Publisher Health

For the millions of people worldwide who have sickle cell disease, there are only a few treatment options, which include risky bone marrow transplants, gene therapy or other treatments that address a subset of symptoms. Today, researchers will describe the discovery of a small molecule with the potential to address the root cause of sickle cell disease by boosting levels of fetal hemoglobin, a healthy form that adults normally do not make. The drug could be formulated into a convenient daily tablet.
The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30. 
“Using our proprietary small molecule probe and CRISPR guide RNA libraries, we screened a disease-relevant cell model that allowed us to pinpoint a treatment target,” says Ivan V. Efremov, Ph.D., senior director, head of medicinal chemistry of Fulcrum Therapeutics, who is presenting the work.
Sickle cell disease occurs when the gene responsible for instructing cells to produce two of hemoglobin’s four proteins contains an error. The mutation causes hemoglobin to adopt a rigid, sickle-like shape, which results in reduced oxygen transport throughout the body. The irregularly shaped cells get stuck in the blood vessels, causing painful episodes known as vaso-occlusive crises. The cells also die much sooner than normal red blood cells, leading to anemia. In addition to these symptoms, patients are at high risk of developing stroke, heart disease, kidney failure and other life-threatening conditions.
Interestingly, sickle cell patients don’t begin life with malfunctioning hemoglobin. While in the womb, humans make “fetal” hemoglobin that carries oxygen normally. Three or four months after birth, however, cells stop expressing fetal hemoglobin and switch to an adult version. The adult hemoglobin expressed by sickle cell patients is defective, but they still carry stem cells in their bone marrow with the potential to produce fetal hemoglobin.
Patients that have what is called a hereditary persistence of fetal hemoglobin tap this resource automatically. “They have the sickle cell mutation, but additional mutations result in continued expression of fetal hemoglobin into adulthood,” says Christopher Moxham, Ph.D., chief scientific officer of Fulcrum Therapeutics. With fetal hemoglobin levels around 25-30%, he says, enough red blood cell function is restored so that these patients may become asymptomatic.
The team developed a drug, called FTX-6058, that mimics the effect seen in patients with the hereditary persistence of fetal hemoglobin, as demonstrated in human-derived cell assay systems and mouse models. The drug attaches to a protein inside bone marrow stem cells destined to become mature red blood cells and reinstates their fetal hemoglobin expression. “What is really key is FTX-6058 upregulates fetal hemoglobin across all red blood cells, a pancellular distribution,” Efremov says. “If some red blood cells did not express this, they could still sickle and cause disease symptoms.” Fulcrum began a phase 1 safety trial in healthy adult volunteers last year after preclinical experiments showed an increase in fetal hemoglobin levels to around 25-30%.
“What distinguishes FTX-6058 is that we are targeting the root cause of sickle cell disease,” Moxham says. “Other drugs approved in this space, particularly since 2019, are treating the disease’s symptoms, either the anemia or the vaso-occlusive crises.” Preclinical experiments comparing FTX-6058 with another fetal hemoglobin booster, hydroxyurea, approved in the 1990s, showed the new drug candidate outperforms the current treatment and, according to Moxham, offers the potential for a transformative therapy.
The team is currently designing a phase 2 clinical trial for people living with sickle cell disease that they plan to initiate by the end of 2021. They are also in the process of characterizing the therapeutic molecule further, using genomic technologies and additional cell assay systems to fill in the details of exactly how it works. Beyond sickle cell disease, Fulcrum is also considering a clinical strategy to explore the use of FTX-6058 in people living with ?-thalassemia, a blood disorder in which hemoglobin production is reduced.
Story Source:
Materials provided by American Chemical Society. Note: Content may be edited for style and length.

A dementia diagnosis turns the world upside down, not only for the person affected but also for their relatives, as brain function gradually declines. Those affected lose their ability to plan, remember things or behave appropriately. At the same time, their motor skills also deteriorate. Ultimately, dementia patients are no longer able to handle daily life alone and need comprehensive care. In Switzerland alone, more than 150,000 people share this fate, and each year a further 30,000 new cases are diagnosed.
To date, all attempts to find a drug to cure this disease have failed. Dementia, including Alzheimer’s — the most common of several forms of dementia — remains incurable. However, a clinical study carried out in Belgium with the involvement of ETH researcher Eling de Bruin has now shown for the first time that cognitive motor training improves both the cognitive and physical skills of significantly impaired dementia patients. A fitness game, known as “Exergame,” developed by the ETH spin-off Dividat was used in the study.
Better cognitive ability thanks to training
In 2015, a team of scientists led by ETH researcher Patrick Eggenberger showed that older people who train both body and mind simultaneously demonstrate better cognitive performance and can thereby also prevent cognitive impairment (as reported by ETH News). However, this study was carried out on healthy subjects only.
“It has been suspected for some time that physical and cognitive training also have a positive effect on dementia,” explains de Bruin, who worked with Eggenberger at the Institute of Human Movement Sciences and Sport at ETH Zurich. “However, in the past it has been difficult to motivate dementia patients to undertake physical activity over extended periods.”
ETH spin-off combines exercise and fun
With a view to changing this, Eva van het Reve, a former ETH doctoral student, founded the ETH spin-off Dividat in 2013 together with her PhD supervisor Eling de Bruin and another doctoral student. “We wanted to devise a customised training programme that would improve the lives of older people,” says van het Reve. Fun exercises were developed in order to encourage people who were already experiencing physical and cognitive impairments to participate in training, and the Senso training platform was born.

Exercise and a healthy diet in childhood leads to adults with bigger brains and lower levels of anxiety, according to new UC Riverside research in mice.
Though diet and exercise are consistently recommended as ways to promote health, this study is the first to examine the long-lasting, combined effects of both factors when they are experienced early in life.
“Any time you go to the doctor with concerns about your weight, almost without fail, they recommend you exercise and eat less,” said study lead and UCR physiology doctoral student Marcell Cadney. “That’s why it’s surprising most studies only look at diet or exercise separately. In this study, we wanted to include both.”
The researchers determined that early-life exercise generally reduced anxious behaviors in adults. It also led to an increase in adult muscle and brain mass. When fed “Western” style diets high in fat and sugar, the mice not only became fatter, but also grew into adults that preferred unhealthy foods.
These findings have recently been published in the journal Physiology and Behavior. To obtain them, the researchers divided the young mice into four groups — those with access to exercise, those without access, those fed a standard, healthy diet and those who ate a Western diet.
Mice started on their diets immediately after weaning, and continued on them for three weeks, until they reached sexual maturity. After an additional eight weeks of “washout,” during which all mice were housed without wheels and on the healthy diet, the researchers did behavioral analysis, measured aerobic capacity, and levels of several different hormones.

As demonstrated by multiple studies over the years, women who breastfeed have a lower risk for developing cardiovascular disease and diabetes when compared to those who don’t or can’t. However, the mechanisms by which these risks are reduced for lactating women are still not fully understood.
Duke Appiah, Ph.D., an assistant professor of public health at the Texas Tech University Health Sciences Center and director of the university’s master’s program in public health, said the presence of excess fat, specifically visceral and pericardial fat could help explain this finding. Using that hypothesis, Appiah and a team of researchers recently completed a study titled, “The Association of Lactation Duration with Visceral and Pericardial Fat Volumes in Parous Women: The CARDIA Study.” The Journal of Clinical Endocrinology & Metabolism published the results in its February issue.
The Appiah team included Cora E. Lewis, M.D., and James M. Shikany (University of Alabama at Birmingham); David R. Jacobs, Jr., Ph.D., and Myron Gross, Ph.D., (University of Minnesota); Jeff Carr, M.D., (Vanderbilt University Medical Center); and Charles P. Quesenberry, Jr., Ph.D., Stephen Sidney, M.D., and senior research scientist Erica P. Gunderson, Ph.D., (Kaiser Permanente Northern California). The National Institute of Diabetes and Digestive and Kidney Diseases provided funding to Gunderson, the study’s senior author, for creating the pregnancy-related derived variables, and for the analysis of lactation and the development of cardiometabolic diseases in Coronary Artery Risk Development in Young Adults (CARDIA) study women.
Visceral fat, often referred to as active fat, potentially can increase the risk of developing dangerous health issues such as cardiovascular disease, heart attacks, Type 2 diabetes, stroke, breast and colorectal cancer and Alzheimer’s disease. Though it can build up in the arteries, visceral fat typically is stored within the abdominal cavity near critical organs such as the stomach, liver and intestines.
Pericardial fat, a deposit of fatty tissue located on the outside of the heart, also may influence certain cardiovascular conditions.
“We know these two organ-related fats contribute to diabetes as well as cardiovascular disease, so we wanted to see how breastfeeding influences these types of fat,” Appiah explained. “If breastfeeding does affect these fats, then it means it could provide a physiologic mechanism by which we can understand how breastfeeding actually affects these two main diseases. That was basically the motivation for this study.”
Because these fats are related to insulin production and other cardio metabolic factors, Appiah said weight change could influence the relationship between breastfeeding and these fats. For instance, the visceral fat that builds up around the abdomen tends to also include adipokines, which are cytokines produced by fatty tissue. Adipokines also secrete hormones, which influence the insulin sensitivity of the muscles. When the amount of visceral fat increases, so too does the competition for insulin binding sites, which increases the risk of developing insulin resistance or glucose intolerance.

The good news: There are more shots available. The challenge is getting people to take them.When it comes to getting the coronavirus vaccine, Mississippi residents have an abundance of options. On Thursday, there were more than 73,000 slots to be had on the state’s scheduling website, up from 68,000 on Tuesday.In some ways, the growing glut of appointments in Mississippi is something to celebrate: It reflects the mounting supplies that have prompted states across the country to open up eligibility to anyone over 16.But public health experts say the pileup of unclaimed appointments in Mississippi exposes something more worrisome: the large number of people who are reluctant to get inoculated.“It’s time to do the heavy lifting needed to overcome the hesitancy we’re encountering,” said Dr. Obie McNair, an internal medicine practitioner in Jackson, the state capital, whose office has a plentiful supply of vaccines but not enough takers.Though access remains a problem in rural Mississippi, experts say that the state — one of the first to open eligibility to all adults three weeks ago — may be a harbinger of what much of the country will confront in the coming weeks, as increasing supplies enable most Americans who want the vaccine to easily make appointments.The hesitancy has national implications. Experts say between 70 percent to 90 percent of all Americans must be vaccinated for the country to reach herd immunity, the point at which the virus can no longer spread through the population.When it comes to rates of vaccination, Mississippi still has a way to go, with just a quarter of all residents having received at least one dose compared to the nationwide average of 33 percent, according to state data. Other southern states, among them Tennessee, Arkansas, Alabama and Georgia, have similarly low rates of vaccination.A closer look at Mississippi’s demographics explains why hesitancy may be especially pronounced.The state reliably votes Republican, a group that remains highly skeptical of the coronavirus vaccine. Nearly half of all Republican men and 40 percent of Republicans over all have said they do not plan to get vaccinated, according to several recent surveys. Those figures have barely budged in the months since vaccines first became available. By contrast, just 4 percent of Democrats have said they will not get the vaccine.Another factor in the state’s low vaccination rate may be Mississippi’s large Black community, which comprises 38 percent of the state’s population but accounts for 31 percent of the doses administered, according to state data. Vaccine hesitancy remains somewhat high among African-Americans, though the doubts and distrust — tied largely to past government malfeasance like the notorious Tuskegee syphilis experiments — have markedly declined in recent months.According to a survey by the Kaiser Family Foundation released last week, about 55 percent of Black adults said they had been vaccinated or planned to be soon, up 14 percentage points from February, a rate that approaches those of Hispanics, at 61 percent, and whites, at 64 percent.Gov. Tate Reeves of Mississippi during a Covid briefing in February. “I feel much better waking up every day knowing that I have been vaccinated,” Governor Reeves said on Tuesday.Rogelio V. Solis/Associated PressA number of other heavily Republican states are also finding themselves with surfeits of doses. On Thursday, officials in Oklahoma, which has delivered at least one dose to 34 percent of its residents, announced they would open up eligibility to out-of-state residents, and in recent weeks, Republican governors in Ohio and Georgia voiced concern about the lackluster vaccine demand among their residents.Tim Callaghan, an assistant professor at the Texas A&M University School of Public Health and an expert on vaccine skepticism, said that more research was needed to divine the reasons behind Mississippi’s slackening vaccine demand but that states with large rural populations, Republican voters and African-Americans were likely to be the first to confront the problem. “If you’re looking to see vaccine hesitancy to emerge, it’s going to be in red states like Mississippi,” he said.Mississippi officials are well aware of the challenge. On Tuesday, Gov. Tate Reeves held a news conference with a panel of medical experts who sought to dispel some of the misinformation surrounding the vaccines. They tried to explain the vaccine development process, rebutted claims that the vaccine can cause miscarriages and recounted their own personal experiences after getting the shot.“I had about 18 hours of turbulence,” Governor Reeves said, describing the mild, flulike symptoms he had felt after his second injection. “But I was able to continue and move on and work, and I feel much better waking up every day knowing that I have been vaccinated.”Access is still a challenge in swaths of rural Mississippi, especially among African-Americans who live far from the drive-through vaccination sites in urban areas that account for roughly half the doses administered by the state. The scheduling system has also proved frustrating for the poor and for older people, who often lack internet access to book appointments or the transportation to get them to distant vaccination sites.“We’ve got to take the vaccines to the people, to pop-up locations that don’t require internet or registration in advance,” said Pam Chatman, the founder of Boss Lady Workforce Transportation, a system of minivans that has been ferrying residents in the Mississippi Delta to mass vaccination locations.Demand among African-Americans was still robust, she said, noting long lines that formed this week outside a tent in Indianola, a small city in the Delta, where the single-dose Johnson & Johnson vaccine was being offered. (The tents offering the Pfizer and Moderna vaccines, which require two doses, were nearly empty.)But hesitancy is rife. Dr. Vernon Rayford, an internal medicine doctor in Tupelo, said he had been frustrated by patients who offered up a variety of reasons for rejecting the vaccine. They claim it will give them Covid-19 or render them infertile, and they worry about unknown repercussions that might emerge decades down the road. “I’ve heard some really wacky theories,” he said.A drive-through vaccination site on the campus of Delta State University in Cleveland, Miss., last month.Rory Doyle for The New York TimesDr. Rayford, who sees patients of all races, said he had discerned subtle differences in the skepticism: African-Americans voice mistrust of the health care system, while whites express a more amorphous distrust of government. “It’s like that line from ‘Anna Karenina,’” he said. “‘All happy families are alike; each unhappy family is unhappy in its own way.’”Dr. Brian Castrucci, president of the de Beaumont Foundation, which focuses on public health, has been working on ways to allay such fears. Dr. Castrucci, an epidemiologist, is especially worried about young conservatives, ages 18 to 34; he cited a recent survey that found that 55 percent of college-educated Republican women under age 49 would not get vaccinated.“Its polls like these that keep me awake at night,” he said.The biggest obstacles to greater vaccine acceptance, he said, are the misinformation that flourishes on social media and the mixed messaging from Republican governors that leave people confused.“By relaxing Covid restrictions, elected leaders in states like Florida, Mississippi, Texas and Georgia are pushing narratives about coronavirus that are working against a narrative that promotes the urgency of vaccinations,” he said. “And unfortunately, our vaccine campaigns are being undone late at night by Facebook and Twitter and Instagram.”Until now, Mississippi health officials have been focusing much of their vaccine hesitancy efforts on African-American and Hispanic residents through partnerships with churches and health clinics. Governor Reeves, a Republican, has so far declined to single out skepticism among white conservatives in the state, but health officials said they were planning to address the problem through Facebook and Zoom meetings with local organizations.Public health experts say what’s needed are well-crafted messages delivered by doctors, religious leaders and other figures who are trusted in a particular community. Dr. Thomas Friedan, a former director of the Centers for Disease Control and Prevention who took part in a focus group with vaccine-hesitant Trump voters that was organized last month by the de Beaumont Foundation, said participants wanted their fears acknowledged, and they craved factual information without being lectured or belittled. “There isn’t one right way to communicate about vaccines, but you need multiple messages with multiple messengers,” said Dr. Friedan, who leads the health advocacy group Resolve to Save Lives. “And people don’t want to hear from politicians.”

Data collected from 337 cities across 18 countries show that even slight increases in ambient carbon monoxide levels from automobiles and other sources are associated with increased mortality.
A scientific team led by Yale School of Public Health Assistant Professor Kai Chen analyzed data, including a total of 40 million deaths from 1979 to 2016, and ran it through a statistical model. The research, published today in The Lancet Planetary Health, also found that even short-term exposure to ambient carbon monoxide (CO) — at levels below the current air quality guidelines and considered safe — had an association with increased mortality.
Overall, a 1 mg/m³ increase in the average CO concentration of the previous day was associated with a 0.91% increase in daily total mortality, the study found. This suggests considerable public health benefits could be achieved by reducing ambient CO concentrations through stricter control of traffic emissions and other measures.
Chen and colleagues also discovered that the exposure-response curve was steeper at daily CO levels lower than 1 mg/m³, indicating greater risk of mortality per increment in CO exposure, and this persisted at daily concentrations as low as 0.6 mg/m³ or less. The findings reveal that there is no evidence for a threshold value below which exposure to ambient CO can be considered “safe.”
The U.S. National Ambient Air Quality Standard for ambient CO (approximately 7 mg/m³ for the daily average) was established in 1971 and has not been revisited for the past five decades. The same air quality guideline for CO has been applied in other regions such as Europe, whereas a lower value of 4 mg/m³ was established as China’s air quality standard.
The study’s findings strongly suggest the need to revisit global and national air quality guidelines for CO and, in addition to single-pollutant standards, policies should also be expanded to address traffic-related air pollution mixtures.
“These findings have significant public health implications,” Chen said. “Millions and millions of people live in environments with elevated CO levels and in environments where the CO levels are within the current guidelines considered ‘safe range.'”
The international study is believed to be the largest epidemiological investigation on mortality and short-term CO exposure. Professor Michelle Bell of the Yale School of the Environment is a co-author of the paper.
Chen collaborated with 37 other scientists from the Multi-Country Multi-City (MCC) Collaborative Research Network. The senior authors of this paper are Alexandra Schneider of the Helmholtz Zentrum München in Munich, Germany, and Antonio Gasparrini of the London School of Hygiene & Tropical Medicine.
Story Source:
Materials provided by Yale University. Original written by Michael Greenwood. Note: Content may be edited for style and length.

Dengue risk is exacerbated in highly populated areas of Brazil after extreme drought because of improvised water containers housing mosquitoes, suggests a new study in Lancet Planetary Health.
The research was led by the London School of Hygiene & Tropical Medicine’s (LSHTM) Centre on Climate Change & Planetary Health and Centre for the Mathematical Modelling of Infectious Diseases. Using advanced statistical modelling techniques, the team predicted the timing and intensity of dengue risk in Brazil from extreme weather patterns.
The risk of dengue was high in urban areas three to five months after extreme drought. Extremely wet conditions increased dengue risk in the same month and up to three months later. In rural areas, dengue risk was more readily associated with very wet conditions.
Dengue fever is caused by a virus carried by mosquitoes and is considered one of the top ten threats to global health. Brazil has the greatest number of dengue cases in the world, reporting more than two million cases of dengue in 2019 alone.
Increasing levels of severe droughts and flooding episodes due to climate change has led to interruptions in water supply networks in Brazil. The improvised water storage containers used to combat this have become breeding grounds for mosquitoes.
Dr Rachel Lowe from LSHTM who led the study, said: “The dengue situation in Brazil is extremely concerning. Our work highlights that risk is not only related to extreme weather, but also linked to water management systems and human behaviour in densely populated urban areas.”
In Brazil, large dengue outbreaks are typically observed after wet and warm periods and most interventions are targeted at these times. No studies have previously determined exact timeframes for dengue outbreaks following extreme weather events like droughts and floods across a large and diverse geographical area, although this work confirms initial findings from Barbados.
In this new study, the team combined dengue case data in 558 regions of Brazil between January 2001 and 2019, with information on droughts and wet conditions to assess the dengue risk differences in urban and rural areas.
The results suggest dengue interventions should be timed appropriately in poorly serviced urban areas and not only implemented during the wet and warm season.
In the short term, these include eliminating breeding sites around the home to prevent additional mosquito larval habitats during drought periods. During wet periods, outdoor water storage containers should be well covered and maintained, and discarded waste should be cleared to avoid collecting water.
Dr Lowe said: “It’s imperative that governments invest in local infrastructure to ensure permanent water supply and promote better environmental hygiene in areas prone to epidemics of mosquito-borne diseases.”
The study carries some limitations as the dengue data was obtained from the passive surveillance system, where only a fraction of cases are laboratory confirmed and mild or asymptomatic cases are not accounted for.
Story Source:
Materials provided by London School of Hygiene & Tropical Medicine. Note: Content may be edited for style and length.

Sunnier areas are associated with fewer deaths from Covid-19, an observational study suggests.
Increased exposure to the sun’s rays — specifically UVA — could act as a simple public health intervention if further research establishes it causes a reduction in mortality rates, experts say.
Researchers from the University of Edinburgh compared all recorded deaths from Covid-19 in the continental US from January to April 2020 with UV levels for 2,474 US counties for the same time period.
The study found that people living in areas with the highest level of exposure to UVA rays — which makes up 95 per cent of the sun’s UV light — had a lower risk of dying from Covid-19 compared with those with lower levels. The analysis was repeated in England and Italy with the same results.
The researchers took into account factors known to be associated with increased exposure to the virus and risk of death such as age, ethnicity, socioeconomic status, population density, air pollution, temperature and levels of infection in local areas.
The observed reduction in risk of death from Covid-19 could not be explained by higher levels of vitamin D, the experts said. Only areas, with insufficient levels of UVB to produce significant vitamin D in the body, were included in the study.
One explanation for the lower number of deaths, which the researchers are following up, is that sunlight exposure causes the skin to release nitric oxide. This may reduce the ability of SARS Coronavirus2 — the cause of Covid-19 — to replicate, as has been found in some lab studies.
Previous research from the same group has shown that increased sunlight exposure is linked to improved cardiovascular health, with lower blood pressure and fewer heart attacks. As heart disease is a known risk factor in dying from Covid-19, this could also explain the latest findings.
The team say due to the observational nature of the study it is not possible to establish cause and effect. However, it may lead to interventions that could be tested as potential treatments.
The paper has been published in the British Journal of Dermatology, an official publication of the British Association of Dermatologists.
Dr Richard Weller, corresponding author, consultant dermatologist and Reader at the University of Edinburgh, said: “There is still so much we don’t understand about Covid-19, which has resulted in so many deaths worldwide. These early results open up sunlight exposure as one way of potentially reducing the risk of death.”
Professor Chris Dibben, Chair in Health Geography at the University of Edinburgh and Co-author said: “The relationship between Covid-19 mortality, season and latitude has been quite striking, here we offer an alternative explanation for this phenomenon.”
Story Source:
Materials provided by University of Edinburgh. Note: Content may be edited for style and length.

The first large study showing that leisure time physical activity and occupational physical activity have opposite, and independent, associations with cardiovascular disease risk and longevity is published today in European Heart Journal, a journal of the European Society of Cardiology (ESC).
“We adjusted for multiple factors in our analysis, indicating that the relationships were not explained by lifestyle, health conditions or socioeconomic status,” said study author Professor Andreas Holtermann of the National Research Centre for the Working Environment, Copenhagen, Denmark.
The World Health Organization (WHO) recommends physical activity during both recreation and work to improve health.* Previous studies have suggested that occupational activity is related to an increased risk for heart disease and mortality but have been too small to fully explain whether this was due to the manual work or because employees had unhealthy lifestyles or low socioeconomic status (e.g. low level of education).
This study included 104,046 women and men aged 20-100 years from the Copenhagen General Population Study with baseline measurements in 2003-2014. Participants completed questionnaires about activity during leisure and employment and were categorised as low, moderate, high, or very high activity for each.
During a median follow-up of 10 years, there were 9,846 (9.5%) deaths from all causes and 7,913 (7.6%) major adverse cardiovascular events (MACE, defined as fatal and nonfatal myocardial infarction, fatal and non-fatal stroke, and other coronary death).
Compared to low leisure time physical activity, after adjustment for age, sex, lifestyle, health, and education, moderate, high, and very high activity were associated with 26%, 41%, and 40% reduced risks of early death, respectively. In contrast, compared to low work activity, high and very high activity were associated with 13% and 27% increased risks of death, respectively.

From 12 April people in England will be able to visit shops, gyms and hairdressers, as well as the outdoor spaces of pubs and restaurants.So with the next stages of lockdown easing on the horizon, how can you keep yourself and others safe from transmitting coronavirus in these new locations?The BBC’s science editor David Shukman explains the risks and what to look out for.Producers: Aisha Doherty and Kate StephensGraphics: Mel Lou