2019 Innovation Fund Showcase articles
Read about some of the projects featured at the 2019 Innovation Fund showcase.
The Innovation Fund is a joint initiative between the Ministry of Health (MOH) and the OMA. It provides funding for projects by academic physicians. Learn more about the Innovation Fund.
On this page, we’ve gathered five articles written about the 2019 Innovation Fund Showcase and several projects that were featured.
- Innovation Fund Showcase
- MOLLI (Best in Technological Innovation winner)
- Surgeon Cost Report Card
- Hand hygiene
- Fecal transplants
Innovation Fund Showcase
Health-care research led by Ontario’s physicians honoured at Innovation Fund Showcase
By: Colin Gray
What strikes you first is the extraordinary number of ideas on display. To wander around the Innovation Fund Showcase, held Nov. 14, 2019, at the MaRS Discovery District in Toronto, is to be literally surrounded by large posters promoting and scores of people discussing, health-care innovations of every type.
Virtual clinics to improve quality of care and outcomes in cases of heart failure. An online resource to support the creation of senior-friendly emergency departments. An opioid safety program for pain clinics. 3D printing of anatomical models to improve training.
These are ideas that have nothing in common, other than the fact that doctors felt strongly enough about them to propose projects around them and were lucky enough to have Ontario's Innovation Fund provide seed money for those projects.
The Innovation Fund was launched in 2008, as a joint initiative of the Ontario Medical Association and the Ministry of Health and Long-Term Care. It is a product of the Academic Health Science Centre Alternative Funding Plan that allows practicing physicians to be compensated for the time spent on teaching, research and related administration.
The fund is directed by the Innovation Fund Provincial Oversight Committee, which consists of 12 members, and is headed by Dr. Richard Weisel. Dr. Weisel is a cardiac surgeon at the University Health Network, and he never misses an opportunity to extol the Innovation Fund's virtues.
“Academic physicians love this fund, because they are curious people, and always looking for new things,” said Dr. Weisel. “And this gives them the chance to get it started. And then, if it works, let's roll it out. Let's take it from a small area in eastern Ontario and let's move it west and let's get it all over the province. That's what our goal is.”
The fund is available to academic physicians working in Ontario’s 17 Academic Health Science Centres. They submit proposals, which are subjected to a competitive peer review to select the most appropriate projects. Since 2008, the Innovation Fund has provided $100 million to seed, or start up, some 1,300. IFPOC also works with other organizations to seek opportunities to find further funding for those projects that turn out to be successful.
Every three years, IFPOC holds a showcase conference to highlight some of the extraordinary work being undertaken by academic physicians from across Ontario, using Innovation Fund support.
This year, the Innovation Fund Showcase highlighted some of the best projects from recent years. Health Minister Christine Elliott handed out this year's awards to the best and most promising innovations.
Dr. Paul Tenenbein welcomed conference attendees on behalf of OMA President Dr. Sohail Gandhi.
“Every one of those 1,300 projects represents the best of what we do,” said Dr. Tenenbein. “Ontario’s academic physicians, bring to work every day: diligence, curiosity, and a laser-beam focus on finding a better way, a faster way, a more patient-friendly way. Because in the end, that’s what we do -- we improve patients' lives.”
This year's showcase also featured a focus on the use of technology and artificial intelligence, or AI. There was a panel discussion on the subject, and a keynote speech from Dr. Toby Cosgrove, formerly CEO of the Cleveland Clinic and now executive adviser to Google Cloud Healthcare, with another keynote by Avi Goldfarb, the Rotman Chair in Artificial Intelligence and Healthcare at the University of Toronto.
For Dr. Weisel, the focus on technology and AI reflects the reality of health care today.
“This technology is not perfect,” he said. “It still requires that the clinician make a decision based on the patient, but it provides information that you wouldn't have had before. It allows you to utilize the entire breadth of our medical libraries right at your fingertips. We have in our phones now the capability that our computers only dreamed of a few years ago. So, let's use it. Let's make it better for patient care.”
One innovation on display this year may be the best example of what this fund is all about. Dr. Stephanie Ameis is a clinical scientist at CAMH. She and her team had a theory that magnetic stimulation – a series of short magnetic pulses to the brain – might be shown to improve executive function in people with autism. The treatment is called repetitive transcranial magnetic stimulation (rTSM).
People with autism often have problems with executive function -- cognitive capacities like planning, working memory, and attention. In the study, which received seed funding in 2014, youths and young adults with ASD were given multiple treatments over four weeks. The results? Well, not really what they'd been hoping for. There were a few positive signs, and nobody is giving up, but Dr. Ameis is the first to admit that the study did not yield the results she had expected. In short, it didn't really work. She credits the Innovation Fund, however, for making projects like hers possible.
“The seed funding provides a great opportunity to test the potential of an idea without having to invest a lot of money,” she said. “It offers the chance to pursue something new and first see if you are on the right or wrong track. It makes sense to pursue a larger investment and a larger project once the potential of the idea is more established and the details of how to take the innovation to the next step are more refined. Helping people take the first step, even when it doesn't always work, that inspires innovation.”
Doctors develop new technology to locate lesions
By: Kurt Kleiner
Doctors at Sunnybrook Health Sciences Centre developed a new technology that uses a small magnetic marker to locate non-palpable breast lesions during surgery. The system is designed to be easier and more comfortable than existing techniques, and a preliminary trial with 20 patients showed that it worked well.
The technique is called Magnetic Occult Lesion Localization and Imaging (MOLLI). It is designed to be used by surgeons performing lumpectomies on non-palpable lesions (a lesion, or change in tissue that cannot be felt), making it easy to locate the lesion and remove it.
“It's kind of like a GPS to find a lesion,” said Dr. Nicole Look Hong, a surgeon at Sunnybrook and the lead researcher on the study. “We don’t have an ultrasound or a mammogram machine in the OR with us, so we can't find things in real time as a radiologist might. The radiologist puts the marker in before the surgery, and we use the magnetic detector in the OR to take it out with guidance.”
Dr. Hong reported on the results at the Innovation Fund Showcase 2019 held in Toronto in November 2019, co-sponsored by the OMA. The work was funded by a previous Innovation Fund Provincial Oversight Committee award.
About 60 per cent of diagnosed breast cancers are non-palpable. So, a surgeon trying to remove the lesion while sparing healthy tissue needs guidance to know just where it is.
One common method is for a radiologist to insert a wire into the lesion, leaving one end on the outside of the breast. The surgeon can then use the wire as a guide. But the wires tend to be uncomfortable for patients, and they must be inserted just before surgery, which can complicate scheduling.
Another existing technique uses a small radioactive pellet implanted by the radiologist. The surgeon then uses a device to detect the radiation and therefore the lesion. This method is more comfortable than a wire and can be done days before the surgery. But because the pellets are radioactive, they require special tracking, handling and disposal that adds complication and expense.
So, doctors and engineers at Sunnybrook developed a system that uses a magnetic marker. Several days before the surgery, a radiologist inserts the 3.8 mm-long marker into the lesion. When it's time for surgery, the surgeon uses a wand-shaped device that is hooked up to a tablet PC running custom software. The surgeon moves the wand over the breast, and the computer screen indicates how far it is from the magnetic marker, and how deep the marker is below the skin. The ability to measure depth is something the radioactive pellets can't do.
“If we know the size of the tumour, and we know where the marker is, we can then figure out where the edge should be, and how much tissue we should take out with precision,” Dr. Hong said. “One of the great advantages for patients, compared to wires, is that this can be implanted many days in advance. It uncouples the surgery and the insertion. And it also prevents the patient from having this big thing from sticking out of their chest, so it's more comfortable and less onerous for them.
“I found it very easy,” she said. “The output shows you the target plus the distance. You can see where you are in space. And then the target says are you close or are you far. It's really dummy-proof. It's very intuitive and easy to use."
In November 2019, Dr. Hong and colleagues published the result of a phase one trial they ran at Sunnybrook.
In previous studies, the doctors had already shown that the markers and probes were not affected by metal instruments or by any of the other equipment in the operating room. And they showed that the probes could reliably detect markers as deep as 53 mm below the surface.
In the phase one study, the MOLLI system was used on 20 patients who had to have lesions removed. Radiologists used ultrasound to insert the markers up to seven days before surgery, and two surgeons performed the surgeries.
Results showed that the system worked as intended. Surgeons and radiologists rated the system as easy to use. The lesions were removed with no need for re-excision, there were no adverse events, and overall patient outcomes were good, according to the study.
Dr. Hong said the plan is to eventually commercialize the technology, and that a company called MOLLI Surgical is already in place. But first the researchers want to begin a larger scale, multi-centre trial that will compare the new system to the current standard of care.
“We're trying to make the science accurate, instead of just marketing based on anecdote,” she said. “So, we're trying to open a registry trial in Canada and the US compared to current standard of care, and then look at both clinical outcomes and cost efficiency outcomes.”
Web-based tool keeps patients and providers in the Loop
By: Kurt Kleiner
Patients with complex medical conditions often struggle to co-ordinate care from multiple doctors, other health-care providers and family members. A new web-based tool that works like a social media network could make it easier to communicate and improve the quality of care the patient receives.
Doctors in Toronto are developing the web-based tool they call Loop. Pilot studies show that patients and doctors found it easy to use and suggest that it could improve continuity of care.
“Often families are left trying to connect all the dots, and we felt there was a better way of doing it,” said Dr. Amna Husain, who is leading a team working on the system. “It's not just families. We as health-care professionals are working in a setting which is distributed geographically, and which has many different organizations involved. We find that the communications are so fragmented that it actually jeopardizes patient safety. It certainly burdens patients and families.”
Dr. Husain is research lead at the Temmy Latner Centre for Palliative Care at Mount Sinai Hospital in Toronto and an associate professor in the Division of Palliative Care of the Department of Family and Community Medicine at the University of Toronto.
She reported on the Loop system at the Innovation Fund Showcase 2019 held in Toronto in November 2019, co-sponsored by the OMA. The work was funded by a previous Innovation Fund Provincial Oversight Committee award.
A number of systems exist or are being developed that allow doctors to communicate with a patient, or for health-care providers to share a patient's medical records. But the Loop system takes a different approach, Dr. Husain said.
“It's essentially like a social network for patient care, but secure,” she said. “The patient is at the centre of a team, and the team is the actual team of care. It's whoever the patient and the other health-care providers identify as being important to the patient's care, and that includes the patient and caregiver.”
Using Loop, the patient's physician creates a separate secure page, or “loop,” for that patient, and the physician and patient invite other members of the team to join. Those team members can include a family doctor, specialists, nurses, family members and caregivers. The front page of the loop shows a brief description of the patient and his or her circumstances, including overall medical condition, home situation, specific medical issues and members of the team.
Anyone in the loop can post on a public wall or have conversations with one another. In a hypothetical example that shows how the system is designed to work, a palliative care physician reports to the team on the results of a home visit to a patient suffering heart failure and asks the nephrologist about possible IV drug treatment for fluid retention. The cardiologist chimes in and suggests they discuss whether the treatment could be delivered at home. The patient can see the conversations, join in, ask questions and make suggestions.
By default, all messages are available for anyone to see, although there is also an option for health-care providers to talk to one another without the patient having access. The separate health-care provider channel was added when patients and practitioners expressed concern. Doctors were worried they might not be able to discuss a case freely without unnecessarily alarming patients. And patients were worried about accidentally receiving bad news, without hearing it in person from a doctor who was prepared to discuss it and answer questions.
In a pilot study, Dr. Husain and her team tested the usability of the system with advanced cancer patients, who often have complex needs. They recruited 19 physicians from the Latner Centre and from the Princess Margaret Cancer Centre in Toronto and enrolled 12 patients to use the Loop system and 11 to receive care as usual to serve as a control.
Results of the pilot study showed that patients were willing and able to sign up for the system and use it without needing instructions. It was mostly used to manage medical care, report symptoms and co-ordinate appointments. And although the sample size was too small to draw strong conclusions, numbers suggested that the patients using Loop enjoyed better continuity of care.
But the system was not used to its full potential in the pilot study. Very little medical collaboration occurred among practitioners. That's partly because doctors who weren't participating in the study tended not to sign up, even when they were invited. Previous studies have shown that doctors worry that new communications tools might be overused by patients, and that the time the doctors spend on them won't be compensated.
Dr. Husain said the pilot study accomplished its main purpose, which was to show the system worked as intended, and it wasn't overused by patients. But for it to be a true success, it will have to be implemented widely, and doctors will have to see that there is an advantage to using it.
“For us in a community based palliative care setting, the way this helps is if it actually saves people time,” Dr. Husain said. “So, if you're chasing people down and making multiple calls and trying to accomplish something that takes you weeks, and this allows you to do it in days, then that's a motivator.”
Success will also require action from the province, she said.
“It doesn't achieve its full potential until we have one or two systems like this that are adopted provincially. What we need for any tool like Loop is a rational regulatory structure that allows dynamic enrolment of patients and health care providers, and also a rational digital infrastructure.”
The next phase of work on Loop will look at how to assemble health-care teams to use the system, and to study how they make use of it. The researchers also want to enrol enough patients so they can study the differences in care between groups of patients who use Loop and those who don't.
Surgeon Cost Report Card
Giving surgeons report cards helps cut costs
By: Kurt Kleiner
Doctors at Toronto Western Hospital discovered an effective way to cut the costs of surgery -- simply tell surgeons how much the supplies they are using cost. By providing a “report card” that shows surgeons how their costs compare with those of others, the hospital was able to cut expenses by 7 per cent in a pilot study.
Surgeons have a choice in the equipment and supplies they use, and different surgeons will make different choices even for the same procedure. But they usually have no idea about the cost differences between alternatives.
This might not matter for reusable equipment such as scalpels or heart monitors. But disposable equipment and supplies that are used just once and then thrown away can add up to big costs, said Dr. Timothy D. Jackson, the surgeon at Toronto Western who ran the study.
“If I use an instrument that's 700 bucks, and there's another one I may not think is any better or worse that could be 500 bucks, there's a $200 difference,” he said. “And I had no knowledge of that, and there's really no mechanism to feed that back to me.”
Just sending surgeons emails that showed the costs of their disposables and how they compared to the costs of other surgeons was enough to get them to cut costs 7 per cent in the pilot study – or $160,000 a year for one type of procedure alone, if it could be duplicated across the hospital, part of the University Health Network.
To conduct the study, Dr. Jackson enrolled four surgeons at Toronto Western who were performing gastric bypass surgery for morbidly obese patients. Every two weeks, the surgeons would get a report card by email. It listed that surgeon's average cost for disposable supplies used for the procedure compared with the average of the entire group. There were line items for specific categories of supplies, such as staples, sutures and ligation devices. And the report also listed the surgeon who had the lowest costs.
Seven months after starting the study, the costs for disposables had decreased 7 per cent -- $410 per operation -- to $2,827 per procedure. If those savings could be found in all gastric bypass operations, the savings would be enough to fund another 64 of the procedures every year, Dr. Jackson said.
He reported on the results at the Innovation Fund Showcase 2019 held in Toronto in November, co-sponsored by the OMA. The work was funded by a previous Innovation Fund Provincial Oversight Committee award.
“It is amazing,” he said. “I would get my own cost report and I'd see my colleagues are more expensive or cheaper, and it just generates a conversation. It was really cool that we could drive the cost down.”
There are other efforts to reign in surgery costs. Some managed care groups in the United States standardize the equipment that surgeons can use. Other efforts aim to educate surgeons on costs through regular meetings, or by sending spreadsheet reports.
Dr. Jackson says the report card method differs in several ways. It provides individual feedback. It's simple to understand, and can be easily read on a smart phone, with relevant numbers coded red, yellow or green depending on whether the costs are over, the same as, or under the average. And finally, it engages the surgeons in healthy competition with one another.
Based on the pilot study funded by the Innovation Fund, Dr. Jackson has received funding for a much larger trial that will include quality of care outcomes as well.
“We call it the Cost, Quality and Outcomes initiative,” he said. “What’s exciting about that is it allows us to look at making sure we're not cutting costs but compromising quality. What's really great is that we can assess the value of the care that we provide.”
The hospital participates in the American College of Surgeons National Surgical Quality Improvement Project, which allows it to track detailed health outcomes of each surgery over 30 days and compares it with information from 800 other hospitals. By combining health quality data from this system with the cost information, Dr. Jackson said, the hospital will be able to create a report card that measures not just cost, but quality. That will help make sure that the lower-cost alternatives are not accidentally causing problems down the line.
“If we spend a little bit more on a stapler but people go home earlier, then that's something that we should be doing,” he said. “But if we buy a cheaper stitch and people get more infections, well then we should know about that. So, it takes down some of those silos we have traditionally had across some of our systems.”
Electronic monitors improve handwashing, cut disease
By: Kurt Kleiner
Physicians working at academic health science centres in Toronto cut the number of hospital-acquired infections by using an electronic monitoring system to increase how often health-care providers washed their hands.
Hospital-acquired infections happen when pathogens are spread from patient to patient, often by doctors and other hospital workers. In Canada about 7.9 per cent of hospital patients acquired an infection in 2017 . These infections are a serious risk because people in hospitals are already sick, and often have suppressed immune systems.
“Hand hygiene is considered the cornerstone of efforts to prevent these infections,” said Dr. Matthew Muller, medical director of infection prevention and control at St. Michael’s Hospital in Toronto, who co-led the electronic-monitoring study. “Having health-care workers, patients and visitors washing their hands is very important. And yet historically health care workers have not done a great job of this.”
Dr. Muller reported on the results at the Innovation Fund Showcase 2019 held in Toronto in November, co-sponsored by the Ontario Medical Association. The work was funded by a previous Innovation Fund Provincial Oversite Committee award.
Although it seems simple, health-care providers moving from patient to patient must wash their hands dozens of times a day.
“It is a burden in the sense that they have to do it many, many times a day, and they often don't realize how often they really should be doing it,” Dr. Muller said.
For this study, a commercial product called DebMed was installed in 26 medical-surgical inpatient units across five hospitals in Ontario. The system uses wall-mounted dispensers that sense when they are activated and report to a central computer, which keeps track of how often each device is used and reports for each unit.
The monitors don't record the comings and goings of individuals. But researchers know from previous studies how often health-care workers would ideally be washing their hands, based on the type of unit and the number of patients. They compare these ideal numbers with the actual numbers recorded by the system to check how well health-care workers in a particular unit are doing.
The first finding was that hand washing compliance is much lower than the hospitals realized. Hand hygiene compliance is usually tracked by a human monitor, who periodically visits units and observes how often people wash their hands. Using this method, hospitals report hand washing rates up around 80 or 90 per cent.
The problem, said Dr. Muller, is that hand hygiene improves when the human observer is there but falls off when they are gone.
“People's behaviour changes when someone is watching them. They get to realize that this person is there to check their hand hygiene, and they'll remember to wash because it's a reminder. But they may forget to wash later when that person has left.”
In the study, the system was installed for a year. For two months it collected baseline data. For the final 10 months, the data was reported to the units, and leaders used the data to try to improve performance.
At the beginning of the study, hand hygiene compliance averaged only 30 per cent across all the units. By the end of the study compliance had increased 1.7 times to more than 50 per cent.
To see if the improved handwashing made a difference, the study also tracked the number of infections of methicillin-resistant Staphylococcus aureus (MRSA), an antibiotic-resistant infection frequently found in hospitals. The study found that MRSA infections went down by 30 per cent as handwashing improved.
The key to the improvements was how the information was used to change behaviour, said Dr. Jerome Leis, a co-author of the study and medical director of infection prevention and control at Sunnybrook Health Sciences Centre in Toronto. Unit leaders could look at information day by day to track whether compliance was improving and try different education and motivation methods to see what worked and what didn't.
Previously, even when hospital leadership was committed to improving hand hygiene, they would have to wait weeks or months before the data was available to show if their efforts were paying off.
“With real-time data, a unit could build an improvement plan, implement it, and know within days or a week what is working, or whether it needs to be tweaked in order to improve,” Dr. Muller said.
Efforts included everything from challenges between units, to games, even pizza parties for hitting a target. But the two most important factors were having dispensers located at the point of care, and having a team meeting every day to discuss how the compliance rates were looking based on recent data, Dr. Muller said.
“Just asking that question seems to drive improvement,” he said.
The five hospitals that participated in the study have adopted the system as their standard, Dr. Leis said. The system will expand to 11 hospitals soon, including use in critical care units, and the study will continue.
They hospitals that participated in the study included Sunnybrook, St. Michael's, Sinai Health System, Michael Garron Hospital, and Lakeridge Health.
Fecal transplants fix leaky intestines
By: Kurt Kleiner
“Leaky” intestines have been implicated in a host of autoimmune and metabolic illnesses. Research by doctors at Western University and St. Joseph's Hospital in London suggest that transplanting gut microbes from healthy people could stop the leakiness and treat the diseases.
The doctors transplanted fecal matter from healthy donors into patients suffering from a condition called non-alcoholic fatty liver disease, which is associated with high intestinal permeability. The study showed that the transplants made the intestines less permeable.
“We did a randomized, controlled trial, giving people back their own poop or somebody else's poop,” said study lead Dr. Michael Silverman. “If you had someone else's poop, your microbiome improved quite dramatically. More importantly, your gut became far less leaky.”
Dr. Silverman is chair of infectious diseases at the Schulich School of Medicine & Dentistry at Western University, and chief of infectious diseases for St. Joseph's Hospital and the London Health Sciences Centre.
Dr. Silverman reported on the results at the Innovation Fund Showcase 2019 held in Toronto in November, co-sponsored by the OMA. The work was funded by a previous Innovation Fund Provincial Oversight Committee award.
A normal intestine allows nutrients from food to pass through its walls while screening out potentially harmful microbial material. But intestines that become too permeable allow antigens and other matter through. High intestinal permeability has been associated with a host of diseases, including Type 1 diabetes, systemic lupus, multiple sclerosis, obesity, metabolic syndrome, depression and autism.
To conduct the study, the researchers took stool samples from healthy donors, and used an oral duodenal tube to transplant some of the sample into the patient's small intestine. As a control, some patients received a sample of their own fecal material. The researchers hoped that the microbes from healthy donors would populate the small intestine and decrease its permeability.
They found significant increase in microbial diversity in the patients who received a transplant from donors, as well as an improvement in bowel permeability, compared with patients in the control group.
“One of the things that seemed to matter most is to have a very diverse microbiome, a diverse number of organisms,” Dr. Silverman said.
The human gut is home to hundreds of species of bacteria, archeae, viruses, phages, yeast and fungi that interact with one another and with the human body in ways that scientists are still working out. Among other things, microbes in the gut are thought to help modulate the immune system and regulate metabolism in complex ways, as well as contribute to inflammation and insulin resistance.
“We used to think of poop as just leftover food,” Dr. Silverman said. “We realize now that it is a very active microbial community that produces many different products. Many of those have very profound effects on our metabolism.”
Dr. Silverman said researchers could not study this in the past because most of these organisms, meaning they do not grow or divide in labs. Now, with advances in PCR, or polymerase chain reaction, a molecular biology mechanism to make millions to billions of copies of a specific DNA sample, it’s possible.
“We're finding all of these different conditions affected by these microbes that we once thought were not doing anything,” he said.
Some of the earliest fecal transplants were done to treat Clostridium difficile infections using simple enemas. They were often extremely successful, with the donor microbiome repopulating the patient's gut and wiping out the infection.
But it turns out that patients infected with C. difficile are relatively receptive to donor microbiomes. Often, the infection targets people whose defences are down because their own microbiomes have been largely wiped out due to strong antibiotics. When a healthy diversity of good microbes is introduced, they easily repopulate.
“It's like throwing a seed or two into the dessert after a rain,” said Dr. Silverman. “It's easy for everything to take over. On the other hand, if it's a full forest it's not so easy.”
When there are already microbes populating the gut, the donor microbiome may not thrive so easily. It can be especially difficult to repopulate the small intestine through an enema, since the new microbes may not travel up beyond the ileocecal valve, which separates the small from the large intestine.
That's why for this study the researchers implanted the microbes directly into the small intestine. In future studies, they will use a new method that allows patients to swallow the material in a capsule that is designed to dissolve in the small intestine.
Because of the small number of patients in the study, Dr. Silverman was not able to determine which microbes were most important for improving bowel permeability, although the patients with the most diverse microbiomes saw the most improvement. In the future, researchers may be able to apply only the microbes that are needed to create the improvement, he said.
“We haven't yet figured out what the perfect flora is, but its probably different flora for different people ... How often do we have to repeat the transplant? Does it have to be coordinated with changes in the diet? Those are all questions we're going to have to answer.”
In addition, even though the treatment caused improvements in bowel permeability, it did not change two other indicators associated with the disease -- insulin resistance, and the amount of fat within the liver. Dr. Silverman said he thinks it's possible that repeated transplants over a longer period might improve those indicators as well.
Dr. Silverman and his colleagues are preparing to do similar trials using patients with multiple sclerosis, HIV and melanoma.