University Hospital Cleveland Medical Center Doctors Successfully Reattach Woman’s Nearly Severed Leg

n August 2020, Caroline Rarick, 18, experienced a horrific trauma. Celebrating the summer with her volleyball team on Lake Roaming Rock in Roaming Shores, Ohio, Caroline enjoyed the day jet skiing and tubing. Toward the end of the afternoon, her friend took off on the jet ski as Caroline stood on the back. A tubing rope got caught around Caroline’s right leg, just below the knee. She was yanked into the water and pulled by her leg for a short distance. After her friend stopped the jet ski, Caroline looked down and saw bone with muscle hanging from her leg.

“When I first saw it I was extremely scared,” said Caroline. “I remember seeing my bone, but I think I was in shock and didn’t completely comprehend what was going on. I didn’t feel any pain initially, but I saw the injury and I knew it was bad.”

“In case I pass out, hold me up!” Caroline told her friend as she bobbed in the water, thankfully wearing a life vest. The pair flagged down another jet skier who pulled Caroline onto his jet ski. None of them had cell phones with them on the water. As they drove toward shore, Caroline’s friend recognized a boat passing by. She knew the owner – a doctor.

They got to the boat and discovered two doctors on board – one pediatrician and one anesthesiologist. They transferred Caroline to the boat, applied a tourniquet and called 911. The doctors detected a slight pulse in Caroline’s leg, but it was growing faint because of so much bleeding.

Fighting To Save Her Leg

An ambulance arrived and rushed Caroline to UH Geauga Medical Center, about 30 miles away. That’s where Caroline’s parents met her. “The color in her leg was gone, it looked dead,” her mother Jennifer said. It was decided Caroline would be transported to UH Cleveland Medical Center, where a trauma team was already assembling. When she arrived, the the trauma team confirmed her artery was completely severed and her tibia suffered a fracture as well.

“Caroline’s injury was extremely severe. Nearly all of the tissue and muscle were pulled from her bone, called a degloving injury,” said vascular surgeon Vikram Kashyap, MD, Division Chief, Vascular Surgery, UH Harrington Heart & Vascular Institute; Alan H. Markowitz, MD Chair for Cardiac and Vascular Surgery. “She had lost a lot of blood, there was no pulse below the injury, and she could barely move her foot indicating either nerve damage or severe ischemia. The injury was severe enough that we were even considering amputation as the best course of action.”

Her team of vascular, orthopedic and plastic surgeons headed into the operating room at 10 p.m., five hours after the initial accident. “Heading into the procedure I was really scared, because I finally understood how serious it was. I was terrified I was going to wake up without a leg. I asked my dad if I was going to lose my leg and he didn’t know what to say. There was a pause and that’s when Dr. Kashyap said, ’We’re not scheduled for an amputation tonight.’ That calmed my nerves,” Caroline said.

During the initial operation, Dr. Kashyap and his team explored the wound, and performed a bypass of the severed artery in the right leg using a vein from the mid-thigh of her left leg. They released the fascia (thin casing of connective tissue) in the lower leg muscle compartments to relieve pressure. Then, pediatric plastic surgery specialist Edward Davidson, MD and the plastic surgery team performed a debridement (removal of damaged tissue or foreign objects from a wound) with coverage of the bypass.

The color returned in Caroline’s leg and her pulse strengthened. Even though the initial operation appeared successful, the odds were against Caroline returning to normal function.

The Long Road to Recovery

Caroline was in the trauma intensive care unit for four days. She was released from the hospital after 12 days. But she faced a long road to normalcy: multiple debridements, fasciotomy, a wound vac, a skin graft, she fought an infection and faced several more surgeries along the way. Her leg atrophied and most of her remaining muscle disappeared.

For months, Caroline worked with determination and dedication during physical therapy and at-home exercises. Over time, she built strength and graduated from a wheelchair to crutches and was walking independently by Christmas. In April 2021, she was cleared to attempt jogging.

Caroline missed her senior year of volleyball at Gilmour Academy, but she never lost her positivity. “Everyone always asks me how I’ve remained so positive. Honestly, when I woke up from the initial surgery and I still had my leg I was just so happy. I was just so thankful to have a leg in the first place. That has kept me going,” said Caroline. “I don’t think it would have been the same outcome if I would have gone anywhere else. I’m so thankful to the doctors and everyone at University Hospitals.”

“2020 was a devastating year for so many people due to the pandemic,” said Dr. Kashyap. “We have seen our share of challenges at UH and many caregivers have witnessed depressing outcomes in patients. I can’t tell you how gratifying it is to see Caroline recover from a life-threatening and limb-threatening accident. She has had a miraculous outcome. She has returned to essentially a normal functional state and is ready to run and participate in competitive sports! Her resilience, positive attitude and mental fortitude should be a shining example for all of us.”

Caroline is thankful to the team of doctors who saved her leg as she prepares to walk onto the campus of Indiana University in fall 2021.

UH Harrington Heart & Vascular Institute

Nationally recognized for heart and vascular care, University Hospitals Harrington Heart & Vascular Institute offers a Limb Salvage Program, one of a select number of such centers in the United States. Thanks to the limb salvage program, patients like Caroline are able to receive life-saving care.

Study identifies mechanisms by which COVID-19 can lead to Alzheimer’s disease-like dementia

A new Cleveland Clinic-led study has identified mechanisms by which COVID-19 can lead to Alzheimer’s disease-like dementia. The findings, published in Alzheimer’s Research & Therapy, indicate an overlap between COVID-19 and brain changes common in Alzheimer’s, and may help inform risk management and therapeutic strategies for COVID-19-associated cognitive impairment.

Reports of neurological complications in COVID-19 patients and “long-hauler” patients whose symptoms persist after the infection clears are becoming more common, suggesting that SARS-CoV-2 (the virus that causes COVID-19) may have lasting effects on brain function. However, it is not yet well understood how the virus leads to neurological issues.

While some studies suggest that SARS-CoV-2 infects brain cells directly, others found no evidence of the virus in the brain. Identifying how COVID-19 and neurological problems are linked will be critical for developing effective preventive and therapeutic strategies to address the surge in neurocognitive impairments that we expect to see in the near future.”

– Feixiong Cheng, PhD, Study Lead Author and Assistant Staff, Cleveland Clinic, Genomic Medicine Institute

In the study, the researchers harnessed artificial intelligence using existing datasets of patients with Alzheimer’s and COVID-19. They measured the proximity between SARS-CoV-2 host genes/proteins and those associated with several neurological diseases where closer proximity suggests related or shared disease pathways. The researchers also analyzed the genetic factors that enabled SARS-COV-2 to infect brain tissues and cells.

While researchers found little evidence that the virus targets the brain directly, they discovered close network relationships between the virus and genes/proteins associated with several neurological diseases, most notably Alzheimer’s, pointing to pathways by which COVID-19 could lead to AD-like dementia. To explore this further, they investigated potential associations between COVID-19 and neuroinflammation and brain microvascular injury, which are both hallmarks of Alzheimer’s.

“We discovered that SARS-CoV-2 infection significantly altered Alzheimer’s markers implicated in brain inflammation and that certain viral entry factors are highly expressed in cells in the blood-brain barrier,” explained Dr. Cheng. “These findings indicate that the virus may impact several genes or pathways involved in neuroinflammation and brain microvascular injury, which could lead to Alzehimer’s disease-like cognitive impairment.”

The researchers also found that individuals with the allele APOE E4/E4, the greatest genetic risk factor for Alzheimer’s, had decreased expression of antiviral defense genes, which could make these patients more susceptible to COVID-19.

“Ultimately, we hope to have paved the way for research that leads to testable and measurable biomarkers that can identify patients at the highest risk for neurological complications with COVID-19,” said Dr. Cheng.

Dr. Cheng and his team are now working to identify actionable biomarkers and new therapeutic targets for COVID-19-associated neurological issues in COVID long-haulers using cutting-edge network medicine and artificial intelligence technologies.


Cleveland ClinicJournal reference:

Zhou, Y., et al. (2021) Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimer’s Research and

Broken Heart Syndrome Linked to the Brain

A chronically stressed amygdala can prime the heart to overreact to acute stress events, a new study shows.

The paper
A. Radfar et al., “Stress-associated neurobiological activity associates with the risk for and timing of subsequent Takotsubo syndrome,” Eur Heart J, ehab029, 2021

Takotsubo syndrome, also known as broken heart syndrome, is a rare, reversible condition with symptoms mimicking a mild heart attack. A disease that disproportionately affects women, TTS is triggered by stressful events such as bankruptcy, the death of a loved one, or divorce, and results in a weakening of the heart’s left ventricle such that it becomes temporarily misshapen.

Previous work has shown that TTS patients have elevated activity in their amygdala, a brain region involved in stress response. What has never been clear, however, is whether “this activity in the brain happens as a result of the syndrome or whether it began many years before,” says Shady Abohashem, a nuclear cardiologist at Harvard Medical School.

Abohashem and his colleagues retrospectively analyzed full-body PET/CT scans from 104 patients, most of whom had cancer and 41 of whom had developed TTS since first being scanned, and 63 individually matched controls. The team calculated ratios of the activity in each person’s amygdala to that of two brain regions that attenuate the stress response, the temporal lobe and the prefrontal cortex. Higher amygdala activity was associated with an increased risk for TTS, and among those with the condition, patients with higher ratios had developed TTS roughly two years earlier following the imaging than those with lower ratios. “We can now show that this syndrome happens as a result of chronic stress over years that makes you vulnerable to developing the syndrome more easily and sooner than [less stressed] people,” Abohashem says.

“This study confirms our suspicion that there’s a relationship between amygdala activity and future risk of Takotsubo,” says Janet Wei, a cardiologist at Cedars-Sinai Medical Center who was not involved in the work. The results, she adds, “necessitate further study to see why these patients have higher amygdala activity and how it actually regulates the acute response.”  

FDA Approves Aduhelm, First of its Kind Amyloid-Targeted Alzheimer’s Therapy

by Marisa Wexler MS

For the first time in almost 18 years, the U.S. Food and Drug Administration (FDA) has approved a new treatment — Aduhelm, formerly known as aducanumab — for Alzheimer’s disease, and a first targeted treatment for patients.

With this approval, Aduhelm becomes the first disease-modifying therapy for Alzheimer’s, and the first such therapy to come under FDA review. Disease-modifying therapies are those capable of slowing the progression of a disease itself, and not just its symptoms.

It is also the first new treatment for Alzheimer’s to be approved by the FDA since October 2003.

“This FDA drug approval ushers in a new era in Alzheimer’s treatment and research. History has shown us that approvals of the first drug in a new category invigorates the field, increases investments in new treatments and encourages greater innovation. We are hopeful and this is the beginning — both for this drug and for better treatments for Alzheimer’s,” Maria Carrillo, PhD, said in an email to Alzheimer’s News TodayCarrillo is chief science officer at the Alzheimer’s Association, which had called on the FDA to approve Aduhelm.

Following an initial titration period, the therapy is administered at a maintenance dose of 10 mg/kg, given as an intravenous infusion over about one hour every four weeks. According to its label, Aduhelm has been known to cause allergic reactions and ARIA-E (fluid accumulation in the brain), which should be monitored in people being treated. 

The FDA approved Aduhelm under the accelerated approval pathway, which is intended to provide earlier access to therapies that are expected to benefit patients with serious diseases, even if there is some residual uncertainty regarding that benefit.

“In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy,” the FDA stated in a press release.

A tumultuous road to approval

Aduhelm, by Biogen and Eisai, is a human-made antibody designed to remove toxic clumps of the protein beta-amyloid, which are thought to drive the death of nerve cells (neurons) in the brains of people with Alzheimer’s.

The therapy’s development has been both unusual and tumultuous. Data from an early Phase 1b clinical trial called PRIME (NCT01677572) suggested that the treatment could safely slow cognitive decline, and indicated that it could remove beta-amyloid plaques as it was designed to do.

Biogen then launched two Phase 3 clinical trials, ENGAGE (NCT02477800) and EMERGE (NCT02484547), to evaluate the therapy’s safety and efficacy in early Alzheimer’s patients. Collectively, these trials enrolled nearly 3,300 people with relatively mild, or early stage, disease.

When an interim analysis using data from these studies’ first 18 months indicated that Aduhelm, given as a monthly intravenous infusion, was unlikely to benefit patients, Biogen halted development of the investigational therapy in 2019.  

After the trials were discontinued, however, an additional three months’ of data from ENGAGE and EMERGE became available. A new analysis using these findings showed that, contrary the interim analysis, EMERGE had actually met its primary efficacy endpoint (goal): relative to placebo, treatment with Aduhelm improved cognition and function, including memory, orientation, language, and activities of daily living.

ENGAGE did not meet its primary goal, but data suggested the therapy benefitted those given the high, up to 10 mg/kg, dose in the trial.

According to Carrillo, these results indicate that the medication would give patients more time in early stages of the disease, before progressing to more substantial dementia.

In an interview, Carrillo said that Aduhelm might enable patients “to do more with their families, to have more quality time with their families at a stage where they can still maintain their independence.”

Based on the new and favorable analysis, in conjunction with the positive results from earlier trials, Biogen and Eisai sought regulatory approval of Aduhelm in the U.S. The FDA put the therapy under priority review in August 2020, which was extended into June after Biogen submitted additional analyses.

Prior to that extension, an FDA advisory committee voted that the available clinical data did not support Aduhelm as an effective Alzheimer’s treatment. Notably, the advisory committee did not consider the possibility of accelerated approval.

Some experts also continued to favor a new Phase 3 trial, testing the treatment at high dose prior to it being approved.

“Based on our review of data presented publicly in December 2019,” neurologists with the Mayo Clinic and Stanford University wrote in a policy forum paper published in November 2020, “we do not agree with Biogen’s claim for efficacy. … Aducanumab’s efficacy as a treatment for the cognitive dysfunction in Alzheimer’s disease cannot be proven by clinical trials with divergent outcomes.”

“We are well-aware of the attention surrounding this approval. … With a treatment for a serious, life-threatening disease in the balance, it makes sense that so many people were following the outcome of this review,” the FDA stated, adding that the clinical trial data on the therapy “were highly complex and left residual uncertainties regarding clinical benefit.”

Accelerated approval

Although the clinical trials were not conclusive on the therapy’s effect on cognition and function, they clearly showed that Aduhelm can reduce levels of beta-amyloid plaques, according to the FDA. These data formed the basis for the FDA’s decision to give the therapy accelerated approval, which allows for earlier approval based on a surrogate endpoint as a marker, such as a laboratory measure (in this case, the reduction in beta-amyloid).

“Treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit,” the FDA wrote.

As a stipulation of the approval, the medication’s manufacturers will be required to conduct additional clinical testing to verify the anticipated clinical benefit, known as Phase 4 confirmatory trials. If data from these trials do not verify the anticipated benefit, the FDA could remove Aduhelm from the market.

“This approval is a victory for people living with Alzheimer’s and their families,” said Harry Johns, president and CEO of the Alzheimer’s Association. “It is a new day. This approval allows people living with Alzheimer’s more time to live better. For families it means being able to hold on to their loved ones longer. It is about reinvigorating scientists and companies in the fight against this scourge of a disease. It is about hope.”

Applications seeking approval of Aduhelm in the European Union and Japan are currently under review.

Biogen has initiated the open-label EMBARK trial (NCT04241068), which is testing Aduhelm at its high dose (up to 10 mg/kg) in people who previously took part in ENGAGE, EMERGE, or other aducanumab clinical trials that were discontinued in 2019.

As graduates cheered, an HBCU president announced that their debt to the university was wiped away

By Jaclyn Peiser

Seated in white folding chairs inside a gymnasium on Saturday morning, the 2020 and 2021 graduating classes of Wilberforce University listened as the president of the historically Black university in Ohio lauded the students for their resilience during an arduous year.

Then he made an unexpected announcement.

“We wish to give you a fresh start,” Elfred Anthony Pinkard, the university’s president, told the students. “Therefore, the Wilberforce University Board of Trustees has authorized me to forgive any debt.”

Students jumped from their seats and cheered; parents clapped from the bleachers. One student stood, awestruck, mouth agape and looking side to side, making sure he had heard Pinkard correctly.

“Your accounts have been cleared,” Pinkard continued, followed by more applause and yelps of joy. “And you don’t owe Wilberforce anything. Congratulations.”

In all, more than $375,000 in student debt was wiped away, said the university, which is about 20 miles east of Dayton.

Wilberforce, which enrolls more than 700 students, 166 of whom were in this year’s graduating class, secured funding to erase the debt through the United Negro College Fund and other nonprofit organizations, including Jack and Jill of America, the school said.

The move came during a week of racial reckoning as President Biden pledged to close the wealth gap between White and Black Americans at an event on Tuesday commemorating the 100th anniversary of a massacre that left hundreds dead and more than 1,250 homes destroyed in a prosperous Black community in Tulsa. But Biden’s proposals did not include plans to alleviate student debt, an omission that attracted criticism from Derrick Johnson, the president of the NAACP.

“Components of the plan are encouraging, but it fails to address the student loan debt crisis that disproportionately affects African Americans,” Johnson said. “You cannot begin to address the racial wealth gap without addressing the student loan debt crisis.”

The problem has been particularly acute at HBCUs like Wilberforce, which enroll a disproportionate number of students from low-income families, according to the United Negro College Fund. Unlike major state schools, most HBCUs have smaller endowments thanks to decades of limited funding, The Washington Post recently reported, which has complicated efforts to help reduce tuitions.About 25 percent of students who attend HBCUs borrow $40,000 or more, according to UNCF.

Wilberforce University, the country’s first private university owned and run by African Americans, was established before the Civil War and named after William Wilberforce, a British abolitionist. Although the university shut down during the war, it became a destination point for the Underground Railroad. In the late 19th century, W.E.B. Du Bois taught at the university and met his wife, who was a student there.

When the pandemic hit last year, Wilberforce transitioned to remote learning. The university resumed in-person learning in February, although students could still choose to take classes from home.

On Sunday, the graduates learned they would leave with a degree and less debt than they planned.Although the Wilberforce graduates are still responsible for paying back their federal, state or private loans, their debts to the university are now wiped clean.

“As these graduates begin their lives as responsible adults, we are honored to be able to give them a fresh start,” Pinkard said in a news release.

Rodman Allen, a member of the 2021 graduating class, said the move gave him a more stable foundation for his future.

“I couldn’t believe it when he said it,” Allen said in a news release from the university. “It’s a blessing. I know God will be with me. I’m not worried. I can use that money and invest it into my future.”

Two years ago, another group of graduating students at an HBCU received a similar surprise at their graduation. During his 2019 commencement address at Morehouse College, an all-male school in Atlanta, billionaire and philanthropist Robert F. Smith told graduates that his family was establishing a grant that would pay off all their student loans. (Last year, Smith admitted to not paying taxes on more than $200 million and agreed to help prosecutors in a case against his associate, Robert Brockman, who is accused of hiding more than $2 billion in offshore accounts.)

Last month, officials at Delaware State University announced they were using stimulus funds to forgive over $730,000 of student debt for recent graduates who faced financial hardships during the coronavirus pandemic.

During his speech at the Wilberforce commencement ceremony, Pinkard stressed that the effort was meant to acknowledge the difficulty of graduating during the pandemic.

“Because we are in awe of your strengths and perseverance; because you have made your family and yourselves proud; because you have shown that you are capable of doing work under difficult circumstances; because you represent the best of your generation, we wish to give you a fresh start,” Pinkard said.

ADHD medications associated with reduced risk of suicidality in certain children

ADHD medications may lower suicide risk in children with hyperactivity, oppositional defiance and other behavioral disorders, according to new research from the Lifespan Brain Institute (LiBI) of Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania. The findings, published today in JAMA Network Open, address a significant knowledge gap in childhood suicide risk and could inform suicide prevention strategies at a time when suicide among children is on the rise.

“This study is an important step in the much-needed effort of childhood suicide prevention, as it leverages data collected from approximately 12,000 U.S. children to identify an actionable target to reduce childhood suicides,” said senior author Ran Barzilay, MD, Ph.D., an assistant professor at LiBI. “Early diagnosis and treatment of behavioral symptoms with ADHD medication, particularly among children with severe externalizing symptoms, may serve not only to improve learning and behavior problems, but also to decrease suicidality risk.”

Suicide rates among children have been steadily rising. According to the CDC, suicide was the second leading cause of death among individuals between the ages of 10 and 24 in 2018. Yet the rates are still relatively low in preadolescent children, making it difficult to identify factors that may lead to or prevent suicidal tendencies in this age range. Additionally, there are ethical limitations in enrolling potentially suicidal youth in placebo-controlled randomized clinical trials.

“In an ideal world, we want to test a medication effect on suicidality with a randomized prospective trial,” Barzilay said. “But given the challenges of conducting such studies, we are obligated as a society and as scientists to generate clinical insights using data collected in large-scale observational studies of children.”

The LiBI researchers, in concert with Gal Shoval, MD of Tel Aviv University, circumvented this barrier by leveraging data from the Adolescent Brain Cognitive Development (ABCD) Study. As the largest long-term study of brain development and health in the country, the ABCD Study sample includes a cohort of 11,878 children between the ages of 9 and 10 who were recruited through school systems. The cohort spans 21 sites across the United States, encompassing more than 20% of the U.S. population in this age group, and includes comprehensive data on child development, including data on mental, social, and emotional health. The magnitude and breadth of data collected in the ABCD study allowed the research team to control for multiple confounders and to dissect specifically the association of ADHD medications with suicidal tendencies.

Performing a secondary analysis of the ABCD Study data, the LiBI researchers found that of the 11,878 children in the study, 8.5% were treated with ADHD medication, such as methylphenidate, Adderall or clonidine, and 8.8% reported past or current suicidality. The researchers found that children expressing suicidal tendencies had more externalizing symptoms and were more likely to receive ADHD medication than non-suicidal children. However, among children who demonstrated significant externalizing behaviors, those taking ADHD medications had lesser odds for suicidality, suggesting a moderating role for ADHD medications in these children.

To study whether this effect endured, the researchers analyzed data from participants’ one-year follow-up assessments. They found that children with high externalizing symptoms who were treated with ADHD medications at baseline were less likely to be suicidal one year later. Children who were not receiving ADHD medications at baseline but had high externalizing symptoms were more likely to be suicidal at the one-year follow up.

“Given the connection between childhood suicidality and poor adult mental health, these findings emphasize the importance of better and more thorough screening of school-aged children for externalizing behavioral symptoms,” Barzilay said. “These symptoms are treatable, and addressing them early has the strong potential to prevent and mitigate serious mental health issues later in life.”

Sleeping and waking one hour earlier cuts risk of depression

Experts know there is a relationship between sleep timing and mood.

A group of researchers wanted to learn if shifting a sleep schedule earlier could affect risk of depression.

In a study of more than 800,000 people, they found that going to bed and waking up one hour earlier cut risk by 23 percent.

Depression affects many aspects of life, and for some people it may mean that they sleep longer or different hours than they would normally. “We have known for some time that there is a relationship between sleep timing and mood, but a question we often hear from clinicians is: How much earlier do we need to shift people to see a benefit?” says senior author Celine Vetter, assistant professor of integrative physiology at Colorado University Boulder, in a press release.

A previous study from Vetter and collaborators found that in a four-year study of 32,000 nurses that “early risers” were 27 percent less likely to develop depression symptoms. But how would shifting a sleep schedule potentially affect people? That’s what this new study focuses on.

The study followed 840,000 people and collected data on their chronotype, meaning what hours of the day they were predisposed to prefer, based on genetic information. One “clock gene” is thought to account for 12 to 42 percent of our sleep timing.

The researchers wanted to know if someone’s genetics makes them more likely to be an “early riser” if they also have lower risk for depression. So they gave some study participants sleep trackers and some filled out a sleep preference questionnaire. They then connected those data to genetic data.

The team focused on the sleep midpoint, calculated as halfway between bedtime and wake time. “We found that even one-hour earlier sleep timing is associated with significantly lower risk of depression,” says Vetter in the press release. So if someone who normally goes to bed at midnight instead goes to bed at 11 PM and sleeps for the same duration, they could cut their risk by 23 percent, according to the study. The effect could be nearly twice that if shifted by two hours.

The researchers aren’t certain why they are seeing these results, but it may have to do with light and darkness and how our bodies react. Light research has shown that light therapy can be helpful for treating some mood disorders.

The connection to depression symptoms could also be a result of societal norms. Simply having a chronotype that does not make you an early riser could be having an effect. “We live in a society that is designed for morning people, and evening people often feel as if they are in a constant state of misalignment with that societal clock,” says lead author Iyas Daghlas at the Broad Institute of MIT and Harvard.

If you want to shift to an earlier sleep schedule, there are some things you can do to help make that process easier. “Keep your days bright and your nights dark,” says Vetter. “Have your morning coffee on the porch. Walk or ride your bike to work if you can, and dim those electronics in the evening.”

Clinical trial launched following discovery that psychiatric drug may prevent bowel cancer

The study, published in the journal Nature, shows how a drug available on the NHS can boost fitness of healthy stem cells in the gut, making them more resistant to sabotage from mutant stem cells that cause cancer.

Researchers in the Netherlands, funded by the UK charity Worldwide Cancer Research, have discovered a way to boost the fitness of healthy cells in the gut to prevent the development of bowel cancer. The findings have led to the initiation of a clinical trial to find out if a commonly used psychiatric drug could be used to prevent bowel cancer in people. The trial will recruit patients with a genetic mutation that means they are virtually 100% certain to develop bowel cancer in their lifetime, unless the entire large bowel is removed.

Bowel cancer affects more than 43,000 people each year in the UK and just over half of the people diagnosed survive their disease for 10 years or longer. It is thought that the majority of bowel cancer cases are caused by mutations in a gene called APC.

Intestinal stem cells with mutations to the APC gene have been shown to have a competitive advantage over their healthy counterparts and frequently outcompete them, leading to unrestricted growth and cancer.

Up until now it was unclear how the mutant stem cells win the upper hand, but new research, published in the journal Nature, now shows that the mutant stem cells actively emit signals that sabotage the function of healthy stem cells in the gut.

Professor Louis Vermeulen, Group Leader at the Center for Experimental Molecular Medicine at Amsterdam UMC, and senior author of the paper explained: “We have uncovered the very first steps in the development of bowel cancer. We found that following the occurrence of a mutation in a key gene that regulates stem cells in the intestine, these cells turn into cheaters that actively suppress the normal cells in the environment.

“This is a totally new concept as it was always thought that mutant cells that can turn into cancer simply proliferate faster or are resistant to cell death. But our findings indicate that cells on their way to a full malignancy can actively suppress the stem cells in the vicinity to gain a competitive edge. This is a concept we refer to as supercompetition.”

Critically, the researchers also discovered a way to prevent the mutant stem cells from interfering with the healthy ones. Lithium, a commonly used drug for the treatment of several psychiatric disorders, prevented the mutant stem cells from taking over and forming tumours in mice by rendering the healthy stem cells insensitive to the damaging signals.

A clinical trial funded by the Dutch Cancer Society (KWF) testing the effect of lithium of bowel cancer development in individuals with familial adenomatous polyposis (FAP) will now be performed in the Netherlands. FAP is a relatively uncommon genetic syndrome that affects about 1 in 7,000 to 1 in 22,000 people. FAP patients have mutations in their APC gene and develop hundreds of non-cancerous polyps and adenomas in their bowel. Without treatment nearly all of them will develop bowel cancer between the ages of 35 and 45.

The trial is set to recruit 10 young adult patients with FAP and will observe the patients before, during and after treatment with lithium for a total of 18 months. The researchers will collect evidence on the preventive effect of lithium on mutant stem cells and polyp formation, as well as test the safety profile of lithium. Results of the clinical trial are likely to build the basis for larger trials with more patients.

Sanne van Neerven, Ph.D. student who conducted the research, said: “Our clinical trial may reveal that lithium can be used to prevent cancer development in FAP individuals. But what is also important is that this trial can establish a proof of concept that manipulating competition between mutant cells and normal cells can be manipulated in such a way that the healthy cell outcompete the mutant cells. This is a novel strategy for cancer prevention and could be applied to many heritable cancer syndromes involving different mutations and organs, but more research is warranted in this area.”

Dr. Helen Rippon, chief executive at Worldwide Cancer Research said: “The discoveries made by Professor Vermeulen and his team are a huge breakthrough in our understanding of how bowel cancer develops. It’s amazing to see innovative research like this go from the lab to the clinic as it shows just how important early-stage discovery research is to starting new cancer cures. We are all very excited to see the results from this clinical trial and the future impact these findings might have on other people with inherited cancer syndromes.

“Around 1% of bowel cancers are caused by familial adenomatous polyposis (FAP). This may seem like a small number, but in the UK alone this means that over 400 people are diagnosed with bowel cancer caused by FAP every year. The only treatment option available for people with FAP is major surgery to remove the entire colon, which can be life altering and unfortunately cannot guarantee that cancer won’t develop. The launch of a clinical trial thanks to this incredible research will offer real hope to people that there could be a simple way to prevent bowel cancer in the future.”

The Relatable Emotions of Depressed People From 3,000 Years Ago

By Shayla Love

There is a surprisingly relatable description of depression and heartbreak from 3,000 years ago in Mesopotamia, the land between the Euphrates and Tigris rivers that hosted the peoples of Babylon and Assyria: 

“If Depression continually falls upon him, he continually sighs, he eats bread and drinks beer but it does not go well for him, then says, ‘Oh, my heart!’ and is dejected, he is sick with Lovesickness; it is the same for a man and a woman.”

Sighing, eating bread, and drinking beer, but not feeling better: These are all recognizable qualities of a low mood or break-up in the 21st century. And yet this text was translated from what’s known as the Diagnostic Handbook— a series of 40 clay tablets that date to the first millennium B.C.E. Portions of copies of the tablets were recovered in what is now Iraq and Syria, and put together to make a complete book.

The tablets were written in the Akkadian language in a writing system called cuneiform, which involved the text being impressed onto wet clay tablets and then dried—not chiseled into hard stone, as it may look.

The clay tablets are almost alien in their appearance—these are strange, geometric grooves imprinted into rock— but they contain a treasure trove of all-too-human experiences that can feel uncannily similar to emotions we feel today. 

Though the handbook and other similar texts from this period describe physical conditions including epilepsy, seizure, and skin lesions, Moudhy Al-Rashid, an assyriologist at the University of Oxford, has been especially focused on unearthing the parts that have an emotional or mental component to them, like the depression-like symptoms in this passage from a medical text that describes ailments caused by witchcraft: 

“If a man eats (and) drinks, but it does not approach his flesh, he is sometimes pale, sometimes red, sometimes his face becomes darker and darker, he is worried, he is depressed, his heart is not up to speaking.” 

A text from around 900 to 600 B.C.E. described people forgetting speech, losing their appetite, having nightmares, struggling to fall asleep, or having low libido: “He has no desire for [bread and] beer, he has no desire to go to a woman, his ‘heart’ cannot arouse him toward a woman; he babbles, he has repeated cramps, he is depressed, he continually pours out, he says, ‘Have mercy on me!’” (A note on the translations: When brackets are used, it means a word missing in the original text, and inferred from other original materials or copies. Parentheses are used to denote words that were added to make the phrases more legible in English.)  

Behaviors that suggested confusion— like wandering around without realizing what you’re doing, laughing without reason, or crying out—were recorded. There are, in fact, two phrases referring to crying out—one is just a sound, and the other translates to, “Oh my heart!” or “Oh my insides!”

The Diagnostic Handbook also includes, alongside the main emotional symptoms that Al-Rashid studies, many bodily complaints familiar to those dealing with anxiety or depression: stomach issues like indigestion, vertigo, dizziness, fatigue, sweating, weakness, and restlessness. 

These documents are striking for how detailed they are, and also for the resonance a modern reader can find within them. They reveal how what we recognize in the present day as symptoms of mental and emotional distress have long existed in some form, even if they’ve been explained in different ways, depending on historical time and place. Sometimes, emotions are extreme enough that we enlist the help of others—in Mesopotamia that meant intervention from “exorcists” and “healers,” while today it’s psychotherapy or medication.

But the interpretation of these cuneiform texts raises an issue that we still struggle with: How best to categorize emotional distress in order to make sense of it. A previous tendency in the field, called “retrospective diagnosis,” is now being resisted by the next generation of interpreters, who do not want scholars to simply assign our contemporary diagnostic categories to translations from the Diagnostic Handbook, like Obsessive Compulsive Disorder (OCD), schizophrenia, or psychopathy.

Looking at the ways mental symptoms were described forces us to reckon with our own meaning-making structures around emotional distress and place them in our specific cultural and historical contexts. It also, though, connects us to a broader legacy: For thousands of years, humans have been trying to make sense of their emotions as they exist in relationship with the world; our distant ancestors struggled with similar agonies we do; and all along, people have sought to treat, be treated for, and understand that distress.

“They, too, were trying to bring some kind of order to the chaos,” Al-Rashid said. 

Al-Rashid has had depression sporadically since childhood, and the intricate characterizations of depression-like symptoms resonated with her lived experience. Similarly, I came to this topic through a paper from 2012 presenting what the authors called a description of “OCD” behaviors in Babylon. Because I have OCD, I was curious if the symptoms would be similar. 

The paper was written by a pioneer translator of the Diagnostic Handbook, British assyriologist James Kinnier Wilson, in collaboration with the neurologist Edwards Reynolds. They translated the “OCD” behaviors as such: 

“He does not not know why he is compelled to take (things), to hide (things)… to step in blood or walk about over a place where blood has been shed…(or why) he has a phobia of meeting an accursed person or of an accursed person meeting him, or of sleeping in the bed, sitting in the chair, eating at the table, or drinking from the cup of an accursed person.”

Kinnier Wilson also translated what he called “phobias”: “He does not know why he has a (morbid) fear of beds, chairs, tables, lighted stoves, lamps… of leaving or entering (such and such) city, city gate, or house, or of (such and such) a street, temple, or road.” Other “phobias” included fear of certain days or months, of hunger, or of having the name of a god invoked in his presence. 

I have certainly felt anxiety around sharing another person’s cup due to intrusive thoughts around contamination, but it’s not accurate to project my experience of OCD into the past to describe what a person was going through, said Chiara Thumiger, a historian of medicine at Kiel University in Germany. 

Al-Rashid said that in her opinion, Kinnier Wilson’s translations are quite liberal; the original work they are excerpting from is called Shurpu, a collection of incantations to accompany a particular ritual, and it includes lists of potential sins committed by someone who might need to consult that text.

“This list method follows established methods of recording and presenting information in Assyrian and Babylonian scholarly texts where they basically try to be exhaustive by listing possibilities of things,” she explained. 

Calling these sins “phobias” is at best a metaphor; this could be seen as a case where retrospective diagnosis can distract from the original meaning. “The modern psychiatrist will recognize a remarkably accurate description of an agitated depression with biological features including insomnia, anorexia, weakness (and probably weight loss), impaired concentration and memory,” Kennier Wilson and Reynolds wrote. 

While the symptoms may be similar, our languages are different, as is our understanding of the body, science, and medicine. Retrospective diagnosis can obscure what the texts have recorded by trying to map modern illness concepts onto them, Al-Rashid said. It doesn’t tell us the complete story. 

Diseases, including what we call mental illness, were understood in Mesopotamia to come from outside the body. Whether it was a seizure, skin lesion, or depression, the cause was usually understood as being supernatural. When a person had a broken heart, it could, people thought, have been caused by a goddess that needed to be appeased. Demons could cause illness, including specific demons which were associated with specific ailments. Gods and goddesses like Ishtar, the godless of love and fertility, were responsible for a wide variety of illnesses. Ghosts could also be responsible, and were often implicated as having caused mental symptoms. Depression was often tied to the figure of the witch, which was not wielded as a personal accusation against specific others, but against a demonic and chaotic unidentified figure. 

These supernatural causes weren’t thought of as unusual. Our view, and word, for the supernatural implies that it’s beyond the natural. But to the Mesopotamians, the supernatural was part of the everyday. 

The ašipu—translated as exorcists—who would often be called on to treat the mental symptoms were not shocking horror-movie-like figures. They were part of a regulated office. Calling on them was as normal as calling any kind of other doctor or official.

“I tell my students sometimes you should think of it as if, in America, alongside the IRS, we also had the Department of Exorcism,” said Gina Konstantopoulos, an assistant professor in assyriology and cuneiform studies at the University of California, Los Angeles.”It was part of an administrative and bureaucratic framework, and was a technical profession that someone trained extensively in.” 

Elsewhere in the Diagnostic Handbook are detailed descriptions that are very similar to what we understand as stroke or epilepsy—neurological conditions. In a description of what we might call today a focal motor seizure, a text describes how a person’s left eye will move to the side, his lips will pucker, spit will come out from his mouth, and the left side of his body will jerk “like a newly-slaughtered sheep.” 

The authors of the text did not share our understanding of the causes of such seizures, but knew they were dangerous, and offered a quantified approach to assessing their effects: “If an epilepsy demon falls many times upon him and on a given day he seven times pursues and possesses him, his life will be spared. If he should fall upon him eight times his life may not be spared.” 

Al-Rashid takes a philological approach, which means studying the language in its context and deriving its meaning from when the words are used, when they’re used with other words, and how frequently they appear. This is a lot of work—her dissertation on the context, meaning, and use of just three Akkadian words runs around 400 pages.

One of the phrases that Al-Rashid is working on right now is ḫīp libbi, which means the breaking of the heart—a literal translation. “I think it refers to a type of anxiety in some context,” she said. “But then you read another context and it’s quite clearly a stomachache.” 

These complications around retrospective diagnosis don’t mean we can’t compare ancient texts to modern understandings—we just have to be thoughtful in the interpretations. “What I do think is useful is looking at symptoms, rather than disease or illness, and there is a lot of overlap there with what we experience today,” she said.

Al-Rashid is currently looking at the metaphors people use to describe their experiences, and where there are poignant overlaps to the present. For example, there are descriptions in the ancient texts that describe the heart as being low, or the face being downcast.

“I think it’s interesting that the ‘sad is down’ metaphor appears 3000 years ago,” Al-Rashid said. “And we still do that. The word depression literally means a sunken down place.”

“When is an emotional excess a sign of mental illness?” said Marke Ahonen, a lecturer and researcher at the University of Helsinki. “Is mental illness a thing of the body or a thing of the soul? Can philosophers treat mental illness or is it the prerogative of a medical doctor?”

These are disputes that are still unresolved, and it’s meaningful that the same issues arise in the study of the past. Today, there is ongoing discussion around the validity and application of the Diagnostic and Statistical Manual of Mental Disorders, or DSM, and whether its classifications lead to over diagnosis and the medicalization of normal human emotions. 

“You can go on psychiatric Twitter almost any day and find people arguing that depression and anxiety are normal parts of life,” said Jonathan Sadowsky, a historian of psychiatry at Case Western Reserve University, and author of The Empire of Depression

Sadowsky agreed that sadness and anxiety are typical parts of life, and responses to all sorts of life events and circumstances. But something we gain from looking to the past is an understanding that as long as people felt sad or anxious within an expected everyday range, there have also been chronic and extreme forms of these emotions that people have been trying to understand, and come up with treatments for. 

“Many of the people who want to deny depression and anxiety illness status want to focus on how it’s a new construction that came out of modern psychiatry,” Sadowsky said. “And in that sense, I think understanding that these observations of severe mood disorders in medical traditions are common and ancient does have some value.”

“From quite early on, we find the idea that low mood, fear and anxiety can sometimes arise without an adequate cause and are symptoms of an illness rather than ‘normal’ emotional states,” Ahonen said. 

Melancholy, as a defined illness, appeared around the 1st century B.C.E to the 1st century A.D. “In melancholy, people experience distress and fear that can be extreme and the condition often involves fanciful delusions,” Ahonen said. “It could even involve lycanthopy, the delusion that one was turned into a wolf or a wild dog. This melancholy resembles modern depression, but is also quite different from it.”

The fact that the Mesopotamian descriptions were found in the Diagnostic Handbook means that “presumably the stuff that makes it into the medical corpus is something that is sufficiently chronic or extreme to be considered not a part of normal expectable response to something,” Al-Rashid said. 

But Sadowsky doesn’t think it’s the “oldness” of these emotions that definitively legitimizes depression as an illness. “I think what qualifies something as an illness category is actually a social decision that is made in different contexts,” he said. “It depends on how the culture regards the symptoms, or if they even regard them as symptoms of an illness, and how they treat them.” Depression and anxiety should be under the purview of medicine because there are treatments, Sadowsky said, both pharmacological and non-pharmacological, that can help people.

For depression, one part of the Diagnostic Handbook outlines a treatment for a person who “has frequent nervous breakdowns,” “shakes with fear in his bedroom and his limbs have become ‘weak,’” “his limbs often hang limp, and he is sometimes so frightened that he cannot sleep by day or night and constantly sees disturbing dreams,” “has a ‘weakness’ in his limbs (from) not having enough food and drink,” and “he forgets (cannot find) the word which he is trying to say.” To treat such a condition requires a ritual of creating clay figurines, sacrificing a sheep, and chanting and incantation appealing to the god and goddess that has bestowed these ill wills on them. 

“There’s an understanding of extreme emotion and there’s an understanding of grief and sorrow and certainly rage,” said Konstantopoulos. “But there is also an understanding that these emotions which we would think of, at least at present, as depression and extreme anxiety can be fixed within a system that has treatments and ritual procedures to address them and ritual specialists trained in those procedures.”

The past can provide lessons for the future too; Sadowsky said that looking at how antiquity and other cultures dealt with depression can help us remember that there are forms of social support and ritual that can be helpful outside of treatments like drugs or ECT.

“As to treatment,” Ahonen said, “their methods often vary from cruel to ludicrous, but there are also quite sensible approaches: alleviating fear, instilling joy, bringing distraction, correcting erratic thoughts. Physical treatment, [like] drugs or bloodletting, and psychological treatment were often combined, as they still are.” 

Mesopotamian treatments were often about a practitioner spending a lot of time with a person. “They would make them these fancy necklaces with shiny, precious stones, putting them on the patient, saying incantations over the patient,” said Willis Monroe, a historian at the University of British Columba who studies astronomy and astrology in cuneiform texts. “You’re probably going to feel better after that to some degree. You walk away with a shiny necklace, a nice smelling sachet, and things seem a little bit brighter.” 

In one of the medical texts, Monroe said, it begins by describing all the things a practitioner may see on their way to a sick person’s house. “In our modern conception, we wouldn’t think that has anything to do with a patient presenting symptoms,” he said. “But this text is teaching  the practitioner to observe on the way to the house and think about what they see. It did train the practitioner to be observant in a way that I think we’re learning more to do now as well.”

Another facet of the texts is that physical illnesses aren’t privileged over mental illness, Konstantopoulos said. They were equally recognizable problems. And there wasn’t as much moralizing involved in mental symptoms, because they were caused by external forces. 

“When we think about the stigmatization against mental illness that is present in the modern world, looking at a system where that isn’t

necessarily present in the diagnostic handbooks in how it’s being presented and treated is a helpful thing to look at,” she said. 

Thumiger, who studies Greco-Roman antiquity, said that there’s also a lack of a sharp separation between mind and body. “Mind and body are really in a continuum and the doctor looks at both things as if they were of equal importance,” Thumiger said. 

Al-Rashid believes that the messy, imperfect process of naming is important, both in past and present, because it can help make sense of what we’re experiencing. Monroe said that the fact that these texts exist, that there were practitioners who specialize in these texts, and made a living off their services shows how deep down, humans have long been trying to understand and soothe the anxiety they have about the world. 

“People have always been worried about their future and about how they’re feeling,” Monroe said. “And there has long been a whole genre of knowledge that has dealt with this issue: what is the future, what’s going to happen to you, how can we make you feel better in the moment.”

It can be incredibly soothing to know that people have felt like you did, when you were at your lowest. I still remember vividly the first International OCD Foundation conference I went to, at the start of my OCD treatment, where I listened to panelists describe feelings and challenges that I myself was experiencing. Warm feelings of camaraderie and solidarity—and also hope—washed over me. I was not the only one to feel the way I did, and it was possible to get through it. 

To Al-Rashid, one example from the Mesopomtamian texts that also serves that role is the Epic of Gilgamesh, often called the first story in the world. In it, the legendary ruler Gilgamesh grieved the loss of his friend and lover, Enkidu. Gilgamesh’s experience perfectly described what happens when you lose a person you love. 

“Gilgamesh’s journey reminds anyone who has ever grieved that they’re not alone—the experience of extreme loss transcends the millennia-long gap between what it meant to be human then and what it means now,” Al-Rashid wrote recently in Psyche

After the shock of Enkidu’s death and the subsequent funeral, Gilgamesh said, “Sorrow has entered my belly. I became afraid of death and go wandering the wild.”

“Even if the symptoms get organized slightly differently, or the labels are slightly different from one time period or place to the next, I think it’s important to show how old our experiences are,” Al-Rashid said. “There are these common denominators in our experiences of mental distress that have always been there. And a lot of people say it makes them feel less alone.”

Potatoes that glow when stressed: Scientists tap into tubers in trouble

Hebrew University researchers implant gene with fluorescent protein that changes color according to levels of stress indicated by quantity of potentially harmful free radicals

Scientists at Jerusalem’s Hebrew University have managed to genetically engineer a potato to glow in a particular color when it is feeling under the weather.

Like humans, plants suffer stress if it is too hot or cold, or if they don’t get enough food or water.

New research published in Plant Physiology by Matanel Hipsch under the direction of Dr. Shilo Rosenwasser of the university’s Department of Plant Sciences describes the implanting of a gene with a fluorescent protein that changes color according to the level of free radicals — oxygen-containing molecules that accumulate when an organism is experiencing stress. High levels of free radicals can cause significant damage. The fluorescent signaling is picked up by a special fluorescent camera.

Dr. Rosenwasser told The Times of Israel that the work was still at the research and development stage and that the team planned to develop an easy-to-use and affordable camera for farmers to use. The hope is also to extend and if necessary adapt the technology to measure stress in other crops, he added.

The genetic engineering approach contrasts with the more mechanical field of plant nanobionics being advanced at the Massachusetts Institute of Technology.

Rather than tampering with genes to

get plants to do certain things, plant nanobionics uses minuscule sensors — tiny engineered particles that can access a plant’s cells and even subcellular structures, such as chloroplasts.

The MIT sensors are made by combining infinitesimally small tubes with a polymer coating to create fluorescence and emit light. The fluorescence changes color the moment a target material binds with the polymer coating. This color change is picked up by an infrared camera, which sends an alert to a cellphone or email address.

Used to detect the presence of materials such as arsenic in groundwater — a real problem for many rice farmers who cannot afford laboratory testing — MIT’s laboratory, led by Prof. Michael Strano, has also begun to use the sensors to intercept chemical signals that the plant sends when it is under stress.

Plants don’t only detect problems, but also have “internal signaling like humans have nerves,” Strano told The Times of Israel earlier this year.

MIT has even stretched the technology to make plants glow.

Rosenwasser said that the genetic approach had pros and cons. One advantage was that the genetic encoding only has to be done once. The characteristic passes on to all future generations of the plant that was tweaked. The downside was the fear that people have of genetically modified crops.

One way to counter the latter, Rosenwasser continued, was to plant a certain number of modified potatoes in a field that would communicate stress, and to remove them before the other potatoes are harvested for sale.

The research is being carried out at Hebrew University’s Robert H. Smith Faculty of Agriculture, Food and Environment.