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The new drug sotorasib reduces tumor size and shows promise in improving survival among patients with lung tumors caused by a specific DNA mutation, according to results of a global phase 2 clinical trial. The drug is designed to shut down the effects of the mutation, which is found in about 13% of patients with lung adenocarcinoma, a common type of non-small-cell lung cancer.

The Food and Drug Administration approved sotorasib May 28 as a targeted therapy for patients with non-small-cell lung cancer whose tumors express a specific mutation -- called G12C -- in the KRAS gene and who have undergone at least one previous therapy for their cancer.

Non-small-cell lung cancer makes up over 80% of all lung cancers. More than 200,000 new cases of non-small-cell lung cancer are diagnosed annually in the United States.

The study, led by researchers at Washington University School of Medicine in St. Louis, Perlmutter Cancer Center at NYU Langone Health in New York, MD Anderson Cancer Center in Houston, and Memorial Sloan Kettering Cancer Center in New York, will be presented June 4 at the annual meeting of the American Society of Clinical Oncology and published the same day in The New England Journal of Medicine.

Sotorasib, also known by the brand name Lumakras, is made by Amgen, which funded the trial.

"This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies," said co-senior author and medical oncologist Ramaswamy Govindan, MD, the Anheuser Busch Endowed Chair in Medical Oncology at Washington University. "The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. We're also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival."

The study involved 126 patients with non-small-cell lung cancer that had a specific mutation in the KRAS gene. A single DNA error swaps out an important protein building block, placing a cysteine where a glycine should be. Tumors with the mutation manufacture a version of the KRAS protein that is almost constantly active, driving tumor growth. Sotorasib, taken daily by mouth, blocks tumor growth by trapping the KRAS protein in its inactive form.

Most patients in the trial previously had been treated with standard chemotherapy along with an immunotherapy drug that targets a protein called PD-1. To evaluate this new therapy, all patients enrolled in the study were treated with sotorasib; phase 2 trials evaluating safety and effectiveness often do not include a placebo group.

The drug caused at least some tumor shrinkage in 102 out of 126 patients (82%). About 37% of the patients' tumors reduced in size at least 30%. In contrast, response rates to standard therapy in these patients range from 6% to 20%.

Forty-two patients' tumors (34%) showed a partial response to the therapy, meaning the tumor shrank substantially and its growth was controlled for a period of time; and four patients (3%) showed a complete response that left no evidence of disease. For tumors that shrank, the tumor size was reduced by about 60%, on average.

The effects of sotorasib lasted an average of 11 months, and the drug also showed progression-free survival -- meaning the tumor did not continue growing during this time -- of almost seven months. In contrast, patients with this lung cancer who receive standard therapy have an average progression-free survival of two to four months. The average overall survival for all patients in the trial was 12 ½ months.

"We are hopeful that this approach will be a new option for patients with lung cancer driven by this specific type of KRAS gene alteration," said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "KRAS gene alterations have long been considered not amenable for targeted therapies. A number of combination regimens are being tested here at the Siteman Cancer Center and at other leading cancer centers around the world. This highlights work that Washington University has excelled at over the past few decades -- studying the genomic alterations in tumors with the goal of identifying treatment targets. This early cancer genome research is now coming full circle to help our patients."

Govindan and his team have led pioneering studies to define genomic alterations in lung cancer, including making key contributions to The Cancer Genome Atlas, a national effort supported by the National Institutes of Health (NIH).

"The excitement surrounding this trial result is that sotorasib is now the first targeted therapy for lung cancer patients with KRAS mutations," said co-corresponding author Vamsidhar Velcheti, MD, of NYU Langone Health. "KRAS-targeted treatments, decades in the making, are urgently needed for these patients with limited treatment options."

About 7% of patients stopped sotorasib treatment because of severe side effects, but no side effects were life-threatening, and no patient died as a result of the treatment. The drug caused adverse events severe enough to require a reduced dose of the drug in about 22% of patients. Almost 70% of patients experienced side effects of some kind related to the drug; the most common were diarrhea, fatigue, nausea and increased liver enzyme levels, the latter an indicator of liver damage.

"Sotorasib showed clinically significant benefit without any new safety concerns in patients with this specific form of KRAS mutant lung cancer," Govindan said. "Moving forward, our team will seek to inform the development of combination therapies featuring sotorasib and other emerging drugs, and to determine which best fit the mix of mutations in each patient's cancer cells."

The researchers currently are conducting a phase 3 clinical trial comparing the effectiveness of sotorasib with a chemotherapy drug called docetaxel in 345 patients who have non-small-cell lung cancer and this specific KRAS mutation.

Leesburg, VA, June 4, 2021--According to a pilot study published in ARRS' American Journal of Roentgenology (AJR), the flexed elbow valgus external rotation (FEVER) view can improve MRI evaluation of the ulnar collateral ligament (UCL) in Major League Baseball (MLB) pitchers.

"The increased joint space width confirms elbow valgus stress with FEVER view," wrote corresponding author Thomas Knoblauch at the University of Nevada Las Vegas. "Diagnostic confidence increased, and additional UCLs were identified as abnormal."

Due to repetitive extreme valgus stress during overhead throwing maneuvers, UCL injuries remain common in throwing athletes. Because standard positioning for elbow MRI is often suboptimal for UCL rendering, Knoblauch, Arizona Diamondbacks head team physician Gary Waslewski, and colleagues piloted their study to assess FEVER view impact on ulnotrochlear (UT) joint space measurement and UCL reader evaluation, as incorporated with conventional elbow MRI.

A total of 44 MLB pitchers underwent elbow MRI, including both standard sequences and a coronal fat-saturated proton density-weighted sequence in the FEVER view using specific positioning maneuvers and sandbags to immobilize the elbow in valgus stress, while visualizing the UCL parallel to its long axis. To measure UT joint space and assess confidence in UCL-related findings with overall UCL normality, two radiologists independently evaluated standard and FEVER views.

"Among 44 MLB pitchers undergoing elbow MRI," Knoblauch et al. continued, "the FEVER view, compared with standard view, yielded increased UT joint space width (mean increase, 1.80 mm) and increased confidence for three of five UCL-related findings (mean increase, -0.14 to 0.98)." Readers 1 and 2 classified 3 and 2 additional UCLs as abnormal on FEVER compared with standard view; neither reader classified any UCL as abnormal in standard view but normal in FEVER view.

"The findings support the FEVER view as a practical addition to standard elbow MRI protocols for achieving elbow valgus stress in throwing athletes," the authors of this AJR article concluded, "thereby providing functional information to complement the high-resolution anatomic assessment provided by MRI."

Hospital price transparency is intended to help inform patients about the cost of services and procedures before they receive them. Since Jan. 1, 2021, hospitals in the U.S. have been required by The Centers for Medicare and Medicaid Services (CMS) to provide pricing information online about items and services. A team of researchers from Brigham and Women's Hospital and Massachusetts Eye and Ear leveraged the newly available data to analyze price transparency and price variation for the treatment of thyroid cancer. The team found that both transparency and price varied widely, with only half of the cancer centers studied reporting disclosure of payer-negotiated prices and the cost of some services ranging by as much as 70-fold. Results are published in JAMA.

"Reporting payer-negotiated prices is an important first step toward helping patients estimate the cost of care before receiving treatment," said corresponding author Roy Xiao, MD, MS, a resident in Otolaryngology-Head and Neck Surgery at the Brigham and Mass Eye and Ear. "Based on previous work, we expected to see some degree of variation, but the full range that we saw in our study was certainly surprising."

While CMS requires rates for all kinds of procedures to be disclosed, Xiao and colleagues focused on thyroid cancer as a case study. Treatment for thyroid cancer is known to impose substantial financial burdens on patients. Among cancer patients, bankruptcy rates are highest for patients with thyroid cancer.

The researchers characterized price availability and variation for thyroid cancer care at 52 National Cancer Institute (NCI)-designated centers as of March 25, 2021. Half of the centers disclosed commercial payer-negotiated prices for any items or services. Even after normalizing for factors affecting the cost of delivery of care, the team found wide variation across centers, with a 70-fold difference in the cost of radioactive iodine treatment and a 44-fold difference in the cost of neck computed tomography. Within centers, costs also varied widely, depending upon the insurer. On average, procedures such as fine needle aspirate biopsy and thyroid uptake scan varied by almost 5-fold within centers.

The authors note that CMS requires hospitals to disclose negotiated rates for hospital-employed physicians, but physicians practicing at hospitals are often employed by affiliated physician organizations, which may account for why many centers did not report surgeon professional fees for thyroid surgery. They also note that the study was conducted shortly after implementation of price transparency requirements. As centers overcome obstacles to compliance, disclosure rates and transparency may increase.

"Centers are facing a new reality when it comes to price transparency -- never before have they been required to make these rates available, and it's a huge lift to collect this information and make it available in a way that is intelligible to patients," said co-first author Vinay Rathi, MD, MBA, a resident in Otolaryngology-Head and Neck Surgery at the Brigham and Mass Eye and Ear. "As this information becomes available, we're interested in exploring how it can be used to help our patients."

"The cost of health care is a fundamentally important issue," said senior author Rosh K.V. Sethi, MD, MPH, a head and neck surgeon at the Brigham and Dana-Farber Cancer Institute. "The introduction of price transparency is a step in the right direction for both patients and clinicians to understand discrepancies in cost."

ABSTRACT #9003

HOUSTON - Results from the Phase II cohort of the CodeBreaK 100 study showed that treatment with the KRAS G12C inhibitor sotorasib achieved a 37.1% objective response rate and 12.5 months median overall survival in previously treated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), according to researchers from The University of Texas MD Anderson Cancer Center. The findings were presented today at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine.

Trial results indicated the targeted therapy was safe and tolerable in a heavily pre-treated patient population. The reported findings make sotorasib the first KRAS G12C inhibitor to demonstrate overall survival benefit in a registrational Phase II clinical trial.

Sotorasib was approved by the Food and Drug Administration on May 28, 2021, based on previously reported results from the CodeBreaK 100 trial. It is the first ever direct KRAS inhibitor to earn regulatory approval.

"KRAS has been an elusive therapeutic target for more than 30 years and was deemed 'undruggable.' This trial provides convincing evidence that mutant KRAS can be successfully and selectively targeted, resulting in meaningful prolongation of survival without compromising quality of life," said lead author Ferdinandos Skoulidis, M.D., Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology. "These results, along with the regulatory approval of sotorasib, represent a major landmark for patients with KRAS G12C-mutated lung cancer, who now have an approved targeted therapy option."

KRAS is the most common oncogenic driver in NSCLC, found to be mutated in 25-30% of patients. Sotorasib (AMG 510) is an irreversible and selective small-molecule inhibitor that targets a specific type of mutant KRAS protein called KRAS G12C, which is found in approximately 13% of all lung adenocarcinomas.

Study reveals rapid, durable clinical benefit with tolerable side effects

The single-arm, multi-center trial enrolled 126 patients with locally advanced or metastatic KRAS G12C-mutated NSCLC that had progressed after receiving immune checkpoint inhibitors and/or platinum-based chemotherapy. Sotorasib is a once-daily oral drug. The primary endpoint was objective response, assessed by independent central review.

The study found an objective response in 46 patients (37.1%), including four complete responses (3.2%) and 42 partial responses (33.9%). One hundred patients (80.6%) had disease control, with tumors shrinking or remaining stable. The median overall survival was 12.5 months, median duration of response was 11.1 months and median progression-free survival was 6.8 months.

Toxicities were manageable and primarily low grade, with only nine patients (7.1%) discontinuing therapy due to treatment-related adverse events. Of the 88 patients (69.8%) who had treatment-related adverse events, 25 (19.8%) were Grade 3 events and one (0.8%) was a Grade 4 event.

Study participants had a median age of 63.5 and were evenly split (50%) between men and women. The majority of patients (81.7%) were white, followed by Asian (15.1%), Black (1.6%) and other races (1.6%). Patients had received up to three previous lines of therapy and 96.8% had metastatic disease. A total of 81% of patients previously received both platinum-based chemotherapy and immune checkpoint inhibitors.

"In eight out of 10 patients, the tumor either shrank or remained stable, and these patients frequently saw improvement in their symptoms," Skoulidis said. "They're able to lead longer, active lives, because this targeted therapy is not associated with any major toxicities that would adversely affect the patient's quality of life."

Sotorasib effective in challenging subgroup and more research is underway

The study also analyzed responses among molecular subgroups and found particularly encouraging results among patients with STK11 co-mutations, without concurrent mutations in KEAP1. The 50% objective response rate and 11-month median progression-free survival in this group is notable because STK11-mutated tumors tend to respond poorly to standard of care therapies, including immunotherapy and chemotherapy.

Study investigators found response to sotorasib across other molecular subgroups, as well. The drug showed broad and consistent activity across patients with a wide range of baseline characteristics related to age, previous lines of therapy and other demographics.

"These study results are practice-changing, but our work isn't done," Skoulidis said. "Extensive efforts are underway to understand the determinants of response to sotorasib and to characterize the full spectrum of possible mechanisms of resistance. These results represent a foundational step in our progress against KRAS-mutant tumors and will likely be a stepping stone for even more effective combination regimens. The future looks promising."

Tuberculosis (TB) is a deadly infection that occurs in every part of the world. The standard treatment for TB, a six-month multidrug regimen, has not changed in more than 40 years. Patients can find it difficult to complete the lengthy regimen, making it more likely that treatment resistance will develop.

A research team led by a Medical University of South Carolina (MUSC) investigator reports in the May 6 issue of the New England Journal of Medicine that a four-month treatment regimen using rifapentine is effective for treating TB. Shortening the treatment duration is an important step toward increased patient adherence.

In 2019 alone, 1.4 million people died from TB worldwide. TB is caused by a bacterial infection that attacks the lungs of those infected. The World Health Organization estimates that one-quarter of the world's population has a TB infection, and those individuals will have a 5% to 10% lifetime risk of developing full TB disease. Individuals with compromised immune systems, such as people with HIV, have a much higher risk of developing TB.

"TB often affects adults in the prime of their lives," said Susan Dorman, M.D., a professor in the College of Medicine at MUSC and first author of the study. "This disease and treatment can disrupt lives and pull families into poverty."

While TB is curable and preventable, multidrug-resistant TB remains a top public health threat.
Resistance occurs when bacteria develop the ability to defeat drugs that are designed to kill them. When one bacterium in the colony figures out how to defeat a particular drug, it can quickly communicate out those instructions to neighboring bacteria, similar to sending out a group text message.

The current treatment for those with an active TB infection is a multidrug regimen over the course of six to nine months. Because different antibiotics use different mechanisms to defeat bacteria, TB is treated with several antibiotics at once to decrease the chances that the bacteria will become resistant to the drugs.

"Patient adherence to the taxing drug regimen has been a huge problem worldwide, and it is the main factor that has given rise to the very drug-resistant forms of TB that are much more toxic, expensive and time-consuming to treat," said Dorman.

Reducing the length of time needed to treat tuberculosis has long been an important public health goal. The more patients who complete their treatments for TB, the less likely it is for bacteria to escape with knowledge to defeat a particular drug and continue the group message thread to other bacteria.

"Shortening the treatment time improves adherence, decreases costs to programs and decreases the burdens on patients themselves," explained Dorman.

Dorman and her team at MUSC worked with both a Centers for Disease Control and Prevention (CDC) and a National Institutes of Health trials group to find a way to shorten the overall duration of treatment needed to cure the disease completely.

The team focused on a drug called rifapentine. This drug is similar to the antibiotic used in the current TB treatment protocol but remains effective in the body for longer periods of time. Over the course of 15 years, Dorman and her team performed preclinical and early phase clinical studies to determine how best to use this drug. They determined what dosage to give, how often the drug can be administered and what other antibiotics to pair with it. They then launched a worldwide phase III study with the TB Trials Consortium and the AIDS clinical trial group.

Patients with active TB infections were treated with one of two four-month rifapentine-based regimens or the standard six-month regimen. They were followed for 12 months. The results of the trial revealed that the four-month regimen containing rifapentine and another antibiotic, moxifloxacin, worked just as well as the six-month regimen. It was also safe and well-tolerated by the patients.

Dorman and her team hope these results will change how TB is currently being treated. In the U.S., their trial results will be submitted to the Food and Drug Administration (FDA). After the FDA reviews the data, the CDC will get involved and issue guidance on changing the treatment regimen. This process could take another 12 months to complete. In the meantime, Dorman and her team have been meeting with WHO representatives to develop guidelines for the new treatment.

"We're hopeful that the WHO will adopt this regimen and recommend it worldwide," said Dorman.

The results of this large phase III trial emphasize the importance of global participation and collaboration.

"Our intent was to enroll participants who reflected the overall world population of people with TB so that our results would be generalizable," said Dorman.

They also made sure to include those under the age of 18, along with people who have HIV. People living with HIV are 18 times more likely to develop active TB compared with people without HIV. The combination of HIV and TB is particularly lethal because the HIV virus attacks the main immune cells that help to coordinate a defense against the tuberculosis bacteria. Importantly, patients with HIV cleared their TB just as well as those without HIV in this phase III study.

"This work really represents a landmark in tuberculosis care, and some of the scientific work embedded in this trial will help us and others to understand how to improve TB treatment even more," said Dorman. "Four months is still too long."

A study of more than 1,000 demographically representative participants found that about 22 percent of Americans self-identify as anti-vaxxers, and tend to embrace the label as a form of social identity.

According to the study by researchers including Texas A&M University School of Public Health assistant professor Timothy Callaghan, 8 percent of this group "always" self-identify this way, with 14 percent "sometimes" identifying as part of the anti-vaccine movement. The results were published in the journal Politics, Groups, and Identities.

"We found these results both surprising and concerning," Callaghan said. "The fact that 22 percent of Americans at least sometimes identify as anti-vaxxers was much higher than expected and demonstrates the scope of the challenge in vaccinating the population against COVID-19 and other vaccine-preventable diseases."

Researchers also found that participants who scored high on the anti-vaccine identity measure were less trusting of scientific experts and more individualistic. Additionally, study results show that there is increased opposition to childhood vaccine requirements among those who self-identify as anti-vaxxers.

The study serves as a "blueprint" for other researchers to further examine how socially identifying as an anti-vaxxer impacts health policies and public health. Callaghan notes that Americans socially identifying as anti-vaxxers adds another layer of complexity to mitigating the anti-vaccine movement. Changing a core feature of one's underlying social identity is a difficult task -- one that likely cannot be fixed with traditional public health messaging.

Moving forward, Callaghan and other members of the research team hope to investigate how endorsement of the anti-vaccine label varies across the country based on states and levels of rurality, as well as interventions that might reduce individuals' social attachment to the label.

Most Americans should get screened for colorectal cancer beginning at age 45 instead of age 50, according to new recommendations from the U.S. Preventive Services Task Force, which includes UVA Health's Li Li, MD, PhD, MPH. This recommendation applies to Americans without symptoms who do not have a history of colorectal polyps or a personal or family health history of genetic disorders that increase the risk of colorectal cancer.

Colorectal cancer is the third-leading cause of cancer death in America, according to the Task Force, and an increasing number of cases are being diagnosed in younger Americans. The Task Force notes that colorectal cancer diagnoses among Americans ages 40 to 49 increased by almost 15% from 2000-02 to 2014-16. Black Panther star Chadwick Boseman was only 43 when he died of colon cancer in August.

"With colorectal cancer diagnoses becoming more common among younger people and the latest science showing that it is beneficial to screen younger people, the Task Force determined that regular screenings should begin at age 45," Li said.

The updated recommendation also encourages all Americans ages 45 to 75 get screened, with some people continuing screening through age 85. The Task Force's report noted that "in 2016, 25.6% of eligible adults in the U.S. had never been screened for colorectal cancer, and in 2018, 31.2% were not up to date with screening."

"If detected early, colorectal cancer is very treatable, which highlights the importance of beginning your screenings at the appropriate age," Li said.

The Task Force recommends two types of screening strategies: direct visualization tests - such as colonoscopies - and stool-based tests. Patients should discuss their screening options with their healthcare provider.

At Boston University, a team of researchers is working to better understand how language and speech is processed in the brain, and how to best rehabilitate people who have lost their ability to communicate due to brain damage caused by a stroke, trauma, or another type of brain injury. This type of language loss is called aphasia, a long-term neurological disorder caused by damage to the part of the brain responsible for language production and processing that impacts over a million people in the US.

"It's a huge problem," says Swathi Kiran, director of BU's Aphasia Research Lab, and College of Health & Rehabilitation Sciences: Sargent College associate dean for research and James and Cecilia Tse Ying Professor in Neurorehabilitation. "It's something our lab is working to tackle at multiple levels."

For the last decade, Kiran and her team have studied the brain to see how it changes as people's language skills improve with speech therapy. More recently, they've developed new methods to predict a person's ability to improve even before they start therapy. In a new paper published in Scientific Reports, Kiran and collaborators at BU and the University of Texas at Austin report they can predict language recovery in Hispanic patients who speak both English and Spanish fluently--a group of aphasia patients particularly at risk of long-term language loss--using sophisticated computer models of the brain. They say the breakthrough could be a game changer for the field of speech therapy and for stroke survivors impacted by aphasia.

"This [paper] uses computational modeling to predict rehabilitation outcomes in a population of neurological disorders that are really underserved," Kiran says. In the US, Hispanic stroke survivors are nearly two times less likely to be insured than all other racial or ethnic groups, Kiran says, and therefore they experience greater difficulties in accessing language rehabilitation. On top of that, oftentimes speech therapy is only available in one language, even though patients may speak multiple languages at home, making it difficult for clinicians to prioritize which language a patient should receive therapy in.

"This work started with the question, 'If someone had a stroke in this country and [the patient] speaks two languages, which language should they receive therapy in?'" says Kiran. "Are they more likely to improve if they receive therapy in English? Or in Spanish?"

This first-of-its-kind technology addresses that need by using sophisticated neural network models that simulate the brain of a bilingual person that is language impaired, and their brain's response to therapy in English and Spanish. The model can then identify the optimal language to target during treatment, and predict the outcome after therapy to forecast how well a person will recover their language skills. They found that the models predicted treatment effects accurately in the treated language, meaning these computational tools could guide healthcare providers to prescribe the best possible rehabilitation plan.

"There is more recognition with the pandemic that people from different populations--whether [those be differences of] race, ethnicity, different disability, socioeconomic status--don't receive the same level of [healthcare]," says Kiran. "The problem we're trying to solve here is, for our patients, health disparities at their worst; they are from a population that, the data shows, does not have great access to care, and they have communication problems [due to aphasia]."

As part of this work, the team is examining how recovery in one language impacts recovery of the other--will learning the word "dog" in English lead to a patient recalling the word "perro," the word for dog in Spanish?

"If you're bilingual you may go back and forth between languages, and what we're trying to do [in our lab] is use that as a therapy piece," says Kiran.

Clinical trials using this technology are already underway, which will soon provide an even clearer picture of how the models can potentially be implemented in hospital and clinical settings.

"We are trying to develop effective therapy programs, but we also try to deal with the patient as a whole," Kiran says. "This is why we care deeply about these health disparities and the patient's overall well-being."

An international subject pool was studied to confirm the effectiveness of a whole food complete vitamin and meal replacement product, IQed. The article, co-authored by Lisa Geng; Francine Hamel, EdD, SLP-CCC; Doreen Lewis, Ph.D., appeared in the peer-reviewed journal, Alternative Therapies (Altern Ther Health Med 2021 Mar;27(2):11-20(.

The findings indicate that the carefully developed nutritional supplement, IQed Smart Nutrition, can help bolster key functions for people with a wide range of prevalent diagnoses including Autism, Apraxia, and ADHD, and other obscure, but equally challenging, diagnoses encompassing speech and motor processing disorders.  

Deficits in speech and communication were the highest reported area of difficulty for this population, prior to taking the supplement, afflicting 83.8% of respondents. After supplementation, expressive speech improved for 85.7% of the participants with the increased vocalizations (sounds, words) factor showing the highest observed improvement (88.1%) among all speech and communication factors combined.

In all other categories, more than 67% of the survey respondents reported improvements in all measured areas: speech (77.6%), oral motor skills (63.2%), receptive ability (69.6%), focus (65.1%), motor planning (77.6%), mood (62.3%), social skills (59.3%), and physical/ behavioral health (47.3%).

"As a mom of special needs children that runs a nonprofit, I have found that specific essential nutrients are key for the acceleration of progress," said Co-author Lisa Geng, founder, and president of the Cherab Foundation. 

The main aim of this study funded by the nonprofit Cherab Foundation, and its subsequent article, is to guide future research into the dietary interventions and potential management of neurological conditions using natural food products, vitamin and mineral supplements, and Ayurvedic and botanical ingredients, with a focus on improving the quality of daily living and specific developmental milestones for children and adults with disabilities. 

Neurological and psychiatric symptoms such as fatigue and depression are common among people with Covid-19 and may be just as likely in people with mild cases, according to a new review study led by a UCL researcher.

By reviewing evidence from 215 studies of Covid-19, the meta-analysis published in the Journal of Neurology, Neurosurgery and Psychiatry reports a wide range of ways that Covid-19 can affect mental health and the brain.

Lead author Dr Jonathan Rogers (UCL Psychiatry and South London and Maudsley NHS Foundation Trust) said: "We had expected that neurological and psychiatric symptoms would be more common in severe Covid-19 cases, but instead we found that some symptoms appeared to be more common in mild cases. It appears that Covid-19 affecting mental health and the brain is the norm, rather than the exception."

The research team systematically reviewed evidence from 215 studies of Covid-19 from 30 countries, involving a total of 105,638 people with acute symptoms of Covid-19, including data up until July 2020 (acute refers to the main disease stage, rather than longer-term impacts). The studies varied as to which symptoms they were tracking, and the research team pooled data to compare how common each symptom was among the studies that tracked it.

Across the whole dataset, the most common neurological and psychiatric symptoms were: anosmia (loss of smell; reported by 43% of patients with Covid-19), weakness (40%), fatigue (38%), dysgeusia (loss of taste; 37%), myalgia (muscle pain; 25%), depression (23%), headache (21%) and anxiety (16%). They also identified the presence of major neurological disorders such as ischaemic stroke (1.9% of cases in the dataset), haemorrhagic stroke (0.4%) and seizure (0.06%). Patients with severe Covid-19 were overrepresented in the dataset as a whole, as most of the studies focused on hospitalised patients, and even the studies of people outside of hospital included few people with very mild or no symptoms.

But among people with symptomatic acute Covid-19 who were not hospitalised, neurological and psychiatric symptoms were still common: 55% reported fatigue, 52% loss of smell, 47% muscle pain, 45% loss of taste, and 44% reported headaches. The researchers say it's still possible that such symptoms are just as common in severe cases, as mild symptoms might not be reported by a patient in critical care.

While this review did not investigate causal mechanisms, the researchers suggest a few possible explanations. In the acute phase of the illness, inflammation has been found in the brain, which may explain some of the symptoms. Psychosocial factors relating to the context of the global pandemic may play a role, as people who are acutely ill may feel isolated when they cannot see their family or friends, which may explain why depression and anxiety have been found in some Covid-19 studies to be more common than in other viral illnesses such as the flu.

Dr Rogers said: "Many factors could contribute to neurological and psychiatric symptoms in the early stages of infection with Covid-19, including inflammation, impaired oxygen delivery to the brain, and psychological factors. More studies are needed to understand these links better."

Joint senior author Dr Alasdair Rooney (University of Edinburgh) said: "Neurological and psychiatric symptoms are very common in people with Covid-19. With millions of people infected globally even the rarer symptoms could affect substantially more people than in usual times. Mental health services and neurological rehabilitation services should be resourced for an increase in referrals."

The researchers found that most of the studies looked at a small subset of neurological symptoms, such as fatigue or muscle aches, while often neglecting symptoms of mental illnesses such as depression, anxiety and post-traumatic stress disorder (PTSD), as well as stroke and seizures, so they say more studies are required into the full range of symptoms linked to Covid-19.

A biomarker in the blood of patients with bowel cancer may provide valuable insight into the risk of cancer relapse after surgery and the effectiveness of chemotherapy.

Research published in PLOS found circulating tumour DNA (ctDNA) measured before and after surgery provided a reliable marker for predicting whether the cancer would recur following chemotherapy treatment.

The ctDNA also provided a real-time measure of the effectiveness of chemotherapy, highlighting the potential for this test to provide an early indication of the success of chemotherapy in eradicating microscopic cancer.

At a glance

By measuring levels of ctDNA present in the blood of bowel cancer patients after surgery, researchers were able to predict the likelihood of the cancer recurring.

Measuring the presence of ctDNA after chemotherapy provided a real time indication of whether the chemotherapy had cleared the cancer.

ctDNA could be used as a biomarker in the future to improve patient care and treatment

Prognostic impact of ctDNA

Led by Associate Professor Jeanne Tie, who is also a medical oncologist at the Peter MacCallum Cancer Centre and Western Health, the research followed a group of patients with metastatic bowel cancer who had secondary cancer in the liver that had been removed by surgery. The study builds on earlier research reported in 2018.

The ctDNA test looks for fragments of tumour DNA in a patient's blood before and after the removal of a cancerous tumour.

The presence of ctDNA in the blood of patients after surgery provides evidence of remaining microscopic tumours, enabling researchers to predict the likelihood of the cancer reoccurring.

Associate Professor Tie said the study once again confirmed the prognostic impact of ctDNA.

"What we found is that if ctDNA is present after surgery, it predicts an almost 100 per cent recurrence rate for these patients," she said.

"In contrast, for patients who were ctDNA-negative after surgery, the likelihood of the cancer reoccurring was far lower, about 25 per cent."

Measuring chemotherapy in real time

Associate Professor Tie said ctDNA also provided an indication of the effectiveness of chemotherapy.

"This biomarker could also identify whether patients would respond to chemotherapy treatment," she said.

"Until now, we had no way of measuring the effectiveness of chemotherapy in real time. The usual process is to do the surgery to remove the cancer metastases, give the patient chemotherapy, and then follow up with CT scans every six to 12 months, to see if the cancer recurs. And if the cancer does recur, you know the treatment hasn't worked. By measuring the ctDNA in the blood, we could immediately see whether the chemotherapy had cleared the cancer and were therefore able to predict the likelihood of the cancer recurring."

Associate Professor Tie said ctDNA biomarkers might allow clinicians to intervene earlier.

"Cancer that can be detected on a CT scan is unlikely to be curable by chemotherapy. But if we are able to detect microscopic disease, that we can't pick up on a scan, we can intervene earlier and potentially still offer the patient a chance of cure."

Promising sign for the future of cancer treatment

Associate Professor Tie said while ctDNA technology was already being used in the US, further research was needed before it could be rolled out in Australia.

"The test needs to be very sensitive to be able to pick up microscopic cancer cells. I am hopeful the new technology coming through will have enough sensitivity that we will be able to use this technique in the years ahead to improve patient care and treatment," she said.

"With further development of this technology, this could also mean patients with a low recurrence risk could avoid unnecessary chemotherapy."

If insomnia keeps you awake at night, Flinders University researchers recommend a trip to the doctor - not for a sleeping pill prescription but for a short course of intensive behavioural therapy.

Researchers have developed new clinical guidelines for Australian doctors to give family GPs insights into the most effective treatment for insomnia - Cognitive Behavioural Therapy for insomnia (or 'CBTi').

CBTi improves insomnia, mental health and quality of life, and can be more successful than sleeping pills, say Adelaide Institute for Sleep Health (AISH) sleep experts from Flinders University in a new paper in the Australian Journal of General Practice.

Most patients with insomnia managed in general practice are prescribed potentially addictive sedative-hypnotic medicines (e.g. benzodiazepines), and never access the CBTi that would treat their underlying condition, they say.

"We are aiming to provide GPs with more information, accessible guidelines and tools, as well as referral and treatment options to manage insomnia with CBTi," says lead researcher Dr Alex Sweetman from Flinders University.

"To get the ball rolling, our step-by-step model for GPs will identify, assess and treat insomnia with a Brief Behavioural Treatment for Insomnia program (BBTi)."

Brief Behavioural Treatment for insomnia leads to long-term improvement of insomnia, mental health, and overall quality of life, and can help patients reduce their use of sedative-hypnotic medicines.

This clinical review published in the Australian Journal of General Practice provides GPs with a description of a four-session insomnia treatment program that is tailored to the time limitations, knowledge, and capacity of general practice staff.

Dr Sweetman and his team are currently running two trials to provide GPs with a suite of tools and treatment options to manage patients with insomnia.

Chronic insomnia is characterised by difficulties getting to sleep, staying asleep, and/or early morning awakenings from sleep - with daytime impairments including reduced work productivity, fatigue and concentration difficulties.

Common in approximately 15% of the general population, it can persist for many years unless treated - ideally with non-pharmaceutical interventions.

Meanwhile, AISH and other sleep experts have also expanded ongoing investigations into better treatments for complex cases of combined insomnia, and sleep apnoea (COMISA), all conditions leading to doctor diagnoses and the need for targeted interventions.

The study of 2044 adult Australians found COMISA disorders are common and associated with increased medical and psychiatric co-morbidity, as well as poor general health.

"Much more investigation is required understand these combined disorders and improve diagnostic and treatment approaches," researchers say in their paper, Prevalence and associations of co-morbid insomnia and sleep apnoea in an Australian population-based sample (2021) by A Sweetman, YA Melaku, L Lack, A Reynolds, TK Bill, R Adams and S Appleton has been published in Sleep Medicine (Elsevier) DOI: 10.1016/j.sleep.2021.03.023

More information at A step-by-step model for a brief behavioural treatment for insomnia in Australian general practice (2021) by Alexander Sweetman, Nicholas A Zwar, Nicole Grivell, Nicole Lovato and Leon Lack has been published in the Australian Journal of General Practice Volume 50, Issue 5, DOI: 10.31128/AJGP-04-20-5391

Insomnia is a common and debilitating disorder that is frequently associated with important consequences for physical and mental health and wellbeing. It often occurs in tandem with another common sleep disorder, obstructive sleep apnoea (OSA).

Along with daytime sleepiness and fatigue, these debilitating disorders can be treated in a number of ways to reduce long-term health issues including diabetes, heart disease, anxiety and depression.

Researchers at the University of Turku, Finland, showed that the antibody treatment reactivates the immune defense in patients with advanced-stage cancer. The treatment alters the function of the body's phagocytes and facilitates extensive activation of the immune system.

The immune defense is the body's own defense system equipped to combat cancer. However, cancer learns to hide from immune attacks and harnesses this system to promote its own growth. Therefore, it would be beneficial to be able to return the immune defense back to restricting the advancement of cancer.

Macrophages, a type of white blood cell, are central in the fight against cancer. Cancer educates macrophages to subdue the defense system and renders many treatments targeting the immune system ineffective.

Academy Research Fellow Maija Hollmén's research group has searched for means of altering the activity of macrophages in order to direct the immune defense to attack cancer. The antibody bexmarilimab, developed based on this research and in collaboration with Faron Pharmaceuticals, is currently undergoing clinical trials in patients. Hollmén's group has studied the changes occurring in the defense systems of patients with cancer following antibody treatment.

"In the majority of patients, the antibody treatment activated killer T cells, which are the body's strike force against cancer. Additionally, the antibody treatment successfully lowered the suppressive potential of macrophage precursors travelling in the blood circulation. The patients also showed increases in certain mediators of inflammation and types of white blood cell in the blood," describes Hollmén.

"The activation of the killer T cells is a very promising demonstration of the antibody's capability to boost the defense system against cancer. The treated patients had very advanced and poorly treatable cancers, which highlights the significance of the results," says Doctoral Candidate Jenna Rannikko.

Bexmarilimab May Benefit Patients for Whom Current Treatment Options Are Ineffective

The research also yielded new information on the mode of action of bexmarilimab. The antibody binds the molecule Clever-1 present on macrophages and alters its function.

Clever-1 transports material needless to the body inside macrophages to be degraded. Objects disposed in this manner are swept under the rug, in a manner of speaking. This kind of concealment is beneficial for the body's natural balance and helps to avoid stirring the immune defense unnecessarily.

"However, cells originating from cancer should be detected. When the antibody is used to block Clever-1 from performing its cleaning job, it facilitates the activation of cells of the immune defense. This in part leads to the waking up of the T cells in patients," describes Doctoral Candidate Miro Viitala.

There is demand for treatments that boost the activity of the immune defense since the current options on the market only help some patients.

"Bexmarilimab's mode of action is different from the drug treatments against cancer currently on the market. Therefore, it can be beneficial for patients for whom current treatment options are ineffective," concludes Postdoctoral Researcher Reetta Virtakoivu.

Maija Hollmén's research group is part of the InFLAMES Flagship which is a joint initiative of University of Turku and Åbo Akademi University. The goal of the Flagship is to integrate immunological and immunology-related research activities to develop and exploit new diagnostic and therapeutic tools.

The research article has been published in the esteemed Clinical Cancer Research publication series.

Building on their previous findings, scientists from the Immuno-Pharmacology and Interactomics group at the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH), in collaboration with the Center for Drug Discovery at RTI International (RTI), a nonprofit research institute, have demonstrated that conolidine, a natural painkiller derived from the pinwheel flower and traditionally used in Chinese medicine, interacts with the newly identified opioid receptor ACKR3/CXCR7 that regulates opioid peptides naturally produced in the brain. The researchers also developed a synthetic analogue of conolidine, RTI-5152-12, which displays an even greater activity on the receptor. These findings, which were published on June 3rd in the prestigious international journal Signal Transduction and Targeted Therapy (Nature publishing group), further advance the understanding of pain regulation and open alternative therapeutic avenues for the treatment of chronic pain.

Opioid peptides are small proteins that mediate pain relief and emotions, including euphoria, anxiety, stress and depression, by interacting with four classical receptors ("molecular switches") in the brain. Dr Andy Chevigné, Head of Immuno-Pharmacology and Interactomics, and his team had previously identified the chemokine receptor ACKR3 as a novel fifth atypical opioid receptor, with high affinity for various natural opioids (Nature Communications, Meyrath et al. 2020). ACKR3 functions as a 'scavenger' that 'traps' the secreted opioids and prevents them from binding to the classical receptors, thereby dampening their analgesic activity and acting as a regulator of the opioid system.

In the current study, the researchers identified ACKR3 as the most responsive target for conolidine, an alkaloid with analgesic properties, by screening over 240 receptors for their ability to be activated or inhibited by this molecule.

"We confirmed that conolidine binds to the newly identified opioid receptor ACKR3, while showing no affinity for the other four classical opioid receptors. By doing so, conolidine blocks ACKR3 and prevents it from trapping the naturally secreted opioids, which in turn increases their availability for interacting with classical receptors. We believe that this molecular mechanism is at the basis of the beneficial effects of this traditionally used medicine on pain relief", said Dr Martyna Szpakowska, first author of the publication and scientist within the LIH Immuno-Pharmacology and Interactomics group.

In parallel to characterising the interaction between conolidine and ACKR3, the two teams went a step further. The scientists developed a modified variant of conolidine -- which they called "RTI-5152-12" -- which exclusively binds to ACKR3 with an even higher affinity. Like LIH383, a patented compound previously developed by Dr. Andy Chevigné and his team, RTI-5152-12 is postulated to increase the levels of opioid peptides that bind to classical opioid receptors in the brain, resulting in heightened painkilling activity. The LIH-RTI research teams established a collaboration agreement and filed a joint patent application in December 2020.

"The discovery of ACKR3 as a target of conolidine further emphasises the role of this newly discovered receptor in modulating the opioid system and, consequently, in regulating our perception of pain", said Dr. Chevigné, corresponding author of the publication and leader of the LIH Immuno-Pharmacology and Interactomics group.

"Our findings could also mean that conolidine, and potentially also its synthetic analogues, could carry new hope for the treatment of chronic pain and depression, particularly given the fact that conolidine was reported to trigger fewer of the detrimental side-effects -- namely addiction, tolerance and respiratory problems -- associated with commonly used opioid drugs like morphine and fentanyl".

"Our work could therefore set the basis for the development of a new class of drugs with alternative mechanism of action, thereby contributing to tackling the public health crisis linked to the increasing misuse of and addiction to opioid drugs", says Dr. Ojas Namjoshi, co-corresponding author of the publication and lead scientist on the study at RTI.

"Once again, we have built on the findings of our excellent fundamental research and translated them into applications with the potential of tangibly improving clinical outcomes for patients", said Prof Markus Ollert, Director of the LIH Department of Infection and Immunity. "We are grateful to the Luxembourg National Research Fund, the Ministry of Higher Education and Research and the European Commission for the generous support".

Philadelphia, June 3, 2021 - Researchers at Children's Hospital of Philadelphia (CHOP) have demonstrated how to use standardized reporting of clinical data for seizures caused by a variety of neurological disorders, providing fundamental baseline information that can determine what methods work best for keeping seizures under control. The findings were published today in the journal Epilepsia.

In order to make improvements in epilepsy care, clinicians need a reliable and efficient method to measure outcomes. While Electronic Medical Records (EMR) are being used more frequently for research and quality improvement, important epilepsy outcome measures such as seizure frequency or quality of life are not documented in a standardized way that enables researchers to process large-scale data on the subject.

To help standardize how clinical data is recorded for epilepsy visits, the team at CHOP began using common data elements (CDEs) to ensure that relevant data is captured in a comparable way across studies and clinical visits. In this study, the researchers assessed the results from using CDEs in routine care for pediatric epilepsy over a 12-month period.

"For those of us who treat pediatric epilepsy patients, we are constantly trying to assess how we're doing and how we can improve outcomes for our patients," said Mark P. Fitzgerald, MD, PhD, a pediatric neurologist in the Division of Neurology at CHOP and first author of the study. "This study provides us with fundamental data that will serve as the foundation for how we treat our patients and inform how we achieve the best patient-centered outcomes possible."

The researchers looked at almost 1,700 visits by more than 1,000 individual patients with childhood epilepsies. The study covered a period of approximately one year, with visits conducted by 32 different providers across the CHOP Network. Overall, 43% of patients had at least one seizure a month, 17% had at least one seizure each day, and 18% of patients were free of seizures for at least one year. The most common epilepsy syndromes were Childhood Absence Epilepsy, Lennox-Gastaut Syndrome, and Dravet Syndrome. The researchers were able to quantify the absolute seizure burden as well as changes in seizure burden over time and the differences between syndromes.

Additionally, because this study was conducted as the COVID-19 pandemic began, the researchers assessed the use of telemedicine to record this information. They found that patients had comparable seizure frequencies whether assessed in-person or via telemedicine. The study also found that patients identifying as Hispanic or Latino, particular from areas with lower median household incomes, were more likely to have ongoing seizures that worsened over time.

"Currently, CHOP is the only neurology program that generates this level of patient information from ongoing care rather than research studies only," said senior author Ingo Helbig, MD, attending physician and director of the genomic and data science core of Epilepsy Neurogenetics Initiative (ENGIN) at CHOP. "This study represents a major paradigm shift in how we assess and deliver care to our pediatric neurology patients."