Thursday, April 17, 2014

Dual Clinical Trial Announcements Offers New Hope for Treating Spinal Cord Injury

In a move that takes stem cell-based therapies for spinal cord injury one step closer in the long march from the lab bench to routine clinic use, StemCells, Inc., today announce that they have completed enrollment in a clinical trial that aims to treat chronic spinal cord injury.

This Phase I/II trial will evaluate the safety and early signs of effectiveness of the Company’s human neural stem cells in patients with varying degrees of injury. The cells that the company has branded HuCNS-SC were surgically transplanted into the enrolled patients. The Company is now monitoring changes in neurological function over a period of several years.

CIRM fostered this clinical trial by funding earlier basic research at the University of California at Irvine. Based in California, StemCells, Inc., states this trial holds promise for one day soon treating patients suffering from chronic spinal injury and paralysis. The Company’s Vice President Dr. Stephen Huhn said in a news release picked up by the Sacramento Business Journal:
"This is the first clinical trial evaluating stem cell transplantation in spinal cord injury to successfully complete enrollment. Successful dosing of all subjects in the trial is a major accomplishment for the field and the spinal cord injury program at StemCells, Inc.”
This advance comes on the heels of more clinical trial news from Neuralstem, Inc., and the University of California, San Diego School of Medicine. Yesterday they announced that the University’s review board had approval a Phase I trial to treat spinal cord injury patients with the company’s adult neural stem cells, NSI-566. This trial builds on successful results in animal models, which showed that paralyzed rats exhibited significant improvement in motor function—just days after being transplanted with the cells.

Neuralstem’s technology has already led to initially successful clinical trials in patients suffering from ALS, also known as Lou Gehrig’s disease. With the new spinal cord injury trial, the Company believes it can confirm a therapeutic strategy for reversing the debilitating effects of spinal injury. Karl Johe, Neuralstem's Chairman of the Board and Chief Scientific Officer, said in a recent news release picked up by Reuters: “
"With 30 successful spinal surgeries completed in our ALS trials, we feel we are ready to tackle spinal cord injury and are excited to begin this ground-breaking study.”
Researchers have often looked to regenerative medicine to treat conditions such as paralysis caused by spinal injury. Now, as companies like StemCells, Inc., and Neuralstem begin to move their technology from the lab and into patients, the long-held hopes of scientists, patients and their families is closer to becoming reality.

You can read about CIRM’s funded projects in the field in our spinal cord injury fact sheet.

Anne Holden

Wednesday, April 16, 2014

Genetically modified stem cells offer potential new path to treating Alzheimer’s disease

Dr. Mathew Blurton-Jones of U.C. Irvine: his new study may help open new approaches to Alzheimer's
The Holy Grail of medical research is to find a cure for deadly diseases. But in the case of diseases like Alzheimer’s, where we don’t even have any truly effective treatments, any research that offers the potential of a new approach to slowing the progression of the disease has to be considered an advance. That’s why research from the University of California at Irvine is encouraging news indeed.

One of the characteristics of Alzheimer’s is a build-up of plaques in the brain caused by too much of the protein amyloid-beta. It’s not known if that build-up is a cause or an effect of the disease but if it is a cause then, in theory at least, reducing that build-up could help stop or slow the progression of Alzheimer’s.

This is where an enzyme called neprilysin comes in. Neprilysin helps break down the accumulation of amyloid-beta. As researcher Dr. Mathew Blurton-Jones says in a news release:

"Studies suggest that neprilysin decreases with age and may therefore influence the risk of Alzheimer's disease. If amyloid accumulation is the driving cause of Alzheimer's disease, then therapies that either decrease amyloid-beta production or increase its degradation could be beneficial, especially if they are started early enough." 

So the researchers at U.C. Irvine took some neural or brain stem cells and genetically modified them so that they would produce 25 times more neprilysin than ordinary neural stem cells. They then injected them into two different kinds of mice that had forms of Alzheimer’s, targeting the areas that are most affected by the disease, the hippocampus and the subiculum.

The results, published in the journal Stem Cells Research and Therapy, showed some promising results. The mice given the genetically modified stem cells were found to have significantly reduced amounts of the amyloid-beta plaques in their brain. This result continued for at least one month after the transplant.

Now a lot of encouraging results in mice haven’t panned out in humans, but Dr. Blurton-Jones points out the importance of seeing this result in mice with two different forms of Alzheimer’s:

"Every mouse model of Alzheimer's disease is different and develops varying amounts, distribution, and types of amyloid-beta pathology. By studying the same question in two independent transgenic models, we can increase our confidence that these results are meaningful and broadly applicable to Alzheimer's disease."

 It still remains to be seen whether this approach will improve the functioning of the brain, that’s research that still has to be done, but it does suggest that it might offer a new approach to reducing the build-up of plaques in the brain, and so possibly slow the progression of the disease.

We have awarded almost $50 million in funding for more than a dozen different research projects focusing on finding ways to develop new treatments and even a cure for Alzheimer’s.

kevin mccormack

Tuesday, April 15, 2014

A placebo-controlled trial in cerebral palsy might unlock some answers for parents

The parents of children with cerebral palsy (CP) rank high in number among the desperate calls that come to CIRM wanting to know about stem cell therapies offered on the internet. They don’t like to hear that we have very little information suggesting benefit from stem cells in these kids and that there is little reason to believe the types of cells being offered could grow new brain tissue to repair the abnormal brain development seen in CP.

They like hearing that there is some evidence that the type of stem cells being used might be able to tamp down any inflammatory process that is hampering brain function, and that it might be possible for these cells to trigger some sort of innate repair mechanism within the child. But the bottom line is that we really don’t know, and we certainly don’t know what is the best cell type to use and how, when and where to deliver the cells to get the maximum benefit if there is any.

So, it was heartening to see that a clinical trial registered with the Food and Drug Administration is enrolling patients in a study designed to answer some of these questions. Sponsored by Cord Blood Registry and conducted at the University of Texas Health Sciences Center at Houston the trial will compare two types of stem cells that came from the children themselves. They will compare stem cells from some children’s own stored cord blood with stem cells from other children’s bone marrow.

The research team plans to recruit 15 children into each group and 10 in each will receive the stem cells and five will receive a placebo injection, containing no cells. The parents will not know which injection their children received but at the end of one year, the parents of those who received the placebo will be told and given the option of a stem cell injection.

The Los Angeles Business Journal was one of many outlets that picked up the company’s press release. In it, the lead researcher, UT’s Charles Cox, explained the effect they hoped to see: "There is preclinical data indicating that the ongoing neuro-inflammatory response is a driver of further injury in cerebral palsy so the hope is to reduce this neuro-inflammation. Our goal is to break the cycle of inflammation and injury." They plan to evaluate the children as six months, one year and 24 months. So, anxious parents may start to get a few answers in a year or so. CIRM convened a workshop on how stem cell science could impact CP and that cerebral palsy report is available online.

Don Gibbons

Monday, April 14, 2014

Changing landscape of funding stem cell therapies: not just a venture capitalist’s game

Entrepreneurs and researchers are finding new sources to cross the "valley of death" funding gap.
Neil Littman is the Business Development Officer at CIRM

In February I gave a talk at the Phaciliate Conference in Washington D.C. entitled Bridging the Funding Gap: Non-Profit and Industry Collaborations, CIRM’s Perspective. Phacilitate is an annual conference focused on the cell and gene therapy industry and attracts a variety of attendees from around the country. Beyond showcasing the latest technologies and scientific advancements, one of the major areas of focus of the conference is on raising money, collaborations and industry partnerships. The conference provides a great chance to reflect on the prior year’s activity and discuss the trends that may continue into the upcoming year.

One of the cornerstone pieces of my talk, and a theme I heard repeated throughout the conference, was the shift in the traditional funding continuum. What this means is that traditional sources of capital for early stage life science investments have shifted from venture capitalists to other sources of funding. Many life sciences focused venture funds have had a hard time raising new funds due to lackluster performance of their prior funds. This has served to shrink the available pool of venture capital and also consolidate it into the hands of those that have been able to raise new funds. Entrepreneurs and researchers have, therefore, had to look to other sources of capital to fund their research.

Fortunately, disease foundations have stepped in to help alleviate the funding gap. JDRF (the Juvenile Diabetes Research Foundation), for example, has become a significant source of funding for Type 1 diabetes. Their research funding has grown on an annual basis from a few hundred thousand dollars in the organization’s early years to over an estimated $110 million in 2012. In fact, CIRM has successfully partnered with JDRF to jointly provide over $50 million in funding to ViaCyte, a San Diego-based company developing an embryonic stem cell-derived product for the treatment of Type 1 diabetes.

In addition to disease foundations, venture philanthropists have become increasingly important in funding translational medicine and research. For example, in November 2013 Denny Sanford announced plans to donate $100 million to UC San Diego to accelerate discoveries in human stem cells into drugs and therapies to treat a wide range of diseases, from cancer to Alzheimer’s disease to neurological injury and stroke.

Finally, many large multinational pharmaceutical and biotechnology companies are looking at earlier stage opportunities in an effort to externalize R&D costs as a way to bolster lackluster pipelines beset by a plethora of late stage product failures. For example, Capricor, a CIRM grantee, recently announced a deal with Janssen (a division of Johnson & Johnson) for $12.5 million upfront and up to $300 million of potential milestones. CIRM is partially funding Capricor’s Phase 2 trial for myocardial infarction. Another example is Biogen Idec’s recent deal with another CIRM grantee, Sangamo Biosciences, in which Biogen agreed to pay Sangamo $20 million upfront and up to $300 million of potential milestones for the development of treatments for blood disorders. This includes the beta-thalassemia program funded under CIRM’s Strategic Partnership 2 Award.

It is imperative that CIRM leverage our resources with these other sources of capital in order to bring promising new therapies to patients and bridge the funding gap, often called the “valley of death”. Only by working together will we all be successful in delivering novel therapies to the patients who need them most.

-Neil Littman

Friday, April 11, 2014

Stem cell stories that caught our eye: cancer therapy with broad aim, lupus and politics again

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Attack on cancer stem cell advancing with a broad aim. Most of the advances in cancer in recent years require matching very specific therapies to a narrow set of patients with a specific genetic vulnerability—so called personalized cancer care. But this type of therapy is very expensive and frankly disappointing to the majority of patients who don’t fit the profile of responders. This week a CIRM-funded Disease Team was in the spotlight at the annual meeting of the American Association for Cancer Research for a therapy that has a very broad aim. The Stanford team plans to begin clinical trials later this year with a protein called an antibody that blocks a signal on the surface of cancer stem cells that inhibits our immune system’s ability to seek out and destroy tumors. The researchers have dubbed this signal the “don’t eat me gene” and this gene, CD47, seems to be present on a wide array of tumor types, which means the antibody might work in many cancers. It has in mice, but . . .

The cancer researchers are meeting in San Diego this year, and the San Diego Union Tribune ran a story about the Stanford presentation there. The clinical trial we will be funding with the therapy targets leukemia and you can read about our work to target those cancer stem cells in our leukemia fact sheet.

Cord Blood Benefit seen in lupus, but transient. medpageTODAY did a nice analysis of a study using stem cells from umbilical cord blood for treating lupus in patients that had failed conventional therapy. The Chinese team had used the mesenchymal type stem cells in the cord blood, which are known to have some anti-inflammatory properties. In the multicenter trial, 60 percent of the 40 patients who had received the stem cells had a major or partial clinical response to the therapy. But as usual with medpageTODAY, the author put the numbers in perspective. She noted that we don’t know what the cells do to elicit the response, and can only speculate that they secrete chemicals that tamp down the autoimmune reaction of the disease. Also, they noted that the cells do no stay in the patients for long periods and a third of the responders had relapsed within a year, suggesting the need for retreatment.

Scarless, baby-smooth wound healing possible? While it is easy to dismiss the social value of scarless wound healing—envisioning waiting rooms at cosmetic surgery centers—severe scaring can be very debilitating such as with severe injuries around the eyes or fingers. It turns out that babies are born with legendary soft skin, in part, because if they have any skin tears in the womb, their skin stem cells are different from our adult skin stem cells. They can heal wounds without any scaring. A team at Stanford has now isolated and identified these fetal skin stem cells opening up the possibility of finding out how they accomplish the scarless healing and replicating that method in adult tissue. Science Codex picked up a press release from the journal Advances in Wound Care and the release has a link to the free-access journal.

A week to remember the controversies underlying our field. Scientific American posted a blog this week with a nice time of the various actions by Congress and the executive branch that have impacted our ability to study and gain the benefits from stem cells. Then Nature posted a blog announcing that the National Institutes of Health had closed its center dedicated to stem cell research for no disclosed reason, although there is much buzzing in the community. Next, Inside Science posted that the anti-embryonic stem cell forces in the European Union had gathered enough signatures to put a measure on the ballot there. Then today, numerous outlets ran a story about South Carolina joining the long list of states that have introduced “personhood” legislation that would declare a fertilized egg a person and end up banning much stem cell research. Here is a version from the Charlotte Observer. Let’s hope the voters in this state, like every prior state where the measure has been introduced, muster the will to defeat it.

Don Gibbons

Thursday, April 10, 2014

Living proof exercising the brain helps it function, provides clues to improving stem cell therapy

Get in that wheel and exercise little guy; it's good for your brain.
We have long known the brain is not static. Parts of it change and become stronger in response to being stimulated. This “plasticity” as it is called, is generally attributed to changes in the nerves themselves. But a CIRM-funded Stanford team now has proof that strengthening the insulating myelin that wraps the nerves may have a critical role in this plasticity. Think of it as improving the roadbed for the signals being sent along the nerve highway.

A few recent studies have suggested this role for myelin, but they have looked at nerves growing in a lab dish. The tests that could have proved this is really happening in living animals have been too invasive until now. The Stanford team, led by Michelle Monje, used a new technique called optogenetics to make the connection in living mice. The procedure inserts the genes for light-sensitive neural switches into specific nerves. Those nerves then fire when researchers expose them to certain wavelengths of light. Because the light can diffuse through the brain from the surface, no invasive probes are necessary.

In this case, the light became the brain’s exercise bike. The nerves that had the added gene were the motor nerves, and after a period of stimulation the researchers saw myelin growth and in the following weeks improved muscle function in the mice.

Monje’s team attributed the improved myelin status to activity of a type of cell called an oligodendroctye precursor cell, which is the type of brain cell many stem cell scientists target for transplanting into patients. In stem cell therapy, many researchers consider it better to transplant these middle-man cells created from stem cells rather than the stem cells themselves. The current study gives the stem cell community ways to think about improving the results after transplant. Following up with brain stimulation may be important.

A press release from Stanford quotes Monje on the broad implications for her finding:
“Myelin plasticity is a fascinating concept that may help to explain how the brain adapts in response to experience or training. . . and future work on the molecular mechanisms responsible may ultimately shed light on a broad range of neurological and psychiatric diseases.”
In the CIRM-funded project using these findings, Monje’s goal is to find small molecules that could stimulate the activity of the oligodendrocyte precursor cells in patients who have undergone chemotherapy and are experiencing the mental decline dubbed “chemo brain.” The researchers’ findings are described in a paper that was published online today in Science Express.

Don Gibbons

CIRM funding: RN3-06510

Early results from stem cell-based trial for stroke give tangible hope to millions

We never would have expected two years or more out that patients could recover from a stroke. We thought the circuits were dead. Now we know they're still viable.
That encouraging soundbite by Stanford’s Dr. Gary Steinberg in Monday’s Health Day News is based on his team’s preliminary, unpublished results of a stem cell-based clinical trial for treating stroke. The trial is the first of its kind in North America, according to an American Association of Neurological Surgeons press release.

A stroke is a brain attack that occurs when blood flow to the brain is blocked either by a clot or a ruptured blood vessel. This attack disrupts the delivery of nutrients and oxygen to the brain and leads to cell death. Depending on the area of the stroke, survivors may lose their ability to speak, swallow, move their body, or recall memories. It is a leading cause of death, killing 130,000 people each year in the U.S., according to the National Stroke Association. There are about 7 million stroke survivors in the US over the age of 20.

Steinberg’s clinical trial was motivated by the many encouraging animal studies that have shown the promise of stem cells to improve stroke symptoms. In fact, a report in this week’s issue of Neurology by Drs. Steven Cramer and Weian Zhao of UC-Irvine’s Sue & Bill Gross Stem Cell Research Center, showed in 44 out of 46 preclinical animal studies that mesenchymal stem cells (MSCs) helped heal the damage wreaked by stroke.

In the Steinberg-led trial, MSCs isolated from the bone marrow of unrelated donors were injected into the brains of 18 people who had suffered strokes. The main goal of the study was to ensure safety of the injections. Three patients experience adverse events (bleeding, seizure, pneumonia) related to the surgery and they all recovered.

In addition to the good safety profile, all patients showed some signs of improvement. Two patients, both women, had dramatic recoveries. In describing one of the two patients, Dr. Steinberg told Health Day News that:
The 71-year-old could only move her left thumb. She couldn't move the arm or hand and could barely get her leg off the bed. The day after surgery, she was lifting her arm over her head, and lifting her leg off the bed. She's walking now. She was wheelchair-bound before.
The other patient, a 33 year-old, regained movement of her paralyzed arm as well as had improvement in her speech. Steinberg was careful to not draw too much from such phenomenal recoveries. He pointed out that these types of responses are far from typical. Also, the trial was not designed to include a “control” group; that is, patients who did not receive the stem cell injections. So it’s difficult to say with full assurance that the improvements were caused by the stem cells themselves or something about the surgical procedure, or something spontaneous that would have occurred without any intervention.

Still Dr. Cramer, who was not part of the study, is encouraged:
It's a small, early human study. It takes multiple steps to get to something clinically useful, and this is a nice, early step.
He also gave his take on how these mesenchymal stem cells work their magic, which appears not to be a replacement function:
What these cells seem to do instead is to modulate repair processes. They don't replace the damaged brain so much as massaging the bits that are left, to get maximum function out of them.
What is very clear is that these results justify larger trials with more patients using this MSC-based therapy approach. In addition, Steinberg also has a $20 million CIRM-funded Disease Team grant that aims to test embryonic stem cell-derived neuronal cells in stroke patients. This project’s goal is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA), a requirement to begin clinical trials.

With these multi pronged approaches to tackling disease, hopefully researchers will find the most safe and effective therapies sooner and help the millions who are stricken by the devastating effects of stroke.

For more information about CIRM-funded stroke research, visit our stroke fact sheet.

Todd Dubnicoff

Wednesday, April 9, 2014

Stem cell agency educating patients on how they can make a difference


New brochure that describes our stem cell bank initiative [download pdf]
Geoff Lomax is CIRM's Senior Officer for Medical & Ethical Standards

One thing patients and their families can do to advance the role of stem cells in curing disease is to donate a small skin or blood sample if asked. How can this help? Here is an anecdote from recently published research.

Perhaps you heard the recent news about a breakthrough that provides new hope for treating ALS, also known as Lou Gehrig's disease. Researchers at Harvard University used patients’ skin cells to create stem cells that can form any cell in the body. The researchers then transformed the stem cells into motor neurons. ALS is a disease where motor neuron death leads to the death of the patient. The research team observed that ALS patients’ motor neurons behaved differently that those of people without the disease. Specifically, the neurons were over stimulated and “firing” too rapidly. Based on this observation, the team conducted a clinical trial in a “dish.” They tested an anti-epilepsy medication on the ALS patient neurons to reduce their rate of firing, and in fact, the treatment slowed the cells down (read the Harvard Gazette report on the research). Experiments such as these (1) help explain the disease process and (2) allow testing of treatments in the laboratory.

CIRM believes success stories such as these will become more and more common as scientists use stem cells to study different diseases. In 2013, CIRM announced the creation of a stem cell bank designed to store and distribute cells representing different diseases including autism, blindness, cardiovascular disease, Alzheimer’s and liver disease. The bank is specifically intended to make stem cells available to researchers so they can better explain these diseases and test new treatments just like the Harvard team did.

One critical aspect of the project involves obtaining skin or blood samples from thousands of patient donors so they can be transformed into stem cells. The process of obtaining permissions from patients is called “informed consent.” Informed consent always includes information about the purpose of the research and disclosure of any risks to the participant. In the context of the CIRM stem cell bank, donors receive detailed information about how the cells might be used and distributed. Spelling all this out is rather lengthy with some consent forms running as long as 22 pages.

While providing comprehensive consent to donors in writing is necessary, we also believe it is helpful to give them easy to understand information about the essential and unique aspects of the research. To address this need, CIRM worked with experts in health communication to develop a brochure describing the Induced Pluripotent Stem Cell Initiative.

CIRM has distributed the brochure to researchers who are collecting cells from donors. The researchers have been pleased to receive this supplemental information to support the consent process. Again, the major purpose of the brochure is to highlight the unique and essential aspect of the stem cell bank. Thus, it emphasizes:
  • What are stem cells and why are they unique
  • How the donation process works
  • How donated cells will be used and
  • Where and to whom the stem cells will be distributed
These points are explained in plain English with many illustrations. We hope this level of information serves to reinforce the overall informed consent process. We hope patients come away from this experience feeling they have made a substantial contribution to science and medicine.

Geoff Lomax

Tuesday, April 8, 2014

Start the conversation, ask your relatives about stem cell value

Cynthia Schaffer supports CIRM’s Business Development and Industry Engagement and Commercialization activities.

We always consider ourselves on the front wave of technology here in California. We have Silicon Valley and a huge biotechnology sector. We are also the state that voted to create CIRM, the largest funder of stem cell research outside of the National Institutes of Health, which became even more relevant after this morning’s news that NIH is closing its stem cell center.

Yet, I was surprised by my recent conversation with an older relative in Florida. I was discussing the future of CIRM and what will happen as CIRM’s initial bolus of funding runs down? You know how it is with relatives, they care and they try to listen when you are talking about your life, but they don’t always get the story straight. So, I was not expecting much in the way of a reply. I was just sharing. But my relative’s reply was unexpected. He said:
“Oh, don’t worry. Stem cells are the wave of the future. Everyone wants to see stem cell research continue. We all want a longer, healthier life and stem cells are the best thing out there that can help us achieve those aims. Don’t worry, there will be another grant coming.”
Wow – I was shocked, happy, but shocked. My older, fiscally conservative relative believes in the future of stem cell research. And, he thinks it is worthy of continued funding. Great. Of course, after all the years of talking with me, he still does not understand that CIRM is the funding agency that makes the grants. But still, his heart was in the right place and, his answer gives me hope that the public education outreach efforts of CIRM and stem cell societies like The International Society of Stem Cell Research (ISSCR) and the Alliance for Regenerative Medicine (ARM) are working.

So, what do your relatives think about the future of stem cell research? It is an interesting topic of conversation and hopefully their answers will delight you. One thing is for sure, the conversation matters, and after this morning’s NIH news, state level programs may be even more important.

Cynthia Schaffer

Guest blogger Alan Trounson — March’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

This month’s report discusses a couple very pragmatic but elegant riffs on scientific methods that could make creation of two types of stem cells more practical. One laid out a path to nuclear transfer, or therapeutic cloning, that eliminates the need for donor eggs, something that has always put the brakes on creating stem cells via this route. The Oregon team that first reported success with nuclear transfer in humans developed the new method, which I won’t go into here in detail, but I do spell it out in my full report.

The other practical advance yielded a method to create iPS type reprogrammed stem cells from as little as a drop of blood instead of the table spoon generally needed by other methods. I find this worthy of highlighting in my monthly blog because it has such potential to make it feasible for the various stem cell banks around the world to include a broadly diverse set of cell lines that come closer to representing the population as a whole.

Requiring a tablespoon of blood means the donation needs to be drawn by a healthcare professional, which does not make it easy to extend creation of iPS cells lines to remote settings or to populations fearful of the procedure. Reducing the amount of blood required to less than a milliliter makes a simple finger prick sufficient to collect the sample. The Singapore team adjusted a number of kits readily available from research supply companies to create this protocol that seems to be at least as efficient in creating stem cells lines as other current techniques using blood samples.

This method could be ideally used with umbilical cord blood banking where a small aliquot could be retained for iPS cell development without significantly reducing the amount of cord blood available for immune or blood disease therapies.

This new method has potential to make it easier to fulfill the goals of an international network I helped to found. A group of us published an article in Cell Stem Cell last October in which we laid out the possibility of creating libraries of stem cell lines with sufficiently varied samples that 90 percent of the world’s population could find repair cells from the banks that reasonable matched their immune system. This would reduce the chances of complications from the donor tissue. A colleague wrote about the effort to create this international bank in this blog last fall.

My full report is available online, along with links to my reports from previous months.

A.T.