Culture

KINGSTON, R.I. - Aug. 16, 2018 - In 2008, a contaminant eluded the quality safeguards in the pharmaceutical industry and infiltrated a large portion of the supply of the popular blood thinner heparin, sickening hundreds and killing about 100 in the U.S.

It took a team of researchers led by the U.S. Food and Drug Administration to confirm the contaminant, a toxin structurally similar to heparin that was traced to a Chinese supplier. But detection of the impurity required "a tremendous effort by heavy hitters in the chemistry world," said Jason Dwyer, associate professor of chemistry at the University of Rhode Island.

After nearly eight years of research, Dwyer has developed a simpler and quicker method for detecting the impurity in heparin, along with creating a process that could have wider benefits. His research was unveiled today in the prestigious online journal Nature Communications, part of the suite of journals from the publisher of Nature.

"There are tests that are much more sophisticated and expensive to detect the impurity," said Dwyer, of Providence, R.I. "What we were able to do is - in a very inexpensive and rapid fashion - fingerprint heparin and tell when there is a contaminant in it."

The research, "Surveying Silicon Nitride Nanopores for Glycomics and Heparin Quality Assurance," could also be used to analyze the entire class of molecules to which heparin belongs with broad use in biomedical diagnostics, pharmaceuticals and environmental sensing. Dwyer's wider studies of sugars were bolstered in July by a $318,000 grant from the National Science Foundation.

For example, Dwyer said, the new detection technique could serve as a quality assurance tool across the pharmaceutical industry, especially with an increased push to develop more sugar-based drugs, such as heparin. "Sugars are incredibly important," said Dwyer, whose research in the past has garnered publication in the high-profile journals Nature and Science. "They're how bacteria communicate with each other. They're how we're going to be designing a lot of new drugs. So we need new tools to analyze sugars."

To develop the new detection technique, Dwyer turned to a sensing method proven in the sequencing of DNA and proteins. The sensor consists of a hole, or nanopore, less than a thousandth the thickness of a human hair, sitting on a membrane that is even thinner, and tests substances at the smallest detectable level - a single molecule.

While the sensor, a solid-state silicon nitride nanopore, worked well for DNA, it had to be retooled for sugar molecules, which are far more complex, said Dwyer, whose group was one of the first to focus on sugars.

Starting in 2010, the project developed along with other work by Dwyer's team. It took years to fabricate and fine-tune devices, refine the nanopore and prevent the opening from clogging. "A fair number of students have worked on this project over the years," Dwyer said. "We have not relented. We butted our heads against the wall for a period of time and we realized we needed to do a fair amount of fundamental work before we could get to the point of detecting."

One unexpected problem was solved by Buddini Karawdeniya, lead author of the paper who completed her doctorate in chemistry at URI in the spring. When she attempted to run sugar molecules through the nanopore, they went backwards. "In 1996, people figured out how DNA could be sensed with a nanopore," Dwyer said. "There were some oddities but it worked the way it was expected. Sugars right off the bat did not act as expected. So Buddini had to look at what had been done for 20 years, but know she had to start over at some level."

With the 2008 crisis, researchers had managed to identify and detect the oversulfated chondroitin sulfate contaminant, which was nearly identical to the heparin. Using the fine-tuned nanopore, Dwyer's research looked at both samples, determined that the signals they generated were 99-percent identical, and devised analysis techniques to use the 1-percent difference to reliably detect the impurity.

"The test we came up with takes about 20 minutes," he said, "and works at clinically relevant concentrations."

The goal is to make detection of the impurity even quicker, down to minutes and seconds. At the same time, the device will have to be adapted for a commercial user who may lack the expertise of a researcher in a technology development lab. Also, the tool would have to perform accurately in a less-controlled environment.

"This is where research starts to transition into development, and we start to refine the conditions and the devices even more," Dwyer said. "Often discovery is the easiest part. Refining it for the end user takes time."

The nanopore that came out of the heparin research was designed with that in mind. It uses technology similar to that found in nearly every piece of consumer electronics, said Dwyer, so there is already an industry ready to produce the sensors on a large scale.

"We always try to think about the consumer market," he said. "What we do in the lab is one thing -- and it is a vital thing -- but how do we translate it into the real world?"

Scientists have confirmed that the 3.4 billion year old Strelley Pool microfossils had chemical characteristics similar to modern bacteria. This all but confirms their biological origin and ranks them amongst the world's oldest microfossils. The work is presented at the Goldschmidt geochemistry conference in Boston, with simultaneous publication in the peer-reviewed journal Geochemical Perspectives Letters (see below for reference).

A team of scientists, led by Dr Julien Alleon (IMPMC, Paris, France; and MIT, Cambridge, MA, USA) have been able to show that the chemical residuals from ancient microfossils match those of younger bacterial fossils, and so are likely to have been laid down by early life forms.

They compared the results of synchrotron-based X-ray absorption spectroscopy analysis of the Strelley Pool microfossils with more recent ones from the Gunflint Formation (1.9 billion years old, found on the shores of Lake Superior, Ontario, Canada) and with modern bacteria.
All showed similar absorption features, indicating that the residual chemicals were made from the same building blocks, thereby supporting a biological origin (see illustration below).

Dr Jullien Alleon said:

"There are a couple of important points which come out of this work. Firstly, we demonstrate that the elemental and molecular characteristics of these 3.4 Ga microfossils are consistent with biological remains, slightly degraded by fossilization processes. This effectively supports the biological origin of the Strelley Pool microfossils. There are competing claims over which microfossils are actually the world's oldest, this analytical strategy needs to be applied to other ancient samples to help settle the controversy.

Secondly, it is remarkable that these echoes of past life have survived the extreme conditions they have experienced over the last 3.4 billion years: we know from the molecular structure of the microfossils that they have been exposed to temperatures of up to 300 °C for long periods. And yet we are still able to see signs of their original chemistry.

This is a step forward to confirming that these are indeed the oldest fossils yet discovered."

Commenting, Professor Vickie Bennett (Australian National University) said:

"This is exciting work with the new types of analyses providing compelling evidence that the cherts contain biogenic microfossils. This is in line with other observations for early life from the Strelley Pool rocks, including stromatolites interpreted as microbial mats, and further confirming that the minimum age for life on Earth is 3.4 billion years.

The techniques used here are not applicable to the older rocks that host the claims for the oldest terrestrial life, as these rocks were exposed to much higher temperatures. These samples include the 3.7 billion year old stromatolites from Isua, Greenland and the 4.1 billion year old Canadian microfossils. However, this work shows how quickly the field is developing and that new capabilities for testing and confirming earlier evidence of life are in reach".

Fragility fractures are a serious yet neglected complication of both type 1 and type 2 diabetes, with increased risk of fragility fractures in people with diabetes extending across the life span.

This is a concern as, globally, the prevalence of diabetes in adults is expected to increase from almost 425 million today, to approximately 629 million by 2045. At the same time, many clinicians who treat patients with diabetes are not aware of their patients' heightened risk of disabling and potentially life-threatening fractures.

Given this scenario, the International Osteoporosis Foundation (IOF) Bone and Diabetes Working Group has published a new expert review that summarizes key research, highlights clinical issues, and provides a helpful 'decision-tree' style algorithm for the identification and management of diabetic patients at increased fracture risk.

Download: Diagnosis and management of bone fragility in diabetes: an emerging challenge

Professor Serge Ferrari, chair of the IOF Committee of Scientific Advisors and of the IOF Bone and Diabetes Working Group, stated:

"The link between diabetes and skeletal health is complex and the optimal approach to the management of bone health in patients with diabetes is not yet definitive and may change over time as findings of new clinical studies become available. This new review will inform clinicians about the current state of knowledge, and, importantly, the clear algorithm will facilitate the clinical assessment and management of fragility fracture risk in their patients according to current best practice."

The review outlines the clinical characteristics of bone fragility in adults with diabetes, and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction (FRAX). It also looks at the impact of diabetes drugs on bone, as well as the efficacy of osteoporosis treatments in these patients.

Key messages include:

The pathophysiology of bone fragility in diabetes is likely multifactorial.

FRAX and BMD T-score predict fracture risk in those with type 2 diabetes, but both require adjustment for diabetes to avoid underestimation of risk.

If a patient has indication for therapy based on criteria developed for non-diabetes patients, these patients should be treated with osteoporosis drugs. In the absence of established osteoporosis, these medications may be used, although with caution as the effects of these drugs in situations where bone fragility is mainly due to alterations in bone quality remain to be thoroughly evaluated.

Future studies should continue to evaluate the structural determinants (microstructure, material properties, etc.) of bone fragility and refine fracture prediction algorithms by including disease-specific determinants of fracture.

New trials will have to prospectively investigate the efficacy and safety of osteoporosis treatment in diabetics with and without low aBMD.

Researchers have developed a new method that aids in the process of making valuable compounds by using a unique combination of catalysts.

A study published in Nature reported a new catalytic method that combines enzymatic catalysts with photocatalysts.

Huimin Zhao, Professor of Chemical and Biomolecular Engineering and leader of the Biosystems Design research theme at the Carl R. Woese Institute for Genomic Biology at the University of Illinois, led the research alongside John Hartwig, Professor of Chemistry at the University of California, Berkeley, who was previously a professor at the University of Illinois and is a longtime collaborator of Zhao's. Coauthors include Yajie Wang, a graduate student in the department of chemical and biomolecular engineering at the University of Illinois, and Zachary Litman, a postdoctoral research fellow at the University of Michigan.

All organisms rely on chemical reactions in order to make various natural products. Chemical reactions can be caused by a number of catalysts, such as enzymatic or chemical catalysts.

Scientists often use combinations of enzymatic and chemical catalysts to cause reactions that result in higher yields than what can be achieved with enzymes alone. Higher yields are beneficial when scientists want to use these reactions to make useful products such as biofuels and pharmaceuticals.

But combining enzymatic and chemical catalysts is difficult to do -- the two catalysts aren't naturally compatible; they work best under different conditions and temperatures.

Seeing the need for new approaches, Wang and Litman came up with an idea: to combine enzymatic catalysis and photocatalysis.

Photocatalysis, which uses light to spur on a chemical reaction, is currently a popular research area.

"Lots of researchers have tried to develop new photocatalysts for different reactions," Zhao said. "And enzyme catalysis is a relatively old field."

While photocatalysis and enzyme catalysis have been studied separately, few researchers have put these two catalysts together.

The team studied several enzymes and photocatalysts and found a pair that works together.

"If you use a light-driven process instead of one driven by heat, then that will be compatible with the enzymes," Hartwig said.

They not only showed that enzymatic catalysts and photocatalysts can be combined, but that this combination can also be productive. Their method was able to create a few important active pharmaceutical intermediates (APIs) for producing pharmaceutical drugs.

"(This research) would be quite useful for synthetic chemistry," Hartwig said.

Zhao said they will pursue further research in this area as a part of Illinois' Center for Advanced Bioenergy and Bioproducts Innovation (CABBI), a collaboration between the Carl R. Woese Institute for Genomic Biology and the Institute for Sustainability, Energy, and Environment.

One of CABBI's goals is to engineer biological systems that produce non-natural compounds, which can be used for biofuels, jet fuels, lubricants, and more.

The researchers hope to find more combinations of photocatalysts and enzymatic catalysts for more chemical reactions.

"This is just a first example," Zhao said. "We want to find more chemoenzymatic systems for different types of reactions."

Zhao expects this research will also inspire new discoveries.

"There are many new photocatalysts for different types of reactions, and there are many enzymes," he said. "So I can see that this will stimulate researchers to develop new systems that can combine these two types of catalysts for making a wide variety of useful compounds."

Low-carb diets that replace carbohydrates with proteins and fats from plant sources associated with lower risk of mortality compared to those that replace carbohydrates with proteins and fat from animal sources.

Eating carbohydrates in moderation seems to be optimal for health and longevity, suggests new research published in The Lancet Public Health journal.

The observational study of more than 15,400 people from the Atherosclerosis Risk in Communities Study (ARIC) in the USA found that diets both low (70% energy) in carbohydrates were linked with an increase in mortality, while moderate consumers of carbohydrates (50-55% of energy) had the lowest risk of mortality.

The primary findings, confirmed in a meta-analysis of studies on carbohydrate intake including more than 432,000 people from over 20 countries, also suggest that not all low-carbohydrate diets appear equal--eating more animal-based proteins and fats from foods like beef, lamb, pork, chicken and cheese instead of carbohydrate was associated with a greater risk of mortality. Alternatively, eating more plant-based proteins and fats from foods such as vegetables, legumes, and nuts was linked to lower mortality.

"We need to look really carefully at what are the healthy compounds in diets that provide protection", says Dr Sara Seidelmann, Clinical and Research Fellow in Cardiovascular Medicine from Brigham and Women's Hospital, Boston, USA who led the research.

"Low-carb diets that replace carbohydrates with protein or fat are gaining widespread popularity as a health and weight loss strategy. However, our data suggests that animal-based low carbohydrate diets, which are prevalent in North America and Europe, might be associated with shorter overall life span and should be discouraged. Instead, if one chooses to follow a low carbohydrate diet, then exchanging carbohydrates for more plant-based fats and proteins might actually promote healthy ageing in the long term."[1]

Previous randomised trials have shown low carbohydrate diets are beneficial for short-term weight loss and improve cardiometabolic risk. However, the long-term impact of carbohydrate restriction on mortality is controversial with prospective research so far producing conflicting results. What's more, earlier studies have not addressed the source or quality of proteins and fats consumed in low-carb diets.

To address this uncertainty, researchers began by studying 15,428 adults aged 45-64 years from diverse socioeconomic backgrounds from four US communities (Forsyth County, NC; Jackson, MS; Minneapolis, MN; and Washington County, MD) enrolled in the ARIC cohort between 1987 and 1989. All participants reported consuming 600-4200 kcal per day for men and 500-3600 kcal per day for women, and participants with extreme (high or low) caloric intake were excluded from the analysis.

At the start of the study and again 6 years later, participants completed a dietary questionnaire on the types of food and beverages they consumed, what portion size and how often, which the researchers used to estimate the cumulative average of calories they derived from carbohydrates, fats, and protein.

The researchers assessed the association between overall carbohydrate intake (categorised by quantiles) and all cause-mortality after adjusting for age, sex, race, total energy intake, education, exercise, income level, smoking, and diabetes. During a median follow-up of 25 years, 6283 people died.

Results showed a U-shape association between overall carbohydrate intake and life expectancy, with low (less than 40% of calories from carbohydrates) and high (more than 70%) intake of carbohydrates associated with a higher risk of mortality compared with moderate intake (50-55% of calories).

The researchers estimated that from age 50, the average life expectancy was an additional 33 years for those with moderate carbohydrate intake--4 years longer than those with very low carbohydrate consumption (29 years), and 1 year longer compared to those with high carbohydrate consumption (32 years). However, the authors highlight that since diets were only measured at the start of the trial and 6 years later, dietary patterns could change over 25 years, which might make the reported effect of carbohydrate consumption on lifespan less certain.

In the next step of the study, the authors performed a meta-analysis of data from eight prospective cohorts (including ARIC) involving data from 432,179 people in North American, European, and Asian countries. This revealed similar trends, with participants whose overall diets were high and low in carbohydrates having a shorter life expectancy than those with moderate consumption (figure 2).

As Seidelmann explains, "A midrange of carbohydrate intake might be considered moderate in North America and Europe where average consumption is about 50% but low in other regions, such as Asia, where the average diet consists of over 60% carbohydrates." [1]

In further analyses examining whether the source of proteins and fats favoured in low-carbohydrate diets--plant-based or animal-based--was associated with length of life, researchers found that replacing carbohydrates with protein and fat from animal sources was associated with a higher risk of mortality than moderate carbohydrate intake. In contrast, replacing carbohydrates with plant-based foods was linked to a lower risk of mortality (table 3).

"These findings bring together several strands that have been controversial. Too much and too little carbohydrate can be harmful but what counts most is the type of fat, protein, and carbohydrate," says Walter Willett, Professor of Epidemiology and Nutrition at Harvard T. H. Chan School of Public Health and co-author of the study. [1]

The findings show observational associations rather than cause and effect. Considering evidence from other studies, the authors speculate that Western-type diets that heavily restrict carbohydrates often result in lower intake of vegetables, fruit, and grains and lead to greater consumption of animal proteins and fats--some of which have been implicated in stimulating inflammatory pathways, biological ageing, and oxidative stress--and could be a contributing factor to the increased risk of mortality. Whilst high carbohydrate diets (common in Asian and less economically advantaged nations) tend to be high in refined carbohydrates such as white rice, may also contribute to a chronically high glycaemic load and worse metabolic outcomes.

"This work provides the most comprehensive study of carbohydrate intake that has been done to date, and helps us better understand the relationship between the specific components of diet and long term health", says Dr Scott Solomon, The Edward D Frohlich Distinguished Chair at Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School, and senior author on the paper. "While a randomized trial has not been performed to compare the longer term effects of different types of low carbohydrate diets, these data suggest that shifting towards a more plant-based consumption is likely to help attenuate major morbid disease."[1]

The authors note some limitations including that dietary patterns were based on self-reported data, which might not accurately represent participants' food consumption; and that their conclusions about animal-based sources of fat and protein might have less generalisability to Asian populations which tend to have diets high in carbohydrates, but often consume fish rather than meat. Finally, given the relatively small number of individuals following plant-based low-carb diets, further research is needed.

Writing in a linked Comment, Dr Andrew Mente and Dr Salim Yusuf from McMaster University, Hamilton, Canada say, "Such differences in risk associated with extreme differences in intake of a nutrient are plausible, but observational studies cannot completely exclude residual confounders when the apparent differences are so modest. Based on first principles, a U-shaped association is logical between most essential nutrients versus health outcomes. Essential nutrients should be consumed above a minimal level to avoid deficiency and below a maximal level to avoid toxicity. This approach maintains physiological processes and health (ie, a so-called sweet spot). Although carbohydrates are technically not an essential nutrient (unlike protein and fats), a certain amount is probably required to meet short-term energy demands during physical activity and to maintain fat and protein intakes within their respective sweet spots. On the basis of these principles, moderate intake of carbohydrate (eg, roughly 50% of energy) is likely to be more appropriate for the general population than are very low or very high intakes."

Arlington, Va., August 16, 2018 - The consequences of healthcare-associated infections (HAIs) reach well beyond patients' physical health, souring social relationships, and leading some healthcare providers (HCP) to distance themselves from affected patients, according to a qualitative, systematic review published in the American Journal of Infection Control (AJIC), the journal of the Association for Professionals in Infection Control and Epidemiology (APIC).

To properly address patients' needs and concerns, researchers at Glasgow Caledonian University in Scotland, and colleagues, conducted a meta-synthesis of qualitative research, looking at 17 studies from five different countries addressing five common types of HAIs, focusing on patient experiences of both colonization and infection from bacteria that commonly cause HAIs.

The authors of this meta-synthesis urge HCP to consider the social circumstances that color patient experiences, including feeling shameful and dirty, and the responses of those around them, especially those of HCP.

According to the analysis, many patients experienced an emotional response to their diagnosis and described "feeling dirty," "having the plague," or "feeling like a leper." While emotional responses varied based on type of HAI, patients with nearly all colonization or infection types reported a fear of transmitting their infection to others. This fear affected patients' personal and workplace relationships. Some patients, particularly those colonized by MRSA, also expressed concern about working in certain professions because of their condition and a fear of rejection by coworkers.

Patients who were able to speak to infection preventionists reported receiving constructive information and feeling reassured about their condition, whereas patients who did not, reported feeling dismissed by staff members.

"Having an HAI is a significant event in the patient's care journey and subsequent life that is influenced by biology, society and context," said Kay Currie, PhD, the paper's lead author. "Understanding the patient experience can help HCP to interact and respond in a constructive way, providing more effective support during this challenging time in a patient's healthcare experience."

The analysis also found:

Concerns about interaction with HCP or restriction to healthcare treatment were particularly prominent among patients with infections caused by resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) or Extended-Spectrum Beta-lactamases (ESBL). The studies highlight patient reports of exclusion from rehabilitation classes, requirements to wait until the end of clinic appointments to be seen, or restrictions on attending clinics.

Many patients with HAIs reported changing their personal hygiene behavior, taking precautions to prevent the transmission of infection, including undergoing extensive cleaning at home and advising family members on hygiene measures.

Many patients reported interactions in a climate that induced fear and uncertainty, particularly when frontline HCP lacked knowledge of the causes and consequences of HAIs and could not provide the patient with adequate information. This finding highlighted the sociocultural context in which the infection or colonization occurs.

"As one in every 25 hospitalized patients in the United States is diagnosed with an HAI, it is critical to understand the long-lasting impact of such infections, not just from a physical perspective, but also from a social and emotional perspective," said 2018 APIC President Janet Haas, PhD, RN, CIC, FSHEA, FAPIC. "This qualitative review provides valuable insight into the patient perspective and how healthcare professionals can more effectively interact with their patients to enhance recovery in all areas of their lives."

GALVESTON, Texas - A new study from The University of Texas Medical Branch at Galveston has uncovered why some people that have brain markers of Alzheimer's never develop the classic dementia that others do. The study is now available in the Journal of Alzheimer's Disease.

Alzheimer's disease, the most common form of dementia, affects more than 5 million Americans. People suffering from Alzheimer's develop a buildup of two proteins that impair communications between nerve cells in the brain - plaques made of amyloid beta proteins and neurofibrillary tangles made of tau proteins.

Intriguingly, not all people with those signs of Alzheimer's show any cognitive decline during their lifetime. The question became, what sets these people apart from those with the same plaques and tangles that develop the signature dementia?

"In previous studies, we found that while the non-demented people with Alzheimer's neuropathology had amyloid plaques and neurofibrillary tangles just like the demented people did, the toxic amyloid beta and tau proteins did not accumulate at synapses, the point of communication between nerve cells," said Giulio Taglialatela, director of the Mitchell Center for Neurodegenerative Diseases. "When nerve cells can't communicate because of the buildup of these toxic proteins that disrupt synapse, thought and memory become impaired. The next key question was then what makes the synapse of these resilient individuals capable of rejecting the dysfunctional binding of amyloid beta and tau?"

In order to answer this question, the researchers used high-throughput electrophoresis and mass spectrometry to analyze the protein composition of synapses isolated from frozen brain tissue donated by people who had participated in brain aging studies and received annual neurological and neuropsychological evaluations during their lifetime. The participants were divided into three groups - those with Alzheimer's dementia, those with Alzheimer's brain features but no signs of dementia and those without any evidence of Alzheimer's.

The results showed that resilient individuals had a unique synaptic protein signature that set them apart from both demented AD patients and normal subjects with no AD pathology. Taglialatela said that this unique protein make-up may underscore the synaptic resistance to amyloid beta and tau, thus enabling these fortunate people to remain cognitively intact despite having Alzheimer's-like pathologies.

"We don't yet fully understand the exact mechanism(s) responsible for this protection," said Taglialatela. "Understanding such protective biological processes could reveal new targets for developing effective Alzheimer's treatments."

On Avoiding Deep Dementia
Norman L. Cantor

To avoid prolonged dementia, the author has written an advanced directive to prohibit the provision of life-sustaining interventions, including hydration and nutrition, should he reach a self-defined point of cognitive debilitation. But if that point is reached, he would be unable to comprehend the reasoning that motivated the advanced directive, and he might enjoy life despite having dementia. Still, surrogate decision-makers and caregivers would have a moral and legal obligation to implement his advanced directive, argues Cantor, a professor emeritus of law at Rutgers University School of Law. Competent individuals should be given control over directing the types of life-sustaining treatments they receive if they develop dementia.

Other Voices: Three commentaries raise concerns about advance directives that limit care for people with dementia.

Are Obese Children Abused Children?
Maura Priest

In 2010, a South Carolina mother was charged with criminal neglect after her 14-year-old son reached 555 pounds, in the first U.S. felony case involving childhood obesity. But this article discusses important ethical and legal distinctions between negligent and abusive caretakers and caretakers of obese children. The former intentionally harm or fail to protect the children under their care, while caretakers of obese children may act in well-intentioned though misguided ways. And environmental, social, and genetic factors are also significant contributors to childhood obesity. Since allowing a child to become obese falls into a different moral and legal category from abusing or neglecting a child, the solutions to protect obese children must be different from those to protect abuse and neglect victims. Priest is an assistant professor of philosophy at Arizona State University and an affiliate researcher at the University of Cologne.

Discriminatory Demands by Patients
Philip M. Rosoff

Many in health care are concerned, even appalled, when patients demand physicians, nurses, and other caregivers of a particular gender or race. While there is evidence that patients from groups that have been victims of discrimination may have better health outcomes if they have clinicians of the same background or gender, how does one distinguish requests that are potentially beneficial from those that are simply discriminatory? Which requests should be honored, and which should be denied? The answers are not straightforward, writes Philip M. Rosoff, a professor of pediatrics and medicine at Duke University School of Medicine and an adjunct professor of clinical science at North Carolina State University College of Veterinary Medicine.

A new study suggests that long-term exposure to secondhand smoke during childhood increases the risk of chronic obstructive pulmonary disease (COPD) death in adulthood. The study also suggests secondhand smoke exposure as an adult increases the risk of death not only from COPD but also several other conditions.

Secondhand smoke is known to have adverse effects on the lung and vascular systems in both children and adults. But it is unknown whether childhood exposure to secondhand smoke is associated with mortality in adulthood. To explore the issue, American Cancer Society epidemiologists led by W. Ryan Diver, MSPH, examined associations of childhood and adult secondhand smoke exposure with death from all causes, ischemic heart disease, stroke, and chronic obstructive pulmonary disease among 70,900 never-smoking men and women from the Cancer Prevention Study II Nutrition Cohort. Study participants, primarily ages 50 to 74 at the beginning of the study, answered questions about their secondhand smoke exposure during childhood and as adults and were followed for 22 years.

Those who reported having lived with a daily smoker throughout their childhood had 31% higher mortality from chronic obstructive pulmonary disease compared to those who did not live with a smoker. In a calculation done for this release, Diver says the increase in COPD mortality corresponds to about 7 additional deaths per year per 100,000 never-smoking study participants. Although the study counted only deaths, the increase in fatal COPD implies that living with a smoker during childhood could also increase risk of non-fatal COPD.

In addition, secondhand smoke exposure (10 or more hours/week) as an adult was associated with a 9% higher risk of all-cause mortality, a 27% higher risk of death from ischemic heart disease, a 23% higher risk of death from stroke, and a 42% higher risk of death from COPD.

"This is the first study to identify an association between childhood exposure to secondhand smoke and death from chronic obstructive pulmonary disease in middle age and beyond," said Diver. "The results also suggest that adult secondhand smoke exposure increases the risk of chronic obstructive pulmonary disease death. Overall, our findings provide further evidence for reducing secondhand smoke exposure throughout life."

Continued growth in global demand for palm oil is expected to mean an expansion in oil palm plantations in Africa. The continent offers the low-lying tropical ecosystems oil palm prefers, hence an opportunity for States, businesses and local farmers to generate income. However, the lessons learned from Southeast Asia, where most oil palm plantations are located, prompted the international team to assess the potential impact on primates of an expansion in oil palm cultivation in Africa.

In the study, the researchers set out to identify 'areas of compromise' in which oil palm cultivation would be most productive while having little impact on primates. They concluded that such areas were rare across Africa, covering only 0.13 to 3.3 million hectares (Mha).

There are only 3.3 million hectares available with little impact on primates

In total, according to the study, 273 Mha of land could be planted with oil palm in Africa: 84 Mha with low yields, 139 Mha with average yields and just 50 Mha with high yields, in view of local soil and climate criteria and assuming crops are solely rain-fed with intermediate use of inputs. "If we combine these figures with the data on primate vulnerability, oil palm could only be grown with little impact on primates on 3.3 Mha. That figure drops to 0.13 Mha if we only consider high-potential land" , says Ghislain Vieilledent, CIRAD ecologist and co-author of the study. Those figures of 3.3 Mha and 0.13 Mha correspond to just 6.2% and 0.2% respectively of the demand for additional land by 2050, given that 53 Mha of additional land is forecast to be needed by then.

There may be mitigation strategies, but the impact remains high

"One potential mitigation strategy would be to identify alternative trajectories for agricultural expansion, using 'smart' criteria to minimize and and delay the loss of primate home range as much as possible," says Ghislain Vieilledent. The researchers compared two income-driven oil palm expansion scenarios and two conservation-driven scenarios. The income-driven scenarios would see the most productive and accessible land converted to oil palm cultivation first. In the conservation-driven scenarios, it is land with low carbon stocks and low primate vulnerability that would be converted first. The researchers showed that even in a scenario seeking to minimize the impact on primates, five species, on average, would lose 1 ha of habitat for every 1 ha of land converted to oil palm cultivation.

Levers to help mitigate the impact of oil palm cultivation

"Levers for the successful conservation of African biodiversity do exist," says Ghislain Vieilledent. "One way could be to increase yields in existing plantations by using high quality seed and adopting better agricultural practices." Initiatives such as the Round Table on Sustainable Palm Oil (RSPO) should also be supported, with a strengthening of the environmental component of this certification. Another possible solution lies in reducing future demand for palm oil in the northern hemisphere by raising consumer awareness and seeking alternatives to biodiesel. However, given the population growth expected across Africa over the next 30 years and the increased food consumption which will inevitably accompany it, the effects could be limited. There is already momentum for change and the researchers hope their findings will contribute to this.

Primates are a good indicator of biodiversity

The researchers focused on primates because they are a good indicator of overall biodiversity. "There is a correlation between primate diversity and the richness of species in other taxonomic groups. They play an important role in seed dispersal and in maintaining the composition of forest ecosystems," explains CIRAD ecologist Ghislain Vieilledent. Populations of many primate species are in decline: 37% of primate species in mainland Africa and 87% of species in Madagascar are under threat of extinction according to International Union for Conservation of Nature (IUCN) criteria. In this study, the distribution of 193 African primate species was taken into account (at a resolution of 10 x 10 km) along with their vulnerability (IUCN conservation status).

Mathematics can help public health workers better understand and influence human behaviours that lead to the spread of infectious disease, according to a study from the University of Waterloo.

Current models used to predict the emergence and evolution of pathogens within host populations do not include social behaviour.

"We tend to treat disease systems in isolation from social systems, and we don't often think about how they connect to each other, or influence each other," said Chris Bauch, co-author and a professor in the Department of Applied Mathematics at Waterloo. "This gives us a better appreciation of how social reactions to infectious diseases can influence which strains become prominent in the population."

By adding dynamic social interactions to the models already used for disease outbreaks and evolution, researchers could better anticipate how a virulent pathogen strain may emerge based on how humans attempt to control the spread of the disease. This new addition to disease modelling could allow scientists to better prevent undesirable outcomes, such as more dangerous mutant strains from evolving and spreading.

The social modelling could impact public health responses to emerging infectious diseases like Ebola and Severe Acute Respiratory Syndrome (SARS). Human behaviour during these outbreaks often changes dramatically during the outbreak. People may start using face masks, or stop using them prematurely. Also, public fear of the pathogens may end up driving the wrong type of behaviour if the public's information is incorrect. The modelling could help public health responses navigate and better channel these kinds of population responses,

Bauch and his co-author Joe Pharaon formulated the new mathematical model to study the influence of social behaviour on the competition between pathogen strains with different virulence. Using computer simulations, they analyzed how the model behaved under various possible scenarios that might occur to populations to explore the logic of the hypothesis that social behaviour plays a role in the evolution of the strain.

"Human behaviour plays a big role in the spread and evolution of an infectious disease," said Pharaon,a PhD candidate at Waterloo's Faculty of Mathematics. "The model we formulated was a general model, but it could be adapted with more biological detail and structure for more specific pathogens."

An opt-out organ donation register is unlikely to increase the number of donations, according to a new study from Queen Mary University of London.

The researchers say donors should actively choose to be on the register by opting-in to ensure they genuinely want to donate their organs and to limit families from refusing the donation of their deceased relatives' organs.

An opt-out system automatically registers everyone and presumes consent to donate so if you do not want to you must take yourself off the register, whereas an opt-in system requires explicit consent to donate and indicates willingness.

However most organ donation legislative systems, whether opt-in or out, include a clause that allows the final decision to donate to be made by family members.

NHS Blood and Transplant reported in 2016 that more than 500 families vetoed organ donations since April 2010 despite being informed that their relative was on the opt-in NHS Organ Donation Register*. This translated into an estimated 1,200 people missing out on potential life-saving transplants.

Plans to introduce an opt-out system in England by 2020 have recently been announced by the government, but the researchers suggest this will create ambiguity and will not reduce veto rates.

In three experiments†, American and European participants from countries that have either a default opt-in or default opt-out system were presented with a fictional scenario and asked to take on the role of a third party to judge the likelihood that an individual's 'true wish' was to actually donate their organs, given that they were registered to donate.

Overall, regardless of which country the participants came from, they perceived the donor's underlying preference to donate as stronger under the default opt-in and mandated choice systems as compared to the default opt-out and mandatory donor systems.

The study was published in Journal of Experimental Psychology: Applied.

Lead author Dr Magda Osman, from Queen Mary University of London, said: "We show it's harder to judge the underlying wishes of the deceased if they were on an opt-out and mandatory donation register. Why? Because making a free choice indicates what your preference is. If you don't actively choose and you are listed as a donor on the register, then it isn't clear if you really wanted to donate your organs. This matters because if in the event of death your relatives have to decide what to do, they may veto the organ donation if they can't tell for sure what your underlying wishes were."

Dr Yiling Lin, also from Queen Mary University of London, added: "There are plans to launch an opt-out organ donation system in England, but what we show is that this system is unlikely to increase actual rates of organ donation or reduce veto rates, all it will do is increase the number of people on the organ donation register."

In 2017/18 there were 6,044 people in the UK waiting for a transplant while 411 patients died while waiting on this list**. Similarly, this year in the US there are 114,000 people on the waiting list to receive an organ and it is estimated that 20 people die each day while waiting on the list***.

To address problems like these, behavioural interventions, such as nudges, have been used to provide practical solutions that are based on psychological and behavioural economic research.

An example of a nudge is an automatic default, such as the ones often used in organ donation legislative system. The rationale behind an automatic default is that it can bridge the gap between a good intention and the effort needed to implement that intention into practice.

Dr Osman said: "Our findings are important because they challenge the efforts of many nudge enthusiasts to promote the use of opt-out defaults in organ donation."

She added: "To help increase actual rates of organ donation, we need more transplant coordinators working with families to help them understand the issues before being faced with a monumental and distressing decision.

"We also need to offer people a way to indicate explicitly what they wish to do. This should involve an expressed statement of intention if their wish is to donate, or an expressed statement of intention if there is an objection to donate. This reduces the ambiguity in trying to infer what one wanted to do when it comes to donating their organs."

A study of more than 1 million pregnancies in Finland reports that elevated levels of a metabolite of the banned insecticide DDT in the blood of pregnant women are linked to increased risk for autism in the offspring. An international research team led by investigators at Columbia University’s Mailman School of Public Health and the Department of Psychiatry published these results in the American Journal of Psychiatry. The study, conducted in collaboration with investigators at the University of Turku and the National Institute of Health and Welfare in Finland, is the first to connect an insecticide with risk for autism using maternal biomarkers of exposure.

Researchers identified 778 cases of childhood autism among offspring born from 1987 to 2005 to women enrolled in the Finnish Maternity Cohort, representing 98 percent of pregnant women in Finland. They matched these mother-child pairs with control offspring of mothers and offspring without autism. Maternal blood taken during early pregnancy was analyzed for DDE, a metabolite of DDT, and PCBs, another class of environmental pollutants.

The investigators found the odds of autism with intellectual disability in offspring were increased by greater than twofold for the mother’s DDE levels in the top quartile. For the overall sample of autism cases, the odds were nearly one-third higher among offspring exposed to elevated maternal DDE levels. The findings persisted after adjusting for several confounding factors such as maternal age and psychiatric history. There was no association between maternal PCBs and autism.

While DDT and PCBs were widely banned in many nations over 30 years ago, including the U.S. and Finland, they persist in the food chain because their breakdown occurs very slowly, as long as several decades, resulting in continuing exposure to populations. These chemicals are transferred across the placenta in concentrations greater than those seen in the mother’s blood.

“We think of these chemicals in the past tense, relegated to a long-gone era of dangerous 20th Century toxins,” says lead author Alan S. Brown, MD, MPH, professor of Epidemiology at Columbia University’s Mailman School of Public Health and of Psychiatry at Columbia University Medical Center. “Unfortunately, they are still present in the environment and are in our blood and tissues. In pregnant women, they are passed along to the developing fetus. Along with genetic and other environmental factors, our findings suggest that prenatal exposure to the DDT toxin may be a trigger for autism.”

The researchers offer two reasons for their observation that maternal exposure to DDE was related to autism while maternal PCB exposure was not. First, maternal DDE is associated with low birthweight, a well-replicated risk factor for autism. In contrast, maternal PCB exposure has not been related to low birthweight. Second, they point to androgen receptor binding, a process key to neurodevelopment. A study in rats found DDE inhibits androgen receptor binding, an outcome also seen in a rat model of autism. In contrast, PCBs increase androgen receptor transcription.

A lineage of type 1 dengue virus found in Brazil is able to prevail over another even though it multiplies less in vector mosquitoes and infected human cells. This discovery was made under the scope of a Thematic Project supported by the São Paulo Research Foundation - FAPESP involving several Brazilian institutions as well as a university in the United States.

According to the study, the lineage activates a weaker immune response in the patient and is less strongly combated. As a result, the virus is able to multiply more in the organism and is more likely to be transmitted to others via infected mosquitoes, so that this lineage supersedes the other owing to its significantly greater overall capacity to multiply in mosquitoes and patients.

The researchers studied lineages 1 and 6 (L1 and L6) of type 1 dengue, which affect the population of São José do Rio Preto, São Paulo State, Brazil. Their findings showed that while L1 had a superior capacity to multiply in mosquitoes and cells, L6 was able to minimize and even deactivate the human immune response, so that this lineage ended up replacing L1.

"There were three approaches to investigating the situations in which dengue virus multiplies and to explain why one lineage supersedes another. Our research brought to light a new phenomenon that explains how a virus survives in a population," said Maurício Lacerda Nogueira, a professor at the São José do Rio Preto Medical School (FAMERP), head of its Dermatological Disease Department's Virology Research Laboratory, and co-author of an article that published the results of the study in PLOS Neglected Tropical Diseases . Nogueira also chairs the Brazilian Society for Virology.

"However, knowing whether the virus multiplies more or less in mosquitoes or human cells isn't enough to understand why one lineage replaces another. We also need to know how the virus interacts with the human organism as a whole," said Nogueira.

The study produced vital new knowledge for the production of dengue vaccines. "A global understanding of how the virus interacts with the population helps us understand how vaccines work and is fundamental to our ability to design them," he said.

Type 1 dengue virus has been circulating in Brazil since the mid-1980s. Three lineages (L1, L3 and L6, all belonging to the same genotype) were introduced at different times. L6 was initially observed in São José do Rio Preto, where it began circulating in 2008. L1 was first identified in the city in 2010. These two lineages cocirculated for a period.

L1 was expected to display a higher capacity to multiply in cells and in the vector mosquito, Aedes aegypti, since it arrived after L6 and its viral fitness appeared to be superior to that of L6. L1 was therefore expected to replace L6 as the dominant strain, but it began to decline in 2013 and eventually disappeared.

This fact contradicted existing scientific knowledge about the prevalence of one lineage over another - a phenomenon called clade replacement (a clade is a branch of a phylogenetic tree comprising all organisms that have evolved from a common ancestor).

Clade replacement occurs if a lineage multiplies more in human cells after being introduced than another lineage that was already living in the same environment, or if a lineage that arrives later multiplies more in the mosquito. In both cases, the lineage that supersedes the other is said to have a higher level of viral fitness.

Epidemiological fitness

A third explanation arose from a 2015 study conducted in Puerto Rico, where a lineage of dengue virus was found to have a lower level of viral fitness than the lineages that were already in the environment yet eventually replaced them. Scientists discovered that this lineage inhibited the interferon system, which acts as the first line of defense against viruses in mammals (interferons are a complex of proteins that interfere with viral replication and protect cells from infection). This phenomenon is called epidemiological fitness - the capacity of a virus to become dominant in the field during epidemic outbreaks.

In the Brazilian case, none of this happened. The researchers first sequenced the genomes of the two viral lineages, which were found to have 47 different amino acids. Despite this significant genetic distance, L6 won the competition between them.

"Based on the information available at the time, it was assumed that L6 multiplied better and therefore became dominant, but when we looked at contaminated human and monkey cells, we found that L1 multiplied ten times more on average than L6," said the coordinator for the FAPESP Thematic Project.

The next hypothesis was that L6's higher viral fitness might be due to its higher multiplication rate in the mosquito. The researchers therefore infected captive mosquitoes (bred for use in scientific experiments) orally, having them feed by biting a membrane that contained mouse blood contaminated with dengue virus L1 and L6. "Again, L1 multiplied ten times better than L6 in the mosquito," Nogueira said.

The researchers then investigated the possibility that the captive mosquitoes were somehow different from those found in the environment. In a new experiment, mosquito eggs were collected in the environment and hatched in the laboratory. The result was the same: L1 continued to be more efficient than L6 in terms of multiplication, although studies showed that patients infected with L6 had a far higher viral load than those infected with L1.

This evidence left the epidemiological fitness hypothesis, as had been the case in Puerto Rico, where a dengue virus that encoded interferon-inhibiting RNA had been found. Interference was not confirmed in the Brazilian case. "We then realized we were dealing with a mechanism that differed from the three known ones," Nogueira said.

To solve the mystery, the researchers began studying the immunological aspects of the virus's interaction with the organism. Using computational prediction systems, they found that L1 was far more likely than L6 to activate B and T lymphocytes, the main cellular components of the adaptive immune response.

Next, in studies involving mice and cells donated by people infected with the virus, the scientists succeeded in stimulating and measuring the activation of the response by B cells and T cells, observing that L6 activated a weaker response than L1. They also measured the level of cytokines present in the patients' serum. Cytokines are signaling molecules that mediate and regulate immunity.

"Generally speaking, we observed that L1 multiplies much better but also strongly activates the immune system in both humans and mice," Nogueira said. "In other words, L1 induces a very robust response against the virus by the organism, whereas L6 multiplies less but either inhibits the immune response or stimulates it little or not at all, so the organism takes longer to recognize the virus."

As a result, the number of L6 viruses in the human organism is tenfold the number of L1 viruses on average, found the FAPESP-supported study. They also observed that L1 multiplies much more in the mosquito and replicates far more locally when it infects a person. This vigorous replication triggers strong activation of B and T cells, leading to an increase in cytokines, and this strong immune response inhibits systemic replication by the virus in the organism. As a result, the viral load is lower and dissemination to mosquitoes is reduced, so that fewer people will be infected by L1.

Despite the lower capacity of L6 to multiply in the mosquito and at the site of initial replication after a person is bitten, it produces only weak activation of B and T cells and stimulates the secretion of cytokines that inhibit the immune response instead of stimulating it.

"So systemic replication in people is much greater," Nogueira said. "This means the number of viruses in the population is higher, and more mosquitoes will be infected. We therefore concluded that the epidemiological fitness of L6 is higher than that of L1, whereas the viral fitness of L1 is higher than that of L6."

The research lasted two and a half years and involved a group of 24 scientists at several Brazilian higher education institutions in addition to FAMERP - Oswaldo Cruz Foundation, the Federal Universities of Rio de Janeiro (UFRJ) and Minas Gerais (UFMG), and São Paulo State University (UNESP) - as well as foreign collaborator Nikos Vasilakis, also a coauthor of the article and a researcher at the Center for Tropical Diseases, University of Texas Medical Branch, in Galveston (USA).

"Using epidemiological, phylogenetic, molecular and immunological analysis, the authors of the research showed that differences in the host's immune response determine the dynamics of circulation in two lineages of dengue virus found in the city, suggesting that the factors that influence the dynamics of dengue transmission are far more complex than was previously thought," Vasilakis said.