Culture

July 30, 2020--(BRONX, NY)--A new study shows how chronic psychological stress leads to painful vessel-clogging episodes--the most common complication of sickle-cell disease (SCD) and a frequent cause of hospitalizations. The findings, made in mice, show that the gut microbiome plays a key role in triggering those episodes and reveals possible ways to prevent them. The research was conducted by scientists at Albert Einstein College of Medicine and published online today in Immunity.

SCD occurs in about 1 in 365 African-American births. People with SCD have inherited a gene mutation that leads to abnormal hemoglobin, causing red cells (which contain hemoglobin) to take on a sickle shape and become less flexible. The sickled red cells tend to clog small vessels, impeding blood flow and preventing oxygen from reaching tissues. This can result in painful and debilitating vaso-occlusive episodes, or VOE, which can last for days. No therapies can reverse VOE and, over time, they cause significant damage to internal organs--the major reason that life expectancy for those with severe SCD is 20 to 30 years shorter than for those without the disease.

"Research for sickle-cell disease is chronically underfunded and those with the condition are in need--and deserve--new treatments that can help address this major health disparity," said study leader Paul S. Frenette, M.D., professor of medicine and of cell biology and chair and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein. "We hope our most recent findings can help point to novel solutions for treating this painful and deadly disease."

Using a mouse model, Dr. Frenette and colleagues found that the path to VOE begins in the brain. Stress triggers the secretion of glucocorticoid hormones in the brain, which make their way to the gut and increase its permeability. This greater permeability allows segmented filamentous bacteria (SFB)--a type of beneficial gut bacteria in mice--to interact with Th17 helper immune cells in the lining of the gut. The SFB stimulate those immune cells to produce pro-inflammatory molecules, which enter the circulation and promote the aging and accumulation of neutrophils, a type of white blood cell. In an earlier study, the Frenette laboratory had found that these aged neutrophils are inflammation-inducing cells that drive the VOE.

This chain of events was observed in both SCD mice and healthy mice that were subjected to psychological stress. However, lethal VOE occurred only in the sickle-cell disease mice. "Healthy mice don't have sickled blood cells and therefore don't suffer the ill effects caused by the buildup of aged neutrophils," Dr. Frenette noted.

"Importantly, we found we could markedly reduce stress-induced VOE in mice through several different interventions: inhibiting the synthesis of glucocorticoids, depleting SFB, or blocking the inflammatory molecules induced by these bacteria," Dr. Frenette said. "Each of those actions could potentially limit the impact of psychological stress on people with SCD."

While SFB are found only in rodents, some evidence indicates that similar beneficial bacteria in the human gut can also induce Th17 immune cells to produce inflammatory molecules. "We hope to learn whether there is any correlation between the abundance of these bacteria in patients with sickle-cell disease and the frequency or severity of VOEs that affect them," Dr. Frenette said.

When a natural disaster strikes, it often takes years for vulnerable communities to recover, long after the news coverage fades and the rest of the world seems to move on. A new Portland State University study that followed 400 households after the 2015 Nepal earthquakes provides insight into better understanding the factors that contribute to resilience and change in short-term rural natural disaster recovery.

"Recovery is a dynamic process with multiple dimensions which means that government and outside aid programs cannot be one size fits all," said Jeremy Spoon, the lead researcher and an associate professor of anthropology at PSU.

Spoon's team conducted surveys with 400 households in four communities both nine months and 1.5 years after the April and May 2015 earthquakes. The team also returned at 2.5 years for research workshops to connect the results to the participant experiences and perspectives. They used a novel methodology to document and analyze recovery as a multidimensional phenomenon with more than 30 recovery indicators, from rebuilding of homes and access to electricity to impacts on herding, farming, and wage labor.

Researchers found substantial geographic variation in recovery across the sites but were also able to identify several common patterns in recovery.

The households that appeared the most resilient nine months after the earthquakes were those that had less herding and farming-based livelihoods, more market connections to shops and tourism, and easier access to rebuilding funds from the government and through loans.

The results suggest that a settlement's proximity to the road and access to outside aid and government services may be negatively or marginally benefitting recovery in certain situations.

In Gatlang, a cluster of two settlements in northern Nepal, their growing dependence on outside aid and a more tourism-centric economy as a result of being close to the road actually impeded their recovery. For most households, their circumstances were getting worse a year and a half after the earthquakes. Only 8% of households had returned to their homes from temporary shelters and they were experiencing greater impacts to their herding, farming, and forest product collection.

The study suggests that access may be a trap, where individuals receiving assistance adapted to waiting for help rather than helping themselves. The aid received was also not enough to help the residents recover to a point that was comparable to where they were before the earthquakes and contained generic rebuilding solutions that did not take into account local knowledge or perspectives.

By contrast, in Kashigaun, a cluster of three settlements that is a two- to three-day walk from the road with very few aid organizations serving the area, households pooled their resources and collectively worked together to rebuild their community through work exchange. A year and a half after the earthquakes, 92% of households returned to their homes from temporary shelters; however, few, if any, were rebuilt to code. The earthquakes helped to revive and reinforce communal traditions of work exchange, which served as a safety net for the poorest and most marginal.

Spoon said the lessons learned can help evaluate relief and reconstruction interventions where outside expert knowledge ignores cultural diversity and place-specific dynamics, such as the roles of local knowledge and institutions.

"We feel that governments and aid organizations can use our approach to capture some of the most important facets of recovery in a variety of contexts over the short- and long-term, especially if they use participatory methods and outreach to develop appropriate recovery indicators," Spoon said. "Better understanding recovery dynamics then leads to improved natural disaster response."

Spoon, along with Drew Gerkey from Oregon State University, and their team received another grant from the National Science Foundation to continue their work in Nepal and collect data from the same 400 households in years six through nine. The study was published in the journal World Development. Its co-authors include Alisa Rai and Umesh Basnet from PSU; Gerkey from OSU; and Ram Bahadur Chhetri from Tribhuvan University in Nepal. Additional publications from this study are forthcoming.

The thymus is one of the organs of the immune system where T lymphocytes develop, a type of cells that is essential to fight infections and prevent cancer. Without them, it's impossible to live. The thymus is located just above the heart, being large in children and gradually reduces size as age progresses. In this organ, T lymphocytes develop from progenitor cells, which are born in the bone marrow and travel to the thymus through the blood stream. This is a continuous process, where cells enter the thymus, proliferate and develop into T lymphocytes. In the end, these cells leave the thymus to scout and defend the body.

The development of T lymphocytes is a tightly regulated process that aims at producing cells that protect the organism. However, these cells can also accumulate errors and cause cancer. Blood cell cancers, which include T lymphocytes, are called leukaemia. In the case of this study, the focus was on T cell acute lymphoblastic leukaemia and how it is normally prevented. This type of leukaemia is quite aggressive and, despite rare, it severely impacts mostly children, albeit affecting some adults.

The research team led by Vera Martins, principal investigator at Instituto Gulbenkian de Ciência, proposed to identify the cells that prevent this type of leukaemia and show that they are involved in a process of cell competition in the thymus. In this process, younger (and healthier) cells replace older (and less healthy) ones. Thus, younger cells always "win" and purge the older ones, which have the potential of causing leukaemia. But the researchers managed to go even further in their findings. Besides the leukaemia preventive role of these cells, they were also shown to receive signals that provide information on how fast (or slow) they are supposed to develop. The speed at which the development of T lymphocytes occurs is adjusted according to the intrinsic needs of the pool of precursor cells.

The team of researchers used mice as model organism, since the development of T lymphocytes is similar to what happens in humans, and made use of thymus transplants combined with different genetic models to explore the cellular interactions and the genes involved in this complex process. According to Vera Martins "the competitive cell interactions occur early in development and are regulated by a cytokine (interleukin 7) which is important throughout several developmental processes of the T lymphocytes". "We discovered that it is the availability of this cytokine that defines the size of the competing cell population" explains the researcher, reinforcing that "it is through the adjustment of the duration of the cell cycle during proliferation that interleukin 7 regulates the speed at which these cells differentiate and promote competition".

This study reveals that the development of T lymphocytes in a healthy thymus is not merely achieved because cells follow a pre-determined path of extrinsic signals. Rather, it is achieved through the integration of external signals and intrinsic properties of the cells that contribute to the normal functioning of the thymus.

In the future, it will be important to determine the importance of space constraints and resource availability for T lymphocyte precursor cells in shaping the observed competition. The team is also interested in understanding how deficiencies in cell competition in the thymus may promote the initiation of leukaemia. With this work, the researchers hope to contribute to a better prevention, or earlier diagnostics, of diseases about which very little is still known. "I am convinced that this approach, which integrates the healthy organism and the disease condition, is the best way to understand what causes leukaemia and I hope that the generated knowledge will pave the way to the development of more adequate responses for whomever has to face such a severe disease".

This study is a clear example of the contributions of fundamental science to the understanding of what maintains individuals healthy and what changes to cause disease.

HOUSTON -- According to researchers from The University of Texas MD Anderson Cancer Center, the implementation of social distancing policies corresponded with significant reductions in transmission of the SARS-CoV-2 virus and reduced community mobility, both in the U.S. and globally, providing evidence that social distancing is a useful tool in preventing further spread of COVID-19.

The study, published today in PLOS ONE, estimates that social distancing policies enacted nationally in 46 countries prevented an estimated 1.57 million cases of COVID-19 over a two-week period, representing a 65% reduction in new cases. The researchers suggest these data emphasize the significant benefits that can be achieved by individuals practicing social distancing measures.

"At MD Anderson, we are focused on caring for patients with cancer, and we know that our patients are highly vulnerable to COVID-19," said senior author Raghu Kalluri, M.D., Ph.D., professor and chair of Cancer Biology. "Therefore, we felt it important to conduct an unbiased analysis of safety measures that could benefit our patients as well as society at large. From our data-driven analysis, it became clear that practicing social distancing can have a huge impact on transmission rates."

Impact of social distancing policies in the U.S.

To determine the effectiveness of social distancing policies in the U.S., the researchers analyzed COVID-19 spread across each of the 50 states. Recognizing that many factors contribute to disease spread, they analyzed new cases before and after states enacted social distancing policies.

Three states did not implement such policies, providing an opportunity for comparisons. These were analyzed over similar time periods relative to other states.

"We found that states observed significant reductions in transmission rates following the implementation of social distancing policies, compared to states without such policies," said lead author Daniel McGrail, Ph.D., postdoctoral fellow in Systems Biology. "In fact, two of the smallest reductions in spread were seen in states without social distancing policies."

The 47 states with social distancing policies also saw greater reductions in average community mobility compared to states without policies, which measures the movement trends of residents across residential, workplace, retail and other locations. States without social distancing policies also saw decreased mobility, although the change was significantly smaller than states with distancing policies.

Impact of social distancing policies globally

Understanding that the U.S. analysis was limited by a small number of states without social distancing policies, the researchers analyzed the effects of social distancing policies globally. They were able to obtain sufficient data for 46 countries with national social distancing policies, 74 nations without such policies and 14 with regional policies.

Following a similar analysis, the data indicate that significantly greater reductions in transmission were seen in countries after implementing a national social distancing policy compared to those with regional policies or a matched time frame in countries without policies. No significant difference was observed between countries with regional policies and those without social distancing policies.

Countries with any social distancing policies had significantly reduced community mobility relative to nations without policies, and those with national policies saw greater decreases than countries with regional policies. There was a strong correlation between decreased mobility and decreased transmission of the virus, highlighting the importance of individuals practicing social distancing to effectively prevent transmission of the virus.

"This is clear evidence that social distancing measures can collectively have tremendous impacts on reducing transmission of SARS-CoV-2, and we encourage individuals to practice social distancing to help control spread of infections," said Kalluri. "We believe these data will provide useful evidence for public health officials and policy makers when considering future measures to reduce the spread of COVID-19 in their communities."

The authors acknowledge the study is limited by a reliance on direct COVID-19 testing, which may underestimate prevalence. Also, the researchers focused on spread rates following implementation of social distancing policies as an internal control for the numerous additional factors likely contributing to spread rates.

For the analysis, daily case numbers and population data were gathered from the COVID-19 Data Repository by the Center for Systems Science and Engineering at Johns Hopkins University. Information on social distancing policies was obtained from the Aura Vision Global COVID-19 Lockdown Tracker and mobility data were acquired from Google mobility reports. All data for the study was collected on June 5, 2020.

Philadelphia, July 30, 2020--In the early days of the COVID-19 pandemic, the SARS-CoV-2 virus seemed only rarely to have serious complications in children. However, by April 2020, pediatricians had begun recognizing a syndrome in children who tested positive for COVID-19 involving hyperinflammation and some other attributes found in Kawasaki disease (KD). By May, the Centers for Disease Control and Prevention (CDC) had named the new condition Multisystem Inflammatory Syndrome in Children (MIS-C). Yet the biology of MIS-C and how it relates to or differs from severe COVID-19 in children has largely remained a mystery.

Now, researchers from Children's Hospital of Philadelphia (CHOP) report important data that differentiate MIS-C from severe COVID-19 in children and suggest that MIS-C is a post-infectious syndrome related to COVID-19 but distinct from KD. The findings were published today in The Journal of Clinical Investigation.

"This is the first report comparing, head-to-head, the distinct outcomes of SARS-CoV2 in children and provides novel information on disease biology, as well as clinical information that can help practitioners distinguish between the clinical syndromes," said Edward M. Behrens, MD, Chief of the Division of Rheumatology at CHOP, member of the Immune Dysregulation Frontier Program, and co-senior author of the paper. "The clinical and laboratory measures we describe accurately distinguish between patients with MIS-C and severe COVID-19, which will help physicians provide better, more accurate treatment for their patients."

Differing Cytokine Profiles

The researchers, led by Behrens and fellow Immune Dysregulation co-senior authors David T. Teachey, MD, and Hamid Bassiri MD, PhD, analyzed 20 patients with SARS-CoV-2: nine with severe COVID-19 disease, five with mild COVID-19, and six with MIS-C. To differentiate the biology of these conditions, the research team looked at patients' levels of cytokines, substances secreted by cells that send messages to the immune system and tell it what to do. When the body makes too many cytokines, the immune system to spins out of control, leading to severe inflammation and sometimes shock.

The researchers found that patients with MIS-C had elevated levels of two cytokines - IL-10 and TNF-? - whereas patients with severe or mild COVID-19 had no or minimally elevated levels of these cytokines. This profile for MIS-C is distinct from previously reported cytokine profiles in KD, which tend to be associated with mild elevations of other cytokines and not IL-10.

COVID-19 Connection

Additionally, the so-called viral cycle threshold - meaning how many times a test sample must be multiplied and amplified before SARS-CoV-2 is detected - also distinguished severe COVID-19 and MIS-C. Those with severe COVID-19 had low cycle thresholds, implying the virus was easily detectable and active, but those with MIS-C had high cycle thresholds, indicating the patient had been infected with the virus at some point in the distant past and had cleared most of the active virus. This bolsters the theory that MIS-C is a post-viral hyperinflammatory reaction to SARS-CoV-2.

Aside from patient cytokine profiles, which require sophisticated laboratory equipment, the researchers also found that simple peripheral blood smears could help distinguish the three conditions. Burr cells, which are red blood cells that appear scalloped or serrated when viewed under a microscope, were absent in patients with mild COVID-19 but present in 40% of patients with severe disease. However, all patients with MIS-C had at least some burr cells present, and more than half of them had the majority of their red blood cells appearing as burr cells on a peripheral blood smear.

MIS-C Distinct from Kawasaki

While the researchers did note some overlap in the clinical presentations of KD and MIS-C, they noted predominating symptoms did not overlap. Most patients in the MIS-C cohort had severe ventricular dysfunction at presentation, a finding that is unusual in KD. Patients with MIS-C also tended to have severe gastrointestinal inflammation, which combined with the cytokine data generated by the study, led the team to conclude that MIS-C is a distinct hyperinflammatory syndrome.

"Contrary to early reports that emphasized relatively mild disease outcomes in pediatric patients, we show that in some children SARS-CoV-2 appears to trigger a dysregulated hyperinflammatory pathophysiologic process," Behrens said. "Future work will need to examine why SARS-CoV-2 induces such a damaging inflammatory response in children."

Researchers at the University of Maryland School of Medicine (UMSOM) have for the first time identified stem cells in the region of the optic nerve, which transmits signals from the eye to the brain. The finding, published this week in the journal Proceedings of the National Academy of Sciences (PNAS), presents a new theory on why the most common form of glaucoma may develop and provides potential new ways to treat a leading cause of blindness in American adults.

"We believe these cells, called neural progenitor cells, are present in the optic nerve tissue at birth and remain for decades, helping to nourish the nerve fibers that form the optic nerve," said study leader Steven Bernstein, MD, PhD, Professor and Vice Chair of the Department of Ophthalmology and Visual Sciences at the University of Maryland School of Medicine. "Without these cells, the fibers may lose their resistance to stress, and begin to deteriorate, causing damage to the optic nerve, which may ultimately lead to glaucoma."

The study was funded by the National Institutes of Health's National Eye Institute (NEI), and a number of distinguished researchers served as co-authors on the study.

More than 3 million Americans have glaucoma, which results from damage to the optic nerve, causing blindness in 120,000 U.S. patients. This nerve damage is usually related to increased pressure in the eye due to a buildup of fluid that does not drain properly. Blind spots can develop in a patient's visual field that gradually widen over time.

"This is the first time that neural progenitor cells have been discovered in the optic nerve. Without these cells, the nerve is unable to repair itself from damage caused by glaucoma or other conditions. This may lead to permanent vision loss and disability," said Dr. Bernstein. "The presence of neural stem/progenitor cells opens the door to new treatments to repair damage to the optic nerve, which is very exciting news."

To make the research discovery, Dr. Bernstein and his team examined a narrow band of tissue called the optic nerve lamina. Less than 1 millimeter wide, the lamina lies between the light-sensitive retina tissue at the back of the eye and the optic nerve. The long nerve cell fibers extend from the retina through the lamina, into the optic nerve. What the researchers discovered is that the lamina progenitor cells may be responsible for insulating the fibers immediately after they leave the eye, supporting the connections between nerve cells on the pathway to the brain.

The stem cells in the lamina niche bathes these neuron extensions with growth factors, as well as aiding in the formation of the insulating sheath. The researchers were able to confirm the presence of these stem cells by using antibodies and genetically modified animals that identified the specific protein markers on neuronal stem cells.

"It took 52 trials to successfully grow the lamina progenitor cells in a culture," said Dr. Bernstein, "so this was a challenging process." Dr. Bernstein and his collaborators needed to identify the correct mix of growth factors and other cell culture conditions that would be most conducive for the stem cells to grow and replicate. Eventually the research team found the stem cells could be coaxed into differentiating into several different types of neural cells. These include neurons and glial cells, which are known to be important for cell repair and cell replacement in different brain regions.

This discovery may prove to be game-changing for the treatment of eye diseases that affect the optic nerve. Dr. Bernstein and his research team plan to use genetically modified mice to see how the depletion of lamina progenitor cells contributes to diseases such as glaucoma and prevents repair.

Future research is needed to explore the neural progenitors repair mechanisms. "If we can identify the critical growth factors that these cells secrete, they may be potentially useful as a cocktail to slow the progression of glaucoma and other age-related vision disorders." Dr. Bernstein added.

The work was supported by NEI grant RO1EY015304, and by a National Institutes of Health shared instrument grant 1S10RR26870-1.

"This exciting discovery could usher in a sea change in the field of age-related diseases that cause vision loss," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "New treatment options are desperately needed for the millions of patients whose vision is severely impacted by glaucoma, and I think this research will provide new hope for them."

WOODS HOLE, Mass. --A team at the Marine Biological Laboratory (MBL) has achieved the first gene knockout in a cephalopod using the squid Doryteuthis pealeii, an exceptionally important research organism in biology for nearly a century. The milestone study, led by MBL Senior Scientist Joshua Rosenthal and MBL Whitman Scientist Karen Crawford, is reported in the July 30 issue of Current Biology.

The team used CRISPR-Cas9 genome editing to knock out a pigmentation gene in squid embryos, which eliminated pigmentation in the eye and in skin cells (chromatophores) with high efficiency.

"This is a critical first step toward the ability to knock out -- and knock in -- genes in cephalopods to address a host of biological questions," Rosenthal says.

Cephalopods (squid, octopus and cuttlefish) have the largest brain of all invertebrates, a distributed nervous system capable of instantaneous camouflage and sophisticated behaviors, a unique body plan, and the ability to extensively recode their own genetic information within messenger RNA, along with other distinctive features. These open many avenues for study and have applications in a wide range of fields, from evolution and development, to medicine, robotics, materials science, and artificial intelligence.

The ability to knock out a gene to test its function is an important step in developing cephalopods as genetically tractable organisms for biological research, augmenting the handful of species that currently dominate genetic studies, such as fruit flies, zebrafish, and mice.

It is also a necessary step toward having the capacity to knock in genes that facilitate research, such as genes that encode fluorescent proteins that can be imaged to track neural activity or other dynamic processes.

"CRISPR-Cas9 worked really well in Doryteuthis; it was surprisingly efficient," Rosenthal says. Much more challenging was delivering the CRISPR-Cas system into the one-celled squid embryo, which is surrounded by an exceedingly tough outer layer, and then raising the embryo through hatching. The team developed micro-scissors to clip the egg's surface and a beveled quartz needle to deliver the CRISPR-Cas9 reagents through the clip.

Studies with Doryteuthis pealeii have led to foundational advances in neurobiology, beginning with description of the action potential (nerve impulse) in the 1950s, a discovery for which Alan Hodgkin and Andrew Huxley became Nobel Prize laureates in 1963. For decades D. pealeii has drawn neurobiologists from all over the world to the MBL, which collects the squid from local waters.

Recently, Rosenthal and colleagues discovered extensive recoding of mRNA in the nervous system of Doryteuthis and other cephalopods. This research is under development for potential biomedical applications, such as pain management therapy.

D. pealeii is not, however, an ideal species to develop as a genetic research organism. It's big and takes up a lot of tank space plus, more importantly, no one has been able to culture it through multiple generations in the lab.

For these reasons, the MBL Cephalopod Program's next goal is to transfer the new knockout technology to a smaller cephalopod species, Euprymna berryi (the hummingbird bobtail squid), which is relatively easy to culture to make genetic strains.

Coastal flooding events could threaten assets worth up to 20% of the global GDP by 2100, a study in Scientific Reports suggests. The areas predicted to be most impacted by flooding are north-west Europe, south-east and east Asia, north-east USA and northern Australia, according to the authors.

Ebru Kirezci and colleagues combined data on global sea levels during extreme storms with projections of sea level rises under different greenhouse gas emission scenarios. The authors used these data to model maximum sea levels that may occur by 2100. The researchers combined their model with topographic data to identify areas at risk of coastal flooding. Using data on global population distribution and GDP in affected areas, they estimated the population and assets at risk from flooding.

Under conditions of high greenhouse gas emissions and assuming no flood defences, the authors estimate that the land affected by coastal flooding could increase by 48% by 2100. Areas that could be at risk of extensive flooding include south-eastern China, Australia's Northern Territories, Bangladesh, West Bengal and Gujurat in India, the US states of North Carolina, Virginia and Maryland and north-west Europe including the UK, northern France and northern Germany. The authors suggest that the global population exposed to coastal flooding could be up to 287 million by 2100 (4.1% of the world's population) and that the assets threatened by flooding could be worth up to US $14.2 trillion (20% global GDP).

The findings indicate that without investment in flood defences or a reduction in greenhouse gas emissions, coastal flooding could have major implications for the global population and economy by the end of the century.

Experts add excessive alcohol intake and head injury in mid-life, and exposure to air pollution in later life to list of key modifiable risk factors for dementia - expanding number of preventable causes from 9 to 12 factors that span from childhood to later life

Report also highlights 9 recommendations for policymakers and individuals to help reduce risk, including providing primary and secondary education for all children, decreasing harmful alcohol drinking, preventing head injury, using hearing aids, protecting ears from high noise levels, and urgently improving air quality

The potential to prevent cases of dementia is high, and the biggest impact is likely to be seen in low- and middle-income countries where two-thirds of cases occur

Modifying 12 risk factors over the lifecourse could delay or prevent 40% of dementia cases, according to an update to The Lancet Commission on dementia prevention, intervention, and care, which is being presented at the Alzheimer's Association International Conference (AAIC 2020).

Combined, the three new risk factors are associated with 6% of all dementia cases - with an estimated 3% of cases attributable to head injuries in mid-life, 1% of cases to excessive alcohol consumption (of more than 21 units per week) in mid-life, and 2% to exposure to air pollution in later life.

The remaining risk factors are associated with 34% of all dementia cases [1]. The factors associated with the greatest proportion of dementia cases in the population are less education in early life, hearing loss in mid-life, and smoking in later life (7%, 8%, and 5%, respectively).

Led by 28 world-leading dementia experts, the report builds on the 9 risk factors identified in the 2017 Lancet Commission [2], and provides an up-to-date analysis of the best evidence on the prevention of dementia. The new report calls for nations and individuals to be ambitious about preventing dementia and lays out a set of policies and lifestyle changes to help prevent dementia.

Worldwide around 50 million people live with dementia, and this number is projected to increase to 152 million by 2050, rising particularly in low-income and middle-income countries (LMIC) where around two-thirds of people with dementia live. [3] Dementia affects individuals, their families, and the economy, with global costs estimated at about US$1 trillion annually. [3]

In certain countries, however, the proportion of older people with dementia has fallen, probably due to improvements in education, nutrition, health care, and lifestyle changes, demonstrating the possibility of reducing dementia through preventative measures.

"Our report shows that it is within the power of policy-makers and individuals to prevent and delay a significant proportion of dementia, with opportunities to make an impact at each stage of a person's life," says lead author Professor Gill Livingston, University College London, UK. "Interventions are likely to have the biggest impact on those who are disproportionately affected by dementia risk factors, like those in low- and middle-income countries and vulnerable populations, including Black, Asian and Minority Ethnic communities." [4]

Professor Livingston continues, "As societies, we need to think beyond promoting good health to prevent dementia, and begin tackling inequalities to improve the circumstances in which people live their lives. We can reduce risks by creating active and healthy environments for communities, where physical activity is the norm, better diet is accessible for all, and exposure to excessive alcohol is minimised." [4]

To address dementia risk, the authors call for 9 ambitious recommendations to be undertaken by policymakers and by individuals:

Aim to maintain systolic blood pressure of 130 mm Hg or less in midlife from around age 40 years.

Encourage use of hearing aids for hearing loss and reduce hearing loss by protecting ears from high noise levels.

Reduce exposure to air pollution and second-hand tobacco smoke.

Prevent head injury (particularly by targeting high risk occupations and transport)

Prevent alcohol misuse and limit drinking to less than 21 units per week.

Stop smoking uptake and support individuals to stop smoking (which the authors stress is beneficial at any age).

Provide all children with primary and secondary education.

Lead an active life into mid, and possibly later life.

Reduce obesity and diabetes.

These actions are especially important in LMICs where dementia rates are rising more rapidly than in high-income countries. This is a result of increasing life expectancy, and a higher frequency of certain dementia risk factors - such as lower rates of education; high rates of hypertension, obesity, and hearing loss, and rapidly growing rates of diabetes.

Based on their past model including 9 risk factors, the authors estimated that many more cases of dementia could be prevented in LMICs, compared to globally. While globally the 9 risk factors were estimated to contribute to 35% of all dementia cases, in China they might account for 40% of cases, 41% in India and 56% in Latin America.

The authors warn that estimates could be even higher, as they used conservative estimates for the prevalence of these risk factors in these populations, and because they do not account for the three new risk factors. The authors also note that nearly all the evidence for dementia is from studies in high-income countries, so risks might differ for LMICs and interventions might require modifying to best support different cultures and environments.

The authors note that the modelling for their prevention estimates globally and in LMICs assumes that there is a causal relationship between risk factors and dementia, but were careful to only include risk factors with strong evidence for a causal link.

Report co-author, Professor Adesola Ogunniyi, University of Ibadan, Nigeria, says: "In low- and middle-income countries, the higher prevalence of dementia risk factors means an even greater proportion of dementia is potentially preventable than in "higher-income countries". In this context, national policies addressing dementia risk factors, like primary and secondary education for all and stopping smoking policies, might have the potential for large reductions in dementia and should be prioritised. We also need more dementia research coming from low- and middle-income countries, so we can better understand the risks particular to these settings." [4]

In the final section of the report, the authors advocate for holistic and individualised evidence-based care that addresses physical and mental health, social care, and support that can accommodate complex needs. Keeping people with dementia physically healthy is important for their cognition but they often have other illnesses which they may struggle to manage on their own, resulting in potentially harmful preventable hospitalisations.

They note that people with dementia are particularly at risk from COVID-19 (due to age and having pre-existing illnesses, such as hypertension), and that physical-distancing measures can be challenging for dementia patients, who may find it difficult to adhere to the guidelines or distressing to be unable to have contact with carers and family. The authors call for people with unknown COVID-19 status to not be admitted to care homes to protect the existing residents, regular testing of staff and asymptomatic as well as symptomatic residents when there is exposure, not moving staff or residents between homes, and more research into how to protect dementia patients during the current pandemic and future public health emergencies.

Scientists at St. Jude Children's Research Hospital are studying how hearing loss can affect the neurocognitive abilities of childhood cancer survivors. Findings show that survivors with severe hearing loss are at a significant increased risk for neurocognitive deficits, independent of what type of therapy they receive. The work appears as an advance online publication today in JAMA Oncology.

"There has been a lot of research on how children who are born deaf can be affected academically and psychosocially, but far less for kids who acquire hearing loss at some point during their childhood," said corresponding author Johnnie Bass, Ph.D., of St. Jude Rehabilitation Services. "Our goal was to report on the prevalence, severity and risk of hearing loss in a large cohort of cancer survivors to assess the impact of hearing impairment on neurocognitive function."

The researchers evaluated 1,520 childhood cancer survivors and found that more than one-third had severe hearing loss. Those survivors with severe hearing loss were found to be at increased risk for neurocognitive deficits. This effect was independent of having been exposed to neurotoxic therapy, when compared to survivors with normal hearing or mild hearing loss.

This study is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures.

"Even patients not exposed to neurotoxic therapies who develop mild hearing deficits can have problems with their neurocognitive skills," said senior author Kevin Krull, Ph.D., of St. Jude Epidemiology and Cancer Control. "This makes it important to identify these patients early and suggest interventions to help improve their hearing and thus their neurocognitive outcomes."

Hearing aids are often recommended to assist with treatment-related hearing loss. The researchers found that of 330 survivors with severe hearing loss in the study for whom a hearing aid had been previously recommended, only 23% were consistently using the devices. Research in individuals who are born with hearing loss, as well as in the elderly with hearing loss, suggests that hearing aids can improve neurocognitive outcomes. More research is needed to determine if this is the case for childhood cancer survivors and to better understand barriers that prevent hearing aid use.

The work relied on hearing assessments gathered through the St. Jude Lifetime Cohort study (St. Jude LIFE). St. Jude LIFE brings long-term childhood cancer survivors back to the hospital for regular health screenings throughout their adult lives. Findings from the study help childhood cancer survivors learn more about their health needs, while providing novel insights into the late effects of childhood cancer treatment.

What The Article Says: Researchers review evidence on the risks of aerosolization and transmission of SARS-CoV-2 from patients to health care workers during endoscopy of the upper aerodigestive tract.

Authors: Josh K. Kay, M.D., of Tulane University in New Orleans, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaoto.2020.1973)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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What The Study Did: Age-related differences in nasopharyngeal SARS-CoV-2 levels in patients with mild to moderate COVID-19 were investigated in this observational study.

Authors: Taylor Heald-Sargent, M.D., Ph.D., of the Ann & Robert H. Lurie Children's Hospital in Chicago, is the corresponding author.

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(doi:10.1001/jamapediatrics.2020.3651)

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Melbourne researchers have revealed the multiple, intertwined cell death systems that prevent the spread of the 'intracellular' bacterium Salmonella, an important cause of typhoid fever which kills more than 100,000 people annually.

The team revealed that the spread of Salmonella is curtailed by the death of infected cells, but surprisingly cells can die in several distinct ways. Although Salmonella continuously seeks to outsmart infected cells by blocking their suicide, cells have evolved impressive 'back-up' strategies to ensure that the infected cell can still die and thus protect the body from Salmonella infection and consequent typhoid fever.

The research, published in the journal Immunity, was led by a collaborative team including Walter and Eliza Hall Institute researchers Dr Marcel Doerflinger, Ms Yexuan Deng, Dr Ranja Salvamoser, Associate Professor Marco Herold and Professor Andreas Strasser, and University of Melbourne Professor Sammy Bedoui and Dr Paul Whitney, researchers from the Peter Doherty Institute for Infection and Immunity (Doherty Institute).

**At a glance

- Some disease-causing bacteria, including Salmonella, can grow within cells - a tactic that helps them avoid the body's immune defences.

- Melbourne researchers have revealed that cells infected with Salmonella can die - helping to clear the infection - this death can occur in surprisingly different ways, a system that has evolved fail-safe backups.

- The research also revealed unexpected connections between different members of a family of cell death proteins called caspases in helping Salmonella-infected cells to die.

**Fighting the enemy within

Many disease-causing bacteria invade cells, surviving and reproducing within the cells and hiding from the body's immune system. Salmonella, a cause of serious food-borne infections, is one such 'intracellular' bacterium. Cells have developed a range of defences against intracellular bacteria, Professor Bedoui said.

"The rapid death of infected cells is an important protective strategy against intracellular bacteria. This stops the reproduction and spread of the bacteria, and can trigger protective immune defences at the site of the infection, which further control the infection," he said.

"Many proteins have been thought to be important for driving the death of bacteria-infected cells, which signal within cells and also degrade key components of the cell to bring about its death. However, there has been uncertainty about precisely how bacteria-infected cells die, the key molecules involved, and what this means for controlling an infection," Professor Bedoui said.

**Backup cell death pathways

The team used laboratory models lacking different combinations of cell death proteins to understand their contribution to the control of Salmonella infections, Associate Professor Herold said.

"We investigated the roles of proteins involved in three key types of cell death: apoptosis, pyroptosis and necroptosis," he said. "While these processes all result in cell death, each occurs differently at the molecular level, and has different consequences for triggering immunity and inflammation."

When only one of the three forms of cell death were disabled, there was only a minor impact on how effectively Salmonella infections were controlled - this showed that cells were not reliant on one specific system, Dr Doerflinger said.

"When we disabled two or all three forms of cell death, we saw that Salmonella infections were not controlled and the bacteria rapidly spread. This suggested that cells have developed several 'backups' to ensure cell death happens if there is a fault in one cell death pathway. While we only studied Salmonella, we speculate that our findings might be relevant to other intracellular pathogens such as the bacterium that causes tuberculosis," he said.

The team also revealed unexpected roles for cell death proteins called caspases, Professor Strasser said. "Until now, certain caspases including two known as 'caspase 1' and 'caspase 8' had very well-defined roles as early triggers of two distinct types of cell death. Our results showed that contrary to current perceptions these caspases can act within the 'other pathway' and even at later, critical stages of cell death when the cell is being dismantled.

"This is an example of another fail-safe process in the overall cell death machinery that ensures protection against pathogens like Salmonella," he said.

The flexibility in how cells can die can be explained by the ongoing battle between animals and disease-causing bacteria.

"Throughout evolution, both sides have developed new tactics in an 'arms race' for supremacy. Living and multiplying inside cells - rather than outside - helped the bacteria avoid immune detection, but animals responded by developing ways for infected cells to undergo altruistic suicide - which we have revealed is a highly coordinated but flexible system that has several fail-safe mechanisms," Professor Strasser said.

To determine immunity to Sars-Cov-2 and the effectiveness of potential vaccines, the amount of neutralising antibodies in the blood of recovered or vaccinated individuals must be determined. A traditional neutralisation test usually takes two to three days and must be carried out with infectious coronaviruses in a laboratory complying to biosafety level 3. A Swiss-German research team from Bern and Bochum has launched a test that takes only 18 hours and doesn't have high biosafety requirements. The researchers have published their report in the journal Vaccines on 15 July 2020.

The test was developed at the Institute of Virology and Immunology (IVI) of the University of Bern and the Swiss Federal Office for Food Safety and Animal Health, and evaluated in cooperation with colleagues from the Ruhr-Universität Bochum (RUB) using serum samples from Covid-19 patients.

Disguising a harmless virus as Sars-Cov-2

In order to detect antibodies against Sars-Cov-2, the researchers used another virus that doesn't propagate. They exchanged the envelope protein of this virus for the spike protein of the novel coronavirus, which mediates virus entry and infection. "As a result, the viruses can be identified by antibodies against Sars-Cov-2," explains lead author Toni-Luise Meister from the Department of Molecular and Medical Virology at Ruhr-Universität Bochum. "The antibodies bind to the viruses that have been altered in this way and neutralise them so that no longer can penetrate the host cells."

Luminescence helps determine immunity

Since the virus pseudotyped in this way can't propagate in host cells, no elaborate biosafety precautions are necessary for the test. In order to determine the amount of antibodies, the researchers genetically modified the virus so that green fluorescent protein and a luciferase, an enzyme from fireflies, will be produced by infected cells. "After a single round of infection, we can then determine how many cells show green fluorescence," says lead author Ferdinand Zettl from the Institute of Virology and Immunology in Bern. The green fluorescence is an indicator of infection with the pseudotyped virus. The less green cells the researchers are finding, the more neutralizing antibodies are present which blocked the virus. In addition, a luminometer may be used to read the luminescence signal produced by the luciferase enzyme - another way of evaluating the test.

Quick and reliable

In order to check the reliability and comparability with the conventional neutralisation test, the researchers applied it to blood samples from Covid-19 patients. "The direct comparison showed a good correlation between the two test systems," explains corresponding author Professor Stephanie Pfänder from the Department of Molecular and Medical Virology at RUB. Compared to 56 hours for the conventional test, the new test is much faster, with only 18 hours to the test result. "Another great advantage is that it can be carried out in almost all medical labs, because no sophisticated safety precautions are necessary," points out Dr. Gert Zimmer from the Institute of Virology and Immunology in Bern, corresponding author of the study.

Sitting back and watching your toddler explore their world is good for parent mental health, a new study has found.

As part of her PhD at Edith Cowan University in Western Australia, Mandy Richardson conducted the world's first data-driven study of parenting classes based on the Respectful Approach intervention.

The Respectful Approach, modelled on Resources for Infant Educators (RIE)TM, guides parents to treat young children as capable and independent humans who can flourish if given safe space and freedom from too much adult direction.

Parents were invited to take part in a class for infants or toddlers over six weeks where they observed their children in uninterrupted play in a room with age appropriate toys.

The infants and toddlers were free to investigate their environment and interact with other children while parents sat in the room and watched with a facilitator. After an observation period, each class introduced and discussed a topic related to the Respectful Approach.

At the end of the program, parents reported significantly lower stress levels, with more confidence and a better understanding of their children's capabilities.

Children make progress when given space and time

Ms Richardson said the Respectful Approach is ultimately about building a trusting, lasting bond with positive communication between parents and children. There is less focus on checklists and achieving milestones, with acknowledgement that each child is different.

"Participants in the study reported worrying less about performance pressure after attending the classes, which let them refocus on their relationship with their children," she said.

"As parents we tend to go and 'save' our children when they start to struggle with something, instead of letting them try to resolve their own challenges. But if the children aren't looking for help, perhaps they can be left to do their own thing and work it out themselves."

Ms Richardson explained the Respectful Approach helps to establish good patterns in early years so children learn to build confidence in their abilities and to deal with conflict in emotionally intelligent ways.

"Traditionally early behavioural interventions have predominantly focused on modifying undesirable child behaviours," Ms Richardson said.

"By building good communication and a close parent-child bond, we can potentially prevent problems occurring in the long term."

Ms Richardson and her research supervisor Associate Professor Therese O'Sullivan are now expanding the pilot study to track parents and children over three years to determine whether the decline in parental stress levels has a lasting impact and investigate long term outcomes in child development.