Culture

New research from the Prevention Research Center of the Pacific Institute for Research and Evaluation examines whether recreational marijuana legalization in Oregon and marijuana and alcohol retail outlet density levels are associated with co-use and beliefs supportive of use of each among teens.

Using data from 11th graders who participated in the Student Wellness Survey from 2010-2018, researchers assessed past-30-day co-use changes in counties with low, medium, and high densities of licensed marijuana and alcohol outlets.

Findings include:

A significant post-legalization increase in past-30-day co-use in 2016 in counties with the highest retail outlet density.

Significant post-legalization increases in perceived risk and parent approval of alcohol and marijuana use.

Legalization and greater retail availability of both marijuana and alcohol were positively associated with co-use among teens, and beliefs favorable to alcohol and marijuana use.

Says lead author, Dr. Grisel García-Ramírez: "Our results suggest that adolescents living in communities with greater retail availability of recreational marijuana and alcohol may have greater indirect access to these substances through diversion, as it is illegal for them to purchase and use them. So, their primary sources are likely to be social rather than commercial."

(Singapore--January 30, 2021 11:00 p.m. SPT/January 30, 2021 10:00 a.m. EST)-- Primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study revealed that neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients and met its primary endpoint of 20% major pathologic response rate, according to research presented today at the International Association for the Study of Lung Cancer's World Conference on Lung Cancer.

Dr. Jay M. Lee, chief, Division of Thoracic Surgery at Ronald Reagan UCLA Medical Center in Los Angeles, today reported on results from a study of 181 patients with stage IB to IIIB non-small cell lung cancer (NSCLC) who each received 1,200 mg of neoadjuvant atezolizumab intravenously every three weeks for two cycles followed by resection. Atezolizumab is a monoclonal antibody that was approved by the US Food and Drug Administration in 2020 for the first-line treatment of adult patients with metastatic NSCLC.

Dr. Lee reported earlier that small pilot studies (N Engl J Med. 2018;378:1976) have shown preoperative immune checkpoint inhibitor therapy may be of benefit in resectable NSCLC. Dr. Lee stated that "the LCMC3 study is the largest, monotherapy trial of checkpoint inhibition in resectable NSCLC and is a landmark study to compare future results."

Patients received neoadjuvant atezolizumab for two cycles, followed by resection between 30 and 50 days from the first cycle. Patients who benefitted from the therapy continued adjuvant atezolizumab for 12 months. The primary endpoint was major pathologic response (MPR; less than or equal to 10% viable tumor cells at surgery) in patients without EGFR or ALK mutations.

Of the 181 patients enrolled, the median age was 65 years; 51% were female, 90% were current/former smokers, and 62% had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB; 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

In patients without EGFR/ALK mutations who underwent surgery, the major pathologic response rate was 21% (30/144; 95% CI: 14%-28%) and the pathologic complete response rate was 7% (10/144; 95% CI: 3%-12%).

"It is important to recognize that the preoperative and intraoperative unresectability rates in LCMC3 are comparable to historical neoadjuvant chemotherapy trials and should not raise concern," said Dr. Lee. Following atezolizumab, unresectability was detected preoperatively in only 22 out of 181 (12%) and intraoperatively in 7 out of 159 (4%). The majority of patients (151/159; 95%) had anatomic oncologic resections and only 15 out of 101 (15%) converted to thoracotomy. Pathologic downstaging was seen in 66 out of 155 (%). Only 19 out of 159 (12%) had surgery outside of protocol window.

Intraoperative complications were rare (5/159; 3%) and 145 out of 159 (92%) had complete (R0) resection. Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen. Mortality for 30 days and 30 to 90 days were each 1 out of 159 (0.6%).

"Following neoadjuvant atezolizumab, resection was performed safely with low perioperative morbidity and mortality soon after completion of neoadjuvant therapy, infrequently outside of the protocol window, and with high complete resection rates," Dr. Lee said. "These findings represent the primary analysis of the completed LCMC3 study and are consistent with our previous results, including a preliminary report on a portion of these patients [in] 2019."

"The integration of immunotherapy and targeted therapies in the multidisciplinary approach of early-stage NSCLC represents a priority," said Dr. Scagliotti, interim IASLC CSO. "The IASLC is currently engaged in fostering the international collaboration through multiple initiatives."

CHICAGO (January 30, 2021) -- Select patients born with heart defects and who undergo congenital heart surgery recover with few complications and reduced opioid use when a comprehensive, evidence-based enhanced recovery after surgery (ERAS) program is used, according to research presented at the 57th Annual Meeting of The Society of Thoracic Surgeons.

"We have embarked on a new paradigm for patient care with the goal of improving recovery, patient experience, and the value of care that we provide," said Nathalie Roy, MD, from Boston Children's Hospital in Massachusetts. "The early findings show promise that such programs can be a game-changer in cardiovascular care."

Dr. Roy and colleagues collected data from eligible patients who had elective surgery for simple or moderately complex congenital heart defects at Boston Children's Hospital from October 2018 to February 2020. During the study period, 559 patients underwent congenital heart surgery as part of a protocol-driven, multidisciplinary ERAS cardiac surgery program. The ERAS patients were identified before surgery, while the decision to remain in the program was based on surgical results.

The patient outcomes were reviewed by implementation period (P1): October 2018 to February 2019, and the early experience period (P2): March 2019 to February 2020.

Overall, researchers found that several factors significantly improved from P1 to P2, as the program became more sophisticated and advanced with time, familiarity, and experience. The study showed an increase in operating room extubation, which is the removal of the breathing tube, with 27% of P2 patients being extubated in the OR versus 16% of P1 patients. Patients in the P2 group also experienced shorter ventilation time in the intensive care unit (ICU): 6.1 hours for P2 versus 7.6 hours for P1.

In general, the ICU and postoperative lengths of stay were not significantly different between the two groups, except in the case of lower-risk procedures. Congenital heart operations are grouped by complexity of the procedure in what is known as STAT Categories. STAT Category 1 includes the least complex operations, and STAT Category 5 includes the most complex operations. For STAT Category 2 operations, fewer hours were spent in the ICU: 25.7 hours for P2 patients versus 34.6 hours for P1.

Importantly, the data also demonstrated excellent pain control with an opioid-sparing approach that included adjunct medications and regional anesthetic approaches in certain cases. Reducing opioid utilization has potential benefits for quickening recovery, while research studying regional anesthesia is ongoing at Boston Children's Hospital.

Further, the study showed steady low rates of complications, reoperations, or readmissions.

"Our program defined a comprehensive approach of care throughout the surgical journey," said Dr. Roy. "We were able to remove the breathing tube earlier after surgery and manage pain well with opioid-sparing strategies--these are key components of an enhanced recovery program after congenital cardiac surgery."

ERAS is a set of predetermined activities, steps, and guidance designed to achieve quicker recovery and the best possible outcomes for patients undergoing major surgery. First popularized in Denmark in the 1990s, it since has become more accepted. Over the past several years, ERAS protocols have been incorporated into many surgical specialties, with congenital heart surgery now joining the movement.

"ERAS has been shown to improve important metrics in perioperative surgical care and result in beneficial patient outcomes," said Lauren C. Kane, MD, from Children's Hospital New Orleans in Louisiana, who was not directly involved in this research. "Through the work of Dr. Roy and colleagues, using ERAS programs with pediatric and adult congenital heart patients is closer to universal adoption throughout the country."

Even with the encouraging early results of this step-based approach, the researchers acknowledged that there still is much to do. For example, despite using this comprehensive ERAS program, compliance and use were not optimal for all steps of the program. The challenges of introducing new protocols in a large institution are many, but the regular feedback reviews with multidisciplinary team members are critical to improving the program, compliance, and provider acceptance. In addition, empowering patients and their families by providing education before and throughout the program also is important.

However, this ERAS program, in the early stages, showed promise for decreased variability in care, the optimization of resource use, and expedited recovery after surgery--all of which ultimately have the potential to enhance overall family and patient experiences and improve patient outcomes.

Launched in 2018, the ERAS Cardiac Program at Boston Children's Hospital involves all phases of the patient's surgical care, from before surgery to at-home postsurgical follow-up. The program offers important strategies such as less fasting, multiple approaches to treat pain, smaller surgical incisions when appropriate, blood conservation, early extubation, removal of lines, tubes, and catheters as soon as possible, getting out of bed early after surgery, and a quick return to a normal diet. Expanded surgical follow-up with early virtual visits and patient reported outcomes surveys to monitor for complications also are included in the program.

The Boston Children's ERAS program continues to evolve based on feedback collected in monthly quality improvement meetings. In addition, in order to help enable lasting programmatic improvements, Dr. Roy and colleagues created an interactive dashboard, which is connected to the Boston Children's Hospital ERAS Database. The dashboard, updated in real time, allows visualization of performance metrics that can be filtered by parameters such as age group and surgical complexity for in-depth analyses.

"An ERAS program requires institutional commitment and stakeholder involvement at all levels of the heart center," said Dr. Roy. "In congenital cardiac surgery, our program is in its early phase. Data are promising, but more research is needed, especially related to specific components of care for which there sometimes is low evidence in this population."

Future studies and ongoing efforts by the researchers will focus on pain and opioid-sparing strategies, factors associated with postoperative nausea and vomiting, the effects of transfusions on outcomes, and prehabilitation.

CHICAGO (January 30, 2021) -- The most deadly global health crisis in a century has resulted in a substantial decline in overall heart surgery volume and an unexplained increase in deaths after coronary artery bypass grafting, according to late-breaking research presented at the 57th Annual Meeting of The Society of Thoracic Surgeons.

"This study was a true herculean analysis and tour de force that showed the COVID effect on adult cardiac surgery volume, trends, and outcomes," said Tom C. Nguyen, MD, from the University of California San Francisco. "The pandemic has changed the world as we know it, causing a dramatic drop in adult cardiac surgery volume and worsening patient outcomes."

Dr. Nguyen and colleagues queried the STS Adult Cardiac Surgery Database from January 1, 2018, to June 30, 2020, and The Johns Hopkins COVID-19 Dashboard from February 1, 2020, to January 1, 2021. The researchers examined data from 717,103 adult cardiac surgery patients and more than 20 million COVID-19 patients in an effort to determine how the pandemic affected adult cardiac surgery on national and regional levels.

"Only the STS National Database has the level of granularity, COVID variables, and longitudinal follow-up to answer the questions posed in this important study," said Dr. Nguyen. "Our research also analyzed data by regions to get an idea of how specific areas did during the COVID pandemic."

According to the study results, there was a 53% decrease nationwide in all adult cardiac surgery volume when compared to 2019 and 65% fewer elective cases in the United States. COVID also impacted non-elective cases, resulting in a 40% decrease.

In addition, the data showed that no matter the procedure--isolated coronary artery bypass grafting (CABG), isolated aortic valve replacement (AVR), isolated mitral valve replacement (MVR), CABG+AVR, CABG+MVR, isolated MV repair, and CABG+MV repair--there was a significant decline in case volume--54%--when compared to 2019.

Regionally, the Mid-Atlantic area (New York, New Jersey, and Pennsylvania), was among those most affected by the COVID crisis, experiencing a 71% decrease in overall case volume, 75% fewer elective cases, and a 59% reduction in non-elective cases. Another hotspot, the New England region (Maine, Vermont, New Hampshire, Massachusetts, Connecticut and Rhode Island), showed a 63% reduction in overall case volume.

The researchers also found that prior to the COVID surge, the Mid-Atlantic and New England regions had excellent outcomes with an observed-to-expected (O/E) ratio of less than 1, which represents a better-than-expected mortality rate. However, during the COVID surge, there was a 110% increase in the O/E for all adult cardiac procedures and a 167% increase for isolated CABG, meaning more patients were dying than expected.

Though the data did not directly address the cause of increased mortality, many surgeons say they currently are limited to operating on only the most urgent coronary bypass cases and patients who tend to be sicker. "These numbers should not serve as a deterrent to patients seeking care for chest pain or other cardiac symptoms," said Robbin G. Cohen, MD, MMM, from Keck School of Medicine of the University of Southern California in Los Angeles, who was not directly involved with this study. "If anything, they are a warning to get into the system as soon as possible."

At the time of presentation, there were 95.4 million global cases of COVID-19 with more than 2 million global deaths. The US accounted for more than 24 million cases and approximately 400,000 deaths.

In the past year, this crisis has altered or halted virtually every aspect of society, and the practice of cardiothoracic surgery clearly has not been immune. The abrupt cessation of surgery in mid-March 2020 has proven to have had far-reaching implications, as the negative effects of canceled and postponed procedures on patient health outcomes now are being realized.

"We clearly demonstrated that if you have heart surgery during COVID, you have an increased risk of morbidity and mortality," said Dr. Nguyen. "No doubt that COVID hit us hard."

According to Dr. Nguyen, this study is only the first of many more "granular" analyses to come. The researchers plan to examine trends and outcomes of COVID patients vs. non-COVID patients, as well as delve more into the COVID effect on specific adult cardiac procedures such as aortic dissections.

In northern Canada, the forest floor is carpeted with reindeer lichens. They look like a moss made of tiny gray branches, but they're stranger than that: they're composite organisms, a fungus and algae living together as one. They're a major part of reindeer diets, hence the name, and the forest depends on them to move nutrients through the ecosystem. They also, at least in parts of Quebec, are having a lot more sex than scientists expected. In a new study in the American Journal of Botany, researchers found that the reindeer lichens they examined have unexpected levels of genetic diversity, indicating that the lichens have been doing more gene-mixing with each other than the scientists would have guessed.

"We were surprised because this species of reindeer lichen had always been considered mainly a clonal species that reproduces asexually," says Marta Alonso-García, the paper's lead author and a postdoctoral fellow at Quebec's Université-Laval. "It doesn't follow the expected pattern."

Reindeer lichens swing both ways: they can reproduce sexually via spores, or they can asexually clone themselves. When fungi reproduce sexually, they send out root-like structures toward a neighboring fungus and exchange genetic information when they touch. They then release spores, single cells containing genetic material, which travel on the wind and disperse. When they land, they start growing and produce a new baby fungus that's genetically distinct from its parents. In asexual clonal reproduction, on the other hand, a piece of the entire lichen (fungus and alga), called the thallus, is pinched off and regrows into a whole organism that's genetically identical to its parent.

The two reproductive methods have different advantages. "Sexual reproduction is very costly," says Felix Grewe, the co-director of the Field Museum's Grainger Bioinformatics Center and a co-author of the study. "You have to find your partner, it's more difficult than reproducing asexually. But many organisms do it because when you have this combining and mixing of genetic traits, it enables you to weed out negative mutations long-term among other benefits."

The researchers were examining reindeer lichens (Cladonia stellaris) to learn about their genetic patterns. "We used DNA sequences to tease apart the genetic relationships between populations of this lichen," says Alonso-García. "We tested whether individuals from northern Quebec (Hudson Bay) were genetically different from those from the South (Parc National des Grands-Jardins, two hours from Québec City). At the same time, due to its important role in the colonization process after a fire, we evaluated lichen genetic diversity along a post-fire succession."

Lichens can reveal a lot about how wildfires affect ecosystems. "Wildfire is the most significant disturbance in the world's northernmost forests, and it plays a major role in determining the distribution and composition of plant communities," says Alonso-García. "In Eastern North America, four successional vegetation stages are generally identified after a fire. During the first stage, crustose lichens and mosses colonize the burned surface. Subsequently, the soil is covered by cup and horn lichens. The landscape remains mostly uniform for around 20 years until the arrival of fruticose lichens which replace the previous vegetation. Cladonia stellaris arrives the last one, usually three or four decades after fire." By studying genetic variations in reindeer lichens, the researchers hoped to learn how lichens recolonize an area after a fire.

To study the lichens' DNA, the researchers ground up samples of lichens and extracted their DNA. But lichens present an extra challenge in this process, since they're made up of a fungus and an alga (or a kind of bacteria that performs photosynthesis) living together. "That means that all the DNA is mixed up together, we get one pool that contains fungal DNA and algal DNA," says Grewe. "We have to carefully filter and sort the sequence reads bioinformatically." The main body of a lichen is made up of the fungus, so the researchers wanted to focus on the fungal component's DNA. By comparing the pool of DNA to existing genomes, the researchers were able to pick out the DNA belonging to the fungus, and they could then compare the fungal DNA from reindeer lichens from different areas of Quebec.

What they found was surprising: in general, there was a lot more genetic variation in the lichens than the researchers expected, and that indicates hanky-panky. "It's a general assumption was that these reindeer lichens mainly reproduce asexually because there's little evidence for them producing spores, but now the genetic data shows all this diversity, and that leads to the assumption that might be some form of sex," says Grewe.

"We were expecting that lichens from North Quebec would be more similar to each other than to those from Parc National des Grands-Jardins. However, our results suggest constant migration of C. stellaris between populations throughout Eastern North America," says Alonso-García. "In fact, contrary to the widespread belief, we found many reproductive structures in the species and these structures are formed after sexual reproduction."

But while the lichens are apparently doing more genetic intermingling than expected, the researchers also found that after a forest fire, the new lichens that crop up are genetically similar to the ones that were there before. That was counterintuitive-- the thought had been that the little cloned lichen bits would be destroyed in a fire, and that the repopulation of lichens would be growing from spores that arrived on the wind from other areas. "Regarding the genetic diversity of the species after fires, we found no differences along four stages of the succession. This was also astonishing because time since the last fire increases the probability that clonal fragments successfully reached the sites, enhancing genetic diversity," says Alonso-García.

In addition to revealing the hidden sex lives of reindeer lichen, the study could have implications for forest conservation. "We have learned that time since the last fire does not necessarily mean more genetic diversity, so conservation strategies in boreal forests should take this into account," says Alonso-García. "Prioritizing the protection of an area should not be based exclusively on its age. This is quite important because funding is usually limited, so we cannot carry out conservation activities in the entire forest." In short: if conservation scientists want to protect areas of forest with genetically diverse lichen populations, the forest's age isn't the only indicator of diversity.

Grewe adds the importance of bioinformatics in learning about how organisms are related to each other. "It is astonishing that today we can have such a detailed view of the evolution of populations using bioinformatics," says Grewe. "This is another good example of how advancement in sequencing technology allows us to learn about the evolution of an organism in more detail than ever before."

Researchers at Linköping University, Sweden, have developed a proton trap that makes organic electronic ion pumps more precise when delivering drugs. The new technique may reduce drug side effects, and in the long term, ion pumps may help patients with symptoms of neurological diseases for which effective treatments are not available. The results have been published in Science Advances.

Approximately 6% of the world's population suffer from neurological diseases such as epilepsy, Parkinson's disease, and chronic pain. However, currently available drug delivery methods - mainly tablets and injections - place the drug in locations where it is not required. This can lead to side effects that harm the patient.

"Organic electronic ion pumps have a huge potential for use in the treatment and diagnosis of neurological diseases. They could function in a similar manner to the insulin pumps already in use, but deliver the drug directly into the nervous system. Our most recent discovery is a proton trap that makes the amount delivered even more precise", says Daniel Simon, associate professor in the Laboratory of Organic Electronics, Department of Science and Technology at Linköping University.

Daniel Simon's research group has previously developed an organic electronic ion pump with delivery outlets as small as 20 x 20 micrometres. It should be possible to implant such devices to deliver drugs at exactly the desired location in the nervous system. The scientists hope that it will be possible to use the ion pump to discover and halt the development of neurological symptoms before the patient notices them.

Previous experiments were carried out on slices of mouse brain, using the naturally occurring signal substance GABA (gamma aminobutyric acid) as active drug. GABA is an inhibiting signal substance naturally found in the brain. When the amount of GABA increases, nerve cells are less likely to transfer nerve impulses to the next cell. A neurological seizure, such as occurs in epilepsy, in which the brain's nerve cells become overactive, is in this way prevented. When the ion pump is configured to transport GABA from an electrolyte reservoir outside the body to the desired location in the nervous system, a small voltage is used, which "pumps" the positively charged GABA through a transport channel. The method is known as electrophoresis. However, positive hydrogen ions, protons, from the electrolyte solution accompany the GABA through the channel. This leads to imprecise dosage and a drop in the pH of the tissue (making it more acidic), which can cause side effects.

The research group at Linköping University has now improved the ion pump. By introducing proton traps along the transport channel, the number of protons that pass can be considerably reduced. The proton trap consists of palladium, a noble metal that reacts readily - and nearly exclusively - with hydrogen and thus captures the positively charged protons. The proton traps mean that the ion pump can deliver a more precise dosage of the drug, since the potential applied corresponds almost exactly with the amount of GABA transported by the electrophoresis process.

"I believe that in a few years we will see organic bioelectronic ion pumps being used in the treatment of many neurological diseases. The proton trap can be integrated into all organic bioelectronic ion pumps, and our discovery has brought practical applications a lot closer", says Xenofon Strakosas, staff scientist and co-first-author with Maria Seitanidou, postdoc, both at the Laboratory of Organic Electronics, of the article in Science Advances.

(Singapore--January 29, 2021 9:35 a.m. SPT/January 28, 2021 8:35 p.m. EST)--Two radiation oncology trials presented at the IALSC World Conference on Lung Cancer Singapore highlight how some researchers are exploring use of higher radiation boost doses to only PET-positive regions in locally-advanced non-small cell lung cancer (NSCLC). A previous large RTOG phase III trial revealed that the unform delivery of a high dose to the entire tumor led to poorer survival.

In one study, Prof. Feng-Ming (Spring) Kong, Case Western Reserve University School of Medicine, in Cleveland, Ohio presented the results of a multicenter trial which aimed to determine whether adaptive isotoxic radiation dose escalation to mid-treatment FDG-PET provides superior local tumor control compared to a standard uniform dose of 60 Gy in patients with stage III NSCLC.

Prof. Kong and the research centers involved in the trials enrolled 138 patients with stage III NSCLC who were medically fit for concurrent chemoradiation. The patients were randomly assigned by a 1:2 ratio to standard (60 Gy) arm or to an adaptive-therapy arm, with dose individualized to 20 Gy mean lung dose (MLD), and adapted to residual tumor on the mid-treatment FDG-PET/CT. All patients had FDG-PET performed around 40 Gy mid-treatment, and radiation therapy was delivered in 30 daily fractions (Fx).

Of 138 patients enrolled between February 2012 and March 2017, 127 were eligible and analyzable, with 43 and 84 patients in the standard and adaptive arms, respectively, with a minimum follow-up of 3.7 and 3.4 years for surviving patients, also respectively.

The adaptive arm consisted of an initial plan of 2.2 Gy/Fx for 21 Fx followed by an adaptive radiation therapy boost to mid-treatment FDG-PET target using a variable prescription of 2.2-3.8 Gy/Fx for the final 9 Fx. The primary endpoint of this report was 2-year local-regional tumor progression free (LRPF), with inclusion of overall and in-field LRPF, assessed independently and blindly by radiologists.

There were no significant differences in lung, esophagus, and heart toxicities, though the adaptive arm had numerically higher mean doses of these organs at risk. The 2-year overall LRPF rates were 59.5% (95% CI: 37.9, 75.7) on the standard arm, and 54.6% (95% CI: 39.9, 67.0) on the adaptive arm. The median LRPF time was 27.5 months (95% CI: 14.3, not reached) on the standard arm and 28.4 months (95% CI: 19.1, not reached) on the adaptive arm. There were no significant differences in overall survival, progression-free survival, or lung cancer-specific survival between the two arms, according to the presentation by Dr. Kong.

"This is the first randomized trial that demonstrated the feasibility and safety of performing biologically adaptive radiation therapy escalation in a multicenter setting in patients with stage III NSCLC. This preliminary analysis did not show an improvement in overall local regional tumor control," Dr. Kong reported.

In the second study, Dr. Saskia Cooke, The Netherlands Cancer Institute in Amsterdam, Netherlands, reports on local and regional failure in the phase II PET-Boost trial (NCT01024829). In this study, patients with stage II-III non-small cell lung cancer (NSCLC) were treated with hypofractionated dose escalation to either the primary tumor as a whole (Arm A) or the high fluorodeoxyglucose (FDG)-uptake region inside the PT (> 50% SUVmax; Arm B).

The trial randomly assigned 107 patients--82% had stage III disease and most patients (72%) received concurrent chemoradiotherapy. In Arms A and B, median gross tumor volume (GTV) for the primary tumor was 100 and 115 cm3, respectively; median GTV for the involved lymph nodes was 18 and 20 cm3, respectively. Median fraction dose was 3.25 Gy to planning target volume (PTV) to the entire primary tumor and 3.50 Gy to PTV 50% SUVmax, resulting in total planned physical dose of 78.0 and 84.0 Gy, in 24 fractions. Median overall treatment time was 34 days in both arms, and median follow-up for CT scans in central review was 12.6 months.

In a previous report, the authors revealed that the primary tumor was non-measurable on follow-up in 27% of patients [Cooke S, 2020]. Of the 12 patients in Arm A who experienced locoregional failure, 2 had local failure (LF) without regional failure (RF) and 9 had RF without LF. Of the 15 patients in Arm B, 4 had LF without RF and 10 had RF without LF. In Arms A and B, respectively, the 2-year cumulative incidence of LF was 11% and 18%, and 28% and 25% for RF. The authors concluded that "dose escalation to the whole PT or 50% SUVmax in patients with NSCLC led to excellent local control rates in both treatment arms". However, few patients were evaluable for assessment of local failure at 2-years, grade 5 toxicity rates was previously reported to be 16% [van Diessen J, 2018], with 3-year OS rates of only 37% in armA and 33% in armB, respectively.

CAMBRIDGE, MA -- In many ways, our brain and our digestive tract are deeply connected. Feeling nervous may lead to physical pain in the stomach, while hunger signals from the gut make us feel irritable. Recent studies have even suggested that the bacteria living in our gut can influence some neurological diseases.

Modeling these complex interactions in animals such as mice is difficult to do, because their physiology is very different from humans'. To help researchers better understa nd the gut-brain axis, MIT researchers have developed an "organs-on-a-chip" system that replicates interactions between the brain, liver, and colon.

Using that system, the researchers were able to model the influence that microbes living in the gut have on both healthy brain tissue and tissue samples derived from patients with Parkinson's disease. They found that short-chain fatty acids, which are produced by microbes in the gut and are transported to the brain, can have very different effects on healthy and diseased brain cells.

"While short-chain fatty acids are largely beneficial to human health, we observed that under certain conditions they can further exacerbate certain brain pathologies, such as protein misfolding and neuronal death, related to Parkinson's disease," says Martin Trapecar, an MIT postdoc and the lead author of the study.

Linda Griffith, the School of Engineering Professor of Teaching Innovation and a professor of biological engineering and mechanical engineering, and Rudolf Jaenisch, an MIT professor of biology and a member of MIT's Whitehead Institute for Medical Research, are the senior authors of the paper, which appears today in Science Advances.

The gut-brain connection

For several years, Griffith's lab has been developing microphysiological systems -- small devices that can be used to grow engineered tissue models of different organs, connected by microfluidic channels. In some cases, these models can offer more accurate information on human disease than animal models can, Griffith says.

In a paper published last year, Griffith and Trapecar used a microphysiological system to model interactions between the liver and the colon. In that study, they found that short-chain fatty acids (SCFAs), molecules produced by microbes in the gut, can worsen autoimmune inflammation associated with ulcerative colitis under certain conditions. SCFAs, which include butyrate, propionate, and acetate, can also have beneficial effects on tissues, including increased immune tolerance, and they account for about 10 percent of the energy that we get from food.

In the new study, the MIT team decided to add the brain and circulating immune cells to their multiorgan system. The brain has many interactions with the digestive tract, which can occur via the enteric nervous system or through the circulation of immune cells, nutrients, and hormones between organs.

Several years ago, Sarkis Mazmanian, a professor of microbiology at Caltech, discovered a connection between SCFAs and Parkinson's disease in mice. He showed that SCFAs, which are produced by bacteria as they consume undigested fiber in the gut, sped up the progression of the disease, while mice raised in a germ-free environment were slower to develop the disease.

Griffith and Trapecar decided to further explore Mazmanian's findings, using their microphysiological model. To do that, they teamed up with Jaenisch's lab at the Whitehead Institute. Jaenisch had previously developed a way to transform fibroblast cells from Parkinson's patients into pluripotent stem cells, which can then be induced to differentiate into different types of brain cells -- neurons, astrocytes, and microglia.

More than 80 percent of Parkinson's cases cannot be linked to a specific gene mutation, but the rest do have a genetic cause. The cells that the MIT researchers used for their Parkinson's model carry a mutation that causes accumulation of a protein called alpha synuclein, which damages neurons and causes inflammation in brain cells. Jaenisch's lab has also generated brain cells that have this mutation corrected but are otherwise genetically identical and from the same patient as the diseased cells.

Griffith and Trapecar first studied these two sets of brain cells in microphysiological systems that were not connected to any other tissues, and found that the Parkinson's cells showed more inflammation than the healthy, corrected cells. The Parkinson's cells also had impairments in their ability to metabolize lipids and cholesterol.

Opposite effects

The researchers then connected the brain cells to tissue models of the colon and liver, using channels that allow immune cells and nutrients, including SCFAs, to flow between them. They found that for healthy brain cells, being exposed to SCFAs is beneficial, and helps them to mature. However, when brain cells derived from Parkinson's patients were exposed to SCFAs, the beneficial effects disappeared. Instead, the cells experienced higher levels of protein misfolding and cell death.

These effects were seen even when immune cells were removed from the system, leading the researchers to hypothesize that the effects are mediated by changes to lipid metabolism.

"It seems that short-chain fatty acids can be linked to neurodegenerative diseases by affecting lipid metabolism rather than directly affecting a certain immune cell population," Trapecar says. "Now the goal for us is to try to understand this."

The researchers also plan to model other types of neurological diseases that may be influenced by the gut microbiome. The findings offer support for the idea that human tissue models could yield information that animal models cannot, Griffith says. She is now working on a new version of the model that will include micro blood vessels connecting different tissue types, allowing researchers to study how blood flow between tissues influences them.

"We should be really pushing development of these, because it is important to start bringing more human features into our models," Griffith says. "We have been able to start getting insights into the human condition that are hard to get from mice."

What The Study Did: This study investigated how unemployment insurance and a $600 per week federal supplement to unemployment insurance were associated with food insecurity among people in low- and middle-income households who lost jobs during the COVID-19 pandemic.

Authors: Julia Raifman, Sc.D., of the Boston University School of Public Health, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.35884)

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

What The Study Did: Researchers examined if the use of diagnostic imaging for children receiving care in pediatric emergency departments in the United States differs by race and ethnicity.

Authors: Jennifer R. Marin, M.D., M.Sc., of the University of Pittsburgh School of Medicine, is the corresponding author.

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

(doi:10.1001/jamanetworkopen.2020.33710)

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In 2017, the Nobel Prize in Physiology or Medicine went to three scientists who uncovered the molecular mechanisms that control the circadian rhythm, otherwise known as the "wake-sleep" cycle. To carry out their work, the scientists used the common fruit fly Drosophila melanogaster, making this the sixth Nobel to be awarded to research involving it.

Fruitful fruit flies

Life scientists have been using Drosophila for over a century now. First proposed by entomologist Charles W. Woodworth as a model organism, its use in research was pioneered by geneticist Thomas H. Morgan who ran his famous Fly Room at Columbia University in the early 1900's.

Sharing around 60% of human DNA, the humble insect has been the linchpin of countless scientific discoveries, from genetic inheritance and gene mutation to neurodegenerative disorders like Alzheimer's and Parkinson's.

Circadian rhythms

Drosophila has also been used extensively in the study of the circadian rhythm, a process shared by virtually all living organisms, including animals, plants, and even microbes. Apart from sleeping and waking, it affects multiple aspects of our bodies, including hormone release, eating and digestion, as well as body temperature.

In fact, the study of circadian rhythms has grown into its own field: chronobiology. And given that a person's circadian rhythm seems to dictate when certain drugs must be taken in order to maximize their effects, a new branch of medicine has also emerged recently: chronopharmacology.

Gene rhythms

Now, scientists led by Maria Litovchenko and Bart Deplancke at EPFL's School of Life Sciences have carried out an extensive study using Drosophila to study how different genes in various tissues of the animal are regulated so that they "know" when to turn on and off during the course of a day, i.e. in function of the circadian clock. "We wanted to assess how these molecular rhythms vary in a natural fruit fly population and how they are affected by genomic variation," adds Deplancke. The study is published in Science Advances.

The scientists turned to a fly resource called the Drosophila Genetic Reference Panel (DGRP), which contains more than 200 genetically distinct lines of the insect. Each line's genome has been fully sequenced so that scientists can spot differences between genotypes and then connect them to differences between phenotypes, thereby linking genes to their functions.

From the DGRP, the scientists sampled more than 700 tissue-specific "transcriptomes". In an organism or a tissue or just a cell, genes are decoded or "transcribed" into mRNA, which is then used to put together a protein. So a transcriptome is essentially a set of all RNA transcripts from an organism's DNA, coding or non-coding.

In this study, the scientists used the mRNA from a reference, "control", fly strain and then sampled the mRNA from 141 individual DGRP lines at high resolution - at about nine-minute intervals between each line. The idea behind this was to see how the gene transcripts changed over time in different lines, and get a handle on how the fruit fly's genetic background and circadian rhythm together affect the expression of different genes in distinct tissues.

"It allowed us to generate the first tissue-specific reference circadian gene expression time series in Drosophila; a comprehensive circadian gene-expression atlas," says Litovchenko. "But it also let us gain unprecedented insights into the extent and genome-wide nature of circadian gene expression variation using an innovative approach that allowed the reconstruction of dynamic cycling patterns from statically collected samples."

The study revealed three major points about the circadian rhythm.

The Clock reigns supreme

First, the scientists detected more than 1700 genes whose expression cycles under the control of the circadian clock, with only fourteen of those genes being the same across all tissues in the fruit fly.

"At least two of these fourteen were so far uncharacterized and significantly impact several locomotor activity rhythms parameters," says Litovchenko, referring to the fruit fly's behavioral patterns that depend on its circadian clock. "Since these genes have orthologs (similar genes) in mice, baboons, and humans, our findings strongly suggest that they are novel, core clock-regulators in mammals as well," she adds.

Morning person or night owl?

Second, that each individual may have its own circadian rhythm, which may explain the large range of human behaviors, such as morning people, nappers, evening people, night owls etc. The researchers used a state-of-the-art statistical approach to work out the natural circadian rhythm for every tissue in every DGRP fruit fly transcriptome.

What they found was that the physiological clock in about a third of Drosophila lines significantly deviates from the "natural" time by more than three hours. And most of the lines showed a circadian expression variation only in one or two tissues.

"Humans may also be impacted by such extensive variation," says Deplancke. "There seems to be an abundant, natural circadian asynchrony in molecular circadian rhythms between various tissues, which has to our knowledge not been observed before and which may have all kinds of physiological consequences in metabolic patterns, digestive fluctuations etc."

Light, dark, and a mutation

Finally, that a small genetic mutation can disrupt an individual's "photoentrainment", which refers to the aligning of the circadian rhythm to the pattern of light and dark in its environment.

Focusing on a Drosophila line with the highest unaligned circadian rhythm (more than 10 hours), the researchers found that it contains a novel, loss-of-function deletion in the Drosophila clock- and light-regulated gene "cry" (for "cryptochrome").

"This small deletion disrupts the light-driven FAD cofactor photoreduction," says Deplancke. "It confirms in vivo the importance of the evolutionary conserved photo-entrainment mechanism in the circadian pacemaker."

From fly to human

The study also reconfirmed that Drosophila is an excellent model for studying the circadian rhythm in humans, as it identified several new core clock genes that the two species share. "We have gained unique insights as to what extent the circadian clock is molecularly variable not only between individuals, but even between tissues of the same individual," says Deplancke.

"Obviously, we will never be able to achieve such insights in humans, as we cannot sample human tissues across 24 hours," he adds. "But what we learned is that this variation is very extensive. Given the increasing importance of chronopharmacology, it may be good to infer the innate circadian cycle of individuals before starting important drug treatments."

CHICAGO (January 29, 2021): Trauma patients and patients who need emergency surgery have little to no opportunity to get acquainted with the surgeon and team that will perform their operation. However, a large study has found that effective and meaningful physician communication is a more important contributor to the overall satisfaction of trauma patients and those having emergency surgery than it is for patients admitted to the hospital for medical reasons or for elective procedures.

The study was selected for the 2020 Southern Surgical Association Program and published as an "article in press" on the website of the Journal of the American College of Surgeons in advance of print.

The researchers found an unexpectedly significant effect of physician communication among patients admitted through a hospital's trauma bay or emergency department. They analyzed patient survey data to determine how several factors, including interactions with nurses and doctors, contributed to satisfaction ratings in five different patient categories: trauma, direct-admit (elective) surgery, emergency department (ED)-admitted (emergency) surgery, ED-admitted medical, and direct-admit medical.

"Nurses uniformly come out as the most highly ranked, and that's because they provide wonderful bedside care and have so much contact with the patients," said lead study author Samir M. Fakhry, MD, FACS, vice president of the Center for Trauma and Acute Care Surgery Research for HCA Healthcare, a publicly traded company based in Nashville, Tenn., that operates 187 hospitals and other health care facilities. "But in the case of the trauma patients, and to a lesser degree the emergency surgical patients, physician communication ranked as the number two factor," he said.

Among elective surgery and medical admission patients, physician communication didn't register even as a third or fourth factor. "There's something about the way the trauma surgeons are delivering their care that is an important driver of the satisfaction scoring that is provided by our patients," Dr. Fakhry said.

The authors noted that no previous large study has investigated overall satisfaction among trauma and emergency surgery patients. Study investigators analyzed Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey data of 186,779 non-maternity patients discharged from 168 HCA Healthcare hospitals in 2018 and 2019. HCAHPS is a post-discharge survey that asks patients about their hospital experience. The Centers for Medicare and Medicaid Services uses HCAHPS data to generate hospital ratings reported on its Hospital Compare website. The survey captures patient impressions of a number of factors about the hospital experience, including communication with doctors and nurses.

The researchers found that physician communication had a greater impact on overall satisfaction after accounting for nursing factors among trauma and emergency surgery patients, representing a 12 percent boost in the former and an 8.6 percent boost in the latter. In categories in which physician communication received low ratings, it was unlikely that high scores in other factors could compensate to bring the overall satisfaction score above the 50th percentile.

"The things trauma surgeons and the people around them are doing seem to be very important to their patients," Dr. Fakhry said. "For many people in hospital leadership, the trauma service is an important mission of the hospital, but they wouldn't expect the trauma service to contribute very much to a positive patient experience because we're dealing with injured people. However, this study shows trauma care has a significant impact on hospital ratings."

The authors noted that future research should explore what specific aspects of the physician's behavior in trauma, emergency surgery, and ED admissions contribute to patient satisfaction.

"We like to say in the world of trauma that the 't' in trauma is for team, so it would be important to stress that the team approach we employ in trauma may be an important part of the findings of the study," Dr. Fakhry said. "That's something we're going to explore in future studies to try to determine what it is, specifically, that trauma surgeons are doing, how they relate to the nurses, and if the interaction between the doctor and the nurse are all something we can turn into an even more positive experience for the patient."

In an invited commentary, Thomas J. Esposito, MD, MPH, FACS, a professor at the University of Illinois College of Medicine, Peoria, noted the study focuses attention on the importance of communication, but also expressed reservations about the "reliability and veracity" of surveys, citing the inaccuracy of pre-election opinion polls in the last two presidential election cycles. "I would encourage these investigators to expand their research and further dive into the data as well as the survey process," Dr. Esposito wrote.

An international team of scientists, coordinated by the Seville Institute of Biomedicine (IBiS) and the University of Seville has solved one of the hitherto unresolved enigmas of basic biology: how exactly do lipids distribute proteins within a cell? To do this, they used a new, completely innovative microscopy technology, which they applied to "mutant" cells they designed in their laboratory.

This discovery represents a major advance in understanding how proteins are distributed in cells to perform their vital functions, and could open the door to understanding the causes of diseases associated with failures in protein distribution at the cellular level: from cancer to neurodegenerative diseases, such as Alzheimer's.

The study was carried out by the Department of Cell Biology's "Membrane Trafficking" research group, part of the Faculty of Biology of the University of Seville and the IBiS, led by Professor Manuel Muñiz Guinea, in collaboration with the universities of Hiroshima (Japan), Geneva and Fribourg (Switzerland). The RIKEN Institute in Japan, where the "Super-resolution Living Cell Microscopy" Laboratory is located, also participated in this project. This is a unique facility in the world which conducted analyses using a high resolution fluorescence microscope that allows the study of very fast and dynamic processes in living cells on an incredibly small scale.

As Manuel Muñiz explains, "the cell is the basic unit of life and, at the same time, an extremely complex and sophisticated machine in which thousands of proteins, among other components, are strategically located in different compartments where they carry out cellular functions". The cell must ensure that its proteins are properly distributed to their place of function, because if this fails and they do not reach their destination, the proteins either stop working or get out of control, causing diseases ranging from genetic syndromes to cancer or neurological diseases. Therefore, it is important to investigate how proteins are distributed towards their functional destination.

Many years ago it was suggested that, in addition to cells' conventional protein transportation machinery (whose discovery received the Nobel Prize for Medicine in 2013), the lipids that make up the cell membranes may also play an additional role in the distribution of proteins within cells. This work by the Seville researchers solves this enigma of basic biology, demonstrating for the first time how lipids can distribute proteins at the cellular level.

Molecular exit doors

The proteins are manufactured in a compartment of the cell and then have to be distributed correctly by exiting through specific "doors". In this study, scientists from Seville discovered that membrane lipids are responsible for selecting and directing certain proteins to the correct exit doors.

To make this discovery, they designed a "mutant cell" that was programmed to manufacture a shortened version of cellular lipids called ceramides. The researchers suspected that the length of these lipids could be a determining factor in choosing the appropriate exit door.

"And that's exactly what we found," explains the IBiS researcher. "Thanks to the short ceramides we generated, we were able to demonstrate for the first time that lipids are only able to guide proteins during transport if they are the right length. Moreover, by using such a powerful 'super microscope' we were able to capture for the first time on an ultra small scale and in vivo how proteins exit through these molecular doors".

Yeast model

As a curiosity, this study was carried out using yeast cells (the same unicellular fungus used to make bread, beer and wine) as a model organism, "because, being eukaryotic cells just like ours, they perform the same basic cellular processes in a very similar way, so the observations can be extrapolated to human cells", explains the University of Seville professor.

However, because they are also simpler and can be genetically manipulated very effectively, "yeast cells are an excellent model to understand the fundamental workings of the human cell and what causes disease, as demonstrated by the fact that several Nobel Prize for Medicine have been awarded to researchers who used this microorganism in their studies, including Paul Nurse or Randy Schekman".

In conclusion, Manuel Muñiz explains that the article published in Science Advances "has also served to demonstrate that lipids and proteins influence each other to self-organise together within the cell", and points out that the mechanism they have discovered and used for this "could be used in other processes, such as the entry and exit of certain viruses from the cell, as well as in the formation of exosomes (extra-cellular lipid vesicles involved in communication between cells, particularly in cancer)".

Knowledge about health is a cornerstone in a child's development of physical and psychosocial health.

Since 2016, around 25,000 pupils in years 4-6 in 86 of Denmark's municipalities have taken part in the project "11 for Health in Denmark", an 11-week exercise and health education programme offered to all schools in a collaboration between the University of Southern Denmark and the Danish Football Association.

More than 3,000 of these pupils completed questionnaires before and after the programme aimed at determining their knowledge about health and understanding their experience of the 11-week programme.

An increase of 10 percentage points in health knowledge

The main article from this study, which has now been published in leading sports science journal the British Journal of Sports Medicine, confirms that the programme is meeting its key objectives:

"The participating children increased their knowledge about health in the areas of diet, exercise, hygiene and wellbeing to a greater extent than the control group, which followed the originally planned lessons in the 11 weeks between the questionnaires. There was a difference between the groups of more than 7 percentage points for both boys and girls, and in a number of key health areas the difference was more than 10 percentage points," says postdoc Malte Nejst Larsen, the article's lead author.

"The idea that children learn best if they can connect the learning to relevant activities is not new, but it's rare for such large studies to be carried out in real-world schools - and with such unambiguous results," he says.

Physical activity during coronavirus

The "11 for Health" concept was developed long before the coronavirus epidemic, but it has proven effective in relation to all the current challenges around health, fitness, physical activity, wellbeing and knowledge about hygiene.

The latest results show very clearly that it is possible to combine health learning with exercise that is fun, motivational and inclusive for all children - including those who have very little experience of sport. A good example is that the children doubled their knowledge about hand hygiene through the programme.

This was explained by the project's lead researcher Professor Peter Krustrup of the Department of Sports Science and Clinical Biomechanics at the University of Southern Denmark, who stresses that there was record-high participation in autumn 2020.

The researchers are also, therefore, delighted that the Nordea Foundation (Nordea-fonden), which has been supporting the project since 2018, has extended its support through to summer 2021. The project group is currently seeking funding for an ambitious expansion of the concept and a research study of the concept's long-term effects.

Both boys and girls like the project

The article also provides data on the children's opinion of the programme. These show very encouragingly that the girls rate the programme just as highly as the boys (4 on a scale of 1-5), despite the fact that the girls generally have considerably less experience of football than the boys.

Bent Clausen, Vice President of the Danish Football Association with a focus on amateur football, is delighted about this:

"It is great that '11 for Health' is able to have a broad reach and spark an interest in football in all children, both boys and girls, beginners and experienced players. After all, that is what football is really good at - including everyone no matter what their background. And with the school programme a natural next step, and an important aid for the associations, is getting new players and including them in the valuable communities within the football clubs."

Research on manufacturing battery cells is gaining momentum - and there is a strong need, considering the future demand for energy storage: For the year 2030, global production of rechargeable batteries will double from today's 750 gigawatt hours (GWh) per year to 1,500 GWh. A recently published review article in the magazine "Nature Energy" on cell production of various battery types suggests that the currently established lithium-ion batteries (LIB) dominate the market of rechargeable high-energy batteries in the coming years. Alternative battery technologies, in particular solid batteries, but also lithium-sulphur or lithium-air batteries are being researched intensively, but production on an industrial large scale is not yet taking place. Based on currently numerous emerging production capacities for LIBs, a switch to so-called post-lithium-ion batteries (PLIBs) with new process technologies, manufacturing environments and skills would require billion-dollar investments.

"Lithium-ion technology is expected to still dominate the market for high-energy rechargeable batteries over the next 10 years. It combines advantageous properties such as energy, power density, safety, durability and low costs in one. In addition, the production facilities currently being set worldwide are already creating facts that are likely to make it more difficult for the possible follow-up technologies to catch up," explains Dr Richard Schmuch, Deputy Head of Materials at MEET Battery Research Center at the University of Münster (Germany). He and Dr Fabian Duffner, Institute for Business Management in the Department of Chemistry and Pharmacy at the University of Münster and Porsche Consulting GmbH, led the analysis. Together with other battery and production researchers, they figured that production processes of LIBs cannot be transferred 1:1 to the vast majority of follow-up technologies. Dr Richard Schmuch states: "Here, numerous challenges and high investments await cell production."

Intensive Research and Development Activities Required

Only the production of sodium-ion batteries is comparable to lithium-ion batteries in many process steps. However, since this type of battery provides lower energy compared to LIB, it does not currently represent a perspective for the mass market that LIB has. The production processes of other post-lithium-ion batteries, such as solid-state, lithium-sulfur and lithium-air batteries, differ significantly from the production of lithium-ion batteries: Steps such as electrode manufacture, cell construction or cyclization require different techniques, manufacturing environments or machines.

Dr Fabian Duffner explains: "We currently know neither all the high-volume machines required nor the associated process parameters for cell production of post-lithium-ion batteries. Their industrialisation requires intensive research and development activities that focus on building up new manufacturing competences and developing new machines." In addition, post-LIBs would have to compete comprehensively in terms of all key performance parameters such as energy, performance, safety, durability and cost to become an alternative to the mass market.