Publisher Health

When Hurricane Maria slammed into Puerto Rico in September 2017 as a high-end category 4 storm, it left in its wake the largest catastrophe in the history of the island. The storm killed over 3,000 people in its immediate aftermath, knocked out power to nearly all of the island’s 3.4 million residents, and caused more than $100 billion in damages.
What was the toll of this stress and adversity on the long-term health of its population? And could exposure to extreme weather events accelerate the aging process?
“While everyone ages, we don’t all age at the same rate, and our lived experiences, both negative and positive, can alter this pace of aging. One negative life experience, surviving an extreme event, can lead to chronic inflammation and the early onset of some age-related diseases, like heart disease,” said corresponding author Noah Snyder-Mackler, an assistant professor at Arizona State University’s School of Life Sciences. “But we still don’t know exactly how these events get embedded in our bodies leading to negative health effects that may not show up until decades after the event itself.”
As the final impact on the survivors’ mental and physical health remains to be tallied, a group of biologists led by Snyder-Mackler have looked toward one of our close evolutionary cousins for the first clues.
Along with the human toll, the devastation impacted all the island’s wildlife, including a group of free-ranging rhesus macaques living on the isolated Cayo Santiago island near Puerto Rico. The animals have lived on the island since 1938, when the Caribbean Primate Research Center field station first opened.
Now, the ASU team, led by Snyder-Mackler and lead author Marina Watowich-a graduate student at the University of Washington and research scientist at ASU, and their collaborators at the Caribbean Primate Research Center, University of Pennsylvania, University of Exeter and New York University, have published (will include DOI) one of the first results that shows the effects of natural disasters may have molecularly accelerated aging in the monkeys’ immune systems.

New research discovered that the fungus Rhizopus fights back against soil predators and human immune cells by partnering with a bacteria called Ralstonia in a two way partnership.
The microscopic world resembles our world in some surprising ways. The environment around us is inhabited by microbes living in complex communities — some friendly and some not so friendly. Microbes compete with each other for resources and must also hide from or fight predators. One example of this is the fungus Rhizopus, which grows in the soil and on spoiled food and is the cause of “black fungus” outbreaks in covid patients.
In the soil, its predator is the amoeba Dictyostelium, a single celled microbe that can move through the soil and engulf Rhizopus, devouring it for nutrients. Scientists from the universities of Exeter and Birmingham found Rhizopus fights back against this predator by partnering with a bacteria called Ralstonia in a two way partnership. By living inside Rhizopus, Ralstonia hides from the predator. In return, Ralstonia makes a toxin that Rhizopus can use to neutralize the predator, preventing it from feeding on the pair.
Why does this matter to human disease? Our immune cells are very much like the predator Dictyostelium: They seek out, engulf, and destroy foreign microbes that enter our bodies, protecting us from infection. This means that Rhizopus and Ralstonia can use the same strategy to avoid predators in the soil to evade our own immune systems. By learning to fight off predators in the soil, Rhizopus has also learned how to cause disease in humans.
This work showed that when its partnership with Ralstonia is disrupted, animals infected with Rhizopus are able to survive this devastating disease. The hope is that by better understanding the ecology and strategies for survival that Rhizopus and other pathogens use in their normal environments, we will be better prepared to combat these microbes when they cause human disease.
“This work is really important because while its been known that fungal-bacterial partnerships in the soil impact plant disease for many years, this is the first example of a bacterial-fungal partnership contributing to mucormycosis in humans. We hope this will help us develop better strategies for treating this devastating disease,” says Dr Elizabeth Ballou, one of the Principal Investigators for this project.
This work was led by Dr. Herbert Itabangi, who was a joint student between Dr. Elizabeth Ballou (Exeter) and Dr. Kerstin Voelz (Birmingham). Dr. Itabangi was funded by a Wellcome Trust Strategic Award (led by Prof Neil Gow while at Aberdeen). Dr. Itabangi’s discovery is a key step forward in our understanding of the “black fungus” that causes mucormycosis and was responsible for nearly 40,000 deaths in 2021 as part of the COVID-19 pandemic.
Story Source:
Materials provided by University of Exeter. Note: Content may be edited for style and length.

Researchers from UConn Heath and Yale University have made new advances connecting the evolution of pregnancy and cancer metastasis.
Publishing in the Proceedings of the National Academy of Sciences, Yasir Suhail, a postdoctoral researcher working alongside Kshitiz, assistant professor in the Department of Biomedical Engineering, uncovered regulatory sequences in the genomes of mammals including cows, pigs, horses, and humans that explain how endometrium is invaded by the placenta, and how normal tissue is invaded by cancer.
Suhail and Kshitiz were joined in their efforts by Gunter Wagner, professor in evolutionary biology and ecology at Yale University.
In many mammals including humans, the placenta invades the wall of the uterus during pregnancy in the same way that cancer cells invade surrounding tissues.
“When you look at a picture of placentation, it looks eerily similar to cancer in any other part of the body,” says Kshitiz, “Even the molecular mechanisms are quite similar. This is quite a contrast from cows and horses, where the placenta does not invade into the mother. In these mammals, cancer cells also do not invade into their surroundings as they do in humans.”
Kshitiz, along with Gunter Wagner and Andre Levchenko at Yale first drew the comparison between cancer metastasizing in cows and humans in a seminal finding in Nature Ecology & Evolution. Looking at cells from the endometrium of various species, Kshitiz found that in order to resist invasion of the placenta, certain species have evolved over time to make their stromal cells — the connective tissue cells in an organ — highly resistant to any invasion.
The latest research is a deeper dive into the comparative genetics between mammals, which shows how changes in genetic regulation informs this resistance in cows and horses and makes humans vulnerable to cancer malignancy. With comparative data generated by Wagner and Jamie Maziarz at Yale, Suhail developed a model to identify how the binding of transcription factors — the proteins that regulate the expression of genes — explain changes in resistance to invasion across different species of mammals.
“Our new framework identifies key transcription factors and examines how their targets differ from cows, pigs, and horses to humans,” says Suhail. “What we learned from other species has direct applications in advancing our understanding of human cancer.”
Suhail used the genomic sequences and gene expression information to predict specific signaling proteins that drive the expression of genes that decrease the susceptibility of invasion in human cells. Using a custom fabricated bio chip, the researchers were able to confirm that these predicted proteins did in fact decrease the invasion of both cancer and placental cells. Evolutionary predictions across species are difficult to test experimentally, so confirmation of the theory experimentally is very satisfying to the researchers.
“We all think about human cancers are an outcome of cancer cells themselves. But what we’ve proposed is that mammals have very different mechanisms to resist cancer spread, and that these mechanisms have actually been derived to resist fetal invasion into the mother,” Kshitiz says. “To be vulnerable to malignancy may partly be an evolutionary compromise to allow an invasive pregnancy.”
While other researchers are targeting cancer and immune cells, Kshitiz’s lab focuses on how healthy cells limit cancer growth around them. This approach can help us rethink the way we approach cancer therapies.
“This study identifies specific genetic regulatory mechanisms which explain these differences, and point us towards many directions to rethink about anti-cancer therapy, from those that kill cancer to creating new therapies which “contain” cancer within its boundaries.”
Story Source:
Materials provided by University of Connecticut. Original written by Courtney Chandler. Note: Content may be edited for style and length.

Johns Hopkins Medicine researchers report that a prospective study of 14 infants and children demonstrated that convalescent plasma — a blood product collected from patients recovered from infections with the coronavirus (SARS-CoV-2) that causes COVID-19 — was safe in high risk children infected with or exposed to the virus. The study, published Jan. 25 in the journal JCI Insight, showed that SARS-CoV-2 antibodies were metabolized similarly in children of all ages and weights.
“Even once a SARS-CoV-2 vaccine is available for all ages, there are going to be some immunocompromised children who won’t be able to mount a robust enough immune response from the vaccine, so it’s incredibly important that we study all possible therapies to treat them,” says Oren Gordon, M.D., Ph.D., M.Sc., a pediatric infectious disease fellow at Johns Hopkins Medicine and lead author of the paper.
“We knew that our population would be too small to analyze the effectiveness of convalescent plasma, so we set out to study whether the metabolism of the antibodies delivered with this therapy are the same in adults and kids,” says Sanjay Jain, M.D., M.B.B.S., professor of pediatrics, radiology and radiological science at the Johns Hopkins University School of Medicine and senior author of the paper. “As is often said, kids are not just small adults. Their metabolism is often different, and we didn’t know whether that was true of metabolizing these antibodies.”
Convalescent plasma has been used throughout the COVID-19 pandemic to provide naturally generated antibodies against the virus for high risk people. A recent Johns Hopkins Medicine clinical trial of more than 1,000 high risk adults, for example, found that the use of plasma early in the course of infection can decrease the risk of hospitalization for adults by 54%. However, data on children has been harder to come by, the researchers noted.
In the new study, designed to fill the information gap and carried out between May 2020 and April 2021, 14 children age 3 months to 17 years were given convalescent plasma within four days of exposure to the coronavirus, or within five days of the onset of COVID-19 symptoms. Six of the children were hospitalized, and the other eight remained outpatients. The children — treated at Johns Hopkins Children’s Center — were all considered high risk, with factors including chronic lung disease, cerebral palsy, liver failure and cancer, making them more likely to develop severe COVID-19 symptoms. The researchers collected blood samples from the children over the two months following their transfusions to study how their bodies metabolized the plasma.
Three study participants developed a temporary rash and no further complications. No other side effects of the treatment were reported. On average, 30 minutes after administration of plasma, the levels of antibodies in the blood of recipients were 6.2% of the antibody concentration seen in donors. This antibody level was expected due to dilution of the donor plasma by the recipients’ blood during transfusion. Studies of adults have suggested that amount of antibody — while much lower than in the plasma donors — is enough to protect recipients from severe COVID-19.

New research from North Carolina State University has found that an imprinted gene associated with development of non-alcoholic fatty liver disease (NAFLD) is switched on in mice who nurse from mothers with metabolic syndrome, even when those mice are not biologically related. The finding supports the hypothesis that imprinted genes play important roles in this metabolic disease, and could lead to the development of preventative treatments.
NAFLD is a condition where excess fat builds up in liver tissue for reasons unrelated to alcohol consumption. If untreated, the excess fat can lead to inflammation, scarring and increased risk of liver cancer. The incidence of NAFLD is increasing among children and adolescents, with 10% of children in the U.S. currently affected. This number is expected to increase within the next decade.
“We know that development of NAFLD is partly to do with diet and lack of exercise, but there is an environmental component that primes an infant’s liver to develop it as well; specifically, the metabolic state of the mother,” says Michael Cowley, associate professor of biology at NC State and corresponding author of the work.
Metabolic syndrome, or MetS, is a catchall term for a number of health issues including high blood sugar, obesity and elevated blood pressure. Previous studies had shown a link between MetS in mothers and increased NAFLD susceptibility in infants.
“We wanted to look specifically at mothers with MetS to see whether infants are affected pre- or post-natally, and tease out what is happening on the molecular level to trigger the disease,” Cowley says.
In a mouse model of MetS, Cowley and his colleagues compared offspring of mice with MetS to those from control mice, or mice without MetS. They studied four groups: offspring of control mice nursed by control mice, offspring of MetS mice nursed by MetS mice, and cross-fostered offspring from both groups. Cross-fostered means that the offspring of one group were nursed by mothers from the other group. They compared offspring at birth and at three weeks after birth, just before weaning.
They found that mice born to MetS mothers and nursed by control mice did not develop NAFLD, whereas most mice from both control and MetS groups nursed by MetS mothers did.
Using RNA sequencing, the researchers found that the imprinted gene network (IGN), including its regulator, an imprinted gene called Zac1, was upregulated, or more active, in mice nursed by the MetS mothers.
Imprinted genes are a small set of genes which are expressed from a single parental allele. Most genes consist of two copies (one inherited from each parent) which activate and influence inherited traits. Imprinted genes are expressed by a single active copy, and have been shown to be susceptible to changes in environmental factors.
“Zac1 is acting as the master switch here,” Cowley says. “It was activated in pups that nursed from MetS mothers, and this has downstream effects in the IGN that lead to an increased susceptibility to NAFLD.
“Researchers have proposed that imprinted genes play a role in this process — we’re showing here that they do,” Cowley continues. “The work also confirms the post-natal environment is more important to the development of the disease than pre-natal exposure. Our next steps will involve looking at what happens once potential environmental stressors such as the mother’s milk are removed. Can Zac1 be switched off again?”
The research appears in Hepatology and was supported by the National Institutes of Health (grant numbers K22ES027510, R01ES031596, P30ES025128 and P30DK034987) and by Oak Ridge Associated Universities through a Ralph E. Powe Junior Faculty Enhancement Award. Marine Baptissart, former postdoctoral researcher at NC State, is first author.
Story Source:
Materials provided by North Carolina State University. Original written by Tracey Peake. Note: Content may be edited for style and length.

Critically ill COVID-19 patients on a mechanical ventilator or extracorporeal membrane oxygenation (ECMO) lived more often when randomized to receive baricitinib. Doctors call this drug ‘bari,’ and receiving the pill once a day for up to 14 days yielded one of the largest a survival advantages seen yet in the COVID pandemic, according to a study published in The Lancet Respiratory Medicine.
It is the first randomized study of the drug in ventilated ICU patients, half of whom received the study drug while the other received placebo. It is also the very drug predicted most likely to benefit COVID-19 patients in a recent AI study to determine which drugs could likely be repurposed to treat COVID-19.
“This study found that among COVID patients who were already critically ill on a mechanical ventilator, adding baricitinib to usual care (steroids) saved lives,” said first author E. Wes Ely, MD, professor of Medicine and Critical Care at Vanderbilt University Medical Center and associate director of aging research at the Nashville VA GRECC.
“At 60 days, 62% of patients given placebo had died versus only 45% of those receiving bari. This means that for every 6 people treated with bari as opposed to the placebo, one additional life was saved,” he said.
Baricitinib is an oral, selective Janus kinase (JAK) 1,2 inhibitor used in the treatment of rheumatoid arthritis that has previously shown efficacy in studies of hospitalized adults with COVID-19, including the COV-BARRIER multinational trial with study patients enrolled from 101 sites in 12 countries.
In designing this investigation, Ely partnered with Vince Marconi, MD, professor of Infectious Diseases at Emory University. Marconi and colleagues had been interested in using JAK inhibitors for more than a decade to suppress inflammation in HIV. When the computer determined baricitinib was the prime suspect to save lives in COVID-19, it set the physician-scientists in motion with other collaborators at Eli Lilly and around the world.

Researchers have developed a new protocol for monitoring acute lymphoblastic leukemia (ALL), the most common cancer in children, to inform more effective treatment strategies and detect disease recurrence. The personalized mediator probe PCR (MP PCR) uses multiple genomic cancer cell markers in a single assay and is simpler than current techniques. It improves monitoring clonal tumor evolution to detect a relapse sooner and avoid false negative results. Their protocol is detailed in The Journal of Molecular Diagnostics, published by Elsevier.
The survival rate for children with ALL has increased impressively to over 80% over the last several decades. However, the prognosis for children whose cancer recurs remains unfavorable. Therefore, minimal residual disease (MRD) monitoring is an important prognostic factor for treatment response and patient stratification. MRD monitoring uses highly sensitive real-time PCR to measure the amount of cancer cells among normal cells.
“MRD markers can disappear during treatment, which can lead to false-negative results and poor decision-making in personalized treatments,” explains Principal investigator Cornelia Eckert, PhD, Department of Pediatric Oncology/Hematology, Charité — Universitätsmedizin Berlin, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ). Consequently, monitoring at least two independent markers per patient is recommended. Dr. Eckert continues, “The current gold standard EuroMRD consortium guidelines call for amplification using singleplex real-time PCR quantification, making testing additional markers more laborious and expensive. They also lead to a higher consumption of patient material.”
To overcome these limitations, Dr. Eckert and co-investigators established the personalized MP PCR, an iterative workflow and guidelines for designing multiplex real-time PCRs to monitor up to four MRD markers for ALL simultaneously in one assay. When tested on DNA in bone marrow samples from patients with ALL, the MP PCRs met the EuroMRD gold standard guidelines and level of sensitivity for clinical decision-making.
Co-investigator Michael Lehnert, PhD, Hahn-Schickard Freiburg, states, “Multiplexing can significantly improve personalized MRD monitoring of patients, because a higher number of MRD markers per patient can be analyzed at the same time. Even though these patient-specific sequences of cancer cells only differ in a few DNA nucleotides from healthy cells, our multiplex assay can still distinguish between these DNA sequences. Therefore, a broader range of patient-specific sequences can be included in the assay.”
The MRD-MP guidelines are simple and may allow assay standardization across different laboratories. To demonstrate the potential transfer of the duplex MP PCR into a routine diagnostic setting, the new assay was applied in a prospectively assessed patient case in comparison with the gold standard singleplex test. Both fulfilled the EuroMRD guidelines and led to a similar quantitative range and sensitivity.
In order to deal with challenges inherent to multiplex PCR, the researchers developed an efficient iterative workflow for PCR design and optimization. DNA primer titration is only involved and extended if the assay performance is not sufficient in the first step, so that the number of iterations is minimized.
“There is a vast variety of DNA marker sequences unique to each leukemia,” adds first author Elena Kipf, PhD, Hahn-Schickard Freiburg. “The MRD-multiplex workflow provides a systematic and reliable way of effective MRD-MP PCR design and optimization and helps the standardization of personal diagnostics.”
While their work demonstrates that multiplex MP PCR has the potential to set a new standard in personalized MRD monitoring, the researchers note it must be clinically validated in a representative cohort of ALL patients. “Cancer is a fatal disease from which not every patient can be cured,” Dr. Eckert stresses. “After successful clinical validation, patients could benefit from extended MRD monitoring, leading to more precise predictions of therapy response and better patient stratification and outcomes.”
Story Source:
Materials provided by Elsevier. Note: Content may be edited for style and length.

An in-depth analysis of federal health data indicates that people who have had COVID-19 are at increased risk of developing cardiovascular complications within the first month to a year after infection. Such complications include disruptive heart rhythms, inflammation of the heart, blood clots, stroke, coronary artery disease, heart attack, heart failure or even death.
Such problems occur even among previously healthy individuals and those who have had mild COVID-19 infections, according to the study, from researchers at Washington University School of Medicine in St. Louis and the Veterans Affairs St. Louis Health Care System.
The research is published Feb. 7 in Nature Medicine.
“We wanted to build upon our past research on COVID’s long-term effects by taking a closer look at what’s happening in people’s hearts,” said senior author Ziyad Al-Aly, MD, an assistant professor of medicine at Washington University. “What we’re seeing isn’t good. COVID-19 can lead to serious cardiovascular complications and death. The heart does not regenerate or easily mend after heart damage. These are diseases that will affect people for a lifetime.”
More than 380 million people globally have been infected with the virus since the pandemic started.
“Consequently, COVID-19 infections have, thus far, contributed to 15 million new cases of heart disease worldwide,” said Al-Aly, who treats patients within the VA St. Louis Health Care System. “This is quite significant. For anyone who has had an infection, it is essential that heart health be an integral part of post-acute COVID care.”
Cardiovascular disease — an umbrella term that refers to various heart conditions, thrombosis and stroke — is the leading cause of death in the United States and the world. The Centers for Disease Control and Prevention (CDC) estimates that one out of every four Americans dies of heart disease each year.

Among the many hard lessons from the COVID-19 pandemic is that SARS-CoV-2, the virus that causes COVID-19 infections, can affect every organ system in the body, including the brain.
Approximately one third of all patients with COVID-19 may develop neurological complications from infection, and many patients present to hospitals with acute ischemic stroke (AIS) or “brain attack,” caused by the sudden blockage of blood flow to or within the brain.
As clinicians from Massachusetts General Hospital (MGH) and 29 other stroke centers across the U.S. and Canada now report, patients with COVID-19 who experience AIS appear to be at higher risk for severe disability and death compared with stroke patients treated in the pre-COVID era.
Adam A. Dmytriw, MD, MPH, MSc, an interventional neuroradiology & endovascular neurosurgery fellow at MGH and colleagues looked at records of 230 patients with AIS who were seen at the stroke centers during the first wave of the pandemic, from mid-March through the end of August 2020.
As they reported in a freely available study in the Journal of Neurology, Neurosurgery & Psychiatry, a little more than half (51%) of all patients had poor outcomes, with 39.1% dying either in hospital or within 30 days of being discharged. In contrast, data from large clinical trials conducted before the pandemic show death rates of 27.6% among all patients with ischemic strokes, and 11.6% among patients with strokes caused by blockage of one or more large blood vessels that supply blood to much of the brain.
“There is an interaction that is still unknown between COVID respiratory disease and stroke, because the rate of poor outcomes or mortality is clearly greater than it would be in someone who had just an acute respiratory distress syndrome or COVID pneumonia, and also worse than someone who would have an equivalently large stroke in the pre-COVID era,” Dmytriw says.
The still-growing North American Neurovascular COVID-19 (NAN-C) Consortium was founded by Dmytriw in collaboration with centers in New York and is supervised by Aman B. Patel, MD and Robert W. Regenhardt, MD, PhD at MGH.The hospitals participating in the study represent a broad spectrum of stroke centers with patients from a wide variety of socioeconomic backgrounds and varying access to care, Dmytriw notes.
“This study is something of a post-mortem of how the hardest hit areas responded to the first wave of the pandemic,” he says. “Some of the initial reports we had came out of hospitals in more affluent areas such as central Manhattan where people with lower socioeconomic status were less likely to present. Even though Mass General is one such hospital, our goal was to create a consortium including hospitals in outer boroughs of New York, outside of the greater Boston area, within and around Detroit, as well as diverse centers from coast to coast.”
“This study revealed how great the mortality was from COVID-associated stroke during the first wave, how high the rates of disability were for many patients, and that these mortality rates and disabilities were greater than those experienced in the first wave in other countries,” he says.
The data suggest that patients from less affluent areas may have been at greater risk for serious complications such as stroke because of their inability to carry out protective measures such as social distancing or working at home, Dmytriw says.
The research was internally funded by participating institutions.
Story Source:
Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.

With the COVID-19 pandemic entering its third year, efforts to mitigate the risk for infection remain vitally important, especially for vulnerable populations. A recent study from Massachusetts General Hospital (MGH) showed vaccination during pregnancy resulted in more lasting antibody levels in infants, when compared to babies born to unvaccinated, COVID-infected mothers.
The study, published in The Journal of the American Medical Association (JAMA), included individuals vaccinated with two doses of an mRNA vaccine or infected at 20 to 32 weeks’ gestation, when transfer of antibodies through the life-giving placenta has shown to be at its peak.
Titers — or antibody levels — were higher in vaccinated mothers and their umbilical cord blood at delivery than in those study participants infected with COVID. After two months, 98% of the infants (48 of 49) born to vaccinated mothers had detectable levels of the protective Immunoglobulin G (IgG), the most common antibody found in blood. At six months, the researchers looked at 28 of the infants born to vaccinated mothers and found 57% (16 of 28) still had detectable IgG. That was compared with just 8% (1 of 12) born to infected mothers.
“While it’s still unclear just how high the titer needs to be to completely protect an infant from COVID, we know anti-spike IgG levels correlate with protection from serious illness,” says Andrea Edlow, MD, MSc, a Maternal-Fetal Medicine specialist at MGH, director of the Edlow Lab in the Vincent Center for Reproductive Biology and co-senior author of the publication. “The durability of the antibody response here shows vaccination not only provides lasting protection for mothers but also antibodies that persist in a majority of infants to at least six months of age. Many interested parties from parents to pediatricians want to know how long maternal antibodies persist in infants after vaccination, and now we can provide some answers. We hope these findings will provide further incentive for pregnant people to get vaccinated, especially with the emergence of new variants of concern like Omicron.”
The authors note limitations to their research, including the small study cohort, delays in follow-up with the infected group (due to participants’ availability and COVID-19 surges in Boston), as well as reporting of titers as opposed to clinical outcomes.
“Pregnant women are at extremely high risk for serious complications from COVID,” says Galit Alter, PhD, core member of the Ragon Institute of MGH, MIT and Harvard, and co-senior author of the study. “And given the lag in development of COVID-19 vaccines for infants, these data should motivate mothers to get vaccinated and even boosted during pregnancy to empower their babies’ defenses against COVID.”
Funding for this study included grants from the National Institute of Child Health and Human Development (NICHD), March of Dimes, the Gates Foundation and The National Institute of Allergy and Infectious Diseases (NIAID).
Co-authors include Caroline Atyeo (Ragon Institute); Lydia Shook, MD, Lael Yonker, MD, and Alessio Fasano, MD (MGH); and Kathryn J. Gray, MD, PhD, (Brigham and Women’s Hospital).
Story Source:
Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.