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The 2019 Research Rally Breakfast at the NDSC Annual Convention was attended by 400 families of loved ones with DS with over 200 questions for the Research and Medical Care Q&A Panel with Dr. Skotko, Dr. Pipan, Dr. Capone, and Dr. Chicoine. Not all could be answered that morning, so LuMind IDSC and the panelists collaborated to produce the following FAQ to include all unanswered questions and topics.


Below are questions that the panel did not have time to cover during the June 29th Research Rally at NDSC. The answers represent the opinions of the expert panelist Dr. George Capone of the Kennedy Krieger Institute, Dr. Brian Chicoine of Advocate Health, Dr. Mary Pipan of the Children’s Hospital of Philadelphia, and Dr. Brian Skotko of Massachusetts General Hospital and Harvard Medical School. The panel was moderated by Dr. James Hendrix, the Chief Scientific Officer of LuMind IDSC. This post will be updated with a transcript of the questions answered in the video.

Alzheimer's and Dementia

Q: What initiatives are underway to alert family physicians and the general medical community to the symptoms of Alzheimer’s disease that they need to watch for?

A: Primary care physicians may not know individuals with DS are at higher risk for Alzheimer’s at younger ages than the general public. Families should discuss this issue with their physicians. Early symptoms that can include memory or behavioral changes such as increased agitation, changes in routine, more oppositional behaviors, more depression, memory loss and new onset of seizures. Often, caregivers are in the best position to detect these changes, but you should feel free to discuss any concerns with your family physician.

It is also important to ask your physician to rule out other causes of behavior change, such as hypothyroidism, sleep disturbance, depression, or Celiac disease. Alzheimer’s dementia is hardly ever seen in individuals with DS before the age of 40, and usually has an onset at age 50 or older.

Some resources for families and physicians are described below.

  • Brian Skotko and his team at Massachusetts General Hospital are in the process of creating an online tool to assist families and primary care physicians in detecting co-occurring conditions, like Alzheimer’s disease, in people with Down syndrome. This online tool, called “Down Syndrome Clinic to You,” should be available by the end of this year. You can learn more at
  • The Advocate Medical Group Adult Down Syndrome Center web page has information for people with Down syndrome; families and care providers; and health care professionals. There are several resources on Alzheimer’s disease (as well as numerous other articles, videos, links to other web sites, and more.
  • The Down Syndrome Medical Interest Group-USA and American Academy of Developmental Medicine and Dentistry are working together on developing webinars for health care providers that will provide information on a variety of topics regarding health of people with Down syndrome. Alzheimer’s disease and the evaluation of an adult with Down syndrome who has lost skills are a few of the first webinars being developed. Physicians can fulfill some of their required Certified Medical Education requirements by participating in the live webinars or watching the online saved versions at a later time. More information will be available in the near future.

Q: How close are we now in preventing Alzheimer’s in people who are currently adults with DS?

A: There are several new drug candidates in phase 3 clinical trials for Alzheimer’s being tested in the general population. It will be, at least, several more years before these proposed medications are ready for FDA review and approval, if the studies are deemed effective. We hope that if a drug is approved to treat or prevent Alzheimer’s in the general population, that it will also work for people with DS. However, research should also be done to be sure that the drugs are safe and effective for people with DS. Right now, there is a Phase 1b clinical trial for a vaccine (ACI-24) that is hoped to prevent Alzheimer’s disease in people with Down syndrome. LuMind was instrumental in the co-funding of this clinical trial, which is co-sponsored by the National Institutes of Health and AC Immune, the Switzerland-based company that has made the vaccine. More details can be found at

One thing that you can do now is encourage exercise. In people without DS, there are data to indicate regular exercise may delay or prevent Alzheimer’s disease. While it hasn’t been studied in people with DS, there isn’t any reason to suspect it isn’t beneficial for people with DS and it certainly has many other health benefits.

Q: How do we identify normal aging from beginnings of Alzheimer’s? And what should we be doing about this?

A: The question of diagnosing Alzheimer’s at an early stage and knowing if observed changes are due to a disease or due to normal aging is difficult in adults with DS and in the general population. If you have observed changes in behavior such as increased agitation, changes in routine, more oppositional behaviors, more depression or memory loss, take your concerns to your physician. Neuropsychological testing can be helpful in establishing a cognitive decline, especially if baseline testing was performed when the persons with Down syndrome was younger. If Alzheimer’s disease is diagnosed, discuss treatment options with your physician. You should also work with your case manager, other caregivers, and your physician to develop a plan in case an increase in care and support is needed in the future. More details at

However, families and physicians should not assume a person has Alzheimer’s without first ruling out other causes of the symptoms. There are many other reasons people with DS can develop a decline in skills such as sleep apnea, hypothyroidism, and depression. There are effective treatments for these conditions. Furthermore, an individual with AD may also have one or more of those other conditions. While, at this time, we don’t have effective treatments for AD, the person may still get benefit from treating those other conditions even if they have AD.

Q: Any research out there about whether or not people with DS should take statins for high cholesterol?

A: There has also been some research that shows that people with Down syndrome on statins may reduce their risk of Alzheimer’s disease. This is early research and needs to be supported by larger, randomized placebo-controlled trials. So currently, there is no data to tell us if taking statins are the right thing for people with DS and we recommend discussing this with your doctor.

Q: How does the protein markers enhance or complement previous method of investigation or scanning for plaques? Or does this most recent procedure eliminate the need of previous ones?

A: Currently, there is one FDA-approved test to detect for the presence of amyloid plaques (one of the two proteins associated with Alzheimer’s disease). This test is a brain imaging test called PET (Positron Emission Tomography). While it is FDA-approved, it is not reimbursed by insurance. Most adults with DS above the age of 40 will show evidence of amyloid on a PET scan even if they don’t have symptoms. In fact, amyloid plaques begin to appear at 10 to 20 years before the onset of Alzheimer’s symptoms. Since people with trisomy 21 have 3 copies of the APP (amyloid precursor protein) gene, they are more likely to have amyloid plaques and are at a higher risk of Alzheimer’s. However, having amyloid plaques do not automatically mean that the individual will develop Alzheimer’s. More tests are needed that can more accurately predict if and when someone will start to develop symptoms.

Q: I have Translocation DS, are my chances of having Alzheimer higher?

A: No. People who have three copies of chromosome 21—whether by trisomy or translocation–will have an extra copy of the Amyloid Precursor protein (APP) gene. This is believed to be the reason that people with Down syndrome are at very high risk for Alzheimer’s.

Q: In regard to research being done with older adults with DS, is the research ONLY being focused on Alzheimer’s or does it include other types of dementia (there are over 300 problems that cause dementia)?

A: It is true that Alzheimer’s is not the only cause of dementia, but, in the general population, it is the most common cause. In Down syndrome, Alzheimer’s is by far the most common cause of dementia and Alzheimer’s in people with DS has been called a genetic form of Alzheimer’s disease due to the extra copy of the Amyloid Precursor protein (APP) gene that is located on chromosome 21. However, there are cases of misdiagnosis, and caregivers and physicians should not assume that all changes in memory and/or behavior in adults are due to Alzheimer’s.

Q: Is coffee a good thing for people to drink to help prevent Alzheimer’s?

A: The research is mixed, and we really don’t know. Someone would need to do a double-blind, placebo-controlled clinical trial with coffee to see if it can lower the risk of Alzheimer’s to know for sure. However, it is unlikely that such a study would be funded. Coffee, like all things, in moderation, is probably fine. However, we do know that disrupted sleep is strongly associated with Alzheimer’s, so the general recommendation is to avoid caffeine before bedtime.

Q: What is the role of inflammation in the genesis of Alzheimer’s disease in the DS population?

A: The short answer is that we don’t know. We do know that neuroinflammation is a component of Alzheimer’s disease and seems to get worse as the disease progresses. However, we don’t know if neuroinflammation is causing this progression or is a response to the changes occurring in the brain as Alzheimer’s progresses. It is believed that at the early stages of Alzheimer’s disease, neuroinflammation may occur as an immune response to the appearance of amyloid plaques or other changes. This could be good as the body is trying to fend off disease. However, if the neuroinflammation becomes chronic, it starts to harm the brain and could exacerbate the progression of the disease.

Q: What is the study population and time span forming the basis of the statistical prediction of the age of onset of AD (symptoms?)?

A: There is no documented evidence of a bona fide diagnosis of Alzheimer’s disease in someone with Down syndrome before the age of 35. It is estimated that the prevalence of clinical dementia in DS is about 9% for people in their 40s and rises dramatically to 80% in those over age 54 and even over 95% in those who live to the age of 68. The most common cause of this dementia is Alzheimer’s disease. These estimates are based on longitudinal studies of 14 and 20 years of people with Down syndrome. (McCarron, et. al. A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome. J Intellect Disabil Res. 2017;61(9):843-52. and McCarron et. al. A prospective 14-year longitudinal follow-up of dementia in persons with Down syndrome. J Intellect Disability Res. 2014;58(1):61-70.).

Autoimmune Disease

Q: What is the link between Down syndrome and autoimmune disorders?

A: Autoimmune diseases are known to occur more commonly in people with DS, especially common are hypothyroidism, celiac disease, type 1 diabetes mellitus, and alopecia areata. It is believed that the increased risk of autoimmune diseases is linked to the genetics of DS, although the exact mechanisms are unknown.

Q: Is an endocrinologist required to manage Thyroid medications?

A: Most primary care physicians can manage thyroid medications in cases of uncomplicated hypothyroidism. Thyroid Stimulating Hormone (TSH) should be checked at least 1-2 times a year when on medication for hypothyroidism. Hyperthyroidism (Grave’s disease) is also more common in individuals with DS. Grave’s disease is more complicated to manage and does often require an endocrinologist.

Educational and Society

Q: Advantages and disadvantages of full inclusion with regards to only academic development.

A: This is a BIG topic. For a nice review on this topic, see

Q: Are there particular issues in raising a child with Down syndrome in a cross-cultural setting?

A: No. If it is important for a child to be bilingual, children can learn to understand and sometimes to speak both languages.

Q: How can I help her with her verbal skills so she can interact with her friends?

A: Language development depends on language exposure and practice using language throughout the day and across contexts (home, school, community). Talking to your child, reading to your child, and having conversations about the world around you (even if you can’t understand what they’re saying) is important from even before the time they can talk. Playing with your child, taking turns, pretending, singing, also promotes language development. Electronic exposure (TV, phone, IPAD, games) is not known to help language development, and heavy exposure may result in your child getting less exposure to language and less practice talking. The American Academy of Pediatrics recommends limiting electronic device exposure to 2 hours per day.

Q: Should a parent advocate for a child academically? Steer them into a Regents Program?

A: Yes, of course. Academic development starts with reading to your baby. More formal academic teaching starts in the preschool years and continues throughout life. Most children benefit from learning alongside typical peers in inclusive settings. Some children require more individualized attention in smaller classrooms. Many children with DS can start reading at the same time as same aged peers. Some may not be able to learn to read until later. Many children can also benefit from additional tutoring. An academic program should focus on making progress year to year.

General Research

Q: As part of your vast research portfolio, have you considered conducting anthropometric studies on the Down syndrome population in order to create immediate and direct improvement of quality of life?

A: New growth curves for people with Down syndrome were published in 2015, funded by the Centers for Disease Control and Prevention. You can find the results, as associated research papers, at Further research using this data, as well as measuring skin folds and fat free mass in school age children with DS showed that the degree of overweight/obesity in children with DS is best measured by using the BMI curves developed for the general population (the CDC curves). Thus, your doctor should chart your child’s BMI on the CDC BMI chart, not on the Down syndrome chart.


Q: How do you think about smart home technology and the opportunity to integrate it into the lives of people with DS as a tool for habit forming, therapy, and activity monitoring?

A: Smart home technology is an emerging and exciting new area that could be very beneficial for people with disabilities by providing them with greater independence. This could also reduce the burden on caregivers. A new digital treatment to improve cognition is currently in clinical trials for the typical population. We are just at the beginning of new digital approaches to health care.


Q: I have spent a great deal of time with my father who has Parkinson’s. I see many similarities with my daughter with DS. The reassurance and repeating are consistent. Have there been any studies that the medication that helps with memory loss assist people with DS to learn at a higher rate?

A: While the outward symptoms of Parkinson’s disease and cognitive deficits in DS may look similar, the underlying biological causes are different. Dementia symptoms are common in Parkinson’s disease so seeing common symptoms between your father and daughter may not be surprising. There has been research focused on improving cognition in people with DS but so far, these approaches have not shown significant improvements in clinical trials.

Q: If someone who has a PhD in molecular biology and has a child with Down syndrome wants to get involved with DS research, where can they get information?

A: Please contact LuMind IDSC. We will be happy to discuss your research interests.


Q: Is there any research related to cord blood cells from a sibling to potentially assist DS sibling in future related to cognitive decline?

A: None currently. However, there is a ~1% chance that children with Down syndrome will develop leukemia. Fortunately, most of these patients are responsive to chemotherapy. In very rare circumstances, a person with Down syndrome and leukemia might need a bone marrow transplant and, in these cases, a sibling’s cord blood might be a match.


Q: What is the status on research of the tumor type cancer not experienced by people with Down syndrome? Also, is there research on the chromosome “identities” or what traits are on the extra chromosome?

A: There is a lot of cancer research looking at the genetic factors that lead to disease or that provide protection. As such, Down syndrome has drawn considerable attention from researchers hoping to better understand the role that the extra chromosome plays in protection against specific cancers. The hope is that this research could lead to better cancer treatments. The second question is complex. Most human traits (intelligence, personality, height, skin tone, eye color, etc.) are a result of multiple genes. Some even have postulated that all genes contribute in large or small ways to many human traits. So, attributing the traits common in Down syndrome to specific genes on chromosome 21 has not been possible in most cases. The role of the extra copy of the APP gene in increasing the risk for Alzheimer’s disease is generally accepted, however.

Q: How common is it for young people in their 20s to have an onset of Epilepsy?

A: It is uncommon, but partial complex or generalized epilepsy can occur at this age in about 1-2% of people with DS.


Q: What new research is being done with young adults with Down syndrome?

A: There are several areas of active research being done with young adults with Down syndrome. Below are some examples.

  • Amyloid accumulation is a feature of Alzheimer disease and also found in people with Down syndrome. ACI-24 is a vaccine that may interfere with accumulation of amyloid. Researchers are conducting a 24-month study (12 months of treatment, 12 months of observation) to test the safety and tolerability of ACI-24 in adults with Down syndrome age 25-45 years. This preliminary study is an important first step in determining if ACI-24 can ultimately prevent or delay Alzheimer disease in Down Syndrome.
  • Obstructive sleep apnea is common in people with Down Syndrome and frequently is incompletely treated by the removal of the adenoids and tonsils. The use of a hypoglossal nerve stimulator is being tested in adolescents and young adults age 10-21 years with moderate-severe obstructive sleep apnea despite removal of the adenoids and tonsils. This device is placed surgically and works by stimulating the jaw muscles to keep the airway open.
  • It is common for people with Down syndrome to be overweight, but whether this is also associated with increased risk of diabetes and heart disease is not clear. A study of diabetes and heart health risk was recently completed in 154 adolescents age 10-20 years with Down syndrome and 103 individuals without Down syndrome of similar age and body mass index (BMI, a measure of body fat). Work from this study found that the Down syndrome BMI growth curves can mis-classify overweight and obesity status in youth with Down syndrome—a subset of youth with Down Syndrome classified as normal weight on the Down Syndrome BMI curves are actually overweight or obese on the typical CDC growth curves. Clinicians should use caution when interpreting the Down syndrome BMI curves. Additionally, studies in these 154 adolescents also found that they tended to have worse cholesterol and lipids even at normal BMI (normal weight) and more blood sugar abnormalities. Their left ventricles, the chamber of the heart that pumps blood to the body, were also smaller and worked less well in the relaxed state. The reasons for these differences are not clear, but additional work to test the impact of obstructive sleep apnea upon cholesterol, sugar, and heart function are being pursued. This study also found that although youth with Down Syndrome tend to engage in less moderate-vigorous physical activity (like running) that they do pursue lighter physical activity. This light physical activity may be beneficial for their body weight. Additional studies will test if increasing light physical activity can help with body weight.


Q: What new research is being done on Down syndrome disintegrative disorder?

A: Our understanding of this condition is in early stages. In fact, there is not yet agreement on the name (Regression syndrome, Down syndrome disintegrative disorder, and others) or definition of the condition. There is agreement in a general sense, that Down syndrome disintegrative disorder (DSDD) is a rare condition characterized by a rapid development of cognitive decline, autistic characteristics, insomnia, catatonia, and psychosis in adolescents and young adults with DS. There is early research on some treatment approaches on a small number of patients (with no placebo control) on-going but much more research is needed before strong conclusions can be made and treatments can be recommended. The Down Syndrome Medical Interest Group-USA (DSMIG) regularly discusses the clinical and research experience of DSMIG members and others as part of an effort to improve our understanding of this condition.

Hearing Loss

Q: Any new research to deal with chronic ear drainage & hearing loss in children & adults with Down syndrome?

A: There has not been any recent research specific to Down syndrome. We recommend working closely with an ENT physician with expertise in chronic ear problems. People with Down syndrome can and should benefit from the same treatments that are available for the general population.

Q: I’d like to understand more about the connection in ear fluid management, hearing loss, and speech development. Our daughter is 4, on her 10th set of tubes, now has a hole i/n her ear drum, and is somewhat behind her peers with DS in speech. What do we do to get ahead of this? Someone has to know something about this.

A: Continue to work with her ENT doctors to manage PE tubes, and ear drum rupture, and continue to get audiology evaluations at least every year. Some children require longer more permanent PE tubes. Holes in the ear drum are common and may be helpful as they provide the drainage that the PE tube does. Later, holes in the ear drum can often be patched. ENT doctors, audiologists and speech therapists recognize the importance of good hearing at any age. Many individuals with DS benefit from hearing aids. Many individuals also benefit from continued speech therapy into adolescence and if needed into adulthood.


Q: As people with DS live longer, what do we know about the onset, occurrence, and manifestation of musculoskeletal degenerative diseases, like osteoarthritis in people with DS?

A: Osteoarthritis is usually due to joint injury or aging and not due to Down syndrome specifically. Obesity is also a risk factor for osteoarthritis as the extra weight puts more stress on the joints. As people with DS live longer, it is likely that osteoarthritis may become more common but more research in this area is needed. However, there may be more osteoarthritis in people with DS as they age because of joint laxity. That observation is based on clinical experience not research studies. In people without DS, we know for example, a joint that has been sprained repeatedly, may develop more arthritis. The laxity of the joint causes, in a sense, the joint to be used in a way it was not intended. Interestingly, possibly due to differences in pain tolerance, some people with DS may not complain much about joint pain but the arthritis only becomes apparent when they develop “joint dysfunction”. We have seen a number of people with DS who developed significant changes in their gait due to osteoarthritis but had not complained of pain at all or only for a relatively short time before enough arthritic change had occurred resulting in change in joint function.

People with Down syndrome are more prone to osteoporosis, a disease in which the density of the bone is reduced. Working closely with a dietitian is important for ensuring that the calcium intake is sufficient in people with Down syndrome. Weight-bearing exercises might also be of help in preventing osteoporosis in people with Down syndrome, as in the typical population.

Q: What is the research on side effects of Humara on individuals with DS?

A: We are not aware of any specific research on the side effects of Humara (generic name: adalimumab) on people with Down syndrome. You should discuss your concerns about the safety of this or any medication with your doctor. Sometimes, Humara is prescribed for people with Down syndrome arthropathy, who do not respond to the first- or second-line drug treatments. It is also sometimes prescribed for psoriasis, hidradenitis suppurativa, and other auto-immune conditions


Q: Are there any unique things we can do to protect/preserve/prolong our child’s health beyond what’s recommended for the general/typical population (meaning beyond things like eat healthy and exercise)?

A: Whether a person has Down syndrome or not, regular exercise and a healthful diet has been shown, time and time again, to have a positive impact of overall health. In addition, being socially active with family and friends also has been shown to have a positive impact on psychological issues such as depression. Staying mentally active and learning new things also seems to have a positive effect on cognition as we age. Disrupted sleep is also associated with cognitive decline so treating sleep issues such as sleep apnea is recommended. Dr. Brian Skotko has translated these research recommendations into practical suggestions for families at

Q: What type of diet is the best for focus?

A: People with Down syndrome should have a well-balanced diet. No one particular diet is associated with improved focus. Excellent recommendations are available in this book by Joan Medlen:

Medical Care

Q: How do we help young adults with DS to best represent their health issues/needs to those who help them?

A: The Massachusetts General Hospital Down Syndrome Program has created a social story for people with Down syndrome to best advocate for their own health and wellness. More details at

Q: What could possibly cause a child to cycle between appearing to be aware with increased language skills, to being in a fog/ disconnected/ reduced language/ exhibit more repetitive behaviors over longer periods of time?

A: Sleep disturbances, such as apnea, can certainly lead to these symptoms. New onset of or intensification of a neurobehavioral co-occurring condition should also be explored. Depending on the length of time of the times of alertness and ‘fogginess’, additional considerations could include a variety of physical health conditions such as seizures and thyroid disease. Cyclical psychological conditions, particularly bipolar, could be associated with a perceived change in function. It could also occur if a person’s routines and structure are disrupted significantly. Like all of us individuals with DS need structure and activities that hold their interest that they find rewarding, friends and stimulating social interaction, physical activity and leisure activities for relaxation.

Q: What is the efficacy of the Nutrivene D protocol?

A: The Nutrivene D protocol has not been tested in double-blind, placebo-controlled clinical trials, and there is no evidence that it is efficacious. The use of mega doses of vitamins and the use of dietary supplements has been touted as a “natural” and safe way to treat or prevent disease and to aid people with Down syndrome. However, we don’t know if it is safe or effective in people with Down syndrome. Remember, nothing is completely safe, and the risks of side effects increase with higher and higher doses. Please discuss all dietary supplements that you take with your physician as these can have unwanted interactions with prescription medications.

Q: When would you decide to treat hypothyroidism (what lab results)?

A: We are more likely to treat even mild levels of hypothyroidism when children are under 3 years of age because the thyroid hormone contributes to brain development for the first 3 years of life. With older children and adults, TSH levels sometimes go from mildly high to normal and back again. When the TSH is persistently mildly high many physicians will elect to treat. When TSH is above 10 most physicians will start thyroid hormone replacement. A low TSH can be a sign of hyperthyroidism (Grave’s disease) which can have serious health effects so expeditious referral to an endocrinologist is recommended.

Q: What do you recommend for toddlers with mild sleep apnea?

A: Even with mild apnea (meaning AHI between 2 to 5 events/hr), cognition could be affected in toddlers with Down syndrome. In all cases, a consultation with an ENT physician should be sought to see if taking out the adenoids or tonsils is warranted.

Q: Our 38-year-old son with DS has a severe tracheal stenosis, discovered at age 8. He is doing OK, since the tracheal opening became a bit bigger as he grew (but is still dangerously small). At the time this was extremely rare. I understand a number of other cases are now known. Are there any special care issues as he gets older? 2. HE also has severe cataracts. We have delayed surgery because of his trachea (anesthesiology concerns). Are there any issues with cataract surgery and DS that we should be aware of?

A: We recommend that you discuss these issues with your physicians. As I am sure you can understand, we are not able to comment on the specific medical care for patients we’ve not personally examined.


Q: Are intense mood swings a sign of Down syndrome atypical regression (or Down Syndrome Disintegrative Disorder)?

A: While it can be related to regression (also called Down Syndrome Disintegrative Disorder), there are many more common reasons for mood swings including many physical health problems including poor sleep from a variety of reasons including sleep apnea, thyroid disease, chronic pain and many more. There are a number of psychological conditions such as anxiety, depression, bipolar disorder, and others that can also cause mood swings. Social stressors can also be associated with mood swings.
Furthermore, mood (as opposed to behavior) instability or fluctuation can be a sign of an underlying mood disorder. Mood instability may entail shifting between extremes (such as irritability, decreased need for sleep, high energy, low energy, sadness, tearfulness) It is also sometimes seen in fatigue from sleep deprivation, or in women at certain times in the menstrual cycle Down Syndrome Disintegrative Disorder is rare, and requires a work up to be sure there are no medical disorders contributing to the regressive symptoms.

Q: What about regression and PANDAS in individuals with Down syndrome? Is this possible?

A: A hypothesis is that behavioral issues such as OCD in some children are caused by an autoimmune disorder called PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections), particularly if they have tic-like behaviors and known infection(s) of strep throat that was not fully treated . People with Down syndrome, like all persons, can develop PANDAS, but there is no known genetic link between the two entities. Many or most individuals with Down syndrome Disintegrative Disorder do NOT present with a PANDAS-like illness.