Publisher Health

The human immune system is a nearly perfect defense mechanism. It protects the body from disease-causing bacteria, viruses, and other pathogens. It detects nascent tumors and eradicates them. It cleans up cellular debris at the site of injury or infection.
To perform its myriad functions, the immune system must, above all, differentiate between self and non-self — a remarkable selective ability that allows it to detect and disable harmful agents while sparing the body’s own tissues.
If the immune system fails to make this distinction, it can mistakenly launch an assault against the body, causing autoimmune disorders.
Researchers have known the general principle underlying this selective ability for some time, but exactly how immune cells learn to distinguish friend from foe has remained less well understood.
Now, a new study led by researchers at Harvard Medical School identifies a new mechanism that explains how the body’s most powerful immune troops — T cells — learn to tell self and non-self apart.
The work, conducted mainly in mice, was published online June 16 in Cell and is scheduled to appear in the July 7 print issue.

A major clinical trial, led by experts at the University of Nottingham working in partnership with several Universities and NHS hospitals, has found that by interrupting the treatment of vulnerable people on long-term immune supressing medicines for two weeks after a COVID-19 booster vaccination, their antibody response to the jab is doubled.
The Vaccine Response On Off Methotrexate (VROOM) trial, which will have implications for people on immune-supressing medicines, who are among the millions of clinically vulnerable patients advised to ‘shield’ during the pandemic — is funded by the National Institute for Health and Care Research and the Medical Research Council. It was carried out in collaboration with colleagues from the University of Manchester, Imperial College London, the University of Oxford and Queen Mary University London. The study was run by the Oxford Clinical Trials Research Unit (OCTRU).
The results of the study are published in The Lancet Respiratory Medicine.
The study was planned to recruit 560 patients but recruitment was stopped early by the independent study oversight committees when interim results from the first 254 participants showed a clear result.
Methotrexate is the most commonly used immune-suppressing drug, with around 1.3 million people in the UK prescribed this medicine for inflammatory conditions such as rheumatoid arthritis, and skin conditions such as psoriasis. Many of them were among the 2.2 million clinically extremely vulnerable people advised to shield during the first phase of the COVID-19 pandemic, depending on specialist advice and on their risk factors.
While methotrexate is effective at controlling these conditions and has emerged as first line therapy for many illnesses, it reduces the body’s ability to fight infections and the ability to generate robust response to flu and pneumonia vaccines, including those against COVID-19.

A study of 10,775 high-risk adult patients during the COVID-19 delta variant surge in late 2021 finds that treatment with one of three anti-spike neutralizing monoclonal antibodies for mild to moderate symptoms led to low rates of severe disease, hospitalization, ICU admission and mortality, according to Mayo Clinic researchers.
Among patients treated at Mayo Clinic in Minnesota and Wisconsin from Aug. 1 to Dec. 1, 2021, who received bamlanivimab/etesevimab, casirivimab/imdevimab or sotrovimab, 287 patients, or 2.7%, developed severe disease that led to hospitalization, oxygen supplementation or death within 30 days of treatment. The rates of severe disease were 1.2% for patients treated with bamlanivimab/etesevimab, 1.6% for patients with sotrovimab, and 2.9% for casirivimab-imdevimab.
The slightly higher rate of severe outcomes among patients treated with casirivimab/imdevimab may be related to a significantly lower COVID-19 vaccination rate in that group of patients, according to Raymund Razonable, M.D., a Mayo Clinic infectious diseases specialist and first author of the study, published in Mayo Clinic Proceedings. Data show that unvaccinated patients are at higher risk of serious disease. ICU admission was comparable among patients treated with the three anti-spike monoclonal antibody products.
“Anti-spike neutralizing monoclonal antibodies are effective in reducing the risk of hospitalization and severe disease due to COVID-19,” Dr. Razonable says. “The improved clinical outcomes are shown for all three monoclonal antibodies that were used during the delta surge. That surge has passed, and we’re now dealing with omicron and its variants. But the lessons learned from the delta experience are still true: Diagnose early, treat early with monoclonal antibodies, and the risk of severe disease will be reduced.”
The delta COVID-19 variant is nearly twice as contagious as earlier variants and may cause more severe illness. The greatest risk of transmission is among people who are unvaccinated. People who are fully vaccinated still can be infected and spread the virus to others, though it appears that vaccinated people spread COVID-19 for a shorter period than unvaccinated people do.
Patients in the Mayo Clinic study were not confirmed as having the delta variant, but Dr. Razonable says the assumption is that patients were infected with that variant.

The human liver has amazing regeneration capabilities: Even if up to 70 percent of it is removed, the remaining tissue can regrow a full-sized liver within months.
Taking advantage of this regenerative capability could give doctors many more options for treating chronic liver disease. MIT engineers have now taken a step toward that goal, by creating a new liver tissue model that allows them to trace the steps involved in liver regeneration more precisely than has been possible before.
The new model can yield information that couldn’t be gleaned from studies of mice or other animals, whose biology is not identical to that of humans, says Sangeeta Bhatia, the leader of the research team.
“For years, people have been identifying different genes that seem to be involved in mouse liver regeneration, and some of them seem to be important in humans, but they have never managed to figure out all of the cues to make human liver cells proliferate,” says Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and of Electrical Engineering and Computer Science at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.
The new study, which appears this week in the Proceedings of the National Academy of Sciences, has identified one molecule that appears to play a key role, and also yielded several other candidates that the researchers plan to explore further.
The lead author of the paper is Arnav Chhabra, a former MIT graduate student and postdoc.

Disproportionately high COVID-19 mortality rates among Black populations in Louisiana parishes are the result of longstanding health vulnerabilities associated with institutional and societal discrimination, according to research conducted by an interdisciplinary team under the mentorship of University of Maryland (UMD) Clark Distinguished Chair Deb Niemeier and UMD Associate Professor of Kinesiology Jennifer D. Roberts in the School of Public Health.
The team included doctoral students from three different programs at UMD, working together as part of an interdisciplinary fellowship program known as UMD Global STEWARDS, directed by Professor Amy R. Sapkota of the School of Public Health.
“Our results suggest that structural racism and inequities led to severe disparities in initial COVID-19 effects among highly populated Black Louisiana communities, and that as the virus moved into less densely populated Black communities, similar trends emerged,” the researchers concluded in a study published in the Proceedings of the National Academy of Sciences on Monday, June 27.
Over the course of generations, discrimination in employment, education, housing, and access to medical care has led to higher risks of chronic illnesss (including asthma, diabetes, and obesity) among Black communities, as well as a higher likelihood of suffering a stroke, the authors noted. The Centers for Disease Control and Prevention (CDC) have linked these factors to the likelihood of becoming severely ill from COVID-19.
Both nationally and in Louisiana, Black communities encounter inadequate housing and lower rates of home ownership, reduced access to health care, and lower rates of employment. As exemplified by Cancer Alley, Black families are more likely to live in so-called “fence-line” neighborhoods, located near industrial facilities that expose them to pollutants, and typically encounter reduced air and water quality compared to white Americans. Black families are also more likely to be uninsured and face higher rates of unemployment. These and multiple other factors, all reflecting decades of institutional and societal bias, add up to a combination of stressors that undermine health and, in the case of COVID-19, have made Black communities particularly vulnerable.
To obtain their findings, the team members identified the spatial distribution of social and environmental stressors across Louisiana parishes, and used hotspot analyses to develop aggregate stressors. They then tracked the correlations among stressors, cumulative health risks, COVID-19 mortality rates, and the size of Black populations across Louisiana. The results suggest that COVID-19 mortality rates initially spiked in Black communities with high population densities and moderate levels of aggregate stress. Over time, the rates also increased in less densely populated Black communities with higher levels of aggregate stress.

Pain management is one of the biggest challenges of the modern healthcare system. Almost 60% of US adults report having experienced pain in the past three months and pain is one of the main reasons adults seek medical care. Adequate pain management is critical for patient health and wellbeing. A new study published today in The Proceedings of the National Academy of Sciences (PNAS), found that physicians prescribed less pain medication during nightshifts than during the day.
The research was conducted by a multidisciplinary team led by Professor Shoham Choshen-Hillel from the Hebrew University of Jerusalem (HU)’s School of Business Administration and Federmann Center for the Study of Rationality, HU Psychology Department’s Dr. Anat Perry, and Dr. Alex Gileles-Hillel from Hadassah Medical Center and HU.
In the first part of the study, 67 doctors were given empathy assessment tasks in the morning and asked to respond to simulated patient scenarios. These doctors were either at the end of a 26-hour shift or just beginning their workday. The study found that doctors who recently completed night shift showed less empathy for patient’s pain. For example, these physicians’ exhibited decreased emotional responses to pictures of people in pain and consistently scored their patients low on pain assessment charts.
In the second part of the study, the researchers looked at actual medical decisions made by emergency room doctors in the United States and Israel. In all, they analyzed 13,482 discharge letters for patients who came to the hospital in 2013-2020 with a chief complaint of pain (headache, back pain, etc.). Across all data sets, physicians were 20-30% less likely to prescribe an analgesic during nightshifts (compared to daytime shifts) and prescribed fewer painkillers than were generally recommended by the World Health Organization. “They’re tired and therefore they’re less empathic to patients’ pain. When we looked at ER doctors’ discharge papers, we found that they prescribed fewer painkillers,” Choshen-Hillel explained.
This bias remained significant even after adjusting for patients’ reported level of pain, patient and physician’s demographics, type of complaint, and emergency department characteristics. “Our takeaway is that nightshift work is an important and previously unrecognized source of bias in pain management, likely stemming from impaired perception of pain. The researchers explain that even medical experts, who strive to provide the best care for their patients, are susceptible to the effects of a nightshift,” Perry noted.
Looking ahead, the researchers suggest implementing more structured pain management guidelines in hospitals. Another important implication relates to physician work structure, and the need to improve physicians’ working schedules. “Our findings may have implications for other workplaces that involve shiftwork and empathic decision-making, including crisis centers, first responders, and the military. In fact, these results should probably matter to all people who are sleep-deprived,” added Gileles-Hillel.
In addition to the three lead authors, the Israeli authors included Tom Gordon-Hecker, Shir Genzer and Salomon Israel from the Hebrew University and Ido Sadras and David Rekhtman the Hadassah-Hebrew University Medical Center in Jerusalem. The US research team included David Gozal, Koby Clements, and Adrienne Ohler from the University of Missouri, and Eugene M. Caruso from UCLA.
Story Source:
Materials provided by The Hebrew University of Jerusalem. Note: Content may be edited for style and length.

A decade after CRISPR started to become a major tool in genetic research, a new generation of scientists is growing […]

Medicare could waste up to $605 million per year on the controversial Alzheimer’s drug aducanumab if it is eventually approved for widespread use because it is supplied in vials containing fixed doses that may not be appropriate for all patients-resulting in the trashing of large volumes of unused drug, new UCLA research finds.
The drug has been found to have little if any benefit for Alzheimer’s patients. Though Medicare has restricted the drug for use in clinical trials, this decision could be overturned by appeal or legal challenges. Previous UCLA research has found that ancillary care services associated with the medication alone could account for nearly 20% of Medicare costs for patients treated with the drug.
The researchers suggest that aducanumab, currently priced at $28,200 per patient annually, could be supplied in more efficient vial sizes to contain costs, should it be approved for general use.
“With several other Alzheimer’s drugs in the pipeline, aducanumab will not be the last infusion drug to threaten Medicare’s budget,” said Dr. Carlos Irwin Oronce, an assistant project scientist in the UCLA Division of General Internal Medicine and Health Services Research. “Given Medicare’s premium increase in 2022 partly due to aducanumab, greater focus on efficient vial packaging could improve the value of future Medicare spending, slow premium growth, and reduce beneficiaries’ out-of-pocket costs.”
The paper will be published June 27 in the peer-reviewed Journal of the American Geriatrics Society.
The drug comes in fixed-dose vial sizes — 170 mg/1.7 mL and 300 mg/3.0 mL — that are administered based on a patient’s weight and other factors such as amyloid plaque rates. The researchers used data from the 2016 Health and Retirement Study for participants aged 65 years and older who are covered by Medicare Part B insurance and had Mild Cognitive Impairment (MCI) or mild dementia.
For this analysis, the researchers assumed a 10 mg/kg monthly dosage of the drug. Based on the study cohort’s weight distribution, they defined 27 patient weight categories ranging from 47 kg or less (104 lbs) to greater than 150 kg (330 lbs). These categories reflected 27 possible aducanumab vial combinations needed to properly dose the drug for the patients potentially eligible for it. The authors then subtracted the total amount of drug in the vials from the total amount of drug needed for each patient in the survey based on the patient’s weight. For example, an 85 kg patient requires 850 mg of drug provided by three 300 mg/3.0 ml vials (900 mg total), with 50 mg of discarded drug per month. Based on the wasted drug calculated from each patient in the nationally representative survey sample, the authors then estimated the potential amount of drug wasted for the entire U.S. Medicare population of patients who could be expected to receive aducanumab each year.
If approved for widespread use and assuming a 10% drug uptake, about 132,000 to 694,000 vials of the expensive drug would be discarded, amounting to $115 million to $605 million in wasted dollars by Medicare and its enrollees each year. Reducing the vial size could reduce wasteful spending by 60%.
The study has some limitations, the authors noted. For instance, the measures used to classify cognitive impairment may have misclassified some cases; plaque prevalence rates were taken from population studies and not PET scans of the study participants; and the authors assumed that the price of the drug would not change.
Additional study co-authors are Dr. John Mafi, Dr. Catherine Sarkisian, Julia Cave Arbanas, and Mei Leng of UCLA; Dr. Bruce Landon of Harvard University; and Cheryl Damberg of RAND Corporation. Oronce and Sarkisian have appointments with the VA Greater Los Angeles Healthcare System and Mafi has an appointment with RAND.

Researchers at Karolinska Institutet in Sweden have linked resistance to treatment for a deadly form of kidney cancer to low mitochondrial content in the cell. When the researchers increased the mitochondrial content with an inhibitor, the cancer cells responded to the treatment. Their findings, which are published in Nature Metabolism, offer hope for more targeted cancer drugs.
Mitochondria produce energy for the cell and require oxygen to do so. As such, they are the most oxygen-demanding component of the cell. But how mitochondria adapt in a low-oxygen environment and are linked to cancer therapy resistance has remained unknown.
“We’ve shown for the first time how the formation of new mitochondria is regulated in cells that lack oxygen and how this process is altered in cancer cells with VHL mutations,” says Associate Professor Susanne Schlisio, group leader at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.
Healthy cells are prevented from becoming cancerous by a gene called von Hippel-Lindau (VHL). The 2019 Nobel Prize in Physiology or Medicine was awarded to the discovery that VHL was part of the cell’s oxygen detection system. Normally, VHL breaks down another protein called HIF. Consequently, when VHL is mutated, HIF accumulates and causes a disease called VHL syndrome in which the cells react as if they lack oxygen despite oxygen being present. VHL syndrome greatly increases the risk of tumours, both benign and malignant. VHL syndrome-induced kidney cancer has a poor prognosis, with a five-year survival rate of barely 12 per cent.
In the present study, the researchers examined the protein content of cancer cells from patients with different variants of VHL syndrome, and how they differed from another group of individuals with a special VHL mutation called Chuvash, a mutation involved in hypoxia-sensing disorders without any tumor development. Those with the Chuvash VHL-mutation had normal mitochondria in their cells, while those with VHL syndrome mutation had few.
To increase the amount of mitochondrial content in VHL related kidney cancer cells, the researchers treated these tumours with an inhibitor of a mitochondrial protease called “LONP1.” The cells then became susceptible to the cancer drug sorafenib, which they had previously resisted. In mouse studies, this combination treatment led to reduced tumour growth.
“We hope that this new knowledge will pave the way for more specific LONP1 protease inhibitors to treat VHL-related clear cell kidney cancer,” says the study’s first author Shuijie Li, postdoctoral researcher in the Schlisio’s group. “Our finding can be linked to all VHL syndromic cancers, such as the neuroendocrine tumours pheochromocytoma and paraganglioma, and not just kidney cancer.”
The study was supported by grants from the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the European Research Council (Synergy Grant for the “Kill or Differentiate” project) and the Paradifference Foundation.
Story Source:
Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

Georgia State University researchers have found that the Alpha, Beta and Delta variants of SARS-CoV-2 were substantially more fatal in mouse models than the original strain of the virus that causes COVID-19. However, they also found that the Omicron variant, despite having more mutations, led to less severe disease with half as many deaths and longer survival time.
The findings, published in a study in the journal Viruses, offer new information on how the COVID-19 virus changes over time, and how those changes are leading to different kinds of infections.
“Given the speed that variants have emerged over the course of the pandemic, and may continue to emerge, we always want to predict how these variants will behave,” said Mukesh Kumar, assistant professor of biology and the paper’s lead researcher. “We want to know if the next variants will become more lethal than the one before, or weaker, or if it’s a random process.”
In the study, researchers looked at how variants acted in mouse models, examining the effects of the original strain compared to Alpha, Beta, Delta and Omicron variants.
They found that infection with the Alpha, Beta and Delta strains led to higher virus levels in lungs and brains, significant loss of body weight, more inflammation and a 100 percent mortality rate among study subjects.
The Omicron variant was much milder with lower virus levels, less lung inflammation, lower rates of weight loss and a 50 percent mortality rate. This was despite the Omicron variant having more mutations that allow it to bind with angiotensin-converting enzyme 2, also known as the ACE2 “receptor,” which is a protein the virus binds with so it can infect cells.
“In mice, Omicron was significantly less efficient than the other variants we tested, despite carrying the highest number of mutations,” said Kumar. “That tracks along with epidemiological data that suggests that the Omicron virus causes less severe pathology in humans than previous ancestral strains.”
Most studies done in mouse models have been with the original virus strain first identified in Wuhan, China, which has been helpful but not informative in our current variant reality, Kumar said. These insights into the pathogenesis of the earlier and currently circulating variants help in understanding the pathogenesis of emerging COVID-19 variants.
The other authors of the study are biology Ph.D. students Janhavi Prasad Natekar, Heather Pathak, Shannon Stone, Pratima Kumari, Shaligram Sharma and Tabassum Tasnim Auroni; and post-doctoral fellows Komal Arora and Hussin Alwan Rothan, all of Georgia State.
The paper is titled “Differential Pathogenesis of SARS-CoV-2 Variants of Concern in Human ACE2-Expressing Mice.”
Story Source:
Materials provided by Georgia State University. Note: Content may be edited for style and length.