Culture

Darwin's theory of evolution should be expanded to include consideration of a DNA stability "energy code" - so-called "molecular Darwinism" - to further account for the long-term survival of species' characteristics on Earth, according to Rutgers scientists.

The iconic genetic code can be viewed as an "energy code" that evolved by following the laws of thermodynamics (flow of energy), causing its evolution to culminate in a nearly singular code for all living species, according to the Rutgers co-authored study in the journal Quarterly Reviews of Biophysics.

"These revelations matter because they provide entirely new ways of analyzing the human genome and the genome of any living species, the blueprints of life," said senior author Kenneth J. Breslauer, Linus C. Pauling Distinguished University Professor in the Department of Chemistry and Chemical Biology in the School of Arts and Sciences at Rutgers University-New Brunswick. He is also affiliated with the Rutgers Cancer Institute of New Jersey. "The origins of the evolution of the DNA genetic code and the evolution of all living species are embedded in the different energy profiles of their molecular DNA blueprints. Under the influence of the laws of thermodynamics, this energy code evolved, out of an astronomical number of alternative possibilities, into a nearly singular code across all living species."

Scientists investigated this so-called "universal enigma," probing the origins of the astounding observation that the genetic code evolved into a nearly uniform blueprint that arose from trillions of possibilities.

The scientists expanded the underpinnings of the landmark "survival of the fittest" Darwinian evolutionary theory to include "molecular Darwinism." Darwin's revolutionary theory is based on the generational persistence of a species' physical features that allow it to survive in a given environment through "natural selection." Molecular Darwinism refers to physical characteristics that persist through generations because the regions of the molecular DNA that code for those traits are unusually stable.

Different DNA regions can exhibit differential energy signatures that may favor physical structures in organisms that enable specific biological functions, Breslauer said.

Next steps include recasting and mapping the human genome chemical sequence into an "energy genome," so DNA regions with different energy stabilities can be correlated with physical structures and biological functions. That would enable better selection of DNA targets for molecular-based therapeutics.

Population-wide screening for genetic variants linked to hereditary breast and ovarian cancer may be cost effective in women between the ages of 20 and 35, according to a study published in JAMA Network Open.

However, screening for older women was not cost-effective, the researchers found, since the majority of risk-reducing mastectomies and salpingo-oophorectomies occur before age 50 and the majority of hereditary breast and ovarian cancers occur after 50. Older women who learn they are at risk have a smaller window of time to take action.

The study is a product of the RISE (Rational Integration of clinical SEquencing) consortium, which seeks to estimate the long-term clinical and economic value of genetic screening scenarios. Consortium members include Vanderbilt University Medical Center, the University of Washington in Seattle and Geisinger Health.

Josh Peterson, MD, MPH, professor of Medicine and Biomedical Informatics, is one of four Vanderbilt co-authors of the study and a principal investigator for RISE, which is supported with funding from the National Human Genome Research Institute.

"Screening for genetic conditions and risks has become common for the perinatal period, but whether to do so for adults is still debated. This study adds to the growing literature that testing for common genetic risks, such as hereditary breast and ovarian cancer, early in adult life is beneficial to patients and cost-effective from a societal perspective," Peterson said.

David Veenstra, PharmD, PhD, professor of Pharmacy at the University of Washington, a principal investigator for RISE and associate director of Comparative Health Outcomes, Policy and Economics (CHOICE), is the corresponding author for the study, and Gregory Guzauskas, MSPH, PhD, a senior research scientist with CHOICE, is the first author.

The researchers developed a decision-analytic model to compare population screening for hereditary breast and ovarian cancer in an unselected population of previously undiagnosed women versus no screening. They then modeled clinical events in the decision tree. The risk variants included BRCA1, BRCA2, ATM, CHEK2, MSH6, PALB2, RAD51C AND TP53. Estimates were based on extrapolated data from the Geisinger MyCode Community Health Initiative and other published sources.

The results indicated that population screening of 30-year-old women resulted in 75 fewer cancer cases per 100,000 women. With 45-year-old women, the benefit decreased sharply with only 24 fewer cancer cases per 100,000 women. The researchers also analyzed quality-adjusted-life-years (QALYs) with the two scenarios and found that 288 QALYs were gained for women age 30 compared to 97 QALYs for women age 45.

The researchers also sought to determine if "cascade" benefits occurred when women identified at risk shared the information with relatives. They did not find that cascade screening fundamentally impacted clinical and economical values. Although 70% of carriers informed family members, only 20% of those relatives were assumed to undergo testing, which reflects the low rates of cascade testing uptake in practice. The researchers did, however, recommend that cascade testing be implemented where feasible.

The researchers noted that additional research is warranted on the potential impact on women who test negative for genetic risk variants to determine if these noncarriers follow through with recommended screenings for all women. They also noted that a limitation of their study is that it did not evaluate the impacts of patient diversity and disparity and said that "underserved populations such as African Americans represent an important follow-up opportunity."

Genomic screening for hereditary breast and ovarian cancer is a matter of ongoing debate and analysis. Although the U.S. Centers for Disease Control and Prevention lists this genetic syndrome as a Tier 1 genomic application with "significant potential for positive impact on public health," the U.S. Preventive Services Task Force guidelines for BRCA1/2 testing recommend against routine risk assessment for women without personal or family medical histories that suggest a genetic carrier status.

November 16, 2020 - The Center for Justice Research (CJR) at Texas Southern University supports innovative, data-driven solutions for the creation of an equitable criminal justice system. CJR is the premier criminal justice research center located on the campus of a historically Black college or university. Our researchers offer an important voice at this crucial time. A Police Reform Action Brief released today focuses on the chokehold crisis. This is the first in a series of action briefs on police reform that will assist in the reimagination of policing.

Key Observation: National standards are necessary to ensure protection against excessive use of force, including chokeholds. However, states and local jurisdictions cannot wait on Congress to implement reforms that protect their citizens and hold police accountable. Police reform will require support at all levels of government.

The first in the series, Reimagination of Policing Action Brief: Banning Chokeholds, highlights the extensive history of police officer use of chokeholds and similar tactics that often result in unconsciousness, and even death. The May 25, 2020 death of George Floyd under the knee of a Minneapolis police officer has shaken the nation's conscience. Americans are demanding change. The brief's authors, the Center for Justice Research at Texas Southern University, provides support for a zero-tolerance approach to police chokeholds. A chokehold ban will help move this country further toward the elimination of racially-motivated police violence and the longstanding tensions/distrust between minority communities and the police.

George Floyd's murder was egregious but not unique. Many police agencies hold the position that they don't train officers to use chokeholds, but they are continuously used by officers to regain compliance. In fact, when a New York City police officer applied a chokehold that ultimately killed Eric Garner in 2014, they had already been banned some 21 years earlier. In Minneapolis, it is estimated that between 2015 and 2020, some form of a neck restraint was administered 237 times by police officers, with almost 20% of them resulting in unconsciousness.

The Justice Act, put forth by Senator Tim Scott, seeks to discourage chokeholds by way of withholding federal funds to those departments that continue their use or refuse to provide accurate data on their department's use. The George Floyd Justice in Policing Act, passed by the U.S. House, sets federal standards that prohibit the use of deadly force --including chokeholds -- by federal officers except as a last resort to prevent imminent and serious bodily injury following de-escalation techniques. If passed, officers who use chokeholds will be subject to prosecution under federal statute.

The brief concludes with comprehensive recommendations for key stakeholders, at all levels, to consider in the advancement of police reform in their respective jurisdictions.

Find out more here: Reimagination of Policing Action Brief: Banning Chokeholds

Director Dr. Howard Henderson and other criminal justice reform experts at Texas Southern University's Center for Justice Research are available to discuss how they can advise on evidence-supported, police reform policies and practices on the local, state and national levels - concrete steps that law enforcement can take to bridge the racial divide. They can be reached at justice.research@tsu.edu or 713-313-6843.

COLUMBUS, Ohio - After a major corporate fraud case hits a city, financially motivated neighborhood crimes like robbery and theft increase in the area, a new study suggests.

Researchers from The Ohio State University and Indiana University found that the revelation of corporate accounting misconduct is linked to about a 2.3 percent increase in local financially motivated crimes in the following year.

Corporate fraud had the strongest effect on local crimes in smaller cities with fewer job opportunities and higher income inequality.

The researchers confirmed the finding using several different methods and showed the link applied only to financial crimes and not violent offenses like murder or rape.

"Our results suggest that big corporate fraud scandals can have community implications well beyond the firm itself," said Eric Holzman, co-author of the study and assistant professor of accounting at Ohio State's Fisher College of Business.

"The effect is strongest in smaller cities where the economic impact of the fraud is most severe."

Holzman conducted the study with Brian Miller and Brian Williams at Indiana University. It was published yesterday (Nov. 14, 2020) in the journal Contemporary Accounting Research.

The researchers analyzed FBI data on 255 cases of corporate accounting misconduct between 1996 and 2013. They then examined crime rates in the cities where the firms were headquartered.

The 2.3 percent increase in financially motivated crimes was found even after accounting for a variety of other factors, including local unemployment rates at the time of the fraud, poverty rates, and crime rates before the accounting fraud was revealed. The link between the accounting fraud and local crime lasted about three years before it faded.

The findings were strongest when the fraud was associated with a larger drop in the company's stock price and when it received more media attention.

Several of the results suggest crime increased the most in cities where the fraud had the biggest economic impact on the community.

For example, larger impacts occurred when the corporation had to lay off a higher number of employees, when it occurred in smaller cities with fewer job opportunities, and where there were larger income gaps between the rich and poor.

These results didn't surprise Holzman, who spent nine years as a forensic accountant in Washington, D.C., investigating corporate fraud cases.

"I would go to some of these smaller towns and you could see the economic devastation that happened when the big local employer got involved in accounting misconduct and had to close or lay off a lot of employees," he said.

The researchers did several other analyses to confirm their findings. In one, they matched 88 of the cities where fraud occurred to similar cities where there was no corporate malfeasance. They found no similar increases in financially motivated crimes in the cities that had not experienced fraud.

In another analysis, they looked at what would happen if they imagined corporate fraud scandals happening at random times in random cities. Would they still find many cities experiencing increases in financially related crimes the following year?

After running this scenario 10,000 times, they found increases in crime similar to their real findings only 1.7 percent of the time - suggesting their results were unlikely to be random chance.

While the findings are intriguing, Holzman cautioned against drawing too firm a conclusion about why this is happening.

"It doesn't necessarily mean that people who lose their jobs are turning to a life of crime, or that they see this fraud and think it is now OK to steal. It may be something else, like an increase in teen delinquency due to added stress at home linked to the adverse economic conditions brought by the fraud," he said.

"We found a strong association in our study using multiple research designs, but we need different kinds of studies to determine a causal mechanism."

Theories on how the Milky Way formed are set to be rewritten following discoveries about the behaviour of some of its oldest stars.

An investigation into the orbits of the Galaxy's metal-poor stars - assumed to be among the most ancient in existence - has found that some of them travel in previously unpredicted patterns.

"Metal-poor stars - containing less than one-thousandth the amount of iron found in the Sun - are some of the rarest objects in the galaxy," said Professor Gary Da Costa from Australia's ARC Centre of Excellence in All Sky Astrophysics in 3 Dimensions (ASTRO 3D) and the Australian National University.

"We've studied 475 of them and found that about 11 per cent orbit in the almost flat plane that is the Milky Way's disc.

"They follow an almost circular path - very much like the Sun. That was unexpected, so astronomers are going to have to rethink some of our basic ideas."

Previous studies had shown that metal-poor stars were almost exclusively confined to the Galaxy's halo and bulge, but this study revealed a significant number orbiting the disk itself.

The Sun also orbits within the disk, which is why it manifests as the comparatively thin, ribbon-like structure easily visible from Earth in the night sky. In effect, we are seeing it edge-on.

"In the last year our view of the Milky Way has dramatically changed," said lead author Giacomo Cordoni from the University of Padova in Italy, who performed the bulk of the study while on a recent study placement at the ANU, funded by the European Research Council's GALFOR Project.

"This discovery is not consistent with the previous Galaxy formation scenario and adds a new piece to the puzzle that is the Milky Way. Their orbits are very much like that of the Sun, even though they contain just a tiny fraction of its iron. Understanding why they move in the way that they do will likely prompt a significant reassessment of how the Milky Way developed over many billions of years."

The ancient stars were identified using three very high-tech pieces of kit: ANU's SkyMapper and 2.3-metre telescopes, and the European Space Agency's Gaia satellite.

The low metal content was identified by the telescopes, and the satellite was then used to determine their orbits.

The results - crunched by researchers from Australia, Italy, Sweden, the United States and Germany - found that the orbits of ancient stars fell into a number of different patterns, all but one of which matched previous predictions and observations.

As expected, many of the stars had largely spherical orbits, clustering around the Galaxy's "stellar halo" - a structure thought to be at least 10 billion years old.

Others had uneven and "wobbly" paths assumed to be the result of two cataclysmic collisions with smaller galaxies that occurred in the distant past - creating structures known as the Gaia Sausage and the Gaia Sequoia.

Some stars were orbiting retrograde - effectively going the wrong way around the Galaxy - and a few, about five per cent, appeared to be in the process of leaving the Milky Way altogether.

And then there were the remaining 50 or so, with orbits that aligned with the Galaxy's disk.

"I think this work is full of important and new results, but if I had to choose one that would be the discovery of this population of extremely metal-poor disk stars," said Cordoni.

"Future scenarios for the formation of our Galaxy will have to account for this finding - which will change our ideas quite dramatically."

Cordoni's team included scientists from Italy's Centre of Studies and Activities for Space, the Max Planck Institutes for Astrophysics and Astronomy in Germany, the Massachusetts Institute of Technology in the US, Sweden's Uppsala and Stockholm universities, and Australia's Monash University, University of New South Wales and ANU.

The team included Australia's Brian Schmidt, winner of the 2011 Nobel Prize in Physics.

An advance version of the study is now available in the Monthly Notices of the Royal Astronomical Society.

ROCHESTER, Minn. -- In a retrospective case study, Mayo Clinic researchers have found that antibiotics administered to children younger than 2 are associated with several ongoing illnesses or conditions, ranging from allergies to obesity. The findings appear in Mayo Clinic Proceedings.

Using health record data from the Rochester Epidemiology Project, a population-based research collaboration in Minnesota and Wisconsin, researchers analyzed data from over 14,500 children. About 70% of the children had received at least one treatment with antibiotics for illness before age 2. Children receiving multiple antibiotic treatments were more likely to have multiple illnesses or conditions later in childhood.

Types and frequency of illness varied depending on age, type of medication, dose and number of doses. There also were some differences between boys and girls. Conditions associated with early use of antibiotics included asthma, allergic rhinitis, weight issues and obesity, food allergies, attention deficit hyperactivity disorder, celiac disease, and atopic dermatitis. The authors speculate that even though antibiotics may only transiently affect the microbiome, the collection of microbes in the body, this may have long-term health consequences.

"We want to emphasize that this study shows association ? not causation ? of these conditions," says Nathan LeBrasseur, Ph.D., a researcher at Mayo Clinic's Robert and Arlene Kogod Center on Aging and the study's senior author. "These findings offer the opportunity to target future research to determine more reliable and safer approaches to timing, dosing and types of antibiotics for children in this age group."

While recent data show an increase in some of the childhood conditions involved in the study, experts are not sure why. Other than the issue of multidrug resistance, antibiotics have been presumed safe by most pediatricians.

Researchers also say the ultimate goal is to provide practical guidelines for physicians on the safest way to use antibiotics early in life.

A team of researchers at the Medical University of South Carolina (MUSC) has found that the molecule lysyl oxidase (LOX) plays a number of important roles in promoting skin and organ fibrosis in scleroderma, a connective tissue disorder. The researchers have also shown that LOX can be useful in assessing how well an antifibrotic treatment works, suggesting that it may have potential as a biomarker of fibrosis progression or regression.

The team was led by noted fibrosis researcher Carol Feghali-Bostwick, Ph.D., the SmartState and Kitty Trask Holt Endowed Chair for Scleroderma and professor in the Department of Medicine at MUSC, and graduate student Xinh Xinh Nguyen. They report their findings in an article published online ahead of print in the American Journal of Physiology Lung Cellular and Molecular Physiology.

Scleroderma is a connective tissue disease that causes fibrosis, or thickening, of organs such as the lungs, kidneys and heart, along with the skin. In fibrosis, excess connective tissue progressively accumulates around the cells in organs, causing them to lose function and eventually fail. Historically, the only treatment available to these patients has been lung transplantation, which is very invasive and does not stop fibrosis from progressing in other organs. Recently, the Food and Drug Administration approved two new drugs for lung fibrosis, but their usefulness is limited in patients with scleroderma.

"These drugs merely slow the progression of the disease," said Feghali-Bostwick. "They don't stop it. They don't reverse it. New drug targets are urgently needed."

In the study, Feghali-Bostwick and Nguyen assessed whether LOX might be such a target. They were able to show that LOX plays multiple roles, known as "moonlighting," in the development and progression of fibrosis in scleroderma. They did so using a preclinical model of lung fibrosis, cells derived from lung and skin tissue samples of patients with scleroderma, and human lung and skin tissue cores. These cores more realistically mimic the physiologic conditions of living human tissue than just growing cells in a petri dish.

Their findings are important because previous research had only shown that LOX increases fibrosis by crosslinking connective tissue. The MUSC team demonstrated that LOX plays additional roles in the progression of fibrosis by stimulating excess production of connective tissue and increasing interleukin 6 (IL-6), an inflammatory molecule.

The research team showed that LOX expression increased 2.8-fold at 10 days following the initiation of lung fibrosis in the preclinical model. The research team also showed that LOX levels and activity were diminished in the lung fibrosis model, almost to baseline levels observed in the control, after administration of an antifibrotic peptide (E4) that is soon to enter a phase 1 clinical trial. These findings suggest that measuring LOX activity in the blood could be a promising biomarker for monitoring treatment response in patients with scleroderma and other fibrotic diseases.

"LOX has a direct role in fibrosis, and measuring circulating LOX levels is useful in monitoring the response to antifibrotic therapies," said Nguyen, who is a TL1 translational research trainee. The TL1 translational research training program, of which Feghali-Bostwick is the associate director, is funded by the South Carolina Clinical & Translational Research Institute.

Feghali-Bostwick reiterated how important such a biomarker of fibrosis would be.

"It's exciting that LOX is a biomarker that goes up when we induce lung fibrosis in the mice and goes down when we improve the fibrosis," she said. "Having a good biomarker of fibrosis would be invaluable because it would allow us to monitor the response to therapy in patients."

The MUSC team is currently investigating how the E4 peptide reduces fibrosis, not just in the skin and lungs but in other organs as well. Fibrosis is the end-stage of many fibroproliferative diseases that result in organ damage. These include cirrhosis, macular degeneration and cardiovascular disease. If the E4 peptide proves effective at reducing fibrosis in organs beyond the lungs and the skin, it could have potential as an antifibrotic therapy in those patients as well.

This research project was launched by Tetsuya Nishimoto, Ph.D., a postdoctoral fellow in the Feghali-Bostwick laboratory who, in 2016, passed away unexpectedly. Thanks to Nguyen's efforts, the Feghali-Bostwick laboratory was able to see his project to the end.

A metabolic engineering research group at KAIST has developed an engineered Corynebacterium glutamicum strain capable of producing high-level glutaric acid without byproducts from glucose. This new strategy will be useful for developing engineered microorganisms for the bio-based production of value-added chemicals.

Glutaric acid, also known as pentanedioic acid, is a carboxylic acid that is widely used for various applications including the production of polyesters, polyamides, polyurethanes, glutaric anhydride, 1,5-pentanediol, and 5-hydroxyvaleric acid. Glutaric acid has been produced using various petroleum-based chemical methods, relying on non-renewable and toxic starting materials. Thus, various approaches have been taken to biologically produce glutaric acid from renewable resources. Previously, the development of the first glutaric acid producing Escherichia coli by introducing Pseudomonas putida genes was reported by a research group from KAIST, but the titer was low. Glutaric acid production by metabolically engineered Corynebacterium glutamicum has also been reported in several studies, but further improvements in glutaric acid production seemed possible since C. glutamicum has the capability of producing more than 130 g/L of L-lysine.

A research group comprised of Taehee Han, Gi Bae Kim, and Distinguished Professor Sang Yup Lee of the Department of Chemical and Biomolecular Engineering addressed this issue. Their research paper "Glutaric acid production by systems metabolic engineering of an L-lysine-overproducing Corynebacterium glutamicum" was published online in PNAS on November 16, 2020.

This research reports the development of a metabolically engineered C. glutamicum strain capable of efficiently producing glutaric acid, starting from an L-lysine overproducer. The following novel strategies and approaches to achieve high-level glutaric acid production were employed. First, metabolic pathways in C. glutamicum were reconstituted for glutaric acid production by introducing P. putida genes. Then, multi-omics analyses including genome, transcriptome, and fluxome were conducted to understand the phenotype of the L-lysine overproducer strain. In addition to systematic understanding of the host strain, gene manipulation targets were predicted by omics analyses and applied for engineering C. glutamicum, which resulted in the development of an engineered strain capable of efficiently producing glutaric acid. Furthermore, the new glutaric acid exporter was discovered for the first time, which was used to further increase glutaric acid production through enhancing product excretion. Last but not least, culture conditions were optimized for high-level glutaric acid production. As a result, the final engineered strain was able to produce 105.3 g/L glutaric acid, the highest titer ever reported, in 69 hours by fed-batch fermentation.

Professor Sang Yup Lee said, "It is meaningful that we were able to develop a highly efficient glutaric acid producer capable of producing glutaric acid at the world's highest titer without any byproducts from renewable carbon sources. This will further accelerate the bio-based production of valuable chemicals in pharmaceutical/medical/chemical industries."

Significantly higher numbers of Generation Z boys and girls in the UK are dieting to lose weight, and are likely to overestimate their own weight, finds a new UCL-led study.

The research, published in JAMA Pediatrics, found that girls who are trying to lose weight are also more likely to experience depressive symptoms than in previous years.

In 2015, 42% of 14-year-old girls and boys said they currently were trying to lose weight, compared to 30% in 2005.

Lead author Dr Francesca Solmi (UCL Psychiatry) said: "Our findings show how the way we talk about weight, health and appearance can have profound impacts on young people's mental health, and efforts to tackle rising obesity rates may have unintended consequences.

"An increase in dieting among young people is concerning because experimental studies have found that dieting is generally ineffective in the long term at reducing body weight in adolescents, but can instead have greater impacts on mental health. We know, for instance, that dieting is a strong risk factor in the development of eating disorders."

The research team reviewed data from 22,503 adolescents in the UK, in three different decades, who are part of different cohort studies: the British Cohort Study (of people born in 1970; data was collected in 1986), the Children of the 90s study (born 1991-92, data collected in 2005), and Millennium Cohort Study (born 2000-02, data collected in 2015).

The adolescents were all asked questions about whether they were, or had been, trying to lose weight, whether they had dieted or exercised to lose weight, whether they perceived themselves to be underweight, about the right weight or overweight (which was compared to their actual height and weight measurements), and they filled out questionnaires that gauged depressive symptoms.
The researchers found that in 2015, 44% and 60% of all participants had dieted or exercised to lose weight, respectively, compared to 38% and 7% in 1986.

The researchers say other evidence suggests that engagement in vigorous physical activity has remained relatively stable among adolescents over the past few decades.

Senior author Dr Praveetha Patalay (Centre for Longitudinal Studies and MRC Unit for Lifelong Health & Ageing, UCL) said: "It seems that young people are exercising for different reasons than they did before - more adolescents seem to be thinking of exercise predominantly as a means to lose weight rather than exercising for fun, socialising and feeling healthy. We suspect that recent controversial calls to add 'exercise-equivalent' labels on food packaging may exacerbate this."

While girls have consistently been more likely to diet to lose weight, the researchers found a greater increase over the years among boys, who were also becoming more likely to be trying to gain weight.

Dr Patalay said: "Societal pressures for girls to be thin have been around for decades, but body image pressures on boys may be a more recent trend. Our findings underscore the impact that societal pressures and public health messaging around weight can have on children's health behaviours, body image and mental health."

Both girls and boys also became more likely to over-estimate their weight from 1986 to 2005, and even more so by 2015, which the researchers say adds to their concerns that increased efforts to lose weight are not necessarily due to increased obesity rates.

The reported weight-related behaviours and weight misperception were associated with depressive symptoms, and among girls, this relationship was becoming even stronger over the three decades examined in this study. The findings could possibly be part of the explanation for increases in adolescent depressive symptoms that have been observed in recent decades.

Dr Solmi said: "Media portrayals of thinness, the rise of the fitness industry and the advent of social media may all partly explain our results, and public health messaging around calorie restriction and exercise might also be causing unintended harm.

"Public health campaigns around obesity should consider adverse mental health effects, and ensure they avoid weight stigma. By promoting health and wellbeing, as opposed to focusing on 'healthy weight', they could have positive effects on both mental and physical health."

New York, NY (Nov. 16, 2020)--A vaccine created to prevent the recurrence of the deadly skin cancer melanoma is about twice as effective when patients also receive two components that boost the number and effectiveness of immune system cells called dendritic cells, according to phase 2 clinical trial results published in Nature Cancer in November.

These results are important because most cancer vaccine trials have failed to show clinical efficacy. These results show that adding two immune-boosting components can boost the immune response for not only melanoma patients but possibly also others whose cancers express a protein called the vaccine antigen, which is common in some cancers.

Researchers at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, working with colleagues at the National Cancer Institute-funded Cancer Immunotherapy Trials Network (CITN) based at the Fred Hutchinson Cancer Research Center, found that adding the small molecule Flt3L, which increases the number of dendritic cells, boosted the vaccine's effectiveness at producing antibodies and T cells that can later fight melanoma. Adding a second component, called poly-ICLC, also strengthened the dendritic cells' ability to promote antibodies as well as helper and killer T cells.

Sixty patients who had stage 2 or 3 melanoma, and whose cancer was successfully removed via surgery, received the vaccine. Half of the patients received the vaccine alone while the other half received the vaccine with Flt3L and poly-ICLC.

The vaccine is designed to target dendritic cells and is composed of an antigen found in melanoma bound to an antibody to increase the chances of binding with dendritic cells.

The cocktail of the vaccine, Flt3L, and poly-ICLC nearly doubled the vaccine's efficacy, according to analysis of the T cells detected in patients' blood samples after they received four doses over four months. That immune response was seen significantly earlier in the patients who received the cocktail and at much higher levels in many more patients compared to those who received only the vaccine. Researchers found antibodies were still present in blood samples tested 12 weeks after the last dose.

"This is the first randomized clinical trial to show that an immune response to a cancer vaccine can be potentiated by the addition of Flt3L," says Nina Bhardwaj, MD, PhD, Director of the Immunotherapy Program at The Tisch Cancer Institute, and first author and a corresponding author on the study. "The response was achieved because Flt3L mobilized dendritic cells, which are the gold standard in promoting cancer immunity, and improved the overall immunogenicity of the vaccine. This may change the approach of increasing efficacy in other cancer vaccines in the future."

"These positive results are significant not only for improving cancer vaccines, but also potentially for application to other vaccine platforms," reported the study's co-corresponding and senior author Steven Fling, PhD, Director of the CITN Laboratory and Senior Staff Scientist in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, "and we are extremely grateful and indebted to the patients whose unwavering participation made this demanding clinical protocol a success."

These findings also provide a basis for adding immunotherapies called checkpoint inhibitors, which have been successful in treating metastatic melanoma, to vaccines in order to further increase the success in fending off melanoma recurrence. Researchers also plan to follow trial participants over time and measure how many have cancer recurrence to further study the vaccine's efficacy in each group.

"Immunotherapy has already shown great promise for patients with metastatic melanoma who would normally have a difficult, sometimes grave, prognosis," said Philip Friedlander, MD, PhD, Director of the Melanoma Medical Oncology Program at The Tisch Cancer Institute at Mount Sinai and site investigator of the trial. "It's important to work toward developing effective cancer vaccines that can prevent cancer on their own or in addition to the drugs already available."

The current U.S. marketplace for sex robots is geared to fulfilling the needs of young, white, able-bodied, heterosexual males - a population perhaps least in need of such assistance - and simultaneously overlooks a vast demographic of potential customers: senior citizens.

A paper published today in the Journal of Medical Ethics calls out the opportunity among socially isolated, lonely people age 65 and over in aging societies, especially America. Many of them would value a robot's companionship and, yes, even its ability to provide sexual gratification, wrote the author, Nancy Jecker. She is a professor of bioethics and humanities at the University of Washington School of Medicine in Seattle.

"We apply ageist attitudes and negative stereotypes to older adults. We assume they're too old to indulge in sex and think that older adults having interest in sex is weird or dirty," Jecker said. "We have similar attitudes toward people with disabilities, where most research has focused on protecting them from able-bodied sexual predators instead of considering their sexual needs and desires as human beings."

For decades Jecker has studied the aging of individuals and populations, as well as justice and other human traits and ideas. Robotics entered the picture, she said, when she recognized the declining ranks of workers to help care-dependent older adults, many of whom are physically disabled.

"Designing and marketing sex robots for older, disabled people would represent a sea change from current practice. The reason to do it is to support human dignity and to take seriously the claims of those whose sexuality is diminished by disability or isolation. Society needs to make reasonable efforts to help them," Jecker said.

Western cultures tend to see sex narrowly as an expression of lust, and assume that people over 65, who suffer more chronic disease and disability, lose desire for physical affection, she said. This is evident in the scads of inventions aimed at seniors, which focus on monitoring health and easing physical burdens while ignoring social and emotional fulfillment.

Sexual function, Jecker's paper argues, is an essential human value - linked to capacities for bodily integrity, affiliation, and emotions. A sexual identity can provide a basis for self-respect, not merely physical satisfaction.

But it's not all about sex, either.

"There's a whole spectrum of human desires. It's limiting to think only of sex bots or only of friend bots. Some older people want a companion that can provide both social interaction and physical affection," Jecker said.

Among people 60 and older in the United States, 43% report feeling lonely - largely a function of social isolation, according to research published in February 2020 by the National Academies of Sciences, Engineering, and Medicine. Published in book form, the paper described how people 50 and older increasingly live alone, in many wealthy, developed societies. It summarized evidence of the detrimental health effects of loneliness and called on healthcare professionals to try to alleviate the situation.

U.S. and other Western roboticists could take a cue from counterparts in Japan, Jecker said. There, Shinto beliefs hold that spirits (kami) embody both animate and inanimate things, allowing more receptiveness to the idea of robot companions.

"They are much more open to the possibility of pet robots and friend robots. They've been at the forefront of not just the technology but the humanities questions of 'How should we design these robots? What sort of social relationships would you want to have with them?' They don't share the Western roboticists' worry that robots are mechanical empty things that we can't relate to."

Jecker challenges robot designers to "think in terms of robots' capability rather than their utility - not focusing only on the sexual pleasure that a robot gives to an older, disabled adult, but focusing on what the robot enables the person to do and be."

California's Black and Hispanic communities may be falling further behind whites in the quality of care they receive for heart attacks, despite recent medical efforts aimed at improving the standards of care for these populations, according to a new study led by researchers at UC San Francisco.

In response to ongoing health disparities, emergency management services nationwide have implemented protocols to better coordinate care and get patients directly to hospitals that are equipped and staffed to quickly unblock coronary arteries and restore blood circulation to the heart.

Under the new guidelines, which were encouraged by the American Heart Association, California now is organized to deliver treatment to severe heart attack patients through 33 regional emergency response systems for the state's 58 counties. However, the study has found that patients living in minority communities received less benefit from these protocols than patients in non-minority communities.

"Regionalization was an attempt to equalize access to the gold standard of care for severe heart attack patients, but our research shows that inequalities have been exacerbated, not alleviated," said Renee Hsia, MD, MSc, professor in the Department of Emergency Medicine at UCSF and lead author of the study, which was published November 16, 2020, in JAMA Network Open.

The standard of care for a heart attack with complete coronary artery blockage is angioplasty, or "percutaneous coronary intervention" (PCI). A long thin tube called a catheter is threaded through an artery leading from the groin toward the heart, guiding instrumentation used to re-open the artery.

Studies have shown that faster reopening of the artery, especially if it occurs within 90 minutes of seeking care for a heart attack, offers better survival odds, but not every hospital is equipped with a cardiac catheterization lab and staffed at all hours with interventional cardiologists and other trained personnel.

Aside from the established link between speed and survival, previous studies of the regionalized system have failed to detect a mortality benefit at the population level, Hsia said. By further breaking down their analysis by minority and non-minority zip codes and using California vital statistics data, Hsia and colleagues found that one group did have greater survival after regionalization -- whites living in non-minority communities. There were no mortality benefits for whites living in minority communities, or for Blacks or Hispanics in either non-minority or minority communities.

With regionalization, access to PCI-capable hospitals improved 6.3 percent for all patients in non-minority communities, but only 4.5 percent for patients in minority communities, the study found. Same-day PCI increased by 5.1 percent for patients in non-minority communities, but only by 1.7 percent for individuals in minority communities; receipt of PCI any time during hospitalization increased by 5.0 percent for patients in non-minority communities, but only by 0.7 percent for those in minority communities.

The JAMA Network Open study compared changes over time in outcomes during the study period beginning in 2006, when only eight California counties were regionalized for heart attack care, to 2015, when all counties were participating. The researchers analyzed data from139,494 patients who suffered the most severe type of heart attack, as determined by a distinctive electrocardiogram signal. Minority communities were defined as the top third of ZIP codes with the highest percentages of Black and Hispanic residents.

Previous studies have shown that advances in heart attack care have improved care between white and minority patients receiving care within a single hospital, according to Hsia. However, the new study findings, focused on communities rather than on individual hospitals, raise the question as to whether Blacks and Hispanics, depending on their neighborhoods, are more likely to be directed to hospitals where patients do not receive optimal care, even with the new guidelines.

"Given that both emergency care in general and PCI specifically are less available in underserved communities, PCI hospitals in minority communities could already be burdened by a high volume of patients as the result of regionalization, and less able to provide guideline-directed care," according to the study.

In addition, other studies have shown that minority populations use ambulances less often due to concerns about costs and insurance, and individuals who are not taken to hospital by ambulance may not benefit from the newer guidelines as much, Hsia said. The study was not designed to measure ambulance use over time.

"Medical advances do not necessarily benefit all groups equally, and the structure of our health care system may affect how benefits accrue," Hsia said.

A new global study from the University of Sydney has looked at how macronutrient supplies (proteins, carbohydrates and fats) of different countries are associated with the risk of death at different ages. It is the most extensive analysis to date of corresponding national macronutrient supplies, survival statistics and economic data.

The research led by Dr Alistair Senior, a researcher in the Charles Perkins Centre and Faculty of Science at the University of Sydney, found evidence for undernutrition is prevalent in the global data even as recently as 2016; particularly in terms of protein supplies and that the "optimal" supply changes with age.

"We found that the risk of death in early life is minimised where the supply is relatively high in fats and proteins (around 40 and 16 percent of energy, respectively)," Dr Senior said. "However, in later life reducing the supply of energy from fats and substituting it for carbohydrates has the lowest mortality."

The study is published today in the high-impact Proceedings of the National Academy of Sciences.

"It is a fascinating story, which reflects at the level of national food supplies the fact that macronutrient requirements change with age. It is also likely to be of interest when considering the food security of nations, and how changes in supply might translate to patterns of mortality," Dr Senior said.

Co-author Professor Stephen Simpson, the director of the Charles Perkins Centre and co-author of the recent book Eat Like The Animals added: "The study is fascinating. It was intriguing to see that the pattern of reduced rates of mortality in mid- to later-life with an increase in the ratio of carbohydrate-to-protein in the diet reflected studies in the laboratory on the biology of ageing."

Team member Professor David Raubenheimer, who co-authored Eat Like the Animals with Simpson and is the Nutrition Theme Leader at the Charles Perkins Centre, noted: "While food supply data are not a direct indicator of diets, they provide a good measure of differences in national food environments. It is incredible that we are seeing at that level effects also seen in detailed studies of individual diets. This attests to the power of food environments to influence diets and health, a topic that is a central theme of our new book"

Nutrition is a guiding research theme at the Charles Perkins Centre. This theme unites researchers across disciplines in unexpected collaborations, providing unique insights into nutritional ecology.

Why macronutrients matter

Macronutrients are the primary source of energy in the foods we eat, and are categorised into three major groups: proteins, fats and carbohydrates.

The study found the total calorie supply per person associated with minimal mortality is relatively stable (around 3500kcal/cap/day) with age, but the composition of calorie intake in terms of dietary proteins, fats and carbohydrates is not.

Before the age of 50, 40 to 45 percent of energy from each of fat and carbohydrates and 16 percent from protein minimises mortality. However, for later life lower fat and protein supplies at 22 percent and 11 percent, respectively, and replacing these with carbohydrates is associated with the lowest rate of mortality.

"What was really neat was that we saw a clear shift in the supply that minimised mortality at above age 50, where it looked like a high carbohydrate supply becomes important," said Dr Senior. "I think it's important to note though that this is not a guide to what an individual should be eating - we looked at the supply that a country is providing at a per capita level. This theoretically sets the upper limit to what people are eating, but there are a whole range of factors that translate a country's food supply into what ends up actually being consumed; this is something that we are really interested in looking at going forward."

Method

From a methodological perspective the paper is also interesting. Using global supply data and 1,879 lifetables from 103 countries, the researchers tested energy intake (number of calories) and the balance of macronutrients at a macro-level: between the nutrient supplies of nations and their patterns of age-specific mortality. They found that macronutrient supplies are strong predictors of age-specific mortality even after correction for time and economic factors.

"The same statistical approach that we have applied here can be reapplied to look at patterns of the risk of death and all kinds of dietary aspects including different food types (e.g. plant vs animal proteins), or broader dietary patterns (e.g. 'a Mediterranean diet')," said Dr Senior, who is also affiliated with the School of Life and Environmental Sciences and the School of Mathematics and Statistics.

The study found, globally, under-nutrition is evident, even as recently as 2016. However, in wealthy countries the effects of over-nutrition are prominent, where high supplies particularly from fats and carbohydrates are predicted to lead to high levels of mortality.

Major measles outbreaks will likely occur during 2021 as an unexpected consequence of the COVID-19 pandemic, according to a new academic article.

The Lancet article has called for urgent international action to prevent potentially devastating measles epidemics in the coming years.

Lead author Professor Kim Mulholland, from the Murdoch Children's Research Institute and Chair of the World Health Organization's SAGE Working Group on measles and rubella vaccines, said that many children have missed out on measles vaccination this year, making future measles outbreaks inevitable.

Professor Mulholland said while 2020 had been a quiet year for measles, in part due to travel reductions and national COVID-19 control measures, the economic impacts would lead to many cases of childhood malnutrition.

Malnutrition worsens the severity of measles, leading to poorer outcomes and more deaths, especially in low- and middle-income countries.

"Children who die from measles are often malnourished, but acute measles pushes many surviving children into malnutrition," he said. "Malnutrition, along with measles-associated immune suppression, leads to delayed mortality, while co-existing vitamin A deficiency can also lead to measles-associated blindness.

"The coming months are likely to see increasing numbers of unimmunised children who are susceptible to measles. Many live in poor, remote communities where health systems are less resilient, and malnutrition and vitamin A deficiency are already increasing."

Professor Mulholland said the COVID-19 pandemic had also had a profound effect on the control of vaccine preventable diseases, with vaccination campaigns paused in the early months of 2020 and routine immunisation services greatly disrupted in many countries.

The WHO estimates that by the end of October, 2020, delayed vaccination campaigns in 26 countries have led to 94 million children missing scheduled measles vaccine doses.

"All these factors create the environment for severe measles outbreaks in 2021, accompanied by increased death rates and the serious consequences of measles that were common decades ago," Professor Mulholland said.

"This is despite the fact that we have a highly cost effective way to prevent this disease through measles vaccination."

In 2019, before the pandemic started, the world experienced a dramatic return of measles, more than at any time in the past 20 years. WHO data indicates that there were 9.8 million measles cases and 207,000 deaths in 2019, 50 per cent more than in 2016.

Most measles deaths in 2019 have been in Africa, many associated with major outbreaks in Madagascar and the Democratic Republic of the Congo. Measles also re-emerged in South America, especially among Indigenous communities.

"The inadequate vaccination that led to the 2019 measles outbreaks has still not been adequately addressed, and the situation is now exacerbated by service disruptions during the COVID-19 pandemic so that high-risk, unimmunised children are clustered together in unreached communities," Professor Mulholland said.

The article has identified three pillars for immediate action:

Help countries reach unimmunised children through catch-up immunisation and campaigns

Better prepare countries for expected outbreaks. WHO and partners have developed a Strategic Response Plan to assist with measles outbreak prevention, preparedness and response

Maintain measles and rubella elimination targets. WHO's new Measles Rubella Strategic Framework 2021?2030, aligned with the Immunization Agenda 2030 provides a plan for strengthening routine immunisation and surveillance.

Professor Mulholland said the solutions would help end the cycle of inadequate immunisation and outbreaks of the past decade.

"Without concerted efforts now, it is likely that the coming years will see an increase in measles and its severe, frequently fatal, complications," he said.

A drug that acts via the natural 'kisspeptin' hormone system in the body has the potential to treat reproductive health problems in women, according to a new study.

Twenty-four women were injected with a drug called MVT-602 which targets the kisspeptin system to stimulate reproductive hormones that affect fertility, sexual development and menstruation.

The naturally occurring form of kisspeptin called kisspeptin-54 (KP54) has been researched for a number of years to treat reproductive disorders, but in the new study, MVT-602 induced more potent signalling of the kisspeptin system over a longer period of time than KP54.

The researchers behind the study suggest that MVT-602 may be used to effectively treat a range of reproductive conditions that affect fertility such as polycystic ovary syndrome (PCOS) - a common condition that affects how a woman's ovaries work and hypothalamic amenorrhea (HA) - a condition where a woman's periods stop.

The researchers suggest that because of MVT-602's much longer duration of action, it can be given less frequently than the naturally occurring form of kisspeptin, whilst still being able to maintain the degree of stimulation of reproductive hormone levels required to restore reproductive health.

The study, published in the Journal of Clinical Investigation, is led by researchers at Imperial College London and clinicians at Imperial College Healthcare NHS Trust.

Professor Waljit Dhillo, lead author, NIHR Research Professor in Endocrinology and Metabolism at Imperial College London and Consultant in Endocrinology at Imperial College Healthcare NHS Trust said:

"Reproductive health issues are common for women around the world. Infertility as a result of these conditions can cause a lot of distress. Although we have made great strides in developing treatments for infertility and other reproductive disorders there is a need to find more effective treatments. Our previous work showed that kisspeptin can be used to stimulate ovulation in women undergoing in vitro fertilisation (IVF) treatment, but there are some limitations on using the naturally occurring kisspeptin hormone as its effectiveness wares off after a few hours. This study suggests that MVT-602 can stimulate kisspeptin over a longer period of time with no side effects, which means we could potentially use it to treat a wider range of reproductive disorders. This is an early stage study and more research needs to be carried out to fully determine the effects of MVT-602 on more patients."

Dr Ali Abbara, NIHR Clinician Scientist at Imperial College London and Consultant in Endocrinology at Imperial College Healthcare NHS Trust, who co-led the work added: "This is the first study to show that a single dose of MVT-602 can induce a longer duration of hormonal stimulation in women than naturally occurring kisspeptin. Therefore, it reveals exciting potential to treat a range of reproductive health conditions using MVT-602 and offer women improved treatment options. However, further research is needed to fully characterise its effects in specific disorders that affect reproductive health."

One in ten women in the UK are diagnosed with PCOS or HA. Current treatments for these conditions include dietary changes, medicines that treat infertility by restoring ovulation, and IVF treatment for those who still are unable to conceive. However, women with PCOS who undergo IVF treatment are at increased risk of 'ovarian hyperstimulation syndrome' (OHSS) - a potentially life-threatening side-effect of IVF treatment.

Kisspeptin is a naturally occurring hormone that controls the levels of other reproductive hormones in the body and plays an important role in fertility, reproductive health and the regulation of normal menstrual cycles. Previous studies have shown that kisspeptin can be used to safely stimulate reproductive hormones in women undergoing IVF treatment without causing OHSS. The research team wanted to see whether MVT-602 could target the kisspeptin pathway and produce a longer hormonal release than the naturally occurring form of kisspeptin - which is important for using kisspeptin to treat reproductive disorders.

Researchers carried out a trial at Hammersmith Hospital, part of Imperial College Healthcare NHS Trust, on 24 women aged 18-35 from 2017-2019. Twelve of the women were healthy volunteers and 12 of the women had either PCOS or HA. All of the women were given MVT-602. In addition, all of the healthy volunteers were given an injection of the naturally occurring kisspeptin (KP54) and saline placebo for comparison. The researchers then compared the women's reproductive hormone levels after receiving MVT-602 to naturally occurring kisspeptin (KP54). They also compared the reproductive hormone levels after MVT-602 between healthy women, women with HA and those with PCOS.

They found that all of the women given MVT-602 had a longer duration of raised reproductive hormones, specifically luteinising hormone (LH) and follicle stimulating hormone (FSH) levels, than when they received native kisspeptin (KP54). LH levels peaked at 21-22 hours after MVT-602 and remained elevated for 48 hours. This is in comparison to natural kisspeptin (KP54) whereby LH levels peaked at 4.7 hours after administration and remained elevated for 12-14 hours. Therefore, the duration of LH rise was extended by approximately four times using MVT-602.
LH increases following MVT-602 were similar in PCOS and healthy women, but rose more quickly in women in HA. Theoretically, this could be because women with HA have more kisspeptin receptors in the hypothalamus of the brain where kisspeptin acts as a result of their condition.

The researchers will now aim to carry out further studies on the effects of MVT-602 on women with reproductive disorders.