experiments were carried out to probe the flux noise and
found that the spectral density of the low frequency flux noise with the
form $1/f$ \cite{Yoshihara06,Kakuyanagi07,Bialczak07}. Moreover, Shnirman
\emph{et al}. have shown that a collective of TLS's with a natural
distribution accounts for both high frequency and low frequency $1/f$ noise
\cite{Shnirman05}. Therefore, a new explanation for TLS in superconducting
phase qubit was proposed, suggesting that the states of the TLS may modulate
the magnetic flux $\phi _{e}$ threading the superconducting loop \cit
{Cole10}. The resulted coupling is on the variable $\hat{\phi}$ for the
phase qubit. The interaction Hamiltonian can be written a
\begin{equation*}
H_{I}=\upsilon _{\phi }\hat{\phi}(\cos \theta \sigma _{T}^{x}+\sin \theta
\sigma _{T}^{z})
\end{equation*
where $\upsilon _{\phi }=-\frac{\delta \phi _{e}}{L}(\frac{\phi _{0}}{2\pi
)^{2}$. $\delta \phi _{e}$ is the difference of $\phi _{e}$ between the two
configuration states of TLS. $\theta $ is defined the same as before, with
\varepsilon $ and $\Delta $ relying on different physical variables.\newline
\begin{figure}[tbp]
\includegraphics [width=7.5cm,height=6cm]{fig1.eps}
\caption{(Color online) Schematic diagram of the spectrum of a phase qubit
resonantly coupled to a TLS. The green dashed line and red thin solid line
represent the resonant peaks of the two-photon transition from state
1 to state 4 of the composite system without or with longitudinal
coupling, respectively. Without longitudinal coupling, the
two-photon spectrum locates at the exact middle of $1\rightarrow2$ and $1\rightarrow3$ one-photon transition
lines. Note that with longitudinal coupling the two-photon spectrum can move up or
down relative to the middle position, corresponding to positive or negetive sign of
the longitudinal coupling. Here we chose positive sign as an example.
Inset: the energy levels of the resonant qubit-TLS system.}
\end{figure}
\indent The experimental investigation on the coupling mechanism is not very
convincing. Recently, Cole $et$ $al.$ proposed a scheme to probe the
coupling mechanism in a phase qubit \cite{Cole10}. Therein, whether the
longitudinal coupling exists is a crucial clue to decide which model is
true. The longitudinal coupling between resonant qubit-TLS leads to asymmetry of the
two-photon transition spectrum relative to the one-photon transitions
spectra: $\omega _{1\leftrightarrow 4}\neq \omega _{1\leftrightarrow
2}+\omega _{1\leftrightarrow 3}$ (1-4 denote the eigenstates of the coupled
TLS-qubit system), as shown in Fig. 1. Therefore, one could experimentally
resolve the coupling type of qubit-TLS system via spectral analysis.
However, their experiment can not confirm the existence of the longitudinal
coupling because its value is comparable to the measurement uncertainty.
Hence, they could not reach a conclusion on the correct model. In our
opinion, the key reason for the ambiguity is that the longitudinal is much
smaller than the transverse coupling in all three models. To demonstrate
this, we unify the interaction Hamiltonian
\begin{equation*}
H_{I}=\upsilon _{k}\hat{O}(\cos \theta \sigma _{T}^{x}+\sin \theta \sigma
_{T}^{z})
\end{equation*
where $k=i,\phi ,q$ and $\hat{O}=\cos \hat{\phi},\hat{\phi},\hat{q}$. Ignore
the mixed terms such as $\sigma _{q}^{z}\sigma _{T}^{x}$, which have no
effect on the spectrum of the system, we can write the interaction
Hamiltonian in the eigenenergy basis
\begin{equation*}
H_{I}=\upsilon _{k}(o_{x}^{k}\cos \theta \sigma _{q}^{x}\sigma
_{T}^{x}+o_{z}^{k}\sin \theta \sigma _{q}^{z}\sigma _{T}^{z})
\end{equation*
where the factors $o_{x,z}^{k}$ are given by
\begin{equation}
o_{x}^{k}=\frac{|\langle 1|\hat{O}|0\rangle +\langle 0|\hat{O}|1\rangle |}{2
,\indent o_{z}^{k}=\frac{|\langle 1|\hat{O}|1\rangle -\langle 0|\hat{O
|0\rangle |}{2}  \notag
\end{equation
For the electric dipole model, $\hat{q}$ has no diagonal elements,
o_{z}^{q}=0$, so there is no longitudinal coupling in this case. Turning to the other two models, we
numerically calculated $o_{x,z}^{i,\phi}$ as functions of flux bias using
the parameters in Ref. \cite{Cole10}, shown in Fig. 2. It is found that $\frac{o_{z}^{i,\phi }}{o_{x}^{i,\phi }}<\frac{1}{6}$. Moreover, for $\phi_e>0.6$, the qubit can not work
due to the large tunneling rate of the excite state; for $\phi_e<0.57$,
$o_{z}^{i,\phi}$ is at least one order of magnitude smaller than $o_{x}^{i,\phi}$.The much
smaller longitudinal coupling factor relative to the transverse one may be the main reason for which one can not
verify the existence of the longitudinal interaction between qubit and TLS.
Even worse, the corresponding coupling factors of the two models are roughly equal. This
is easy to understand if we notice that in phase qubit, $\phi \simeq \frac
\pi }{2}$. We substitute $\phi $ with $\frac{\pi }{2}+\varphi $, where
\varphi $ is a small quantity,
\begin{equation*}
\cos \phi =\cos (\frac{\pi }{2}+\varphi )=-\sin \varphi \simeq -\varphi
\frac{\pi }{2}-\phi
\end{equation*
\begin{figure}[tbp]
\includegraphics [width=8.5cm]{fig2.eps}
\caption{(Coler Online) Coupling factors of qubit- TLS interaction in phase
qubitb for the critical current fluctuator and flux fluctuator models. The
parameters of the phase qubit are: $C=850fF,L=720pH,I_{0}=984nA$. The green
dash-dotted and cyan dashed line denote the transverse and longitudinal
coupling factor $o_{x}^{i},o_{z}^{i}$ of the critical current fluctuator
model respectively. The red solid and purple dotted line denote $o_{x}^
\protect\phi },o_{z}^{\protect\phi }$ of the flux fluctuator model
respectively.}
\end{figure}
Taking $\cos \phi \simeq \frac{\pi }{2}-\phi $ into the coupling factors
expressions, we can obtain: $o_{x}^{i}\simeq o_{x}^{\phi }$,
o_{z}^{i}\simeq o_{z}^{\phi }$. Therefore, for phase qubits, the
longitudinal coupling is not sensitive to the coupling mechanism. Then, it is
difficult to clarify the coupling nature between TLS and phase qubit .
Although one may argue that the TLS parameter $\theta $ has a crucial effect
on the longitudinal coupling magnitude, unfortunately, till now, people are unable to control the angle $\theta $ due to the poor knowledge of TLS.

\indent Instead of phase qubit, we find that flux qubit is a possible system to
reveal the coupling nature of TLS and qubits. We start from a flux qubit
which consists of a superconducting loop interrupted by three Josephson
junctions \cite{Orlando99}. Two junctions are the same and the other one is
\alpha $ times smaller than them. If we assume that the large junctions have
a critical current $I_{0}$ and a capacitance $C$, then the critical current
and capacitance of the small junction are $\alpha I_{0}$ and $\alpha C,$
respectively. The Hamiltonian of the circuit is \cite{Orlando99}
\begin{eqnarray}
H_{q} &=&4E_{c}{\hat{n}_{1}}^{2}-E_{J}\cos {\hat{\phi}_{1}}+4E_{c}{\hat{n}_{2}}^{2}-E_{J}\cos
{\hat{\phi} _{2}}+\frac{4E_{c}}{\alpha }{\hat{n}_{3}}^{2}  \notag \\
&&-\alpha E_{J}\cos {\hat{\phi} _{3}}+E_{J}(2+\alpha )
\end{eqnarray
where $E_{c}=\frac{e^{2}}{2C}$, $E_{J}=I_{0}\phi _{0}/2\pi $. $\hat{\phi}
_{i} \;(i=1,2,3)$ is the phase difference across each junction, and its
conjugate variable $\hat{n}_{i}$ is the number of Cooper pair through each
junction. If the external magnetic flux $\phi_{ext}=f\phi_{0}$, using the
flux quantization condition, we get $\hat{\phi}_{3}=2\pi f+\hat{\phi}_{1}-\hat{\phi} _{2}$.
Transforming the coordinates $\hat{\phi} _{1}$, $\hat{\phi} _{2}$ to the sum and the
difference of the phases, $\hat{\phi} _{p}=(\hat{\phi}_{1}+\hat{\phi}_{2})/2,\,\hat{\phi}
_{m}=(\hat{\phi} _{1}-\hat{\phi} _{2})/2$, $H_{q}$ is reduced to
\begin{eqnarray}
H_{q} &=&E_{p}{\hat{n}_{p}}^{2}+E_{m}{\hat{n}_{m}}^{2}-2E_{J}\cos {\hat{\phi} _{p}}\cos {\hat{\phi}
_{m}}+E_{J}(2+\alpha)   \notag \\
&&-\alpha E_{J}\cos (2\pi f+2\hat{\phi} _{m}))\nonumber
\end{eqnarray
where $E_{p}=2E_{c},\,\hat{n}_{p}=-i\frac{\partial }{\partial \phi _{p}}$,
E_{m}=E_{p}/(1+2\alpha ),\,\hat{n}_{m}=-i\frac{\partial }{\partial \phi _{m}}$. We
have calculated the lowest three energy levels near $f=0.5$ , with typically
chosen parameters $E_{J}/E_{c}=40$, $\alpha =0.68$. In the region $0.49<f<0.51
$, the energy difference between the lowest two levels (qubit) is much
smaller than that between the upper two levels, showing a very good
nonlinearity which enables the spectroscopic experiment will not involve the
third level of the qubit. \newline
\indent In the three-junction flux qubit, each junction has the possibility
of containing TLS. Even though, we can prove numerically that the location
of the TLS in different junctions would not affect our results
qualitatively. Therefore, we consider that the TLS is in the small junction
without losing generality. For electric dipole model, the interaction term
is
\begin{eqnarray}
H_{I} &=&\vec{\mu}\cdot \vec{E}  \notag \\
&=&\frac{de}{x}\hat{V}(\cos \theta \sigma _{T}^{x}+\sin \theta \sigma
_{T}^{z})\cos \eta  \notag \\
&=&\frac{de}{x}\frac{\phi _{0}}{2\pi }2\dot{\hat{\phi}}_{m}(\cos \theta \sigma
_{T}^{x}+\sin \theta \sigma _{T}^{z})\cos \eta  \notag
\end{eqnarray
Using Heisenberg equation $\dot{\hat{\phi}}_m=\frac{1}{i\hbar }[\hat{\phi} _{m},H_{q}]
$, we obtain
\begin{equation}\label{4}
H_{I}=\frac{\hbar \omega _{q}d\langle 0|\hat{\phi} _{m}|1\rangle }{x}\cos \eta
\cos \theta \cdot \sigma _{q}^{x}\sigma _{T}^{x}
\end{equation
where $\hbar \omega _{q}$ is the eigenenergy of the flux qubit. Obviously,
similar to that in phase qubit the longitudinal coupling is zero.

For the other models, following the same procedures used in the phase qubit,
we can straightforwardly write out the interaction Hamiltonians.\newline
Critical current model:
\begin{eqnarray}
H_{I} &=&-\frac{\alpha \phi _{0}\delta I_{0}}{2\pi }\cos (2\pi f+2\hat{\phi}
_{m})(\cos \theta \sigma _{T}^{x}+\sin \theta \sigma _{T}^{z})  \notag \\
&=&-\frac{\alpha \phi _{0}\delta I_{0}}{2\pi }(o_{x}^{i}\cos \theta \sigma
_{q}^{x}\sigma _{T}^{x}+o_{z}^{i}\sin \theta \sigma _{q}^{z}\sigma _{T}^{z})
\end{eqnarray
\begin{eqnarray}
o_{x}^{i} &=&\frac{|\langle 1|\cos (2\pi f+2\hat{\phi} _{m})|0\rangle +\langle
0|\cos (2\pi f+2\hat{\phi} _{m})|1\rangle |}{2}  \notag \\
o_{z}^{i} &=&\frac{|\langle 1|\cos (2\pi f+2\hat{\phi} _{m})|1\rangle -\langle
0|\cos (2\pi f+2\hat{\phi} _{m})|0\rangle |}{2}  \notag
\end{eqnarray
Magnetic flux fluctuator model
\begin{eqnarray}
H_{I} &=&2\pi \alpha E_{J}\delta\phi_e\sin (2\pi f+2\hat{\phi} _{m})(\cos \theta \sigma
_{T}^{x}+\sin \theta \sigma _{T}^{z})  \notag \\
&=&2\pi \alpha E_{J}\delta\phi_e(o_{x}^{\phi }\cos \theta \sigma _{q}^{x}\sigma
_{T}^{x}+o_{z}^{\phi }\sin \theta \sigma _{q}^{z}\sigma _{T}^{z})
\end{eqnarray
\begin{eqnarray}
o_{x}^{\phi } &=&\frac{|\langle 1|\sin (2\pi f+2\hat{\phi} _{m})|0\rangle +\langle
0|\sin (2\pi f+2\hat{\phi} _{m})|1\rangle |}{2}  \notag \\
o_{z}^{\phi } &=&\frac{|\langle 1|\sin (2\pi f+2\hat{\phi} _{m})|1\rangle -\langle
0|\sin (2\pi f+2\hat{\phi} _{m})|0\rangle |}{2}  \notag
\end{eqnarray
\begin{figure}[tbp]
\includegraphics [width=8cm]{fig3.eps}
\caption{(Color online) Transverse (solid line) and longitudinal (dashed
line) coupling factors for critical current fluctuator model.}
\end{figure}
\begin{figure}[tbp]
\includegraphics [width=8cm]{fig4.eps}
\caption{(Color online) Transverse (solid line) and longitudinal (dashed
line) coupling factors for flux fluctuator model.}
\end{figure}
\indent Now we compare the magnitudes of the transverse and longitudinal
couplings. As discussed before, currently it is impossible to change the
orientation of the TLS basis, we focus on the factors $o_{x,z}^{i,\phi }$.
Using the same parameters as above ($E_{J}/E_{c}=40$, $\alpha =0.68$), we
have numerically calculated $o_{x,z}^{i,\phi }$ as functions of $f,$ shown
in Fig. 3 and 4. When $f$ varies from 0.5 to 0.51, $o_{x,z}^{i,\phi }$
exhibit remarkable changes with totally different trends. For critical
current fluctuator model (Fig. 3), the transverse coupling factor $o_{x}^{i}$
is zero at the degenerate point $f=0.5$ while the longitudinal factor
reaches the maximum. Then, away from $f=0.5$, the transverse factor
increases monotonically while the longitudinal one decreases gradually. At
f=0.51$, the transverse factor becomes much larger than the longitudinal
one. In recent experiments \cite{Lupascedilcu09}, the splitting resulted
from transverse coupling is observed at the degeneracy point of a flux
qubit. In addition, no longitudinal coupling is observed at $f=0.5$. These
behaviors disagree with the predictions of the critical current fluctuator
model, indicating that the critical current fluctuation is not the dominate
mechanism of the qubit-TLS coupling.\newline
\indent For the flux fluctuator model, the trends are totally converse (Fig.
4). The transverse factor reaches maximum at the degenerate point while the
longitudinal magnitude vanishes, indicating that the coupling is pure
transverse at this point. However, the electric dipole model predicts
similar pure transverse coupling [see Eq. (\ref{4})]. we can not
discriminate the flux fluctuator and the electric dipole model at the
degenerate point. When we tune the flux bias away from $f=0.5$, the
transverse factor decreases and the longitudinal one increases gradually. At
$f=0.51$, the longitudinal factor is larger than $1.5$ times of the
transverse one. Therefore, the flux fluctuator model contains both
transverse and longitudinal coupling but in the electric dipole model only
transverse interaction exists. We can clarify the microscopic mechanism of
TLS by studying the coupling term of TLS-flux qubit interaction in a flux
qubit biased away from the degenerate point. In practical, TLSs have been
observed in three-junction flux qubits biased away from the degenerate point
\cite{Plourde05}, suggesting that this spectral method is completely
feasible with the current technique.\newline
\indent In summary, we have calculated the qubit-TLS coupling factors of
both transverse and longitudinal terms under three microscopic models. It is
found that for phase qubits the longitudinal coupling is difficult to
observe because it is always much smaller than the transverse coupling.
Then, we show that in three-junction flux qubit the relative magnitude of
the transverse and longitudinal coupling factors are largely model-dependent
and very sensitive to the external flux bias. We propose that these features
can be used to clarify the microscopic model of TLS.

This work was supported in part by MOST (2011CB922104, 2011CBA00200), NSFC
(91021003, 10725415), and the Natural Science Foundation of Jiangsu Province
(BK2010012).

redpajama_set_name: RedPajamaArXiv


text:
Q: how to zip lists into a dictionary i have 6 lists all of equal length but when i zip them into a dictionary, the length of the dictionary is not equal to the length of the lists. Is my code wrong?
    print len(v)
    print len(t)
    print len(c)
    print len(s)
    print len(o)
    print len(v)

output:
79
79
79
79
79
79
   mydict[country] = dict(zip(v,zip(t,c,s,o,v)))

print len(mydict[country])

output:
22


sangu.me 9 out of 10 based on 844 ratings. 4,316 user reviews.
Washer fluid not spraying so I was wondering the location of the fuse box in the cabin. Can anyone help me find it? Also, if the washer fluid is not spraying, is there a fuse it could be even though the wipers function fine?
Where is the fuse box location for the power windows on a 2005 get turbo? 2 Answers. Seems my battery went dead, and after charging it the left power windows and the convertible top don't work.


text:
James D. Shipman
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text:
Q: Simplify $(x^3+x-1)(x^2+x+1)-(x-1)(x^4+x^2+1)$ Simplify $$A(x)=(x^3+x-1)(x^2+x+1)-(x-1)(x^4+x^2+1)$$
Is there something clever that we can do/notice here? E.g. in the first bracket $x^3-1=(x-1)(x^2+x+1)$. The second term is the same as the second term in $A(x)$. Thank you! I don't see anything else.

A: Alt. hint: $\,x^4+x^2+1\color{red}{+x^2-x^2}=\left(x^2+1\right)^2-x^2=\left(x^2+x+1\right)\left(x^2-x+1\right)\,$, then $\,x^2+x+1\,$ factors out.

A: Even just multiplying out gives directly
$x(2x^3 + x^2 + x - 1)$, which factorises then as
$$
(x^2 + x + 1)(2x - 1)x.
$$
The last step can be seen from the rational root theorem, which yields the factor $2x-1$.


Handmade Blue Round Key chain with bead work.
Blue round keychain with small beads connected at the bottom. Perfect for any set of keys!
Buy Handcrafted Beaded Blue Round Keychain, sold & shipped by Namaste where you can shop online for Indian Gift Store: Handicraft, Home Decor, Wedding, Rakhi & Diwali Gifts.
This Accessories collection has been tagged as handmade Key ring, return gift, indian handicraft.


Alpine Strikers FC welcomes families back to school and sports at our Family Night on Friday, August 24, 5:00-8:00 pm at Burgess Park.
This event is open to the public and raises money for our soccer club scholarship program. Alpine Strikers offers scholarships for our club teams and is committed to never turning away a player based on financial need.
Fun for all ages with food trucks, jump houses, beat the coach games, soccer obstacle courses, dribbling and shooting challenges, juggling competitions, prizes and more! More information is available online.
Rowan Higgins and JJ Jones celebrate father's day by going to the skateboard park at Burgess. Dad's Cory and Clay could not be happier!