Earth

The Journal of Clinical Oncology has published the results of the largest prospective multicenter trial conducted of FDG-PET/CT in head and neck cancer, providing rigorous data about its performance. The nonrandomized phase two trial, ACRIN 6685, followed 287 patients with newly diagnosed stage T2 to T4 disease, all being considered for surgery when at least one side of the neck had no evidence of lymph node involvement based on a physical exam, preoperative MRI and/or a CT evaluation (clinically node-negative or cN0). It found that FDG-PET/CT imaging achieved a true negative in 94 percent of patients (by standardized uptake value (SUV) analysis), or 87 percent of patients (by visual assessment). The trial was designed and conducted by researchers in the ECOG-ACRIN Cancer Researcher Group with support from the National Cancer Institute, part of the National Institutes of Health.

"The information provided by FDG-PET/CT of the cN0 neck changed the surgical plan 22 percent of the time," said the study's principal investigator and lead author Val J. Lowe, MD, a nuclear medicine specialist at Mayo Clinic in Rochester, MN. "These findings suggest that FDG-PET/CT may assist the clinician in deciding on the best therapy for the clinically N0 neck in head and neck squamous cell carcinoma, possibly preventing patient morbidity and/or saving significant costs."

The reliability of FDG-PET/CT in detecting lymph node metastases in head and neck cancer is well proven and is reported to be cost-effective in staging patients with cN0 necks. Most of the data is single-institutional and retrospective. Surgeons often perform elective neck dissections in patients with cN0 necks at high risk for recurrence because clinical exam and structural imaging do not reliably identify all metastatic disease. This approach has been found to improve survival but may be associated with substantial complications for patients.

"A negative scan in the cN0 neck has been demonstrated by our study to have a very high negative predictive value," said co-principal investigator and co-author Brendan C. Stack, Jr., MD, a surgeon at the University of Arkansas for Medical Sciences. "Additionally, the positive PET leads the surgeon to consider resection of nodal levels that might harbor occult metastatic disease."

Participants older than 18 years of age with newly diagnosed, first-time head and neck squamous cell carcinoma were recruited from 22 qualified sites in the United States and one in Beijing, China. FDG-PET/CT was compared with pathology findings at neck dissection. Participants all received a pre-surgical FDG-PET/CT scan to which the surgeon was initially blinded and a contrast-enhanced MRI or CT scan of the neck (all within four weeks of surgery).

The surgical plans were devised by the local surgeons on the basis of physical examination and CT and/or MRI results, but not PET/CT and thereafter formulated with the available PET/CT result. Both plans were collected prospectively with questionnaires. All data were anonymized to protect the identities of the participants.

FDG-PET/CT scans and pathology findings were available for 270 cN0 neck sides from 212 participants. Pathology was randomly over-read by a central pathologist and all scans were reviewed by a team of central readers. For visual assessment, the negative predictive value (NPV) specific to the cN0 sides was 0.868 (95 percent CI, 0.803 to 0.925). For dichotomized maximum SUV, the NPVs specific to the nodal basins were 0.940 (95 percent CI, 0.928 to 0.952) and 0.937 (95 percent CI, 0.925 to 0.949) at prespecified cutoffs of 2.5 and 3.5, respectively. The optimal cutoff maximum SUV was determined to be 1.8, with an NPV of 0.942 (95 percent CI, 0.930 to 0.953).

The FDG-PET/CT-informed surgical treatment plan was changed in 51 of 237 participants (22 percent) compared with the PET/CT-blinded surgical plan. In 34 participants (12 percent), this led to planned dissection of additional nodal levels. In 12 participants (5 percent), this led to fewer planned dissected nodal levels. Negative PET/CT scans in N0 necks were true negative in 87 percent and false negative in 13 percent.

"This trial is an excellent example of a means to implement personalized medicine in the setting of head and neck cancer management," said Dr. Stack.

(Boston) -- Conversion therapy is a broad term used to describe practices and actions aimed at changing people's sexual orientation or gender identity - to turn anyone who doesn't identify as "straight" into a "straight" person. Historically, conversion therapies have used electroshock therapy, chemical drugs, hormone administrations and even surgery. While these extreme practices are becoming rarer, many other harmful actions are still taking place, negatively impacting both children and adolescents as well as adults in the U.S., according to a perspective in this week's New England Journal of Medicine.

Currently, only 18 states have laws banning conversion therapy in the U.S. for people younger than 18 years old. No states have bans on conversion therapies done to adults. "As a result of the lack of regulation on these "therapies" many adults and children continue to be defrauded, harmed, and traumatized in the U.S. every day," explains lead author Carl Streed, Jr., MD, MPH, FACP, a primary care physician at Boston Medical Center (BMC) and assistant professor of medicine at Boston University School of Medicine (BUSM).

According to the authors, the harm these therapies cause is well-documented, including higher rates of depression, suicidal thoughts and suicide attempts. "In addition to the health problems associated with conversion therapies, these practices also carry serious economic burdens for LGBTQ people and the country at large, including low educational achievement, lower income, and lower work performance," said Streed, who also treats patients at the Center for Transgender Medicine & Surgery at BMC.

The perspective encourages physicians to be vigilant about this issue given that many victims of conversion therapy are often silent about it. The authors highlight the importance of teaching physicians about common traits and risk factors to help them better identify patients who underwent or may be undergoing conversion therapy. They also emphasize, for medical professionals, the psychiatric illnesses conversion therapies cause, such as post-traumatic stress disorder (PTSD) that require medical attention.

Of equal importance, they also call to action medical educators to reform the curricula of medical schools and training programs to better prepare future physicians to care for LGBTQ people, including identifying and treating past trauma. There is ample evidence that current physicians are ill-equipped to help victims of conversion therapy and LGBTQ people at large. This is largely because education on LGBTQ health is not a mandated part of medical schools' curricula, and thus most doctors never learn to care for these patients general health needs properly-much less the trauma caused by conversion therapy.

"Put simply, these practices need to end," said Streed. "We need to work across sectors to focus on ensuring that all individuals of all ages receive appropriate, comprehensive care by trained medical professionals in a supportive environment."

Streed, who served as the former chair of the Massachusetts Medical Society Advisory Committee on LGBTQ Matters and the former chair of the American Medical Association Advisory Committee on LGBTQ Issues, advocates to end conversion therapy.

Patients fitted with an orthopedic prosthetic commonly experience a period of intense pain after surgery. In an effort to control the pain, surgeons inject painkillers into the tissue during the operation. When that wears off a day or two later, the patients are given morphine through a catheter placed near the spine. Yet catheters are not particularly comfortable, and the drugs spread throughout the body, affecting all organs.

Researchers in EPFL's Microsystems Laboratory are now working on a biodegradable implant that would release a local anesthetic on-demand over several days. Not only would this implant reduce patients' post-op discomfort, but there would be no need for further surgery to remove it. They developed a tiny biodegradable electronic circuit, made from magnesium, that could be heated wirelessly from outside the body.

Once integrated into the final device, the circuit will allow to release controlled amounts of anesthetic in a specific location over several days. After that, the implant will degrade safely inside the body. This research has been published in Advanced Functional Materials.

One capsule with several reservoirs

The electronic circuit - a resonant circuit in the shape of a small spiral - is just a few microns thick. When exposed to an alternating electromagnetic field, the spiral resonator produces an electric current that creates heat.

The researchers' end-goal is to pair the resonators with painkiller-filled capsules and then insert them into the tissue during surgery. The contents of the capsules could be released when an electromagnetic field sent from outside the body melts the capsule membrane.

"We're at a key stage in our project, because we can now fabricate resonators that work at different wavelengths," says Matthieu Rüegg, a PhD student and the study's lead author. "That means we can release the contents of the capsules individually by selecting different frequencies." The heat-and-release process should take less than a second.

A novel manufacturing technique

The researchers had to get creative when it came time to manufacture their biodegradable resonators. "We immediately ruled out any fabrication process that involved contact with water, since magnesium dissolves in just a few seconds," says Rüegg. They ended up shaping the magnesium by depositing it on a substrate and then showering it with ions. "That gave us more flexibility in the design stage," he adds. They were eventually able to create some of the smallest magnesium resonators in the world: two microns thick, with a diameter of three millimeters.

The team's invention is not quite ready for the operating room. "We still need to work on integrating the resonators into the final device and show that it's possible to release drugs both in vitro and in vivo," concludes Ruegg.

Groundwater - a vital source of water for drinking and irrigation across sub-Saharan Africa - is resilient to climate variability and change, according to a new study led by UCL and Cardiff University.

A consortium of 32 scientists from across Africa and beyond carried out the research, published in Nature, which shows how groundwater replenishment depends upon heavy rainfalls and flood events, amplified by climate change.

The findings are significant given the fact that 1 in 3 people currently lack access to safe water in Sub-Saharan Africa and a dramatic expansion of irrigation is required to feed growing populations.

Groundwater plays a central role in sustaining water supplies and livelihoods in sub-Saharan Africa due to its widespread availability, generally high quality, and intrinsic ability to buffer episodes of drought and increasing climate variability.

Professor Richard Taylor (UCL Geography), co-lead on the study, said: "Groundwater offers a potential pathway to sustain increases in freshwater use required to achieve UN Sustainable Development Goals 2 (zero hunger) and 6 (safe water for all)."

"Our study reveals, for the first time, how climate plays a dominant role in controlling the process by which groundwater is restocked. This improved understanding is critical for producing reliable climate change impact projections and adaptation strategies."

The research involved the collation of multi-decadal records of groundwater levels and rainfall to examine how the replenishment of groundwater has responded to variations in climate and geology. The team analysed observations compiled from nine countries across sub-Saharan Africa representing a range of climates from hyper-arid to humid.

The study shows that in humid areas groundwater is replenished primarily by rainfall that directly infiltrates the land surface, whereas in drylands it occurs predominantly by leakage from temporary streams and ponds. Local geology also plays a role in determining the sensitivity of rates of replenishment to changes in climate.

This research, supported by UK research councils (NERC, ESRC, EPSRC), the Department for International Development (DFID) and The Royal Society, also shows that, in drylands, the heavy rainfalls and flood events generating groundwater replenishment are commonly associated with climate variation phenomena such as El Niño and La Niña.

Dr Mark Cuthbert (Cardiff University), co-lead on the study, said: "Previous regional-level assessments of groundwater resources using large-scale models have ignored the contribution of leaking streams and ponds to groundwater supplies, underestimating its renewability in drylands and resilience to climate change."

"Knowledge of the replenishment process can inform strategies to enhance groundwater supplies. In drylands, where groundwater resources are often the only lasting source of freshwater, such strategies can further exploit the predictability of heavy rainfalls and flood events that generate groundwater," added Dr Cuthbert.

Add another item to the ever-growing list of the dangerous impacts of global climate change: Warming oceans are leading to an increase in the harmful neurotoxicant methylmercury in popular seafood, including cod, Atlantic bluefin tuna and swordfish, according to research led by the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Harvard T. H. Chan School of Public Health (HSPH).

Researchers developed a first-of-its-kind, comprehensive model that simulates how environmental factors, including increasing sea temperatures and overfishing, impact levels of methylmercury in fish. The researchers found that while the regulation of mercury emissions have successfully reduced methylmercury levels in fish, spiking temperatures are driving those levels back up and will play a major role in the methylmercury levels of marine life in the future.

The research is published in Nature.

"This research is a major advance in understanding how and why ocean predators, such as tuna and swordfish, are accumulating mercury," said Elsie Sunderland, the Gordon McKay Professor of Environmental Chemistry at SEAS and HSPH, and senior author of the paper.

"Being able to predict the future of mercury levels in fish is the holy grail of mercury research," said Amina Schartup, former research associate at SEAS and HSPH and first author of the paper. "That question has been so difficult to answer because, until now, we didn't have a good understanding of why methylmercury levels were so high in big fish."

It's been long understood that methylmercury, a type of organic mercury, bioaccumulates in food webs, meaning organisms at the top of the food chain have higher levels of methylmercury than those at the bottom. But to understand all the factors that influence the process, you have to understand how fish live.

If you've ever owned a goldfish, you know that fish do pretty much two things: eat and swim. What they eat, how much they eat, and how much they swim all affect how much methylmercury fish will accumulate in the wild.

Let's start with what fish eat.

The researchers collected and analyzed 30 years of ecosystem data from the Gulf of Maine, including an extensive analysis of the stomach contents of two marine predators, Atlantic cod and spiny dogfish from the 1970s to 2000s.

The researchers modeled methylmercury levels in cod based on their diet and results indicated levels were 6 to 20 percent lower in 1970 than they were in 2000. Modeled concentrations of methylmercury in spiny dogfish, however, were 33 to 61 percent higher in 1970 compared to 2000 despite living in the same ecosystem and occupying a similar place in the food web. What accounts for these differences?

In the 1970s, the Gulf of Maine was experiencing a dramatic loss in herring population due to overfishing. Both cod and spiny dogfish eat herring. Without it, each turned to a different substitute. Cod ate other small fish such as shads and sardines (small herring), which are low in methylmercury. Spiny dogfish however, substituted herring with higher in methylmercury food such as squid and other cephalopods.

When the herring population bounced back in 2000, cod reverted to a diet higher in methylmercury while spiny dogfish reverted to a diet lower in methylmercury.

There's another factor that impacts what fish eat: mouth size.

Unlike humans, fish can't chew - so most fish can only eat what fits in their mouth whole. However, there are a few exceptions. Swordfish, for example, use their titular bills to knock down large prey so they can eat it without resistance. Cephalopods catch prey with their tentacles and use their sharp beaks to rip off mouthfuls.

"There's always been a problem modeling methylmercury levels in organisms like cephalopods and swordfish because they don't follow typical bioaccumulation patterns based on their size," said Sunderland. "Their unique feeding patterns means they can eat bigger prey, which means they're eating things that have bioaccumulated more methylmercury. We were able to represent that in our model."

But what fish eat isn't the only thing that impacts their methylmercury levels.

When Schartup was developing the model, she was having trouble accounting for the methylmercury levels in tuna, which are among the highest of all marine fish. Its place on the top of the food web accounts for part of this but doesn't fully explain just how high its levels are. Schartup solved that mystery with inspiration from an unlikely source: swimmer Michael Phelps.

"I was watching the Olympics and the TV commentators were talking about how Michael Phelps consumes 12,000 calories a day during the competition," Schartup remembered. "I thought, that's six times more calories than I consume. If we were fish, he would be exposed to six times more methylmercury than me."

As it turns out, high-speed hunters and migratory fish use a lot more energy than scavengers and other fish, which requires they consume more calories.

"These Michael Phelps-style fish eat a lot more for their size but, because they swim so much, they don't have compensatory growth that dilutes their body burden. So, you can model that as a function," said Schartup.

Another factor that comes into play is water temperature; as waters get warmer, fish use more energy to swim, which requires more calories.

The Gulf of Maine is one of the fastest warming bodies of water in the world. The researchers found that between 2012 and 2017, methylmercury levels in Atlantic bluefin tuna increased by 3.5 percent per year despite decreasing emissions of mercury.

Based on their model, the researchers predict that an increase of 1 degree Celsius in seawater temperature relative to the year 2000 would lead to a 32 percent increase in methylmercury levels in cod and a 70-percent increase in spiny dogfish.

The model allows the researchers to simulate different scenarios at once. For example:

A 1-degree increase in seawater temperature and a 20-percent decrease in mercury emissions result in increases in methylmercury levels of 10 percent in cod and 20 percent levels in spiny dogfish.

A 1-degree increase in seawater temperature and a collapse in the herring population result in a 10-percent decrease in methylmercury levels in cod and a 70-percent increase in spiny dogfish.

A 20-percent decrease in emissions, with no change in seawater temps, decreases methylmercury levels in both cod and spiny dogfish by 20 percent.

"This model allows us to look at all these different parameters at the same time, just as it happens in the real world," said Schartup.

"We have shown that the benefits of reducing mercury emissions holds, irrespective of what else is happening in the ecosystem. But if we want to continue the trend of reducing methylmercury exposure in the future, we need a two-pronged approach," said Sunderland. "Climate change is going to exacerbate human exposure to methylmercury through seafood, so to protect ecosystems and human health, we need to regulate both mercury emissions and greenhouse gases. It is important also to remember that fish are a very healthy food overall and when people switch away from fish in their diet they generally pick less healthy alternatives. We can all agree less methylmercury in these fish in the future would be a good thing."

First-ever study to examine gun control effects on urban and suburban/rural firearm homicide rates finds different laws are more effective in different areas.

After 34 people were killed in mass shootings in El Paso, Texas, and Dayton, Ohio, this past weekend, bipartisan legislation for universal background checks is gaining traction in the US Senate. Now, a Boston University School of Public Health (BUSPH) study finds that laws restricting who can have a gun are most effective in reducing firearm homicides, but that different laws are more effective in urban and in suburban/rural areas.

The study, published in the Journal of Rural Health, found that universal background checks came with a 13-percent reduction in urban firearm homicide rates but had no association with suburban/rural rates, while laws that disqualify people with violent misdemeanor convictions from purchasing firearms came with 30-percent lower rates in suburban/rural areas but not urban areas. Requiring permits to buy and carry guns was associated with 21-percent lower firearm homicide rates in cities and 20-percent lower rates in suburban and rural areas.

"Taken together and viewed in light of previous research, these findings suggest that a set of laws designed to keep firearms out of the hands of people who are at high risk for violence (especially those with a history of violence) could be effective at substantially reducing overall population rates of firearm homicide," says study lead author Dr. Michael Siegel, professor of community health sciences at BUSPH.

The researchers used the State Firearm Law Database (a public access database created by the BUSPH team) and data from the FBI and the US Census to look at 48 states from 1991 to 2016, and compared firearm homicide rates in large cities (those with more than 100,000 people in 1990) and in all geographic areas outside of those cities.

They also found an association between stringent "may issue" laws, which require concealed carry permit applicants to show why they need to carry a concealed firearm, and a 17-percent lower urban firearm homicide rate.

Novel approaches that have been tested to treat obesity include noninvasive neuromodulation techniques such as transcranial direct current stimulation (tDCS). Studies performed to date have suggested that this method does in fact help reduce appetite, food intake and body weight, but only in some subjects.

New findings published in the journal Appetite by researchers at the University of São Paulo (USP) in Brazil help elucidate the reason for the variability in responses to tDCS treatment.

"The patient's genetic profile, especially variations in the gene COMT, appears to be a key factor in determining the outcome," Priscila Giacomo Fassini, first author of the article, told.

During her postdoctoral research at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP), Fassini conducted a double-blind sham-controlled randomized clinical trial to test the efficacy of tDCS in reducing appetite and weight, with São Paulo Research Foundation - FAPESP's hsupport. In double-blind randomized clinical trials, considered the gold standard for assessing new therapies, volunteers are divided randomly into two groups, and neither they nor the researchers know who receives the treatment or intervention versus the sham treatment or placebo. Fassini's study was supervised by Vivian Marques Miguel Suen a professor in FMRP-USP's Department of Internal Medicine.

In tDCS, two electrodes (a cathode and an anode) are placed on the scalp and are connected to a small portable device, generating a galvanic current that alters the brain's electrical activity in the area of interest. In the case of obesity, the aim is to modulate neuron excitability in the left dorsolateral prefrontal cortex.

"In our trial, we used a current of only 2 milliamperes, which is too weak to be felt by patients," Fassini said. Sham stimulation (placebo group) involved the same procedure, but the current lasted only 30 seconds, a timeframe that is too short to affect neurons.

Starting with a base sample of almost 9,000 volunteers, the researchers selected 38 women who were 20-40 years old as participants in the clinical trial. For all subjects, body mass index (BMI) was between 30 and 35, corresponding to class 1 (mild) obesity.

"The criteria for inclusion were rigorous. We excluded pregnant women and people who were using medications or had significant medical conditions that could influence the results. In addition, because the third stage of the trial involved hospitalization for two weeks, not all those who applied and were eligible had the free time to participate," Fassini said.

The selected volunteers were given 17 thirty-minute sessions of tDCS over the course of a month. Appetite and weight were monitored for six months. According to Fassini, previous trials had only investigated the immediate effects of tDCS on appetite, involved fewer sessions, and performed no follow-up.

The clinical trial comprised four stages. In the first stage, the volunteers were given a single tDCS session and then immediately took a test measuring working memory, the memory system that temporarily stores information for use in specific tasks. According to Fassini, the aim was to confirm that the correct brain region was being stimulated, since the left dorsolateral prefrontal cortex is associated with both working memory and the regulation of appetite.

In both cases, there is evidence that the effects of neuromodulation are mediated by the release of dopamine, a substance produced by neurons (neurotransmitters).

"Dopamine plays a crucial role in the regulation of food reward, feeding and body weight," Fassini said. "It's well established in the literature that palatable foods activate the brain's reward system, contributing to dopamine release. Neuromodulation is apparently capable of mimicking this effect."

In stage two, the volunteers were given ten tDCS sessions (once a day in the morning, Monday-Friday) and then returned to their normal routines after each intervention. In stage three, volunteers were admitted to the hospital for two weeks and were placed on supervised, individualized low-calorie diets with a 30% reduction in energy intake. During this period, they were also given six more tDCS sessions (on Mondays, Wednesdays and Fridays).

The fourth stage consisted of weight and appetite monitoring for six months after the end of the intervention period. The effects of the treatment on appetite during and after neuromodulation were measured using standard scales for the assessment of hunger, fullness, desire to eat, and prospective food consumption.

Analysis of results

After completing data collection in Brazil, Fassini traveled to the US for a research internship at Harvard Medical School that was supported by FAPESP. The results were analyzed under the supervision of Professor Miguel Alonso-Alonso, one of the pioneers of obesity treatment using tDCS. Júlio Sérgio Marchini (FMRP-USP), Sai Krupa Das (Tufts University, Boston) and Greta Magerowski (Harvard Medical School) also participated in the analysis.

Genomic DNA obtained from whole blood samples taken during stage one was sequenced to genotype the volunteers. Because dopamine is known to be important for the tDCS mechanism of action, the research group decided to investigate variations (polymorphisms) in the gene COMT, which encodes catechol-O-methyltransferase, an enzyme that plays a critical role in the degradation of dopamine in the prefrontal cortex.

"Previous research showed that a polymorphism called Valine158Methionine [Val158Met] affects the enzyme's activity and makes it less effective at degrading dopamine. The availability of extracellular dopamine in the prefrontal cortex is higher in people with this variant of the COMT gene," Fassini said.

The results of her trial did, in fact, point to a significant reduction in appetite over time only in individuals with the Met allele of COMTwho also received active neuromodulation treatment. "These individuals responded better to treatment because of higher dopamine availability, displaying lower levels of hunger, less desire to eat, and less prospective food consumption over time," Fassini said.

However, the most striking discovery from the clinical trial, she continued, was the paradoxical effect observed in noncarriers of the COMT Met allele. In these women, tDCS had the opposite effect, increasing their hunger, desire to eat and food consumption throughout the intervention period.

"This paradoxical effect was consistently seen in repeated assessments. It was only present immediately before tDCS, i.e., 23 h after the administration of the previous tDCS session, not acutely after stimulation. The potential mechanisms underlying this effect are unclear," Fassini said.

The results also showed a correlation between performance in the working memory test during stage one and a COMT genotype-dependent subsequent appetite change. "Speed improvements during the memory tests predicted increased appetite in Met carriers and reduced appetite in Met noncarriers," Fassini said.

The effect of the treatment on body weight is still being analyzed and will be the focus for an article to be published shortly. "We did not observe a substantial difference between the groups during the intervention period, which was expected because all participants had a supervised diet. However, we're finding differences in body weight maintenance during the six-month follow-up period," Fassini said.

She and her colleagues continue to follow the same group of volunteers, and the study will soon complete one year. "These first results help us understand why only some people respond to treatment with tDCS. We saw that differences in genotype affect the availability of dopamine and greatly influence the effect of neurostimulation," she said. "There may be other factors, and this possibility will be investigated in future studies."

Another question is whether the alterations in brain functioning induced by neuromodulation entail long-term changes to cerebral plasticity (how the brain is organized). Answers to questions such as these will be vitally important if the technique is to be prescribed safely and effectively as part of the treatment of obesity, Fassini stressed.

Although tDCS is still considered experimental in this context, it has been used to treat neuropsychiatric conditions such as depression and schizophrenia. The method is considered safe and has no known side effects.

New research led by Carnegie Mellon University and the University of Rochester Medical Center indicates that concussions aren't the sole cause of damage to the brain in contact sports. A study of college football players found that typical hits sustained from playing just one season cause structural changes to the brain.

The researchers studied 38 University of Rochester players, putting accelerometers -- devices that measures accelerative force -- in their helmets for every practice and game. The players' brains were scanned in an MRI machine before and after a season of play.

View video: Routine Football Hits Cause Damage to the Brain

While only two players suffered clinically diagnosed concussions during the time they were followed in the study, the comparison of the post- and pre-season MRIs showed greater than two-thirds of the players experienced a decrease in the structural integrity of their brain. Specifically, the researchers found reduced white matter integrity in the midbrain after the season compared to before the season. Furthermore, and indicating the injury was specifically related to playing football, the researchers found the amount of white matter damage was correlated with the number of hits to the head players sustained.

The study is published in the journal Science Advances.

"Public perception is that the big hits are the only ones that matter. It's what people talk about and what we often see being replayed on TV," said senior study author Brad Mahon, an associate professor of psychology at Carnegie Mellon and scientific director of the Program for Translational Brain Mapping at the University of Rochester. "The big hits are definitely bad, but with the focus on the big hits, the public is missing what's likely causing the long-term damage in players' brains. It's not just the concussions. It's everyday hits, too."

The midbrain, located in the center of the head and just beneath the cerebral cortex, is part of a larger stalk-like rigid structure that includes the brain stem and the thalamus. The relative rigidity of the midbrain means it absorbs forces differently than surrounding softer tissues, making it biomechanically susceptible to the forces caused by head hits. The midbrain supports functions like eye movements, which are impacted by concussions and hits to the head. While head hits are known to affect many parts of the brain simultaneously, the researchers decided to focus the study on the midbrain, hypothesizing that this structure would be the "canary in the coal mine" for sub-concussive hits.

"We hypothesized and found that the midbrain is a key structure that can serve as an index of injury in both clinically defined concussions and repetitive head hits," said Adnan Hirad, an M.D./Ph.D. candidate at the University of Rochester's Medical Scientist Training Program and lead author of the study. "What we cataloged in our study are things that can't be observed simply by looking at or behaviorally testing a player, on or off the field. These are 'clinically silent' brain injuries."

Each player in the study received an MRI scan within two weeks of the start of each season and within one week at the end. The helmet accelerometers measured linear and rotational acceleration during all practices and games, recording all contact that produced forces of 10 gs or greater. Astronauts on the space shuttle experienced 3 gs during lift-off. Race car drivers feel the effects of 6 gs, and car crashes can produce brief forces of more than 100 gs.

The 38 NCAA Division III players experienced nearly 20,000 hits across all practices and games. Of those hits, the median force was around 25 gs, with half of the hits exceeding that amount. Only two of the nearly 20,000 hits resulted in concussions.

"We measured the linear acceleration, rotational acceleration and direction of impact of every hit the players sustained. This allowed us to create a three-dimensional map of all of the forces their brains sustained," Hirad said.

The MRI scans measured structural changes in the brain that took place over the course of each season. They found that rotational acceleration (impact causing the head to twist) more so than linear acceleration (head-on impact) is correlated with the observed changes in the structural integrity of white matter in the midbrain.

"This study suggests that midbrain imaging using diffusion MRI might be a way in the future to diagnose injury from a single concussive head hit and/or from repetitive sub-concussive head hits," said Dr. Jeffrey Bazarian, professor of Emergency Medicine, Neurology, Neurosurgery and Public Health Sciences at the University of Rochester Medical Center and a co-author of the study.

The second part of the study served as an independent means to validate the researchers' approach to the football cohort. This group included 29 athletes from various other contact sports who had a clinically defined concussion and 58 who didn't.

The concussed participants underwent MRI scans and offered blood samples within 72 hours of injury. Like the football cohort, those players exhibited reduced structural integrity in the midbrain. In addition, they exhibited increased tau, a protein, in their blood. As structural integrity in the brain decreases, tau increases.

"Tau is an important marker of acute changes in the brain and is thought to be, in the long term, implicated in neurodegenerative diseases like chronic traumatic encephalopathy, also known as CTE," Hirad said.

Given this new insight on repetitive head hits, what should we do?

"Our research, in the context of prior research over the past several years, is beginning to indicate that the accumulation of many sub-concussive hits is instrumental in driving long-term damage in football players' brains," Mahon said. "Future research will be required in order to translate our findings into concrete directives that are relevant to public health. An important direction for future research will be to carry out larger-scale longitudinal studies of contact sports athletes in various ages groups."

"We also need to re-evaluate how we make return-to-play decisions," Hirad said. "Right now, those decisions are made based on whether or not a player is exhibiting symptoms of a concussion like dizziness or loss of consciousness. Even without a concussion, the hits players are taking in practice and games appear to cause brain damage over time."

Blue sharks use large, swirling ocean currents, known as eddies, to fast-track their way down to feed in the ocean twilight zone--a layer of the ocean between 200 and 1000 meters deep containing the largest fish biomass on Earth, according to new research by the Woods Hole Oceanographic Institution (WHOI) and the Applied Physics Lab at the University of Washington (UW). Their findings were published August 6, 2019, in the journal Proceedings of the National Academy of Sciences.

Researchers tagged more than a dozen blue sharks off the U.S. Northeast Coast and monitored them for nine months. The tags relayed data back to the researchers via satellite, revealing that the sharks had spent a good portion of their days diving these whirling pockets of warm water down to the ocean twilight zone hundreds of meters below the surface. There, they'd spend an hour or so foraging for food like small fish and squid before returning to the surface to warm up before diving again.

Dives were less frequent at night, when many twilight zone animals make their daily migration from the ocean's mid-water to feed at the surface. Camrin Braun, an ocean ecologist at UW and lead author of the study, said that an evening trip likely isn't worth the effort for hungry blue sharks since the zone isn't particularly well stocked after dark.

Braun, who conducted the research as a PhD student in the MIT-WHOI Joint Program in Oceanography, says the behavior of the blue sharks was generally similar to that of the white sharks the team tracked in a previous study last year. However, the two species had different preferences when it came to water temperature. White sharks, which are warm-blooded animals, used a combination of warm and cold-water eddies as a conduit to the twilight zone, while blue sharks--a cold-blooded species--relied exclusively on warm-water eddies.

"Blue sharks can't regulate their body temperature internally to stay warmer than the ambient seawater like white sharks can," said Braun. "We think this is why they show a clear preference for the warm-water eddies--it removes a thermal constraint to deep diving."

Blue sharks are considered a "near threatened" species due to heavy fishing pressure on populations across the globe. This research helps fill important knowledge gaps about where they go and why, which can inform decision making to help protect them, said biologist Simon Thorrold, a coauthor of the study and Braun's former advisor.

The work also underscores the importance of the ocean twilight zone as a critical biomass resource.

"The twilight zone is vulnerable to overfishing," Thorrold said. "If we're harvesting low-value fish there at the expense of high-value fish like blue sharks and other pelagic predators, that's probably not a good tradeoff."

New Rochelle, NY, August 5, 2019-Researchers have developed a simple, fast, and standardized method for measuring phage virulence quantitatively, which can expediate phage therapy development by allowing robust individual and combined testing of phage efficacy. The method, which takes into account all factors affecting virulence, is published in a preview issue of PHAGE: Therapy, Applications, and Research, a new peer-reviewed journal from Mary Ann Liebert, Inc., publishers launching in early 2020. Click here to read the full-text article free on the PHAGE website.

In the article entitled "The Virulence Index: A Metric for Quantitative Analysis of Phage Virulence," Dominic Sauvageau, PhD and coauthors from University of Alberta, Edmonton, Canada demonstrate their standardized quantitative method and discuss its implications. They use the method to evaluate the virulence of phages used in specific combinations. The method can not only be used to facilitate and standardize screening steps in selecting phage for certain applications, but it is also useful for evaluating mutations or changes to virulence. For production quality control purposes it can be used to benchmark different phages or production batches.

"This paper is exciting as it describes a method to allow phage researchers to robustly measure and compare phage and phage combination 'efficacy' - it is less subjective than existing methods and should allow better comparisons between different laboratories," says Martha Clokie, PhD, Editor-in-Chief of PHAGE and Professor of Microbiology, University of Leicester (U.K.).

Tumor cells circulating in blood are markers for the early detection and prognosis of cancer. However, detection of these cells is challenging because of their scarcity. In the journal Angewandte Chemie, scientists have now introduced an ultrasensitive method for the direct detection of circulating tumor cells in blood samples. It is based on the amplified, time-resolved fluorescence measurement of luminescent lanthanide ions released from nanoparticles that bind specifically to tumor cells.

Conventional techniques for the detection of circulating tumor cells require complicated enrichment before detection because a sample of 10 million blood cells only contains about one tumor cell. In contrast, the new method developed by a team working with Xiaorong Song, Xueyuan Chen, and Zhuo Chen, at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fujian Agriculture and Forestry University, and Fujian Cancer Hospital (Fuzhou, Fujian, China), works with no enrichment step and directly detects circulating tumor cells in blood samples. The technique is based on a so-called "dissolution-enhanced time-resolved photoluminescence" and uses fluorescing nanoparticles made of lanthanide europium complex.

First the researchers produced antibodies against the epithelial cell adhesion molecule (EpCAM, which is a glycoprotein that is present in very high numbers on the surfaces of many tumor cells and acts as a diagnostic marker for cancer). These antibodies were applied as a coating in the wells of microplates, causing tumor cells contained in the blood sample to remain stuck deep in the wells as other blood components were removed.

The scientists coated the europium-containing nanoparticles with the same antibodies. This caused large numbers of the nanoparticles, added in solution, to specifically bind to the tumor cells. A subsequently added "developer" dissolved the nanoparticles, releasing myriad europium ions. These were immediately bound and tightly locked up by other components of the developer solution. This resulted in a manifold amplification of the fluorescence.

Another essential advantage of this method is that europium ions are very long-lived fluorophores that continue to fluoresce for several microseconds after excitation with a flash of light. Because the measurements are time-resolved, it is possible to start the measurement with a delay. Background signals caused by the autofluorescence of cell components only continue for a few nanoseconds and fade before the measurement begins. This increases the sensitivity of the measurements, making it possible for the researchers to detect a single tumor cell per microplate well.

Tests with blood samples from cancer patients registered as few as 10 cells per milliliter of blood. Fourteen out of fifteen cancer patients were correctly identified by this new method. The number of tumor cells in the samples correlated strongly with the stage of cancer in each patient.

Cancer treatment often involves a combination of chemotherapy and radiotherapy. Chemotherapy uses medication to stop cancer cells reproducing, but the medication affects the entire body. Radiotherapy uses radiation to kill the cancer cells, and it is targeted to the tumour site. In a recent study, published in the journal EPJ D, researchers from the Leopold-Franzens-University Innsbruck, in Innsbruck, Austria, studied selected molecules of relevance in this context. They wanted to see how these molecules were individually affected by radiation similar to that used in radiotherapy.

Certain molecules found in common chemotherapy drugs are known for being radiosensitisers, which means they increase the DNA damage and tumour cell killing rates of radiotherapy. Other types of molecules in chemotherapy drugs have the effect of preventing DNA from being duplicated and repaired. In particular one process which is important for the interaction of such radiation with the molecules of interest is ionization. Ionization happens when a radiation particle collides with a molecule, and subsequently an electron is expelled from the molecule.

One main finding of the study was that the presence of water, which is usually the case in biological matter, can affect the ionization process a lot. This is important because many experiments simulating such radiation damages are conducted in the gas phase. 'However, to describe this process in a more realistic setting, the aqueous environment needs to be taken into account,' says co-author Stefan Huber. The authors hope the results will eventually help to improve the way radiation is used for cancer treatment.

Stereotypically viewed as passive and immobile, a University of Otago, New Zealand, pilot study has shown the powerful influence music and dance can have on older adults with dementia.

Researchers from the Department of Dance and Department of Psychological Medicine used familiar, reminiscent music and the natural gestures of a group of 22 participants to create an original series of dance exercises.

Lead author Ting Choo, Dance Studies Masters graduate, says the aim was to promote a better quality of life for people with dementia by providing memory stimulation, mood moderation and social interaction.

Performed over 10 weekly sessions, the intuitive movement re-embodiment (IMR) programme provided humour, imagination, and intuition which motivated the participants to dance and interact with joy.

The study results, published in the American Journal of Alzheimer's Disease & Other Dementias, show participants reported significant improvements in their quality of life after session six.

"They responded to the music greatly and showed enthusiasm in moving to the music regardless of their physical limitation. Positive responses such as memory recalling, spontaneous dancing and joking with each other were observed in every session.

"These observations have certainly reversed the stereotypical understanding of this group of people being passive and immobile. The music stimulates their responses much better than verbal instructions," Ms Choo says.

The researchers now intend to expand the pilot study, refining and enlarging the IMR programme to better cater to the needs and conditions of the participants.

Ms Choo hopes further research will gain the programme support and recognition from the medical community.

"There is scope for future exploration of creativity and dementia."

She believes the use of arts, including painting, music, drama and dance, has been undervalued in the clinical field, due to a lack of standardized conduct and consistent study results.

"As a former dancer and current dance educator, I understand the 'less important role' of arts in the society, as well as the insignificant therapeutic effects of music and dance for dementia, when compared to clinical research of much larger scale," she says.

A new study of 38,537 persons of European ancestry suggests that a rare variation of a gene called APOE may be protective and prolong life, in sharp contrast to a more widely studied APOE variant that increases risk of death.

The findings by the E2-CHARGE consortium of investigators, led by senior investigator Sudha Seshadri, M.D., of UT Health San Antonio, suggest new research directions that “could lead to novel preventive and treatment options for a wide variety of conditions to promote healthy aging and longevity,” the team wrote.

The findings were published July 29 in the journal PLOS ONE. Dr. Seshadri is professor of neurology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio and founding director of the university’s Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.

APOE and its variants

APOE, a gene located on human chromosome 19, contains the instructions to make apolipoprotein E, a protein that regulates lipid transport and uptake. APOE’s alleles (multiple forms of the gene that are inherited from parents or arise out of mutation) include APOE-epsilon 2 (ε2), APOE-ε3 and APOE-ε4.

Studies long have associated APOE-ε4 with increased risk of Alzheimer’s disease and death. The new study confirmed this. Little was known about APOE-ε2, a rare variant found in only 1% of the population, however.

To learn more, E2-CHARGE examined data from six population-based studies conducted in the U.S., Iceland and the Netherlands. These included the Framingham Heart Study, for which Dr. Seshadri is senior investigator. During a mean follow-up period of 11.7 years, 17,021 individuals died. The researchers found that APOE-ε2 prolonged survival. Results were similar across the six study populations.

Limitations

The researchers said larger studies should be carried out to understand this protective variant of APOE.

Because the study was conducted only in people of European ancestry, its results may not be applicable to other ethnic groups, the researchers said.

Dr. Seshadri and Xianlin Han, Ph.D., professor in the Department of Medicine and the Sam and Ann Barshop Institute for Longevity and Aging Studies at UT Health San Antonio, received a grant in 2018 to understand why APOE-ε2 protects a person from dementia and death.

Ocean acidification is bad news for shellfish, as it makes it harder for them to form their calcium-based shells. But climate change could also have multiple other impacts that make California bays less hospitable to shelled organisms like oysters, which are a key part of the food web.

Changes to water temperature and chemistry resulting from human-caused climate change could shrink the prime habitat and farming locations for oysters in California bays, according to a new study from the University of California, Davis.

The study, published today in the journal Limnology and Oceanography, shows that changes to dissolved oxygen levels, water temperature, and salinity could have an even greater impact than ocean acidification on oyster growth in estuaries and bays.

"The study demonstrates that focusing on ocean acidification alone is misguided," said UC Davis Professor Ted Grosholz, who led the study with funding from California Sea Grant. "Many climate-related stressors contribute to the projected shrinkage of the estuarine zone, where oysters and likely other shellfish would need to flourish."

WHAT'S DIFFERENT ABOUT ESTUARIES

California is home to two oyster species, whose primary habitats are partially enclosed estuaries and bays like Tomales Bay, where Grosholz and colleagues focused their research. The native Olympia oyster is an important foundation species for marine ecosystems, providing structure and food upon which other species rely. The Pacific oyster, though not native to California, is commonly farmed for food in the state, supporting a $25-million industry.

The growing problem of ocean acidification--caused by increased carbon dioxide (CO2) in the atmosphere--has been a subject of concern among oyster growers and biologists in California.

In the estuaries and bays where oysters grow, ocean acidification is a much more complicated process than in the open ocean. Out at sea, the process of ocean acidification is mostly driven by atmosphere CO2 - as concentrations go up in the atmosphere, more CO2 dissolves into the water, making it more acidic.

What's different about estuaries, said Grosholz, is there are lots of other inputs that can influence acidity.

"In an estuary, you have freshwater coming down from rivers, and there are plants, macroalgae, and phytoplankton that are much more abundant and greatly influence pH," he said.

This leads to daily cycle of changes in pH (the measure of acidity) that can far exceed pH changes in the ocean.

Estuarine organisms have evolved with this variable pH regime, which could make them more resilient to ocean acidification. But other factors important to oyster health, such as temperature, salinity, and dissolved oxygen, are also projected to change with climate change.

EXPLORING IMPACTS

Grosholz started the research project in 2014 with UC Davis researcher Ann Russell to explore the impacts of acidification in estuaries and tease out other potential climate change impacts on oyster growth and health.

From 2014 to 2017, the researchers planted juvenile oysters of both species in test beds at nine different locations in Tomales Bay. They monitored their health over one-month periods, during a variety of seasonal conditions. At the same time, they closely monitored water chemistry, temperature, and other conditions at each location, and measured the growth and mortality of the oysters.

They also conducted field experiments with oyster larvae to see how the variations in conditions affected survival and settlement--the process by which shellfish change from free-floating larvae and settle on a hard surface.

A STRESSFUL COMBINATION OF THREATS

The study found that the lowest oyster growth and survival rates were in the parts of the bay most impacted by river runoff and inflow of upwelled ocean waters. While oyster growth and survival rates were better in the spring and summer, upwelled ocean waters low in dissolved oxygen and pH were also detrimental to the oysters.

In California, climate change is expected to lead to increased variability in precipitation, higher water temperatures, and increased upwelling. The study suggests that this combination of effects would lead to greater stress on oysters, particular at the edges of bays that connect to rivers and the ocean.

"This means the oysters will be getting squeezed at both sides, reducing the zone of habitat they can thrive in," said Grosholz.

The study provides insight for oyster restoration projects as well as commercial oyster farmers. For example, projections for suitable oyster habitat could help determine where to site projects and farms for the best chance of success.

"Oysters settle to rocks so they cannot move and track changing water conditions like some other organisms," said UC Davis graduate student Jordan Hollarsmith, who is first author of the study. "The goldilocks zones within California estuaries, where conditions are just right for maximum growth and survival, are incredibly important for the economic success of farmed oysters and the ecological success of native oysters. Our findings help us to understand the environmental factors that make these zones so favorable, which will aid in restoration and aquaculture efforts."