NEARLY A THIRD OF OLDER THYROID PATIENTS TAKE MEDICATIONS THAT INTERFERE WITH THYROID FUNCTION TESTS
Newswise — Nearly one-third of adults age 65 and older who take thyroid hormone also take medications that are known to interfere with thyroid function tests, according to a study presented virtually at ENDO 2021, the Endocrine Society’s annual meeting.“Our findings highlight the complexity of managing thyroid hormone replacement in older adults, many of whom take medications for other medical conditions,” said first author Rachel Beeson, M.D., of the University of Michigan in Ann Arbor, Mich. “Until now, the prevalence of concurrent use of thyroid hormone and interfering medications in older adults, and patient characteristics associated with this practice, has been unknown.”Thyroid hormone use is very common in older adults. Levothyroxine, used to treat hypothyroidism (low thyroid hormone), is one of the most frequently prescribed medications in the United States. Thyroid function tests are used to determine the dose and effectiveness of treatment. The results of these tests can be altered by a variety of medications.Beeson and colleagues analyzed data from 538,137 adults age 65 and older who used thyroid hormone. They looked at how many patients concurrently took thyroid hormone and medications that commonly interfere with thyroid function tests, such as prednisone, prednisolone, carbamazepine, phenytoin, phenobarbital, amiodarone, lithium, interferon-alpha and tamoxifen.Overall, 31.6% of patients were taking medications that have been known to interfere with thyroid function tests.“When we examined patient characteristics associated with concurrent use of thyroid hormone and at least one interfering medication, this was more likely to be seen in patients who were female, non-white and of Hispanic ethnicity,” Beeson said. The researchers also found people who had other chronic medical conditions were more likely to concurrently use thyroid hormone and medications that interfere with thyroid tests.The National Institute on Aging supported the research with a grant to senior author Maria Papaleontiou, M.D.
Researchers at Rutgers School of Dental Medicine have found evidence that two types of mouthwash disrupt the COVID-19 virus under laboratory conditions, preventing it from replicating in a human cell. The study, published in the journal Pathogens, found that Listerine and the prescription mouthwash Chlorhexidine disrupted the virus within seconds after being diluted to concentrations that would mimic actual use. Further studies are needed to test real-life efficacy in humans. The study was conducted in a lab using concentrations of the mouthwash and the time it would take to contact tissues to replicate conditions found in the mouth, said Daniel H. Fine, the paper’s senior author and chair of the school’s Department of Oral Biology. The study found two other mouthwashes showed promise in potentially providing some protection in preventing viral transmission: Betadine, which contains povidone iodine, and Peroxal, which contains hydrogen peroxide. However, only Listerine and Chlorhexidine disrupted the virus with little impact on skin cells inside the mouth that provide a protective barrier against the virus. “Both Povidone iodine and Peroxal caused significant skin cell death in our studies, while both Listerine and Chlorhexidine had minimal skin cell killing at concentrations that simulated what would be found in daily use,” said Fine. The team studied the efficacy of mouthwash potential for preventing viral transmission to better understand how dental providers can be protected from aerosols exhaled by patients. “As dentists, we’re right there in a patient’s face. We wanted to know if there’s something that might lower the viral load,’’ said coauthor Eileen Hoskin, an assistant professor at Rutgers School of Dental Medicine. Fine cautions the public against relying on mouthwash as a way to slow the spread until it is proven in clinical trials on humans. “The ultimate goal would be to determine whether rinsing two or three times a day with an antiseptic agent with active anti-viral activity would have the potential to reduce the ability to transmit the disease. But this needs to be investigated in a real-world situation,’’ he said. Previous research has shown various types of antiseptic mouthwashes can disrupt the novel coronavirus and temporarily prevent transmission, but this was one of the first studies that examined antiseptic rinse concentrations, time of contact and the skin-cell killing properties that simulated oral conditions. The study was conducted by a team of dental school scientists and virologist at the Public Health Research Institute. “Since the SARS CoV-2 virus responsible for COVID-19 enters primarily through the oral and nasal cavity, oral biologists should be included in these studies because they have an in-depth understanding of oral infectious diseases,” said Fine. Other Rutgers authors included Theresa Chang and Chuan Xu at the Public Health Research Institute based at Rutgers New Jersey Medical School and Kenneth Markowitz and Carla Cugini at Rutgers School of Dental Medicine.
Two research papers highlight single-cell dissection of kidney tumors to identify new immunotherapy treatments and targets Newswise — BOSTON - In the last two decades, immunotherapy has emerged as a leading treatment for advanced renal carcinoma cancer (more commonly known as kidney cancer). This therapy is now part of the standard of care, but it doesn’t work for all patients, and almost all patients, no matter how they respond initially, become more resistant to treatment over time. The immune system plays a critical role in kidney cancer disease progression and in response to therapies, and so a fundamental challenge in the field is to understand the underlying “immune circuitry” of this disease. In two new studies published today in Cancer Cell, researchers from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard used the emerging technology of single-cell RNA sequencing to draw a clearer picture of how kidney tumors’ microenvironments change in response to immunotherapy. The researchers believe that this work points to potential targets for new drug therapies. “We have a standard of care for treating kidney cancer patients, but many patients do not respond to existing therapies, and we need to discover new targets,” said Eliezer Van Allen, MD, an oncologist at Dana-Farber, associate professor of medicine at Harvard Medical School, associate member at the Broad Institute, and co-senior author on one of the papers. “These companion studies shed important new light on the biology of advanced kidney tumors and their surrounding environments. With this increased understanding, researchers will be able to identify new potential drug treatment targets and, overall, expand the number of patients who can receive effective treatment,” remarked Catherine J. Wu, MD, chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber, professor of medicine at Harvard Medical School, an institute member at the Broad, and co-senior author on one of the papers. “A patient’s immune system plays a critical role in controlling both the progression of cancer and the response to immune therapies,” adds Toni K. Choueiri, MD director of the Lank Center for Genitourinary Oncology at Dana-Farber, an associate member at the Broad, and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. Choueiri is co-senior author on both papers. “We don’t quite know why some tumors respond and some don’t. We also don’t know why kidney cancers become resistant to immunotherapy. These two studies are a large team effort to give us a sharper image of what happens on not just the cellular level but down to the RNA of each of those cells.” With immunotherapy, patients are typically given an immune checkpoint blockade (ICB) (often in combination with VEGF tyrosine kinase inhibitors; TKIs). The drugs are designed to stop the immune system from stopping itself, thus allowing it to attack the tumor like any other unwanted pathogen. However, immunotherapy is only successful in about half of ccRCC patients, and almost all patients build resistance to the treatment over time. About 76,000 Americans are diagnosed with kidney cancer in the U.S. each year, which is also responsible for more than 13,000 deaths annually, according to the American Cancer Society. Finding new targets to disrupt an immune dysfunction circuit In one study, researchers performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue. These samples came from 13 patients with clear cell renal cell carcinoma (ccRCC), which make up 80 percent of kidney cancer cases, at different stages of disease: early, locally advanced and advanced/metastatic. In most solid tumors, the presence of a specific type of immune cell, the CD8+ T cell is a good thing. Their presence shows the immune system is working. However, researchers found that in advanced stage disease these CD8+ T cells were “exhausted,” and not able to carry out their usual function. They also discovered more anti-inflammatory or “M2-like” macrophages, a type of white blood cell that suppresses the immune system, in advanced stage disease. CD8+ T cells and macrophages were playing off each other and caught in an “immune dysfunction circuit,” said co-lead author David A. Braun, MD, PhD, an oncologist at Dana-Farber and instructor of medicine at Harvard Medical School. In advanced disease samples, macrophages produce molecules that support CD8+ T cell exhaustion, at the same time those CD8+ T cells make molecules that supported the life of pro-tumor macrophages. These findings are important because they “open up a whole new landscape of potential treatment targets,” said Braun. “We already target some of the immune system pathways in kidney cancer, but our work uncovered many other immune inhibitory pathways supporting cell dysfunction. As we move forward, we can look at all of these interactions and identify new opportunities to disrupt the circuit, with the goal of restoring the immune system’s anti-tumor effect and ultimately improving outcomes for patients with kidney cancer.” Choueiri and Wu are co-senior authors on the study, “Progressive immune dysfunction with advancing disease stage in renal cell carcinomas.” Identifying treatments beyond the PD-1/PD-L1 axis The other study published today looks at tumor and immune reprogramming during immunotherapy in ccRCC. Most current immunotherapy treatments for ccRCC target the PD-1/PD-L1 axis, a pathway that makes proteins that halt the immune system from attacking cancer cells. Stop the stoppers, and the immune system can go after cancer cells. But these drugs are only effective in half of ccRCC patients, and almost all patients eventually develop resistance to the drug. “There may be immune evasion mechanisms outside of PD-1/PD-L1 that play an important role in response or resistance,” said Kevin Bi, computational biologist at Dana-Farber and co-lead author on the paper. Researchers used single-cell RNA sequencing to look 34,326 total cells drawn from samples from eight patients, seven of whom had metastatic renal cancer and one with localized disease. Five samples were from patients who had already received treatment, either through ICB, or a combination of ICB and TKI. Those treated with ICB were all given drugs that specifically targeted the PD-1/PD-L1 axis. Researchers found that ICB remodels the cancer microenvironment and changes how cancer and immune cells interact, in a few ways: In patients whose cancer responded to treatment, subsets of cytotoxic T-cells, which are cancer-fighting lymphocytes, express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift towards pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells treated with ICB, researchers found two subpopulations, differing in angiogenic signaling and upregulation of immunosuppressive programs. In advance stage cancers treated with ICB, expression signatures for cancer cell subpopulations and immune evasion were associated with the PBRM1 mutation, the second most commonly mutated gene in ccRCC. These findings show the importance of exploring immune pathways away from the PD-1/PD-L1 axis, said Meng Xiao He, a graduate student in the Harvard Biophysics program, member of the Van Allen lab at Dana-Farber, and a co-lead author on the paper. “We need to look at things that are not just CD8+ T cells. We should look at macrophages, some of the other immune checkpoints, and assess what may be targetable,” he said. “We’re still in the early days of trying to understand the mechanisms of immunotherapy resistance in different diseases. There’s a lot of room to keep trying so that more people respond, and those responses hold.” Choueiri and Van Allen are co-senior authors on the study, "Tumor and immune reprogramming during immunotherapy in advance renal cell carcinoma." The co-authors of “Progressive immune dysfunction with advancing disease stage in renal cell carcinomas” are Kelly Street, PhD, of Dana-Farber and the Harvard T.H. Chan School of Public Health; Kelly P. Burke, MD, PhD, Dana-Farber and Harvard Medical School; David L. Cookmeyer, of Harvard Medical School; Thomas Denize, MD of Harvard Medical School and Brigham and Women’s Hospital (BWH); Christina B. Pedersen, of Technical University of Denmark, Rigshospitalet-Copenhagen University Hospital; Satyen H. Gohil, PhD, of Dana-Farber, Harvard Medical School, the Broad Institute and University College, London; Nicholas Schindler, BSE, of Dana-Farber; Lucas Pomerance, BA of Dana-Farber and Harvard Medical School; Lauren Hirsch, MD, of Dana-Farber and Harvard Medical School; Ziad Bakouny, MD, of Dana-Farber; Yue Hou, PhD, of Dana-Farber; Juliet Forman, of Dana-Farber and the Broad Institute; Teddy Huang, PhD of Dana-Farber; Shuqiang Li, PhD, of Dana-Farber and Harvard Medical School; Ang Cui, MS, of the Broad Institute and Harvard-MIT Division of Health Sciences and Technology; Derin B. Keskin, PhD, of Dana-Farber and the Broad Institute; John Steinharter, MS, of Dana-Farber; Gabrielle Bouchard, BS, of Dana-Farber; Maxine Sun, PhD, MPH, of Dana-Farber; Erica M. Pimenta, MD, PhD, of Dana-Farber and Harvard Medical School; Wenxin Xu, MD of Dana-Farber and Harvard Medical School; Kathleen M. Mahoney, MD, PhD, of Dana-Farber, Harvard Medical School and Beth Israel Deaconess Medical Center; Bradley A. McGregor, MD, of Dana-Farber and Harvard Medical School; Michelle S. Hirsch, MD, PhD, of Harvard Medical School and BWH; Steven L. Chang, MD, of Harvard Medical School and BWH; Kenneth J. Livak, PhD, of Dana-Farber; David F. McDermott, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center; Sachet A. Shukla, PhD, of the Broad Institute and Dana-Farber; Lars R. Olsen, PhD of Technical University of Denmark, Center for Genomic Medicine, Rigshospitalet; Sabina Signoretti, MD, of Harvard Medical School, BWH and Dana-Farber; Arlene H. Sharpe, MD, PhD, of the Broad Institute, Harvard Medical School and BWH; Rafael A. Irizarry, PhD, of Dana-Farber and Harvard T.H. Chan School of Public Health. Financial support was provided Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence (grants P50CA101942-12 and P50CA101942); Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence Career Enhancement Program (grants P50CA101942-15 and P50CA101942), Department of Defense Congressionally Directed Medical Research Programs (grants KC170216 and KC190130); Department of Defense Academy of Kidney Cancer Investigators (grant KC190128), National Institute of General Medical Sciences (grants 5R35GM131802 and 5R01GM083084), National Human Genome Research Institute ENCODE Data Analysis Center (grant 5R01HG009446), Independent Research Fund Denmark (grant 8048-00078B), Kay Kendall Leukemia Fund Fellowship, Foundation de France during her post-doctoral, Bristol-Myers Squibb, Genentech, National Cancer Institute Research Specialist Award (grant R50CA251956), National Cancer Institute (grants R21 CA216772-01A1 and NCI-SPORE-2P50CA101942-11A1), ASCO Conquer Cancer Foundation Young Investigator Award; National Cancer Institute (grant R50RCA211482); National Human Genome Research Institute (grant R35GM131802), Cancer Center Support Grant (P30CA006516), Kohlberg Chair at Harvard Medical School, Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber; National Institute of Health (grants NCI-1RO1CA155010 and NIH/NCI U24 CA224331); G. Harold and Leila Y. Mathers Foundation and the Parker Institute for Cancer Immunotherapy. The co-authors of “Tumor and immune reprogramming during immunotherapy in advance renal cell carcinoma” are Ziad Bakouny, MD, of Dana Farber; Abhay Kanodia, Sara Napolitano, Jingyi Wu, and Grace Grimaldi, BS, of Dana-Farber and the Broad Institute; David A. Braun, MD, PhD, of Dana-Farber, the Broad Institute and Harvard Medical School; Michael S. Cuoco, BS, of the Broad Institute; Angie Mayorga, BA, of Dana-Farber; Laura DelloStritto, MPH, of Dana-Farber and the Broad Institute; Gabrielle Bouchard, BS, of Dana-Farber; John Steinharter, MS, of Dana-Farber; Alok K. Tewari, MD, PhD, of Dana-Farber and Harvard Medical School; Natalie I. Vokes, MD, of Dana-Farber and the Broad Institute; Erin Shannon, BS, of the Broad Institute; Maxine Sun, PhD, MPH of Dana-Farber; Jihye Park, PhD, of Dana-Farber and the Broad Institute; Steven L. Chang, MD, of BWH; Bradley A. McGregor, MD, of Dana-Farber; Rizwan Haq, MD, PhD of Dana-Farber and the Broad Institute; Thomas Denize, MD, of Harvard Medical School and BWH; Sabina Signoretti, MD, of Harvard Medical School, BWH and Dana-Farber; Jennifer L. Guerriero, PhD, of Harvard Medical School and Dana-Farber; Sébastien Vigneau, PhD, of Dana-Farber and the Broad Institute; Orit Rozenblatt-Rosen, PhD, of the Broad Institute; Asaf Rotem, PhD, of Dana-Farber and the Broad Institute; Aviv Regev, PhD, of Genentech. Financial support was provided by the National Institutes of Health (grants U01 CA233100, R01 CA227388, U2C CA233195, T32 GM008313, T32 CA009172); the National Science Foundation (grant GRFP DGE1144152), Novartis-DDP grant, Kure It-AACR grant, Dunkin’ Donuts Breakthrough Grant, Dana-Farber/Harvard Cancer Center Kidney Cancer Specialized Program of Research Excellence (grant P50CA101942-15; Department of Defense Congressionally Directed Medical Research Programs (grants KC170216 and KC190130), Department of Defense Academy of Kidney Cancer Investigators (grant KC190128), Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber. About Dana-Farber Cancer Institute Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. Dana-Farber’s mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. We provide the latest treatments in cancer for adults through Dana-Farber/Brigham and Women’s Cancer Center and for children through Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber is the only hospital nationwide with a top 10 U.S. News & World Report Best Cancer Hospital ranking in both adult and pediatric care. As a global leader in oncology, Dana-Farber is dedicated to a unique and equal balance between cancer research and care, translating the results of discovery into new treatments for patients locally and around the world, offering more than 1,100 clinical trials.
MOUNT SINAI DEVELOPS A SAFE, LOW-COST COVID-19 VACCINE - COULD HELP LOW- AND MIDDLE-INCOME COUNTRIES
Newswise — A low-cost COVID-19 vaccine candidate that could be produced in the United States and worldwide using existing influenza virus manufacturing infrastructure has been developed by researchers at Icahn School of Medicine at Mount Sinai, with the potential to rapidly produce hundreds of millions of vaccine doses to mitigate the impact of the current pandemic and future viral outbreaks. The vaccine, which works the same way many flu vaccines do, is undergoing clinical development planning in several countries (including Mexico) through a licensing agreement with Mount Sinai. Early-stage clinical trials are also underway at Mount Sinai Health System in New York. “To contain the spread of the virus worldwide, a vaccine that is both effective and cost-effective is urgently needed, especially in low- and middle-income countries with limited resources,” says Peter Palese, MD, Horace W. Goldsmith Professor and Chair of Microbiology at Icahn Mount Sinai, and senior author of two studies examining the effects of so-called Newcastle disease virus (NDV) vaccines in animal models (EBioMedicine, November 2020, and Vaccines, December 2020). “Our work suggests that an NDV-based vaccine, which can be produced from embryonated chicken eggs, would be a safe and highly scalable way to meet the vast demands of the global vaccine market.” Most COVID-19 vaccines work by exposing people to the “spike” protein, an important part of the structure of SARS-CoV-2, the virus that causes COVID-19. But they differ in how they get the spike protein into the recipient. Mount Sinai’s vaccine works by introducing the spike protein into the body via the harmless NDV virus, prompting the body’s cells to make copies of the spike protein. When this occurs, the immune system begins to produce antibodies and T cells to specifically target the spike protein; these will neutralize any foreign intruder, like SARS-CoV-2, that contains it. The NDV vaccine against SARS-CoV-2 was created by a globally recognized team of virologists from Mount Sinai, including Dr. Palese; Florian Krammer, PhD, Mount Sinai Professor in Vaccinology; and Adolfo Garcia-Sastre, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Global Health and Emerging Pathogens Institute at Mount Sinai. “Our study demonstrated that the neutralizing antibodies produced by the NDV vaccine provided strong protection in animal models from SARS-CoV-2 infection,” notes Dr. Krammer. “Also, because the NDV is not a human pathogen, the spike antigen could be delivered more efficiently and without being compromised by any pre-existing immunity in humans. Another advantage is the fact that NDV-based vaccines have been tested extensively in human trials and have compiled a very good safety record over the years.” In Mexico, a licensing agreement between Mount Sinai and Laboratorio Avi-Mex S.A. de C.V. (Avimex), a veterinary pharmaceutical company, will enable that country to soon begin Phase 1 trials in humans of a COVID-19 vaccine using NDV vector technology. Avimex began collaborating with Mount Sinai in 2003 on developing veterinary influenza vaccines and has since produced millions of doses based on the NDV vector platform. “Being able to vaccinate populations in all parts of the world, and not just those in high-income countries, is critical if we’re going to establish herd immunity and contain the spread of COVID-19,” says Dr. Palese. “We believe that NDV-based vaccines can be a vital part of the solution. They could lead to vaccination of a large percentage of the world’s population over a very short period by using existing technology and infrastructure in a highly cost-effective, efficient, and safe way.”
Newswise — A new study led by Washington University School of Medicine in St. Louis and the National Cancer Institute (NCI) has identified an association between slow walking pace and an increased risk of death among cancer survivors. While the study does not establish that slow walking is a cause of death, the association persisted across at least nine tumor types. Investigators now call for more research into these relationships and whether targeted interventions such as physical activity programs could help cancer survivors improve their ability to walk and increase survival after cancer diagnosis and treatment. The study, a collaboration between Washington University, the NCI of the National Institutes of Health (NIH), the University of North Carolina and George Washington University, appears March 4 in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. “Cancer survivors are living longer than ever – and that’s good news,” said first author Elizabeth A. Salerno, PhD, an assistant professor of surgery in the Division of Public Health Sciences at Washington University. “But it’s important to improve our understanding of how the diagnosis and treatment of a broad range of cancers may affect walking pace during survivorship — a potentially modifiable risk factor — which could lead to new treatment and rehabilitation strategies to improve the health of these patients.” The researchers studied over 233,000 participants enrolled in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. Participants, who were ages 50 to 71, answered questionnaires about their overall health and walking pace, and whether they had any disability related to walking, such as walking at a very slow pace or being unable to walk. After the assessment, participants were followed for several years. Compared with healthy controls enrolled in the study, cancer survivors were 42% more likely to report walking at the slowest pace and 24% more likely to report being disabled. Among cancer survivors, those who walked at the slowest pace had more than twofold increased risk of death from any cause, compared with those reporting the fastest walking pace. The association between the slowest walking pace and a significantly increased risk of death from any cause held for nine cancer types, including breast, colon, melanoma, Non-Hodgkin lymphoma, oral, prostate, rectal, respiratory and urinary cancers. The association between mobility disability (not just slow pace) and death was even stronger and included all nine of the cancers mentioned above, plus endometrial, endocrine, ovarian and stomach cancers. While slow walking pace also was linked to increased mortality that was due to any cause among individuals without a cancer diagnosis, the risk of death more than doubled for cancer survivors. Compared with individuals without a cancer diagnosis who walked at the fastest pace, cancer survivors who walked the slowest had more than tenfold increased risk of death from any cause. Cancer survivors with mobility disability had more than fivefold increased risk of death compared with individuals with no cancer diagnosis or disability. The researchers noted that cancer survivors reported difficulties walking five years or more after cancer diagnosis and treatment, suggesting that the detrimental effects of cancer diagnosis and therapy are widespread across cancer types and long lasting, creating opportunities for intervening to help such patients improve their walking ability and pace. “To our knowledge, this analysis is the first to explore the relationship between cancer, walking pace and subsequent mortality in 15 different cancer types,” said Salerno, who conducted this research while a postdoctoral researcher at the NCI. “Next steps include identifying the underlying reasons for these associations. It’s possible that slow walking may be due to the cancer itself, adverse effects of treatment, or changes in lifestyle. There is still much to be learned about these complex relationships, but our results highlight the importance of monitoring and even targeting walking pace after cancer.”
Study published in American Journal of Critical Care reports how five years of rapid mortality reviews of 500+ medical ICU patient deaths sparked systemic changes, quality improvements Newswise — An in-person multidisciplinary rapid mortality review (RMR) process helped identify specific areas to improve patient care at a Los Angeles hospital, according to a study published in American Journal of Critical Care (AJCC). The novel approach helped front-line clinicians understand both individual- and systems-level issues that contribute to mortality, with the ultimate aim of optimizing the delivery of patient care. “Rapid Mortality Review in the Intensive Care Unit: an In-Person Multidisciplinary Improvement Initiative” explores the data generated from five years of reviewing patient deaths that occurred in the 24-bed medical intensive care unit (ICU) at Ronald Reagan University of California Los Angeles (UCLA) Medical Center. The analysis found that the RMR process not only identified immediate concerns related to patient care but also yielded valuable insights on potentially preventable patient deaths and areas for hospital improvement initiatives. First author Kristin Schwab, MD, is a pulmonologist and critical care physician at UCLA Health and a clinical instructor in the Division of Pulmonary and Critical Care Medicine, Department of Medicine, at UCLA’s David Geffen School of Medicine. “Our findings suggest that these short and timely in-person meetings can be a powerful tool for efforts to both improve quality and prevent mortality in the ICU,” she said. “Bringing members of the multidisciplinary care team together for regular face-to-face discussions provided a forum that revealed concerns and solicited tangible ideas for solutions.” Retrospective case reviews, provider surveys, and structured morbidity and mortality conferences can be useful tools for discussions about safety and quality issues, but these common tactics are unlikely to provide an efficient and practical means of reviewing all patient deaths. The RMR process began as a pilot in 2013, with a subset of patients who had died in the medical ICU during the prior week. The subset gradually grew and by 2017, the team was attempting, during the weekly meetings, to review every death that occurred in the unit. During the five-year period, the RMR team reviewed 542 deaths, which was more than 80% of all deaths that occurred in the unit. For each patient death, a facilitator reviewed the patient’s chart prior to the meeting to prepare to lead a semistructured interview with the care team. Questions included, “Was the death potentially preventable?” and “Are there any aspects of care that could have been improved?” followed by additional open-ended questions. Following the meeting, the facilitator recorded a summary of the discussion into a database. The quality team reviewed the data from each meeting and referred any action items to the appropriate department. Only 7% of deaths were deemed potentially preventable, as determined by the treatment team, RMR facilitator or both. However, the treatment team believed that care could have been improved in more than 40% of the deaths, while the facilitator identified areas for improvement in more than half of the cases. Cases in which the patient required resuscitation after an in-hospital cardiac arrest or those in which the patient was not receiving comfort care at the time of death were associated with a higher likelihood of generating an action item. Issues included concerns with communication or teamwork, advance care planning, delays in care, medical errors, procedural complications and hospital-acquired infections. Systems-related action items addressed lack of protocols, resource availability and throughput. Among the identified action items, more than one in 10 led to tangible systemic change, with 29 discrete changes occurring during the study period. Examples of completed action items include creating a standardized checklist for inbound patient transfers and changing the electronic health record to separate one-time orders from continuing orders. To access the article and full-text PDF, visit the AJCC website at www.ajcconline.org.
Newswise — Curtin University research has found people grieving a COVID-related death would benefit from timely support and care to reduce the high risk of experiencing problems in important areas of everyday life. Published in Journal of Pain and Symptom Management, the study is the first to focus on psychological factors that explain why people bereaved by COVID-19 might experience challenges in important areas of life, work, leisure, and relationships. Lead author, Associate Professor Lauren Breen from the Curtin School of Population Health worked with American researchers to survey people in the United States who had lost a close person due to COVID-19 and found key psychological factors such as separation distress, dysfunctional grief, and post-traumatic stress explained why they were having trouble coping in key areas of life. "Existing research shows that grief from deaths during the pandemic was felt more acutely than that following both deaths before the pandemic, and deaths from other natural causes," Associate Professor Breen said. "This exacerbation of grief is due to the necessary restrictions that affect people's access to dying loved ones, limit their participation in important rituals like funerals, and reduce the physical social support they would otherwise receive from friends and family." "There is a real need for strategies such as the integration of psychological care into palliative care to facilitate efficient and cost-effective means of supporting people who are grieving," Associate Professor Breen said. "Better screening and assessment of bereaved people is also required, along with more accessible support services, development of improved therapies and grief interventions, and an increased number of grief specialists in the workforce."
Newswise — New Brunswick, N.J February 22, 2021 – The most frequently mutated gene in human cancers is called p53. Patients with Li-Fraumeni syndrome, which is a rare disorder that increases the risk of developing several types of cancer, often have an increased risk to develop cancers at early ages if they inherit p53 mutations. Recent studies suggest that some individuals with inherited p53 mutations do not have the early onset or high frequency of cancers, suggesting that other genetic, environmental, immunological, epigenetic, or random factors play a part in the development of cancers. A recent study from Rutgers Cancer Institute of New Jersey tested this possibility by analyzing tumor formation and p53 mutations in mice from different genetic backgrounds. Observations from this work may further elucidate the diversity of cancers in different Li-Fraumeni patients. Senior and corresponding author of the work Wenwei Hu, PhD, researcher at Rutgers Cancer Institute and professor of radiation oncology at Rutgers Robert Wood Johnson Medical School, along with lead and corresponding author Chang S. Chan, PhD, researcher at Rutgers Cancer Institute and associate professor of medicine at Rutgers Robert Wood Johnson Medical School, share more about the findings published in Life Science Alliance (http://doi.org/10.26508/lsa.202000952). Why is this topic important to explore? Mutations in the p53 gene are the single most common spontaneous genetic alterations observed in human cancers. Approximately one in 20,000 individuals inherit heterozygous p53 mutations, resulting in early onset and high frequency of cancers in each patient over a lifetime. Individuals with an inherited p53 mutation have a much higher risk compared to the general population of developing adrenal cortical carcinoma, choroid plexus carcinoma, medullary blastoma, rhabdomyosarcoma and osteogenic sarcoma. There is also a high relative risk of developing breast cancer, lipomas and liposarcomas, and leiomyosarcomas. However, even within family members who share the same p53 mutation, there is great variability in what cancer types they get and when they get it, thus, it is important to explore the influence of genetics and non-genetic factors on tumor formation and tumor type. These may include environment, immunological or random factors. Describe the work and tell us what the team discovered. We created seven sets of mice with different genetic backgrounds, all having the same p53 mutation. These mice are prone to developing a variety of tumor types because of the p53 mutation they harbor. The tumor types these mice develop are very similar to human Li-Fraumeni patients. The mice from each genetic background are almost genetically identical and the environments are controlled to be the same. This allows us to compare the variability of the tumors within genetically identical mice to mice with different genetic backgrounds, and thus tease apart the contribution of genetics and randomness to tumor formation. We discovered that certain genetic backgrounds greatly increase the chance of developing specific tumor types and the number of tumors in a single mouse. The age at which a tumor occurs is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. Sex of the mice also impact the risk for cancer in certain genetic backgrounds. These observations present evidence for both genetic and random effects upon tumor formation in diverse groups of mice. This helps to explain the great diversity of cancers in different Li-Fraumeni patients over their lifetimes. What are the implications of these findings? Although the results are consistent with a series of genetic modifiers that influence the age of onset of a tumor and the tumor tissue type, the results also support random factors playing a role in the development of tumors. The most obvious random event is a spontaneous mutation in one of the many different tissue specific stem cells of the body that increase cancer risk. Other random factors may include different microbiomes from mouse to mouse, random errors in development and the adaptive immune system which is different between identical strains of mice or identical twins. The approach in this work can lead to the identification of the gene or genes that predispose individuals to early onset tumors, the selection of the tissue type of a tumor, and enhancement of tumor risk. Genome sequencing of these tumors will help identify the genes whose mutations act with p53 mutations to influence benign and malignant tumors. Along with Drs. Hu and Chan, other authors include Yvonne Sun, PMV Pharma; Hua Ke, Yuhan Zhao, Merzu Belete, Cen Zhang and Zhaohui Feng, Rutgers Cancer Institute; and Arnold J. Levine, Simons Center for Systems Biology, Institute for Advanced Study in Princeton. This research was supported by grants from the National Institutes of Health, National Cancer Institute (P01CA087497-18, R01CA203965) and Department of Defense (W81XWH-18-10238). Other acknowledgements, author disclosures and other information can be found here.
Newswise — An international study has shown, for the first time, that the capacity of the human brain to recover and rewire itself peaks around two weeks after a stroke and diminishes over time. The finding, published today in the Neurorehabilitation and Neural Repair journal, is the result of a study in London and Adelaide that followed the recovery of 60 stroke patients up to one year after their stroke. Lead author Dr Brenton Hordacre, from the University of South Australia, says the multi-site study showed conclusive evidence that the brain only has a small window of opportunity to more easily repair itself after stroke. “Earlier animal studies suggested this was the case, but this is the first time we have conclusively demonstrated this phenomenon exists in humans,” Dr Hordacre says. The researchers scanned the brains of stroke survivors as they recovered over 12 months. They found that in the initial days following an ischemic stroke (caused by a blocked artery to the brain), the brain has a greater capacity to modify its neural connections and its plasticity is increased. “It is during this early period after stroke that any physiotherapy is going to be most effective because the brain is more responsive to treatment. “Earlier experiments with rats showed that within five days of an ischemic stroke they were able to repair damaged limbs and neural connections more easily than if therapy was delayed until 30 days post stroke.” The researchers used continuous transcranial magnetic stimulation (cTBS) to repetitively activate different hemispheres of the motor cortex to measure brain plasticity. The Adelaide laboratory tested the stroke damaged motor cortex, which is the main area that controls movement. The London laboratory tested the non-stroke damaged hemisphere which is also important to help recovery. “Our assessments showed that plasticity was strongest around two weeks after stroke in the non-damaged motor cortex. Contrary to what we expected, there was no change in the damaged hemisphere in response to cTBS.” Dr Hordacre says the findings confirm the importance of initiating therapy as soon as possible after a stroke. Current evidence indicates that less than eight minutes of daily therapy is dedicated to upper limb recovery within the first four weeks of a stroke. “Delivering more treatment within this brief window is needed to help people recover after stroke. “The next step is to identify techniques which prolong or even re-open a period of increased brain plasticity, so we can maximise recovery,” Dr Hordacre says. The paper, “Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex following Ischemic Stroke” is available at: https://journals.sagepub.com/doi/full/10.1177/1545968321992330 Researchers from the following institutions were involved in the study: University of South Australia; University College London (UCL); University of Adelaide; Hospital Universitario Ramón y Cajal and Hospital Ruber Internacional in Madrid; Queen Mary University, London; the Royal London Hospital; National Hospital for Neurology and Neurosurgery, London; Murdoch University, WA; Royal Adelaide Hospital; and the Physio Clinic, Adelaide Photo Credit: University of South Australia Less than eight minutes of daily therapy is dedicated to upper limb recovery within the first four weeks of a stroke.
Newswise — DALLAS – Feb. 11, 2021 – A study led by UT Southwestern has identified a mechanism that controls the activity of proteins known as chaperones, which guide proteins to fold into the right shapes. The findings, published online today in Nature Communications, could shed light on hundreds of degenerative and neurodegenerative diseases caused by protein misfolding, such as Alzheimer’s, Parkinson’s, and Huntington’s, potentially leading to new treatments for these devastating conditions. Every protein in the body is originally produced in a linear chain, with amino acid building blocks strung together one after another. But to fulfill their roles in cells, explains study leader Lukasz Joachimiak, Ph.D., assistant professor in the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern, these chains need to fold into precise shapes. Chaperones help proteins accomplish this by protecting their vulnerable portions while they shift into position and steering them to adopt the proper shape. Every cell has a variety of chaperones that recognize and act on individual protein types. However, every chaperone isn’t active all the time, Joachimiak says. Unknown regulatory mechanisms appear to control when certain chaperones step in to guide their respective proteins to fold and when they stand aside. Joachimiak, also a member of the Peter O’Donnell Jr. Brain Institute, and his colleagues studied a family of chaperone proteins known as Hsp40s that work in combination with other chaperones known as Hsp70s. Members of these co-chaperones are involved in the proper folding of many proteins, including tau, which play a key role in causing Alzheimer’s disease when it’s misfolded. Hsp40 chaperones bind to Hsp70s through a specific portion on the Hsp40s called the J domain. But how the Hsp40s turn off this binding when it is not needed has been unclear. To help answer this question, Joachimiak and his colleagues used a specific Hsp40 called DnaJB8 as a model. When the researchers genetically modified these proteins to glow green inside cells, they found that they didn’t just exist as individual, free-floating units – the DnaJB8 chaperones tended to form aggregates, suggesting they had some way to stick to each other. They retained this ability to agglomerate when they were isolated in petri dishes. Using computer modeling and guided by biochemical experiments, the researchers discovered that two separate parts of this chaperone were drawn to each other through a type of chemistry called electrostatic interactions: Part of the J domain was drawn to a different part of this protein called the C-terminal domain through charged interactions. Modeling also showed that the J domain and the C-terminal domain stuck together on single molecules as well. Joachimiak and his team validated these findings on real DnaJB8 proteins using a technique called solid-state nuclear magnetic resonance. They also showed that the J and C-terminal domains stuck to each other when they were isolated from the full DnaJB8 molecule. The researchers suspected that the interaction between these two domains could prevent DnaJB8 from binding to its co-chaperone, an Hsp70, preventing them from jointly doing their job of guiding protein folding. Sure enough, experiments showed that the C-terminal domain of DnaJB8 competed with an Hsp70 called HspA1A when it was added to DnaJB8 in a test tube, blocking HspA1A from binding to the J domain when the C-terminal domain was bound instead. Joachimiak notes that something may go awry in this or other regulatory mechanisms that control the activity of chaperones in protein misfolding diseases. Finding ways to control this activity through pharmaceuticals or other means could provide a new way to treat these conditions to attack the problem at its source. “We may be able to leverage this mechanism to directly target these chaperones, activating them at will,” says Joachimiak, who is also an assistant professor of biochemistry and an Effie Marie Cain Scholar in Medical Research. “Our results could have an impact on hundreds of diseases where proteins become bad players by misfolding.” Other UT Southwestern researchers who contributed to this study include Bryan D. Ryder, Sofia Bali, and Jaime Vaquer-Alicea. This work was supported by a grant from The Welch Foundation (I-1928-20170325). About UT Southwestern Medical Center UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.