€11 million State-of-the-Art Extension for RCSI Teaching Hospital

The three-storey extension marks the third phase of development for the facility

A new €11 million three-storey extension to the Royal College of Surgeons in Ireland (RCSI) Education and Research Centre at Dublin’s Beaumont Hospital is due for completion in May this year. The facility represents the third phase of development for the education and research facilities of the RCSI at Beaumont Hospital.

“The first phase was the development of the library and the education centre at the front of Beaumont Hospital,” RCSI CEO and Registrar, Prof Cathal Kelly, said.

“The second phase was development of the Smurfit building, the first development of a clinical research centre at a public hospital site in 2000.

That has been tremendously successful as a centre for translational research. “The research portfolio goes from strength to strength — that translational research ethos, of bringing basic science expertise of the college with the clinical science expertise of our clinicians, has worked really well, so much so that RCSI is climbing up the word university rankings.

Now we are in the top 2 per cent of the Times Higher Education World University Rankings list and that is based on our research citations, which are based, in large part, on the fact the we are totally focused on healthcare,” Prof Kelly added.

A student concourse at ground-floor level will link the Education and Research Centre with the new facility. The ground floor will provide multi-functional
tutorial rooms, and the first floor will have faculty offices and meeting spaces, while research facilities will be on the second floor.

The three-storey building is to be linked vertically with feature stairs located under a large atrium.

valerie.ryan@imt.ie

Study at RCSI Aims to Improve Care for Hemophilia Patients by Using Personalized Approaches

Clinical Study in Ireland Aims to Improve Care for Hemophilia Patients by Using Personalized Approaches

A novel clinical study called “The Irish Personalized Approach to the Treatment of Hemophilia (iPATH)” will seek to investigate the potential of new personalized treatment approaches in hemophilia by tailoring care based on the needs of individual patients.

The collaborative study will be led by the Irish Hemophilia Society, in partnership with Shire, a global biotech company that specializes in rare diseases, the Royal College of Surgeons Ireland (RCSI) and Science Foundation Ireland (SFI).

iPATH will divert from standardized treatments and study hemophilia patients in Ireland who are registered at a single National Coagulation Centre, where data on the use of factor concentrates and bleeding rates have been collected, to conduct a study aimed at better understand the underlying causes and mechanisms of the blood disease. Ultimately, the parties involved have the goal of developing personalized approaches to care that eventually can be extended to the global community.

“Today, in developed countries, most patients receive prophylactic treatment, which is recognized as the standard of care. For those patients on prophylaxis, treatment should be optimized by combining innovation with personalization,” Peter Turecek, senior director of global medical affairs at Shire, said in a press release. “Through the iPATH study, we hope to uncover new solutions that build on and maximize the role of factor therapy and further personalize care for hemophilia patients.”

“Hoping to enhance quality of life for people with hemophilia … we need to begin developing innovative treatment strategies that can be tailored specifically according to the needs of each individual patient. To achieve this objective, we first need to understand the biological mechanisms that underpin the marked differences in bleeding risks and long-term complications that exist between individual patients with hemophilia,” said James O’Donnell, study leader and director of the Irish Centre for Vascular Biology at RCSI. “By understanding these mechanisms, the iPATH study could potentially pave the way for the introduction of personalized medicine for patients with hemophilia,” he said.

“The future of hemophilia care should be based on a personalized approach to treatment. We anticipate that this exciting, innovative and collaborative research program may provide us with answers to potentially optimize future treatments for individuals with hemophilia in Ireland and to hopefully further apply this research to hemophilia patients globally,” added Brian O’Mahony, chief executive of the Irish Hemophilia Society.

iPATH will be conducted over the course of four years, with the support of a strategic partnership initiative between SFI, RCSI, Trinity College Dublin (TCD) and Shire. The partnership also includes clinical researchers based in several Dublin hospitals and is designed to be potentially adapted for other diseases.

Researchers in Ireland Report – Autoimmune Disease Impacted by Circadian Rhythms

Researchers in Ireland report that immune responses and regulation of autoimmunity are affected by the time of the day when the immune response is activated. Understanding the effect of the interplay between 24-hour day–night cycles and the immune system may help inform drug-targeting strategies to alleviate autoimmune disease, say the scientists who published their study (“Loss of the Molecular Clock in Myeloid Cells Exacerbates T Cell-Mediated CNS Autoimmune Disease”) in Nature Communications.

Using mice as a model organism, they show that a master circadian gene, BMAL1, is responsible for sensing and acting on time-of-the-day cues to suppress inflammation. Loss of BMAL1, or induction of autoimmunity at midday instead of midnight, causes more severe experimental autoimmune encephalomyelitis, which is essentially an analog of multiple sclerosis in mice.

“Loss of myeloid BMAL1 or midday immunizations to induce EAE [experimental autoimmmune encephalomyelitis] create an inflammatory environment in the CNS through expansion and infiltration of IL-1β-secreting CD11b+Ly6Chi monocytes, resulting in increased pathogenic IL-17+/IFN-γ+ T cells,” say the investigators. “These findings demonstrate the importance of the molecular clock in modulating innate and adaptive immune crosstalk under autoimmune conditions.”

“In the year that the Nobel Prize in Medicine was awarded for discoveries on the molecular mechanisms controlling the circadian rhythm, our exciting findings suggest that our immune system is programmed to respond better to infection and insults encountered at different times in the 24-hour clock,”says Kingston Mills, Ph.D., professor of experimental immunology at Trinity College, Dublin. “This has significant implications for the treatment of immune-mediated diseases and suggests there may be important differences in time of day response to drugs used to treat autoimmune diseases such as multiple sclerosis.”

Although further investigations are needed to understand how to precisely modulate circadian rhythm or time-of-the-day cues for beneficial immunity, our findings serve well to remind us the importance of “keeping the time” when dealing with the immune system, he adds.

“Our study also shows how disruption of our body clocks, which is quite common now given our 24/7 lifestyle and erratic eating and sleeping patterns, may have an impact on autoimmune conditions,” notes Annie Curtis, Ph.D., of the Royal College of Surgeons Ireland. “We are really beginning to uncover exactly how important our body clocks are for health and well-being.”

RCSI Signs €3M Contract with Irish IT Services Firm

Written by Robert McHugh, on 30th Nov 2017. Posted in Technology

article headlineTypetec has today announced a €3m contract with the Royal College of Surgeons in Ireland (RCSI) to provide students with Apple MacBook Air notebooks. Typetec will deploy hardware, technical support, professional development and continued ICT planning services as part of the agreement.

The three-year deal follows a 25-year partnership between Typetec and RCSI which was the first college in Ireland to pioneer a one-to-one laptop programme in 1993. Working in partnership with Typetec, RCSI has now rolled out the enhanced service to the whole student body based in RCSI’s new flagship building at No. 26 York Street.

Speaking this week, Chief Technology Officer of RCSI, Justin Ralph said, “Using best-in-class technology is part of the student experience at RCSI. Through their learning journey, our students are encouraged to develop innovation and leadership skills, and technology plays an important role in that. With Typetec we know we have a partner that continually delivers on quality of service, and has the skills and experience to deliver technology that supports and enhances our students’ learning.”

Typetec CEO, Paul Dooley added, “We greatly admire the progressive culture and innovation that RCSI has developed over the last 25 years. Working with an institution that has such a vision for technology in education is truly inspiring. We are delighted as always to once again partner with them on this initiative and look forward to supporting them in developing the provision of educational training and lifelong learning through powerful ICT strategies.”

Source: www.businessworld.ie

RCSI to Train New Generation of Researchers as Part of International Study to Tackle Most Common Brain Disease

RCSI is leading an international team of scientists on a major research study that aims to train the next generation of specialists in purinergic signalling during brain diseases. The project (PurinesDX) aims to establish the potential of newly developed devices to better diagnose and treat patients.

Brain disorders affect 180 million people and their families in Europe alone. PurinesDX has received funding of over €3.5 million from the European Commission’s Horizon 2020 Research and Innovation Framework Programme.

The research project brings together global leaders in translational research in purinergic signalling, Europe’s leading clinical specialists in a broad range of brain diseases, and industrial partners specialising in drug and biomarker development from six different European countries. The main aim of PurinesDX is to train an urgently needed new generation of highly skilled, innovative, creative and entrepreneurial early stage researchers and to tackle brain disorders.

The project is led by Dr Tobias Engel, RCSI Department of Physiology and Medical Physics. “Despite diversity in symptomatology and etiology of brain diseases, it is becoming increasingly clear that neuroinflammation-induced hyperexcitability plays a key role in common mechanisms underlying both primary disorders of the brain and their shared co-morbidities. PurinesDX has identified the ATP-gated purinergic P2X7 receptor as the ideal target. By sharing unique genetic tools, newly developed diagnostic devices and novel, selective and brain-stable P2X7 antagonists, the synergism facilitated within PurinesDX will determine the therapeutic potential of targeting P2X7 in a wide array of the most common brain diseases and provide, at the same time, a high level training in state-of-the-art neuroscience for early stage researchers,” Dr Engel said.

PurinesDX includes major academic and industry researchers from across Europe, including collaborators in Ireland (Longboat Clinical); Germany (University Ludwig Maximilans; Max Planck Institute of Psychiatry; Dr Seibt Genomics; Epilepsy Centre Frankfurt Rhein-Main; Affectis Pharmaceuticals AG); Hungary (Institute of Experimental Medicine, Hungarian Academy of Sciences; Bio Talentum; Semmelweis University); Belgium (Janssen Pharmaceutica NV); Spain (University Complutense Madrid; CIBERNED, CIEN, Foundation Teofilo Hernando; Ramon y Cajal Hospital); and the UK (Sarissa Biomedical).

The four-year project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 766124.

RCSI is ranked among the top 250 (top 2%) of universities worldwide in the Times Higher Education World University Rankings (2018). It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide. RCSI is a signatory of the Athena SWAN Charter.

RCSI Wins Prestigious Tripartite €5.1 Million Award as Part of Global Project to Tackle Colorectal Cancer

RCSI has been successful in a €5.1m tripartite grant award to tackle colorectal cancer. The prestigious US-Ireland partnership award provides a unique opportunity to bring together leading researchers from GE Research in the US, RCSI and Queen’s University Belfast in an interdisciplinary programme of research to develop new approaches to diagnose and treat the deadly disease.

Using Cell DIVE, the state-of-the-art technology developed by GE Research, the RCSI Centre for Systems Medicine in collaboration with Prof. Deborah McNamara and Prof. Elaine Kay from the Departments of Surgery and Pathology at RCSI and Beaumont Hospital and cancer researchers at Queen’s University will comprehensively characterise the gene and protein interactions inside colorectal cancer cells and use this information to select or stratify patients for particular therapeutic interventions.

RCSI’s Prof. Jochen Prehn commented: “This collaborative programme of research shows how a comprehensive knowledge of the tumour, generated through an interdisciplinary tumour profiling and computational analysis approach can not only give us precise insights into the complex biology of cancer, but also allow us to develop new diagnostic and prognostic tools.”
Dr Fiona Ginty from GE Research said: “The Cell DIVE technology that we have developed allows the examination of tumour tissue samples at a level of detail that has not been possible before. Examining multiple proteins and different cell types in a single tissue sample allows us to define more clearly the biology that drives individual tumours. We are delighted to be working with researchers on the island of Ireland to apply this technology and know it will positively influence patient care.”

Colorectal cancer is the third most common cancer worldwide and it is predicted that the number of cases will rise to 2.4 million diagnosed per year by 2035. There are a number of treatment options available to colorectal cancer patients and a patient’s response to treatment will depend on the specific type or makeup of their cancer. As a ‘one-size-fits-all’ treatment approach does not work for all patients, a more precise understanding of what happens inside colorectal cancer cells is required. This study will involve the examination of thousands of tumour samples in a bid to develop a diagnostic test that will enable more precise treatment plans for individual patients.

Prof.Mark Lawler, Chair in Translational Genomics at Queen’s University explains: “Inside the colorectal cancer cell is like a massive series of circuits that are switched on all the time but different subsets of patients have differences in their circuitry. The Cell DIVE technology allows us to take multiple snapshots inside the colorectal cancer cell, defining a particular signature that identifies the patient’s molecular subtype. This will allow us to match the right patient to the right treatment.”

Director of Research and Innovation at RCSI, Prof. Ray Stallings, welcomed the announcement saying: “This exciting project is a great example of how the impact of RCSI’s research, focussed on translating scientific discoveries for patient benefit, can be accelerated through our collaboration with industry. This funding will enable Prof. Jochen Prehn and others in RCSI to carry out research that will lead to the development new diagnostics and treatments of the third most common cancer.”

The research could also lead to improvements in treatment for colorectal cancer, namely immunotherapy, a powerful new approach that has shown to be effective in treating a number of other cancers.

The project is funded by the US National Institutes of Health, Science Foundation Ireland/Health Research Board and the Health and Social Care Research and Development (HSC R&D) Division of the Public Health Agency Northern Ireland/Medical Research Council.

RCSI is ranked among the top 250 (top 2%) of universities worldwide in the Times Higher Education World University Rankings (2018). It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide. RCSI is a signatory of the Athena SWAN Charter.

‘Birthing’ Robot Among Education Tools at €80m RCSI Facility

 

Lucina lies in labour on a hospital bed screaming for an epidural even though she can feel no pain. She is Ireland’s only “birthing mannequin”, a €75,000 life-size robot bought to benefit surgical education at the Royal College of Surgeons in Ireland (RCSI).

The robot, one of many hi-tech tools at the new college building in Dublin, simulates a speeded-up, three-minute version of childbirth to maximise the number of students who can learn from her.

Demonstrated by senior lecturer Kate Flood, the robot is anatomically accurate, wireless and with full-body “skin” and delivers a lifelike baby of realistic weight and proportion and a placenta. Students can even feel her “contractions”.

Tucked away beside St Stephen’s Green, the new €80 million building at 26 York Street is designed to provide “professional healthcare training in multiple learning and study environments”.

Designed by Henry J Lyons Architects and built by Bennett Construction over the last three years, it claims to be the largest and most modern facility of its kind in Europe.

The new building complements the traditional 207-year old RCSI building on St Stephen’s Green on the corner of York Street, creating a campus environment for 3,200 students of medicine, pharmacy and physiotherapy.

Four floors below road-level is a 540-seat auditorium and the college also has a large sports hall, a gym and a separate gym for women.

The 12,000sq ft simulation centre is laid out over three floors of the 10-storey building, where students have access to a surgical and training suite with clinical skills labs, a mock operating theatre and clinical training wards.

RCSI has used a simulation model since 2003 to teach at undergraduate level, but says the newly opened facilities “move postgraduate surgical training in Ireland to a new level”.

Time capsule

An arresting time capsule art installation by Vanessa Donoso Lopez covers an entire wall, holding 448 bulla – clay vessels each containing a message.

The artist set up a studio in the college earlier this year and invited students to make their time capsule and to contribute a secret message outlining their hopes and wishes. That message, later etched on to a thin metal scroll, was then inserted into the bulla and each of them is housed in an acrylic box and hung on an interior wall.

Prof Hannah McGee, dean of the faculty of medicine and health sciences, says the aim is that in 40 years’ time in 2057, and perhaps towards the end of their careers, the students will gather for a reunion and open their time capsule.

“It is a metaphor for the RCSI as a custodian of the career aspirations of our students,” she says.

RCSI chief executive Prof Cathal Kelly said: “In a world where continuous professional development and reaccreditation is essential, these new facilities provide a national capacity for surgeons to refresh their skills and to avail of innovative techniques and international advancements. No 26 York Street represents a world class clinical learning environment, enabling a truly transformative clinical learning experience.”

The college is ranked among the top 250 (top 2 per cent) of universities worldwide in the Times Higher Education World University Rankings (2018). It is an international not-for-profit health sciences institution, with its headquarters in Dublin.

 

Elaine Edwards, The Irish Times

Breakthrough Allows Identification of Resistance to Breast Cancer Treatment

Early detection development by Irish researchers enables different strategy to be put in place

Kevin O’Sullivan

 

Majella O’Donnell at the launch of the Irish Cancer Society’s breast-cancer fundraising campaign “Cups Against Cancer” on Monday
Majella O’Donnell at the launch of the Irish Cancer Society’s breast-cancer fundraising campaign “Cups Against Cancer” on Monday

Irish researchers have developed a way of identifying women with breast cancer who are likely to be “resistant” to some of the most common treatments for the disease.

Their breakthrough comes with the potential to identify such patients more quickly, and in turn develop treatments that increase survival rates.

Prof Leonie Young and Dr Sara Charmsaz of the Royal College of Surgeons in Ireland outlined details of their research at an Irish Cancer Society event to launch a new fundraising drive to fund further scientific work by the Breast-Predict group, which includes the RCSI and five other Irish universities.

The RCSI team with Beaumont Hospital surgery department have found a new way to monitor the treatment of oestrogen-positive (ER-positive) breast cancer patients. Women with this form of cancer, which is one of the most commonly diagnosed, usually take drugs such as Tamoxifen or Aromatose inhibitors to reduce the chances of the cancer coming back.

Some of these patients, however, can become resistant to these treatments and their cancer returns. The team discovered that ER-positive women with a high level of a “biomarker” called S100Beta in their blood and “are significantly more likely to see a recurrence of the disease”.

“The early detection of patients with treatment resistance enables a different strategy to be put in place which can significantly improve there patients’ survival,” explained Prof Young.

Clinical trial

The next stage is for this research to undergo a clinical trial, Dr Charmsaz told The Irish Times. This would, it is hoped, lead to new monitoring strategies which could increase survival of patients, she added. Identifying women in this category quicker would mean that the cancer would be treated before metastasis, when it has spread to other parts of the body.

TV star Majella O’Donnell, who is married to singer Daniel O’Donnell, paid tribute to the researchers and underlined the need for ongoing funding to reduce the incidence of cancer and provide more effective treatments. She was speaking at a launch of the cancer society’s “Cups Against Cancer” campaign which is being staged during October, where members of the public are being asked to host a coffee morning and raise funds for the society.

Four years on from her own encounter with breast cancer, she said eight Irish women a day continue to be diagnosed with the disease. While treatments had improved, “research is the only way to address this”.

She added: “When I found out I had breast cancer I was shocked. The treatment was tough and it was difficult emotionally. Thankfully there are a lot of supports available and more advances are being made as a result of cancer research, which is improving outcomes.”

Phenomenal reaction

She described the constant worry of “looking over the shoulder” to ensure the cancer had not returned. But she had learned to relax and go in and get the reassurance of her oncologist when it was needed. Her appearance on the Late Late Show had prompted a phenomenal reaction, especially “a sharing of support and learning from other people” – it also helped raise more €700,000 for the society.

Her advice to women recently diagnosed was to “take each day at a time” and not to avail of “Dr Google” though human nature was such that searching for information through that source was understandable in the circumstances.

Cancer society head of fundraising Mark Mellett said the “Cups Against Cancer” campaign would enable researchers to continue to find better ways to diagnose and treat this disease, and ensure women were supported “through such a frightening and worrying time”.

Device that could heal diabetic foot ulcers using DNA gets €1.3m funding

Diabetic foot ulcer
Patient with diabetic foot ulcer receiving treatment. Image: kirov1976/Shutterstock

Those living with diabetic foot ulcers will be happy to hear that a new device aims to treat the ailment with DNA.

The AMBER centre and Dr Cathal Kearney of the Royal College of Surgeons in Ireland have been awarded €1.3m to alleviate something that affects thousands of people in Ireland: diabetic foot ulcers.

People living with diabetes across the world are at risk of foot ulcers, with up to a quarter of the 422m-strong diabetic population expected to suffer from the ailment in their lifetime.

The ulcers are very difficult to heal and are often prone to infection, which can lead to amputation. In 2015 in Ireland, 2,400 people were hospitalised with them, with nearly one in five leading to amputations.

The new funding was provided under the European Research Council’s (ERC) Starter Grant for groundbreaking research and will now allow Kearney to assemble a team to develop his research titled ‘BONDS: Bilayered ON-Demand Scaffolds for diabetic foot ulcers’.

The goal of this new programme is to develop a device that will support the body’s own cells to grow new tissues to repair skin damage on the foot caused by ulcers.

The device will be made of a sponge-like material and DNA will be delivered inside it, directing cells to heal the wound.

Could benefit diabetes patients globally

Kearney said: “I am honoured to have been awarded this prestigious research grant from the ERC. This research has the potential to change that for the better for people with diabetes, not only in Ireland but across the world.”

The ERC’s Starter Grant is quite prestigious in European academic circles, with this being just one of two awarded to Irish institutions this year, out of a total of 406.

Carlos Moedas, European commissioner for research, science and innovation, said: “Top talent needs good conditions at the right time to thrive. The EU provides the best possible conditions at the early stages of a researcher’s career through the ERC Starting Grants. That’s why this funding is so crucial for the future of Europe as a science hub: it keeps and attracts young talent.”

The news coincides with the promising results seen in a test that could help those living with metabolic conditions such as diabetes, using a patch that can convert unhealthy white fat into more manageable brown fat.

By Colm Gorey

RCSI Researcher Awarded Research Council Grant for Ground-Breaking Research into Diabetes

Dr Cathal Kearney receives one of just two prestigious grants awarded this year to Irish institutions
Dr Cathal Kearney from RCSI (Royal College of Surgeons in Ireland) Department of Anatomy and the Science Foundation Ireland funded AMBER (Advanced Materials and BioEngineering Research) centre has been awarded a €1.375 million European Research Council’s (ERC) Starter Grant for ground-breaking research to combat diabetic foot ulcers. The highly prestigious grant supports researchers across Europe to set-up their own research teams and pursue potentially life-changing innovations. In total, 406 grants were awarded this year to projects across Europe with Dr Kearney receiving one of just two given to Irish institutions. 
People with diabetes across the world are at risk of diabetic foot ulcers with up to a quarter of the 422 million diabetic population expected to suffer from the ailment in their lifetime. These wounds are very difficult to heal and are often prone to infection which can lead to amputation. It is estimated that every 30 seconds a limb is amputated as a result of a diabetic foot ulcer. In Ireland alone, 2,400 people were hospitalised in 2015 with the condition and 451 of these cases resulted in amputations.
Dr Cathal Kearney, Principal Investigator in the Tissue Engineering Research Group, RCSI received the funding for his research titled ‘BONDS: Bilayered ON-Demand Scaffolds for diabetic foot ulcers’. The goal of this research programme is to develop a new technology-driven device that will support the body’s own cells to grow new tissues to repair skin damage on the foot caused by ulcers. The device will be made of a sponge-like material and DNA will be delivered inside the device using a novel technology. The delivered DNA will then direct cells that enter the device to heal the wound.
Speaking about the funding, Dr Kearney said: “I am honoured to have been awarded this prestigious research grant from the ERC. In Ireland, it is estimated that €70 million/year is spent on the treatment of diabetic foot ulcers, with almost one in five cases resulting in amputation. This research has the potential to change that for the better for people with diabetes not only in Ireland but across the world.”
Director of Research and Innovation at RCSI, Professor Ray Stallings, welcomed the announcement saying: “This award to Dr Kearney is a testament to his stellar research in the area of biomaterials, and the expertise of RCSI’s Tissue Engineering Research Group that is addressing health issues arising from a range of chronic conditions such as diabetes. This innovation could transform the lives of diabetes patients across the world, and we look forward to seeing the outcomes of Dr Kearney’s work as his research expands as a result of this important grant.”
Dr Kearney has previously secured the prestigious Fullbright scholarship to attend MIT and Harvard University and the Marie Sklowdowska-Curie Fellowship at RCSI. His innovative work on drug delivery has been published in a number of high impact journals. Dr Kearney combines his research interests with a passion for teaching, having won the RCSI President’s Teaching Award 2017.
These coveted ERC Starter Grants support research in the life sciences, physical sciences and engineering, and social sciences and humanities and form part of the “Excellent Science” pillar of the European Union research and innovation programme, Horizon 2020.
Carlos Moedas, European Commissioner for Research, Science and Innovation, said: “Top talent needs good conditions at the right time to thrive. The EU provides the best possible conditions at the early stages of a researcher’s career through the ERC Starting Grants. That’s why this funding is so crucial for the future of Europe as a science hub: it keeps and attracts young talent.  This time the ERC attracted researchers of 48 different nationalities based in 23 European countries. It’s an investment that will pay off, boosting the EU’s growth and innovation.”
RCSI is ranked among the top 250 (top 2%) of universities worldwide in the Times Higher Education World University Rankings (2018). It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide.