Editing Out Blood Disease


Gene therapy successful in 22 patients with severe form of the blood disorder beta-thalassemia

 

In a powerful example of bench-to-bedside science showing how observations made in the lab can spark life-altering therapies in the clinic, an international team of investigators has announced that gene therapy can be safe and effective for patients with a severe form of the blood disorder beta-thalassemia.

Led by Philippe Leboulch, lecturer in medicine, part-time, at Harvard Medical School and a sponsored collaborator in the Brigham and Women’s Hospital Division of Genetics, an international research team reports that a one-time treatment with the gene therapy known as LentiGlobin BB305 vector reduced or eliminated the need for blood transfusions in 22 patients with severe beta-thalassemia.

The results have been published in The New England Journal of Medicine.

“It was always our hope to bring our research findings to patients,” said Leboulch, whose primary appointment has transitioned to the University of Paris as professor of medicine and institute director. “We have taken our work from the lab, through preclinical models and past the proof-of-principle stage and are now able to gauge its effectiveness in patients with this disease. It is immensely gratifying.”

Restoring hemoglobin production

Beta-thalassemia is a genetic disorder that impairs the body’s ability to produce a key component of hemoglobin, the protein in red blood cells that carries oxygen to organs and tissue. Beta-thalassemia and sickle-cell disease are related disorders—both hamper hemoglobin production and can have lifelong repercussions.

From toddlerhood on, people with the most severe forms of beta-thalassemia require monthly blood transfusions to replenish their red blood cell supplies along with iron chelation to remove extra iron from the body.

As a postdoctoral fellow at Massachusetts Institute of Technology, Leboulch began researching a therapeutic approach to compensate for the genetic mutations that lead to both sickle-cell disease and beta-thalassemia. In the 1990s, Leboulch joined HMS and Brigham and Women’s, where he continued his work to develop a viral carrier, or vector, that could insert genetic instructions into a patient’s own blood stem cells and restore hemoglobin production.

Leboulch and colleagues hoped that introducing the altered stem cells back into people would allow the cells to make enough hemoglobin, eliminating the need for blood transfusions.

Leboulch and colleagues studied the vector, LentiGlobin, in pre-clinical models, publishing results from mouse studies in Science. In 2010, Leboulch and his collaborator, Marina Cavazzana of University Paris-Descartes, published a paper in Nature detailing the success of using LentiGlobin to genetically correct cells and transplant them into a single beta-thalassemia patient. Last year, they published in NEJM on a successful gene therapy of the first sickle-cell anemia patient using the same vector.

Blood transfusions no more

In the newly published NEJM study, Leboulch, Cavazzana and their colleagues teamed up with a second group of U.S. and international clinical investigators in Australia and Thailand to share data and results from their respective phase II clinical trials.

In total, the two teams treated 22 patients at six different sites around the world. Among nine patients with the most severe form of beta-thalassemia, the one-time treatment reduced the need for red-blood cell transfusions by 73 percent. Three of the nine subsequently discontinued transfusions altogether. Twelve of the 13 patients with a slightly less severe form of the disease no longer needed any blood transfusions after treatment.

The team reports no safety concerns—treatment-related adverse effects were typical of those seen in patients who receive transplants of their own stem cells.

“When you have an anecdote of a single patient, you never know if it will be confirmed. Here, with a multi-center trial in a larger number of patients, we see a convergence of results, and we can measure the magnitude of the therapeutic effect,” said Leboulch.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” he added. “But there is also hope with protocol modifications we have introduced in our phase III trials.”

Based on these results, two pre-drug marketing phase III clinical trials have begun.

Patents on the LentiGlobin BB305 vector are owned by Bluebird Bio, which also sponsored the study. Leboulch is one of the co-founders of Bluebird Bio.

A Surprising Safety Benefit


Firearm injuries drop nationwide during NRA conventions, research shows

 

Thousands of firearm injuries occur in the United States each year, but the likelihood of such injuries appears to drop substantially when gun enthusiasts hold large national meetings, according to research led by Harvard Medical School.

The results, published March 1 in The New England Journal of Medicine, show a 20 percent decline in gun injuries nationwide during the dates of the National Rifle Association’s annual convention.

The decrease, the researchers said, is likely fueled by the brief period of gun abstinence during such conventions—a possibility that warrants further exploration and analysis.

Because such meetings tend to attract gun enthusiasts and business owners who are well trained in gun use and safety, the findings seem to counter the common belief that most unintentional gun injuries result from inexperience and lack of firearms training, the researchers said. Many states require hunters and gun owners to complete mandatory safety classes, and the NRA itself offers courses designed to “ensure the safe and effective use of firearms.”

The study findings, however, suggest that experience and education can only go so far in reducing the risk, the research team said.

“Fewer people using guns means fewer gun injuries, which in some ways is not surprising,” said Anupam Jena, senior author of the study and the Ruth L. Newhouse Associate Professor of Health Care Policy at Harvard Medical School. “But the drop in gun injuries during these large meetings attended by thousands of well-trained gun owners seems to refute the idea that gun injuries stem solely from lack of experience and training in gun use.”

The researchers caution that their findings are based on an observational analysis and that the study was not designed to tease out cause and effect between injury rates and meeting attendance.

Jena and co-author Andrew Olenski, now a doctoral student in the Department of Economics at Columbia University, hypothesized that firearm use would decline during the dates of NRA meetings, which attract 80,000 or more attendees from across the United States.

Since conference visitors include avid firearm users and operators of venues where firearms are used, such as firing ranges and hunting grounds, the researchers suspected that gun use might decline during the dates of the event.

In their analysis, the researchers examined nearly 76 million medical insurance claims for emergency department visits and hospitalizations related to firearm injuries between 2007 and 2015. Then the team compared how many gun injuries occurred during NRA convention dates with the number of injuries that took place on identical days in surrounding weeks. Gun injuries on nonconvention days occurred at a rate of 1.5 per 100,000 people, compared with 1.25 on convention dates—a 20 percent difference, the analysis showed.

Additionally, the analysis revealed that the biggest reductions in injuries during convention dates were among men in states in the South and West that have the country’s highest rates of gun ownership, and among individuals residing in the state hosting the convention, all of which support the notion that the reduction in injury rates is related to attendance at the conventions.

Because of the relative rarity of gun-related homicides, suicides and fatal accidents, the researchers could not measure whether convention dates also coincided with a decline in gun-related deaths.

The new study is the latest in a series of analyses published by Jena looking into the effects of large meetings or events on various health outcomes. In previous research, Jena and colleagues examined what happens to heart patients when large numbers of cardiologists leave their practices to attend scientific meetings. Other studies examined what happens to people who need emergency medical treatment when the streets of a city are shut down and crowded with spectators during major marathon races and how the presence of safety inspectors impacts patient care during hospital accreditation visits.

In the same vein, Jena said, NRA meetings provided an interesting “natural experiment” to see what happens when a large number of avid gun users take a few days off from shooting.

“No matter how one feels about guns,” Jena said, “one thing that we should all recognize is that owning and operating a firearm entails risk.”

In 2014, there were more than 65,000 intentional firearm injuries in the United States and nearly 16,000 unintentional firearm injuries. Nearly 2,000 of the total injuries involved children under 18 years of age, according to the U.S. Centers for Disease Control and Prevention.

Survival Bump in Bladder Cancer with Keytruda


But no outcome advantage for Tecentriq in metastatic urothelial cancer

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Patients with recurrent urothelial cancer lived longer when they received pembrolizumab (Keytruda) instead of chemotherapy as second-line treatment, according to long-term follow of a randomized trial.

After a median follow-up of 28 months, patients treated with pembrolizumab had a median survival of 10.3 months versus 7.3 months for those who received chemotherapy. Both 12- and 24-month survival was significantly better in the group treated with the immunotherapeutic drug, according to Joaquim Bellmunt, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

 PD-L1 expression status did not influence response to treatment with pembrolizumab or the survival benefit, they reported here at the Genitourinary Cancers Symposium.

“Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy,” Bellmunt said. “This study provides level 1 evidence that supports the use of pembrolizumab as a standard of care for this patient population.”

Data from the trial, known as KEYNOTE 045, provided the basis for approval of pembrolizumab for advanced urothelial carcinoma, irrespective of PD-L1 status, in the U.S., Europe, and Japan, he added. The 2-year follow-up data remained consistent with the data that supported the approval.

A different PD-1/PD-L1 inhibitor failed to demonstrate an advantage over chemotherapy for PD-L1-positive locally advanced/metastatic urothelial cancer that progressed or relapsed after initial platinum-based chemotherapy. As previously reported, patients treated with atezolizumab (Tecentriq) had a median overall survival (OS) of 11.1 months versus 10.6 months for investigator’s choice of chemotherapy. An intention-to-treat (ITT) analysis of all treated patients, irrespective of PD-L1 status, yielded a similar result, reported Thomas Powles, MD, of Barts Cancer Institute in London.

The pembrolizumab results should increase confidence in second-line use of the drug, said invited discussant Robert Jones, MD, PhD, of the University of Glasgow in Scotland.

“This helps our patients make an informed decision about whether or not to accept this treatment,” said Jones. “The results remain in keeping with the possibility of a long immunotherapy [survival] tail. None of these data support a role for second-line cytotoxics after failure of platinum in preference to a checkpoint inhibitor.”

The pembrolizumab data affirmed findings initially reported at the 2016 Society for Immunotherapy of Cancer, followed by publication in the New England Journal of Medicine. At that point, after a median follow-up of 14 months, the median OS was 10.3 versus 7.4 months for the pembrolizumab and chemotherapy arms, respectively.

KEYNOTE 045 involved 542 patients whose disease had progressed or relapsed after first-line platinum-based chemotherapy. Almost half the patients had two or more high-risk characteristics.

The patients were randomized to pembrolizumab or the investigators’ choice of three different chemotherapy options: paclitaxel, docetaxel, or vinflunine. The trial had coprimary endpoints of OS and progression-free survival (PFS), as assessed in the ITT population and according to PD-L1 status (using ≥10% PD-L1 expression in tumor cells, lymphocytes, and macrophages to define positivity).

The initial results in favor of pembrolizumab represented a 27% reduction in the survival hazard (P=0.0022). The updated data reflected a 30% reduction in the survival hazard (95% CI 0.57-0.85, P=0.00017). The 12-month survival was 44.4% with pembrolizumab and 29.8% with chemotherapy, and the 24-month survival was 27.0% versus 14.3% with pembrolizumab and chemotherapy, respectively.

“By 24 months, 60% of patients in the chemotherapy arm had received an immunotherapeutic agent, including those who received pembrolizumab at crossover,” said Bellmunt.

Subgroup analysis demonstrated a consistent survival advantage for patients treated with pembrolizumab.

Analysis by PD-L1 status showed a median OS of 8.0 months with pembrolizumab and 4.9 months with chemotherapy in the PD-L1-positive patients (n=124) and 10.8 versus 7.7 months in the PD-L1-negative group.

Median PFS did not differ significantly between treatment groups after 14 or 28 months of follow-up (2.1 vs 3.3 months) although the proportion of patients who remained progression free at 12 months (18.4% vs 9.5%) and 24 months (12.5% vs 2.5%) favored pembrolizumab.

Objective response rate was twice as high with the PD-1 inhibitor than with chemotherapy (21.1% vs 11.0%).

Pembrolizumab was associated with a more favorable adverse-event profile, as patients treated with chemotherapy had more fatigue, diarrhea, asthenia, anemia, constipation peripheral sensory neuropathy, peripheral neuropathy, decreased neutrophil count, neutropenia, and alopecia. Immune-related adverse events occurred more often with pembrolizumab: hypothyroidism, pneumonitis, hyperthyroidism, and colitis.

Investigators in the atezolizumab study, known as IMvigor211, performed extensive exploratory analyses to gain insight into the negative result. They found a correlation between DNA damage response (DDR) mutations tumor mutational burden (TMB). Additional analysis showed no association between DDR and efficacy. However, they identified a significant benefit of atezolizumab in the small subgroup of patients (about 100 of 931) who had high TMB and tested positive for PD-L1 expression (IC 2/3): median OS of 17.8 versus 10.6 months, representing a 50% reduction in the hazard ratio (95% CI 0.29-0.86).

In his review of the two trials, Jones concluded that neither provided compelling evidence of a biomarker to predict response to PD-1/PD-L1 inhibition.

Findings raise new concerns about birth control safety


Birth Control

Since the 1960s, when the birth control pill made its debut, contraceptives have played a major role in family planning. So when researchers discovered that women taking hormone-based birth control had a higher incidence of breast cancer, making the contraceptives safer became an important public health priority. Many experts believed they found a solution in options with far lower doses of estrogen, a hormone long linked to breast cancer occurrence. But a new study suggests that low-dose contraceptives have not had the impact doctors expected, and experts are urging women to talk to their doctors about the implications for their breast health, even though the overall risk remains relatively small.

The study, published in December in The New England Journal of Medicine, followed 1.8 million women for an average of about 11 years, finding that those on hormonal contraception had a 20 percent higher risk of breast cancer—no matter the dose of estrogen—than women who never used those birth control methods. It’s an important discovery, especially with an estimated 140 million women across the globe using some form of hormonal contraception. Now, the findings have experts taking a closer look at another hormone singled out by the study: progestin.

Hormonal birth control methods, which include pills, patches, shots, and vaginal rings or intrauterine devices, prevent pregnancy by delivering combinations of synthetic estrogen and progestin, or just progestin alone, into the body. Estrogen and progestin stop the ovaries from releasing eggs, thicken the cervical mucus to keep sperm from entering the uterus, and thin the lining of the uterus to prevent implantation. Because high estrogen levels may cause certain types of cancer cells to grow, experts have long believed estrogen was the main hormonal culprit linking the contraceptives to an increased breast cancer risk, says Justin Chura, MD, Chief of Surgery and Director of Gynecologic Oncology and Robotic Surgery at our hospital near Philadelphia.

“ Now we see that the progestin plays a role, as well in the risk. We definitely had a faulty assumption going in.” – Justin Chura, MD – Chief of Surgery and Director of Gynecologic Oncology

There’s no reason for panic, Dr. Chura says, since the risk of breast cancer from hormonal contraception remains relatively small for most women. “Oral contraceptives are still a great class of drugs,” he says. “There is no ‘free lunch’ in terms of any of the medications we prescribe. There are always risks and benefits.” Such risks for hormonal contraception include blood clots, strokes and heart attacks. Benefits typically include a reduced risk of other types of cancer, including ovarian and endometrial cancers, as well as lighter or more regulated menstrual cycles, and, of course, help with family planning.

But each woman should weigh her individual risks, Dr. Chura says. Because breast cancer risk increases with both age and the length of time hormonal contraceptives are used, women already at higher risk for breast cancer, and those who are older and no longer planning to have children, may want to consider switching to a hormone-free birth control method, such as a diaphragm or condoms. Older women who have been on hormone-based birth control for a number of years may also consider getting screened for breast cancer at the earliest age that guidelines recommend. And women who are on progestin-only contraception may consider talking to their doctor about changing their birth control method.

For women in their 20s, the benefits of hormonal contraception often outweigh the risks, but medical and family histories still come into play. “Even if you’re 25, if you’re a BRCA mutation carrier, it makes sense for you to factor in the breast cancer risk that comes with hormonal contraception because you’re already at a higher risk for breast cancer than people without that mutation,” Dr. Chura says. Oral contraceptives, though, are also known to decrease the risk of ovarian cancer for patients with and without a BRCA mutation.

Despite the new findings, Dr. Chura says women should talk to their doctor before making any changes to their birth control. “Now women can have more educated discussions with their doctors,” he says.

How 1 Sip of Vodka Tonic Sent a Woman to the ER


One sip of a vodka tonic landed a 35-year-old woman in the emergency room, and seven years later, she’s still dealing with the damage caused by the drink, according to a new report of her case.

The woman had a rare condition called “quinine-induced thrombotic microangiopathy,” which caused a body-wide reaction to quinine, a chemical found in tonic water, the doctors who treated her wrote in the case report, published today (Jan. 4) in The New England Journal of Medicine.

vodka-tonic

 The illness “hit like lightning,” said Dr. James George, a hematologist at the University of Oklahoma and the lead author of the report.

At the time of the incident in 2009, the woman told doctors that she had suddenly become ill when driving home from an office party. She developed chills, muscle aches, nausea and abdominal cramps, the doctors wrote.

That night, she ran a fever of 102 degrees Fahrenheit (38.9 degrees Celcius), and her stomach problems persisted. But by the time she went to the emergency room the next morning, her symptoms had improved. At the time, the ER doctors suspected that the woman had viral gastroenteritis — the stomach flu.

 But the woman returned to the ER two days later; she still had back pain and had not urinated since she got sick, according to the case report. This time, she was admitted to the hospital, where tests showed that she had experienced kidney damage, according to the report.

The doctors suspected that the woman had thrombotic microangiopathy (TMA), which occurs when blood clots form in the tiny vessels in the body and can be caused by a range of factors, George said.

In her case, however, the cause of TMA wasn’t one that doctors often see, such as problems with blood-clotting mechanisms or a particular type of E. coli infection, George said.

Quinine, the chemical found in tonic water, can also cause TMA, but George said the woman told him that she didn’t take quinine pills or drink gin and tonics. (The Food and Drug Administration banned quinine pills in 2007 because of severe reactions linked to them.)

It was only then that the woman recalled having a sip of a vodka tonic at her office holiday party the night she got sick, George said.

In addition, she also realized that she had a similar reaction 16 months earlier, when she drank a vodka tonic at a wedding and also had to go to the hospital, according to the report. That time, however, her major symptom was a severe headache, the doctors wrote.

When a person has quinine-induced TMA, he or she has a particular type of “auto-antibody” in the blood, George told Live Science. Auto-antibodies, which are found in people with autoimmune disease, attack the body as if it were a “foreign” invader.

Normally, these particular auto-antibodies are not very active in the body, George said.

But when the person ingests quinine, the chemical binds to these auto-antibodies and causes them to change their shape, George said. In their new shape, they’re able to attack cells in the body aggressively, inflicting serious damage, he said. Once the quinine is cleared from the body, the auto-antibodies return to their harmless state, he added; only the damage to the body is left. [The 16 Strangest Medical Cases of 2016]

“It’s like a tornado going through town, and then you spend a month cleaning up,” George said.

Indeed, George noted that it was likely that by the time the woman had gone to the emergency room, the quinine had already left her body. However, the auto-antibodies had enough time to do severe damage to her kidneys, in particular, he said. The kidneys are particularly vulnerable to damage from TMA because they have an abundance of very small and delicate blood vessels, he added.

The woman was the 19th patient that George had seen with quinine-induced TMA over a 15-year period, he said. For someone to have a reaction this severe to the concentration of quinine in tonic water, he or she would have to be extremely sensitive to the chemical, he said.

Currently, there is no specific treatment for quinine-induced TMA, George said. The woman did spend about a week in the hospital, but during this time, she was not acutely ill, he said. Because of the damage to her kidneys, she had to undergo dialysis for two months, according to the report.

At a recent follow-up visit seven years later, the woman told doctors that she was doing well and was able to fulfill her responsibilities with her family and her career. She is taking medications for her kidneys, and she often has trouble thinking of “particular words during conversations and [had] to stop in the middle of her sentences to ‘wait for [her] brain to catch up,'” she said, according to the report. The damage from the auto-antibodies also might have affected some of the small blood vessels in her brain, George noted.

NASA Confesses to Dosing Americans with Air-borne Lithium & Other Chemicals


NASA Chemtrials

There’s the official explanation for why NASA is spraying lithium, a pharmaceutical drug most often used to treat people with manic depression or bi-polar disorder, into our ionosphere, and then there is the probable reason(s). It would be easier to accept NASA’s official explanation if they were not so secretive about everything they study and do in space – but one thing is for certain – NASA’s own personnel have admitted that lithium, along with other chemicals, are intentionally being placed into our environment regularly. It is possible that many of NASA’s own employees aren’t even aware of the true motivations for carrying out such a project, ironically displaying the very behaviors that these chemicals/pharmaceuticals are meant to instill.

In the first bomb-shell video a NASA employee (Douglas.e.rowland@nasa.gov) admits that lithium is being sprayed in the atmosphere, and says that it is “harmless to the environment.”

Before I give you NASA’s official explanation of why thy are spraying psych-meds over hundreds of thousands of Americans, I’d like to point you to some references so that you can do your own research, and discover that this is no conspiracy theory. It is very real, and there is ample scientific documentation to corroborate what I put forth here:

A Pub Med abstract titled, Feasibility of Aerosol Vaccinations in Humans discusses how an increase in antigen volumes can be beneficial in aerosol delivery of vaccines, and could be used in “developing countries and disaster areas.” The abstract also admits that several thousand human subjects have already been aerosol vaccinated with live attenuated measles and influenza A vaccines. The executive summary further states that aerosol vaccinations are ideal for “large populations.” This has apparently been happening since as early as 2003.

Another discussion of aerosolized vaccinations can be found in The New England Journal of Medicine. A Randomized, Controlled Trial of Aerosolized Vaccines Against Measles states that these vaccines were tested on children in India that were as young 9 months old.

The World Health Organization has been researching aerosol vaccines for years now, as have “philanthropic” agencies which have clear aims to sterilize the population. It is also worth noting that the pharmaceutical industry has been absolved from any legal responsibility for medicating the masses since they were awarded  legal protection from all lawsuits by Congress in 1986. This law was challenged, but upheld by the U.S. Supreme Court in 2011. Many powerful agencies are making sure that we “take our medicine.”

In fact, many nations are participating in our unwitting, forced vaccination, and the dumping of any number of attenuated viruses, chemical concoctions and other ‘chemtrails’ on our heads with dogged frequency.

The Office of the Gene Technology Regulator (OGTR) considered giving a license application to PaxVax Australia (PaxVax) for the intentional release of a GMO vaccine consisting of live bacteria into the environment in Queensland, South Australia, Western Australia and Victoria. They planned to release cholera on their people.

According to the regulator, this GMO vaccine qualified as a limited and controlled release under section 50A of the Gene Technology Act 2000.

Of course, we can’t ignore the USA. Michael Greenwood wrote an article stating that:

“The incidence of human West Nile virus cases can be significantly reduced through large–scale aerial spraying that targets adult mosquitoes, according to research by the Yale School of Public Health and the California Department of Public Health.”

So, hopefully we’ve established that this IS happening. But why?

As more nations refuse genetically modified food, and refuse to drink fluoridated water, which has beennamed as a neurotoxin by one of the world’s premiere medical journals, the power structure that desires a complicit population has to figure out a way to alter our neurochemistry.

READ: NASA Takes Chemtrail Spraying Program to Outer Space

Lithium alters how we think by changing the levels of serotonin and norepinephrine secreted by our endocrine system. Lithium strongly alters the brain system, yet the NASA employee in the above video states that “it is not dangerous” and doesn’t harm the population. Even doctors who normally prescribe this medication for the mentally ill have said that it is dangerous because it is hard to figure out proper dosing. Surely, spraying copious amounts of lithium indiscriminately into the air via aerosols should be questioned – but here’s NASA’s official stance on this practice:

“The project is studying neutral and charged particles in the ionosphere and how each affects the way the other moves resulting in currents in the region. The variations matter because all of our communications and GPS satellites send signals through the ionosphere. A disturbed ionosphere translates to disturbed signals, so scientists want to know just what causes the ionosphere to behave in specific ways.” (NASA) 

Meanwhile, should the over-medicated start to actually figure out what is being done to them, thegovernment has imposed gag orders on the National Weather Service (NWS) and the National Oceanic and Atmospheric Administration (NOAA) who might easily refute the ridiculous claims of NASA.

The US Navy admits to conducting electromagnetic warfare drills over the Olympic Peninsula. Reader submitted photo.

The US Navy admits to conducting electromagnetic warfare drills over the Olympic Peninsula. Reader submitted photo.

Notably, every single person who works for NASA, the NWS or NOAA are paid with tax payer dollars.This means that we are paying to be medicated and poisoned.

Here, to corroborate information being given by the NASA employee in the video, is the Code 8440 RMMO which states the exact purpose of using Wallops Flight Facility to launch a rocket containing lithium thermite:

Purpose: The primary purpose of this mission was to test the loading methods for lithium canisters to be flown on the upcoming Kudeki (Kwajalein, April 2013) and Pfaff (Wallops, June 2013) missions, and verify their functionality under sounding rocket launch and space flight conditions.

Rocket Type: Two-stage Terrier MK70 Improved-Orion

Location: Wallops Range

Launcher: MRL

Date of Launch: January 29, 2013

Time: 17:50 EST

Experiment results: Thermistor data looked nominal. Good report from airborne optical platform of recorded video and lithium clouds also visible by ground observation.’

We also learn from this specific call that lithium has been dumped in our skies since 1970. If you wanted to medicate the masses to create mindless, slave-like prisoners who didn’t even know they were imprisoned, this is surely a good way to do it. Spraying lithium into our skies, along with countless other bacteria, viruses, prions, parasites, fungi, carcinogens, toxins, hormone-altering drugs, anti-flora and anti-fauna, as well as gene-altering micro-dust is nothing more than bio-warfare against the world’s citizenry. You can call them chemtrails or something else, the effect is the same.

“The conscious and intelligent manipulation of the organized habits and opinions of the masses is an important element in democratic society. Those who manipulate this unseen mechanism of society constitute an invisible government which is the true ruling power of our country. …We are governed, our minds are molded, our tastes formed, our ideas suggested, largely by men we have never heard of. This is a logical result of the way in which our democratic society is organized. Vast numbers of human beings must cooperate in this manner if they are to live together as a smoothly functioning society. …In almost every act of our daily lives, whether in the sphere of politics or business, in our social conduct or our ethical thinking, we are dominated by the relatively small number of personswho understand the mental processes and social patterns of the masses. It is they who pull the wires which control the public mind.” ~ Edward L. Bernays, Master Propagandist

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias.


BACKGROUND

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).

METHODS

We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.

RESULTS

Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

CONCLUSIONS

Ponatinib had significant antileukemic activity across categories of disease stage and mutation status.

 

Source: NEJM

 

CLOTBUST-HF: Hands-Free Ultrasound and tPA in Acute Stroke


Intracranial ultrasound treatment using an operator-independent device together with tissue plasminogen activator (tPA) in stroke patients appears to be safe and produced promising recanalization rates, a new study has shown.

The study, published online in Stroke on October 24, was led by Andrew D. Barreto, MD, University of Texas Health Science Center at Houston.

He explained to Medscape Medical News that ultrasound therapy causes the meshwork of fibrin strands within the clot to disperse, thereby allowing better access of tPA to the clot. “We are particularly targeting patients who have clots that are not likely to lyse completely with tPA — those with moderate to severe strokes,” Dr. Barreto noted.

“Many smaller studies have been performed with transcranial ultrasound and it does seem to have efficacy in helping to dissolve the clot,” he said. The most cited study is the original CLOTBUST(Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic TPA) study published in 2004 in the New England Journal of Medicine, which showed a recanalization rate of 38% with the combination of ultrasound and tPA vs 13% for those given tPA alone.

However, Dr. Barreto noted that delivery of ultrasound via cranial bone windows requires training for both anatomic localization and waveform recognition, which is considered impractical for large-scale use. “As you have to hold the ultrasound device at the same time as identifying the clot, it is too difficult to train enough people to perform the procedure as an emergency bedside therapeutic,” he said.

“Mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle,” the researchers write in the Stroke paper.

Operator-independent transcranial stroke treatment device.Source: The investigators

“To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase 3 clinical trial feasible,” they add.

Hands-Free Device

Such a “hands-free” device has now been manufactured by Cerevast Therapeutics, and the current study represents the first-ever exposure of patients with acute stroke to a combination of tPA and this hands-free ultrasound device. “This device has been manufactured so that it can be used without special training and be applied to all stroke patients by just placing it on their heads,” Dr. Barreto said.

“It is battery powered and easy to fit. One size fits all, with an adjustable head size and ear position,” he explained. “It has been designed so that the probes are positioned in the areas of thinnest bone of the skull: 6 probes on the left and 6 on the right. The device rotates and sequentially fires each probe, thus targeting all the areas of the brain where a large blood clot would be.”

For the current study, known as CLOTBUST-Hands Free (CLOTBUST-HF), 20 stroke patients with a median National Institutes of Health Stroke Scale score of 15 received standard-dose intravenous tPA, along with 2-MHz pulsed-wave ultrasound therapy delivered by the CLOTBUST-HF device used for 2 hours.

Sites of occlusion were middle cerebral artery in 14 patients, terminal internal carotid artery in 3 patients, and vertebral artery in 3 patients. All patients tolerated the entire 2 hours of ultrasound treatment, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device.

40% Recanalization Rate

At 2 hours, 40% of patients had complete recanalization and 10% had partial recanalization. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate at 57%. At 90 days, 5 patients (25%) had an excellent outcome, defined as a modified Rankin scale score of 0 to 1.

“The recanalization rate of 40% is in line with that shown in the NEJM paper. But we did not have a control group in this study,” Dr. Barreto commented. “At day 90 we had a lower percentage of patients with an excellent outcome than in the previous study, but we only had 20 patients so it is difficult to say much about a clinical outcome.”

“This is just a pilot study looking at safety of delivering ultrasound treatment to different areas of the brain. We didn’t see any safety issues and the results definitely suggest the approach is feasible,” he added.

A phase 3 trial — CLOTBUST-ER — is now underway with the hands-free device. The trial is being conducted in 830 patients from 14 countries, with results expected in 2 to 3 years.

This study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Cerevast Therapeutics provided the study devices and was not involved in the study design, analysis, or manuscript preparation. A coauthor serves as a consultant to Cerevast Therapeutics Inc and holds a US patent on the technology.

Use of Oral Fluconazole during Pregnancy and the Risk of Birth Defects.


BACKGROUND

Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects.

METHODS

In a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents.

RESULTS

The majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71).

CONCLUSIONS

Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot.

Source: NEJM

 

 

 

 

 

Anti-Fungal Drug Not Tied to Most Birth Defects.


Although some reports have shown that high doses of the anti-fungal drugfluconazole (Diflucan) may raise the risk of birth defects, a new Danish review finds that more commonly prescribed lower doses of the medicine do not carry the same dangers.

Yet, in spite of this reassurance, experts may remain reluctant to prescribe the drug for expectant mothers who have yeast infections, since it is still linked to an increased risk of a rare congenital heart problem called tetralogy of Fallot.

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“Many pregnant women suffer from a yeast infection called vaginal candidiasis, or vaginal thrush, which is the most common clinical indication for use of oral fluconazole,” explained lead researcher Ditte Molgaard-Nielsen, an epidemiologist at the Statens Serum Institute in Copenhagen.

First-line treatment for vaginal candidiasis during pregnancy is vaginal preparations of topical anti-fungal drugs, she noted.

“However, in cases when topical treatment is ineffective this study provides comprehensive safety information, and may help inform clinical decisions when treatment with oral fluconazole is considered in pregnancy,” Molgaard-Nielsen said.

Specifically, the researchers looked at 15 birth defects linked to fluconazole and found it was not associated with an increased risk for 14 of them, she said.

“However, we did see an increase in the risk of tetralogy of Fallot, an uncommon congenital heart defect, but the number of exposed cases were few and this association should be confirmed in other studies before anything can be concluded with any certainty,” Molgaard-Nielsen added.

The report was published Aug. 29 in the New England Journal of Medicine.

Dr. Scott Berns, senior vice president and deputy medical officer for the March of Dimes, said that “when pregnant it is important to avoid taking any medicines unnecessarily.”

“I would chose the topical drug to treat a yeast infection. That is my first line,” he said. “If I had to use oral fluconazole, this study is reassuring that most of the time the baby is going to be fine. But, there is that small chance of tetralogy of Fallot. So, why take that chance?”

Another expert doesn’t think these findings will change clinical practice.

“Ob/Gyns are still going to be reluctant to prescribe this drug,” said Dr. Kecia Gaither, director of maternal fetal medicine at Brookdale University Hospital and Medical Center in Brooklyn, N.Y.

Gaither prefers to use natural methods for treating yeast infections. “One of them is increasing the use of yogurt intake,” she said. “There is certain bacteria in yogurt that prevents yeast infections. I have not run into a person who continues to have recurrent yeast infections after that is done.”

For the study, Molgaard-Nielsen’s team collected data on more than 7,300 women who took fluconazole during their pregnancy, among whom 210 infants were born with birth defects, and compared them to a control group of more than 968,000 unexposed women, among whom more than 25,000 babies were born with birth defects.

In both groups, the risk for having an infant with a birth defect was 0.6 percent, the researchers found.

Moreover, fluconazole wasn’t linked to a significantly increased risk for 14 of 15 birth defects to which the drug had been previously linked, they added.

These include craniosynostosis (a defect in the baby’s skull), middle ear defects, cleft palate, cleft lip, limb defects, an abnormal number of finger or toes, fused fingers or toes, diaphragmatic hernia, heart defects and shifting of a lung.

There was, however, a significantly increased risk of tetralogy of Fallot, with seven cases (0.10 percent) among women who took fluconazole, compared with 287 cases (0.03 percent) in unexposed women, the researchers found.

According to the U.S. National Institutes of Health, tetralogy of Fallot is a rare, complex birth defect where four different areas of the heart are malformed and the heart cannot pump enough blood or oxygen to the rest of the body. Surgery is usually required shortly after birth, although the long-term outlook for these patients has improved greatly in recent years.

Source: Drugs.com