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New Rochelle, NY, January 25, 2021--Gene editing therapies, including CRISPR-Cas systems, offer the potential to correct mutations causing inherited retinal degenerations, a leading cause of blindness. Technological advances in gene editing, continuing safety concerns, and strategies to overcome these challenges are highlighted in the peer-reviewed journal Human Gene Therapy. Click here to read the full-text article free on the Human Gene Therapy website.

"Currently, the field is undergoing rapid development with a number of competing gene editing strategies, including allele-specific knock-down, base editing, prime editing, and RNA editing, are under investigation. Each offers a different balance of on-target editing efficiency versus off-target risks," state Kanmin Xue, University of Oxford, and coauthors. "Testing these newly-developed CRISPR technologies in human retinal tissue, organoids and in vivo will help to highlight the most-viable therapeutic approaches for treating inherited retinal diseases in the future."

Characterizing the rapidly evolving field of CRISPR-Cas based genome editing and current strategies for extending the capabilities of CRISPR-Cas9, the article also features epigenetic editing, the risks of retinal gene editing, and approaches in development to control Cas9 activity and improve safety.

"The eye is an ideal target for in vivo gene editing. Dr. Xue's review provides an excellent overview of the current state of the art," says Editor-in-Chief of Human Gene Therapy Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School.

WASHINGTON (Jan. 25, 2021) - The majority of dermatology patients surveyed find telehealth appointments to be a suitable alternative to in-person office visits, according to a survey study from researchers at the George Washington University (GW) Department of Dermatology. The results are published in the Journal of Drugs in Dermatology.

The COVID-19 pandemic changed many aspects of everyday life, including how patients interact with the health care system and seek medical care. Social distancing and stay-at-home orders have led to a move from in-office to virtual visits. While many specialties had to shift to the virtual format because of the pandemic, dermatology had already been experiencing an increase in telehealth visits over the last decade.

"Teledermatology boasts a number of benefits, including increased access to care, cost savings for patients, convenience, and, with the current pandemic, avoids physical contact," said Samuel Yeroushalmi, a third-year medical student at the GW School of Medicine and Health Sciences and first author of the study. However, virtual appointments do come with some drawbacks, including privacy and security concerns, appropriate image acquisition, and appropriate provider training or experience.

To evaluate patient satisfaction with teledermatology appointments, the team distributed an online survey to dermatology patients at the GW Medical Faculty Associates. The survey assessed the patients' reasons for scheduling the telehealth visit, as well as any pandemic-related barriers to care and overall satisfaction with the appointment.

Of the respondents to the survey, 47% reported having a previous appointment cancelled due to COVID-19 and 17.7% were new patients who had not previously had an in-office appointment. Patients reported that they most liked their telehealth experience because they were time efficient, did not require transportation, and effectively maintained social distancing. Reasons patients did not like their virtual appointments include lack of physical touch and feeling they received an inadequate assessment.

When asked if they would recommend telehealth services, only a small minority (6.9%) stated they would not.

"Video calling can certainly present challenges with regard to creating an intimate and collaborative physician-patient relationship compared to in-person encounters, not to mention enhancing certain areas that already have deficiencies," said Adam Friedman, MD, interim chair of the Department of Dermatology and professor of dermatology at the GW School of Medicine and Health Sciences. "Accurate diagnosis of hair, skin, and nails in all skin types has been highlighted as an area in great need of improvement. Telemedicine can easily add an additional layer of complexity, widening the gap and impacting care."

Overall, the team concluded that the majority of patients who had teledermatology appointments found the visits to be an adequate substitute for in-person appointments. The authors suggest that telehealth can and should continue to provide high-quality care for patients of dermatologists during the COVID-19 pandemic in tandem with proper education to ensure meaningful use.

Using machine learning, researchers at the UC Davis MIND Institute have identified several patterns of maternal autoantibodies highly associated with the diagnosis and severity of autism.

Their study, published Jan. 22 in Molecular Psychiatry, specifically focused on maternal autoantibody-related autism spectrum disorder (MAR ASD), a condition accounting for around 20% of all autism cases.

"The implications from this study are tremendous," said Judy Van de Water, a professor of rheumatology, allergy and clinical immunology at UC Davis and the lead author of the study. "It's the first time that machine learning has been used to identify with 100% accuracy MAR ASD-specific patterns as potential biomarkers of ASD risk."

Autoantibodies are immune proteins that attack a person's own tissues. Previously, Van de Water found that a pregnant mother's autoantibodies can react with her growing fetus' brain and alter its development.

Machine learning identifies patterns indicating likelihood and severity of autism

The research team obtained plasma samples from mothers enrolled in the CHARGE study. They analyzed the samples from 450 mothers of children with autism and 342 mothers of typically developing children, also from CHARGE, to detect reactivity to eight different proteins that are abundant in fetal brain. They then used a machine learning algorithm to determine which autoantibody patterns were specifically associated with a diagnosis of ASD.

The researchers created and validated a test to identify ASD-specific maternal autoantibody patterns of reactivity against eight proteins highly expressed in the developing brain.

"The big deal about this particular study is that we created a new, very translatable test for future clinical use," said Van de Water. This simple maternal blood test uses an ELISA (Enzyme-Linked-ImmunoSorbent Assay) platform, which is very quick and accurate.

The machine learning program crunched roughly 10,000 patterns and identified three top patterns associated with MAR ASD: CRMP1+GDA, CRMP1+CRMP2 and NSE+STIP1.

"For example, if the mother has autoantibodies to CRIMP1 and GDA (the most common pattern), her odds of having a child with autism is 31 times greater than the general population, based on this current dataset. That's huge," said Van de Water. "There's very little out there that is going to give you that type of risk assessment."

Researchers also found that reactivity to CRMP1 in any of the top patterns significantly increases the odds of a child having more severe autism.

Future implications

Van de Water notes that with these maternal biomarkers, there are possibilities for very early diagnosis of MAR autism and more effective behavioral intervention. The study opens the door for more research on potential pre-conception testing, particularly useful for high-risk women older than 35 or who have already given birth to a child with autism.

"We can envision that a woman could have a blood test for these antibodies prior to getting pregnant. If she had them, she'd know she would be at very high risk of having a child with autism. If not, she has a 43% lower chance of having a child with autism as MAR autism is ruled out," Van de Water said.

Van de Water is currently researching the pathologic effects of maternal autoantibodies using animal models. "We will also use these animal models to develop therapeutic strategies to block the maternal autoantibodies from the fetus," said Van de Water.

"This study is a big deal in terms of early risk assessment for autism, and we're hoping that this technology will become something that will be clinically useful in the future."

DES PLAINES, IL -- In patients matched on complexity and acuity presenting to the emergency department with chest pain and abdominal pain, the care delivered by advanced practice providers (APPs) and emergency physicians is largely similar with respect to diagnostic test ordering and admission decisions. That is the finding of a study just published in the January 2021 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Jesse M. Pines, MD, MBA, MSCE of US Acute Care Solutions, Canton, Ohio and the Department of Emergency Medicine, Allegheny Health Network, Pittsburgh, Pennsylvania. The findings of the study are discussed in a recent AEM podcast titled, "What a Difference an APP Makes? Diagnostic Testing Differences Between APPs and Physicians."

The authors recommend that future research should continue to explore the optimal use of advanced practice providers in the emergency department and the best ways to deploy this expanding part of the United States emergency department workforce.

Leesburg, VA, January 25, 2021--According to an open-access article in ARRS' American Journal of Roentgenology (AJR), in lumbar spine MRI, presumptive pain generators diagnosed using symptom information from brief electronic questionnaires showed almost perfect agreement with pain generators diagnosed using symptom information from direct patient interviews.

"Using patient-reported symptom information from a questionnaire, radiologists interpreting lumbar spine MRI converged on diagnoses of presumptive pain generators and distinguished these from incidental abnormalities," wrote Rene Balza of the department of radiology at Massachusetts General Hospital.

Between February and June 2019, Balza and colleagues recruited 120 participants (70 men, 50 women; median age 64) from patients referred for lumbar spine injections; the participants completed electronic symptom questionnaires before injections. Six radiologists diagnosed pain generators in three research arms:

MRI studies reviewed with symptom information from questionnaires;

MRI studies reviewed without symptom information;

MRI reports.

According to the Massachusetts General Hospital researchers' results: "Radiologists' agreement with reference diagnoses for presumptive pain generator type, level, and side on lumbar spine MRI was almost perfect when knowing symptoms (κ=0.82-0.90), versus fair-moderate without symptom information (κ=0.28-0.51) (p

Diagnostic certainty levels were highest for radiologists performing injections--"significantly higher for MRI review with symptom information versus without symptom information, the authors of this AJR article added.

AURORA, Colo. (Jan. 22, 2021) - Researchers at the University of Colorado Anschutz Medical Campus have discovered a direct association between placental function in pregnant women and future metabolic disorders in children and adults, a finding that could lead to earlier intervention and diagnosis of disease.

"We've known for some time that many major diseases in adults like diabetes and cardiovascular disease are at least partly caused by problems during fetal life," said the study's senior author Thomas Jansson, MD, PhD, professor of Obstetrics & Gynecology at the University of Colorado School of Medicine. "For example, it has been shown that 50% of all type-2 diabetes in young adults are caused by exposure to the intrauterine environment in pregnant women with obesity and/or gestational diabetes."

In this study, published this month in the journal Diabetes, Jansson and the paper's lead author Madeline Rose Keleher, PhD, of the Colorado School of Public Health's LEAD Center (Lifecourse, Epidemiology of Adiposity & Diabetes) have uncovered more about the placenta's role in the future health of a child.

"We are the first to discover associations between placental function and blood pressure, body fat and triglyceride levels in children between the ages of 4-6 years old," Jansson said. "These markers often signal risks for future heart disease, diabetes and obesity."

The researchers used the Healthy Start longitudinal pre-birth cohort study which enrolled 1,410 healthy pregnant women between 2010-2014. The children are now 4-6-years-old.

"What's unique is the time frame. We didn't just stop at newborns," Keleher said. "We followed the kids for one year then four to six years. We see this isn't something they simply outgrow. We will continue to follow them when they are eight to ten years old."

A healthy intrauterine environment is largely determined by the placenta, which nourishes the fetus and protects it against the mother's immune system. Changes in the placenta like inflammation or insulin signaling, the researchers said, can set the stage for later disease.

The study revealed that the placental IGF-1 receptor protein was associated with serum triglycerides in children which could lead to obesity or diabetes later. Other proteins in the placenta were shown to have associations with increased fat tissue on the arms and thighs of children.

"All of these showed a novel link between placental function and long-term metabolic outcomes," Keleher said.

According to Jansson, if doctors discover that a placenta is not functioning properly during pregnancy they may be able to intervene.

"If we know the placenta is impaired or changed during pregnancy we can design interventions to modulate that function and decrease the risk to the fetus," he said. "Treating pregnant women is always difficult but the placenta is accessible whereas the fetus is largely inaccessible."

The findings could ultimately lead to a kind of personalized medicine that begins before birth.

"I think a better understanding of the mechanisms linking placental function to childhood and adult metabolic disease risk may offer innovative avenues to preventing them in future generations," Keleher said.

What The Study Did: In this observational study, the spread of SARS-CoV-2 infection during a period of lockdown in southwest Germany was particularly low in children ages 1 to 10 years old. Overall, this large SARS-CoV-2 prevalence study in children is instructive for how ad hoc mass testing provides the basis for rational political decision-making in a pandemic setting.

Authors: Burkhard Tönshoff, M.D., of the University Children's Hospital in Heidelberg, Germany, and Klaus-Michael Debatin, M.D., of Ulm University Medical Center in Ulm, Germany, are the corresponding authors.

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

(doi:10.1001/jamapediatrics.2021.0001)

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.

Kanazawa, Japan - Liver injury is a rare side effect of nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for daily pain control. This toxicity has been regarded as a "black box" and is mainly managed by an empirical approach, but there is not a clear understanding of the mechanism. Now, researchers from Japan have found that a bit of attention to the types and frequencies of NSAIDs could help people avoid liver injury.

In a study published recently in Biochemical Pharmacology, researchers from Kanazawa University have revealed that specific NSAIDs, including ibuprofen, are metabolized by one of the acyl-CoA synthetases, ACSL1, in a manner that can have toxic effects.

NSAIDs containing a specific chemical group, carboxylic acid, can form "conjugates" with coenzyme A (CoA) or glucuronic acid. Although these conjugates are suspected to cause toxicities, such as liver injury and anaphylaxis, the processes involved in CoA conjugation have been poorly understood, and researchers at Kanazawa University have aimed to address this.

"NSAID toxicities including liver injury and anaphylaxis had been considered to be caused by conjugates with glucuronic acid, another types of metabolite," says senior author of the study, Miki Nakajima. "Because a recent study demonstrated a robust interaction between ibuprofen and CoA, we wanted to investigate how a range of NSAIDs conjugated with CoA in the presence of liver enzymes."

To do this, the researchers performed enzymatic reactions involving human liver extracts, CoA, and representative medications from each of 10 classes of NSAIDs. They used a mass spectrometry method to identify interactions between the NSAIDs and CoA.

"The difference among NSAIDs was striking," explains Tatsuki Fukami, corresponding author. "We found that propionic acid-class NSAIDs, such as ibuprofen, had robust binding interactions with CoA, whereas other NSAIDs, such as salicylic acid, did not. This selectivity was likely determined by ACSL1."

In addition, CoA conjugates of propionic acid-class NSAIDs could strongly bind with liver proteins, while glucuronic acid conjugates of those same NSAIDs formed weaker bonds with liver proteins.

"Our findings suggest that the high covalent binding of CoA-conjugate of propionic acid-class NSAIDs to hepatocellular proteins leads to liver injury. Because there is a large interindividual variation in the hepatic expression of ACSL1 catalyzing CoA conjugation with propionic acid-class NSAIDs, this variation may account for the susceptibility to their toxicities," says Fukami.

Because pain control is an important medical problem for many people worldwide, this new information could help pharmaceutical companies to generate pain control options with fewer risks of severe side effects.

Leesburg, VA, January 22, 2021--According to ARRS' American Journal of Roentgenology (AJR), Fibrosis-4 (FIB-4) and multiple CT findings can identify patients with high-risk nonalcoholic fatty liver disease (NAFLD)--advanced fibrosis or cirrhosis, that is--though the presence of nonalcoholic steatohepatitis (NASH) remains elusive on CT.

"Subjective assessment of multiple morphologic and separately quantified parameters by trained readers and a simple quantitative three-parameter model combining two CT features, liver surface nodularity (LSN) and liver segmental volume ratio (LSVR), and a clinical score (FIB-4) showed good association with presence of advanced fibrosis," wrote first author Meghan G. Lubner from the department of radiology at the University of Wisconsin School of Medicine and Public Health.

Based on a presentation at the ARRS 2019 Annual Meeting, Honolulu, HI, patients with biopsy-proven NAFLD who underwent CT within 1 year of biopsy were included. An experienced gastrointestinal pathologist performed a histopathologic review to determine steatosis, inflammation, and fibrosis. The presence of any lobular inflammation and hepatocyte ballooning was categorized as nonalcoholic steatohepatitis (NASH), while patients with NAFLD and advanced fibrosis (stage F3 or higher) were categorized as having high-risk NAFLD. Two readers subjectively assessed the presence of NASH and fibrosis.

The final cohort consisted of 186 patients (mean age, 49 years; 112 women and 74 men), of whom 87 (47%) had NASH and 112 (60%) had moderate to severe steatosis. A total of 51 patients were classified as fibrosis stage F0, 42 as F1, 23 as F2, 37 as F3, and 33 as F4. Additionally, 70 (38%) had advanced fibrosis (stage F3 or F4) and were considered to have high-risk NAFLD. FIB-4 score showed correlation with fibrosis, and of the individual CT parameters, LSVR and splenic volume had the best performance. Meanwhile, subjective reader assessment performed best among all parameters. FIB-4 and subjective scores were complementary, and for NASH assessment, FIB-4 performed best.

Noting the well-established utility of CT in identifying hepatic steatosis, the authors of this AJR article concluded that CT can also be "a highly accessible, frequently used method for assessment of patients with NAFLD and identification of those with high-risk NAFLD (advanced fibrosis or cirrhosis) who are potentially most in need of intervention."

Most lung cancers are of a type called non-small-cell lung carcinoma (NSCLC). This type of cancer is relatively insensitive to chemotherapy, so NSCLC therapies are usually based on drug treatment. Alectinib is a drug commonly used for treating patients with NSCLC. It addresses a gene rearrangement known as ALK that occurs in 3 to 5% of NSCLC patients (alectinib belongs to a class of drugs called ALK tyrosine kinase inhibitors). It has been unclear, however, whether there is a correlation between the use of alectinib and the poorer prognosis in ALK-NSCLC patients in which secondary cancer mutations are observed -- the latter are known to occur with a frequency of about 25%. Now, Azusa Tanimoto from Kanazawa University and colleagues have investigated this correlation. They found that such secondary mutations reduce the efficacy of alectinib, but they also suggest how to overcome this issue.

The researchers looked at data on 124 NSCLC patients who were treated with ALK tyrosine kinase inhibitors, including alectinib, and who had tested positive for the ALK gene rearrangement. Out of these, for 31 patients, a secondary gene rearrangement known as TP53 mutation was detected. Tanimoto and colleagues looked at whether there is a correlation between alectinib use and TP53 mutations in this group of patients.

The data showed that the cancer's progression-free survival was significantly poorer in patients with TP53 mutations who received alectinib treatment. (The same conclusion was obtained for other treatments with other ALK tyrosine kinase inhibitors.) The resistance to the drugs is linked to the loss of normal p53 function in ALK-rearranged NSCLC; p53 refers to a set of proteins that are known to play a role in preventing cancer formation.

The scientists then investigated how to overcome the adverse effect of alectinib when secondary TP53 mutations occur. Based on their insights into the biochemical mechanisms at play, they proposed to combine alectinib with another drug: ixazomib. The latter is a drug from the class of proteasome inhibitors, which block the action of proteasomes, which in turn break down proteins. Experiments in mice showed promising results: general tumor shrinkage, and complete regression of 3 out of 8 tumors.

The findings of Tanimoto and colleagues show that the combined use of a proteasome inhibitor and alectinib restores the latter's unfavorable efficacy in ALK-rearranged NSCLC. The scientists further conclude: "Based on these [clinical and preclinical] data, this combination therapy is needed to be validated in ... clinical trials."

[Background]

NSCLC

Non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC) are the two types of lung cancer. 85% of all lung cancers are of the NSCLC type. NSCLCs are less sensitive to chemotherapy than SCLCs, making drug treatment of the highest importance.

Alectinib is a drug used for treating NSCLC, normally with good efficiency. However, in certain scenarios where gene alterations occur, the drug has an adverse effect, as now shown by Azusa Tanimoto from Kanazawa University and colleagues. Tanimoto and colleagues further show that in such situations, combining alectinib with another drug (of the proteasome-inhibitor type) restores its efficacy.

Tyrosine kinase inhibitors

A tyrosine kinase inhibitor is a drug inhibiting (that is, preventing or reducing the activity of) a specific tyrosine kinase. A tyrosine kinase is a protein (enzyme) involved in the activation of other proteins by signaling cascades. The activation happens by the addition of a phosphate group to the protein (phosphorylation); it is this step that a tyrosine kinase inhibitor inhibits. Tyrosine kinase inhibitors are used as anticancer drugs. One such drug is alectinib, used to treat NSCLC.

COLUMBUS, Ohio - A new study suggests that a lot of people might be going through life with symptoms that resemble concussion - a finding supporting researchers' argument that athletes recovering from a brain injury should be assessed and treated on a highly individualized basis.

In the national study, between 11% and 27% of healthy college athletes with no history of a recent concussion reported combinations of symptoms that met criteria for post-concussion syndrome (PCS) as defined by an international classification system. Among the nearly 31,000 student-athletes surveyed, three factors stood out as the most likely to predict PCS-like symptoms: lack of sleep, pre-existing mental health problems and stress.

The participants were cadets from four U.S. military service academies - who undergo rigorous training and are required to participate in athletics - and students who competed in NCAA sports at 26 U.S. higher education institutions.

Beyond the substantial numbers of students who reported clusters of PCS-like symptoms, between one-half and three-quarters of all of the athletes surveyed reported one or more symptoms commonly experienced by people who've had a concussion, the most common being fatigue or low energy and drowsiness.

"The numbers were high, and were consistent with previous research in this area, but it is quite shocking," said study lead author Jaclyn Caccese, assistant professor in The Ohio State University School of Health and Rehabilitation Sciences. "These are elite athletes who are physically fit, and they are experiencing that many symptoms commonly reported following concussion. So looking across the general population, they'd probably have even more."

It's important to understand that there are multiple sources of these symptoms, researchers say, so that student-athletes' post-concussion care zeroes in on symptoms caused by the injury. In addition, knowing athletes' medical history and baseline symptom status may help clinicians predict which pre-existing factors could contribute to a slower recovery from a concussion.

"When a patient comes into a clinic and they are a month or more out from their most recent concussion, we need to know what symptoms they were experiencing before their concussion to know if their symptoms are attributable to their concussion or something else. Then we can start treating the concussion-related symptoms to hopefully help people recover more quickly," Caccese said.

This study, published last week in the journal Sports Medicine, was conducted by the Concussion Assessment, Research and Education (CARE) Consortium established by the NCAA and U.S. Department of Defense. Caccese completed the research while she was a PhD student and postdoctoral researcher at the University of Delaware, a consortium member institution.

The initiative is designed to fill gaps in knowledge about concussion effects and recovery among student-athletes at colleges, universities and military service academies by collecting and analyzing data on men and women who compete in a range of sports and undergo military training.

Participants in this study included 12,039 military service academy cadets and 18,548 NCAA student-athletes who completed the Sport Concussion Assessment Tool symptom evaluation as part of the consortium's baseline testing. The consortium also collected demographic data and personal and family medical histories from participants.

Statistical analyses showed which factors in athletes' medical histories were most closely associated with reports of symptoms that aligned with PCS criteria. Among cadets, 17.8% of men and 27.6% of women reported a cluster of symptoms that met PCS criteria. Among NCAA athletes, 11.4% of men and 20% of women reported combined symptoms that mimicked the PCS criteria. (Caccese said the varied timing of data collection at military service academies compared to NCAA preseason testing likely contributed to the symptoms reported by a higher percentage of cadets.)

For both groups, sleep problems - and particularly insufficient sleep the night before the test - and pre-existing psychiatric disorders were the most predictive conditions, and a history of migraines also contributed to symptoms that met PCS criteria. In cadets, academic problems and being a first-year student increased odds of having symptoms that met PCS criteria, and in NCAA athletes, a history of ADHD or depression contributed to meeting PCS criteria.

The International Classification of Diseases, Tenth Revision uses the term post-concussion syndrome for persistent symptoms following concussion, although the cause or causes of these symptoms can be difficult to determine. Symptoms range from persistent headaches, dizziness and fatigue to anxiety, insomnia and loss of concentration and memory.

A complicating factor with high symptom reporting is that recognizing concussion and determining return to play is based on reported symptoms. And while some symptoms may be more closely connected to concussion than others - such as dizziness, pressure in the head, or sensitivity to light or noise - others, like fatigue, drowsiness and even headaches, can be linked to a variety of causes.

"Perhaps we can create a battery of symptoms more specific to concussion," Caccese said. "That is another project in this series - trying to see if there are groups of symptoms or specific symptoms that may be more able to identify individuals with concussion."

The CARE Consortium also aims to identify factors that will help predict outcomes in student-athletes and cadets who suffer concussions.

"This hopefully not only shows clinicians that we need to consider how people would have presented before injury, but also provides some normative data so they can interpret other patients' data," Caccese said. "We really don't know a lot about why people have persistent symptoms, and it seems to be very variable. So we're trying to understand this better to help predict who will have a prolonged recovery, and who will not."

Human papillomavirus (HPV) is the most common sexually transmitted infection, with an estimated 79 million Americans currently infected with the virus, according to the Centers for Disease Control and Prevention. If a high-risk HPV infection does not go away, it can lead to the development of a variety of cancers, including 91% of all cervical cancers, 70% of oropharyngeal cancers and cancers of the vulva, vagina, penis and anus.

HPV vaccination can significantly reduce the number of new cancer diagnoses linked to the virus, in addition to preventing a number of other health complications.

"Given the effect that HPV vaccination has had on cancer prevention, it is important to identify factors influencing HPV vaccination coverage," said Bernard Fuemmeler Ph.D., associate director for population science, the Gordon D. Ginder, M.D., Chair in Cancer Research and co-leader of the Cancer Prevention and Control research program at VCU Massey Cancer Center.

Fuemmeler and his team conducted the first-ever systematic review of area-level data reported in the United States between 2006 and 2020 to determine how geography, neighborhoods and sociodemographic factors impact HPV vaccination rates among adolescents and young adults. The study was published in Cancer Epidemiology, Biomarkers and Prevention.

The CDC recommends two doses of the HPV vaccine six to 12 months apart beginning at age 11 or 12 and for everyone through age 26 if not already vaccinated. Despite this federal recommendation from health experts, Fuemmeler's team found that, across these studies, vaccination uptake is not uniform within the population and existing studies suggest that vaccination coverage varies markedly across the U.S and within local regions of the U.S.

"Understanding how HPV vaccination coverage varies by geography can help to identify areas of need for prevention and control efforts," said Fuemmeler, a professor in the Department of Health Behavior and Policy at the VCU School of Medicine.

Many intervention strategies have been implemented to address several of the factors that contribute to low vaccination rates, including education level, health insurance coverage, income and vaccine awareness, but those efforts are often untargeted or limited to certain areas, creating widespread geographical disparities throughout the country. For example, Fuemmeler's research shows that HPV vaccination completion rates vary from nearly 80% in Rhode Island to less than 29% in Mississippi.

Upon completion of their review, Fuemmeler's team proposed five recommendations and future considerations to overcome the current barriers to effectively address and improve national HPV vaccination coverage: 1) foster interdisciplinary collaborations and research to support more detailed analyses of geographic disparities in HPV vaccination coverage; 2) standardize procedures for immunization reporting systems to make information consistent across states; 3) standardize variable definitions in research on HPV vaccination coverage; 4) incorporate spatial regression modeling approaches to identify where HPV-related burdens are elevated and prevention and intervention efforts are needed; and 5) obtain data on HPV prevalence in smaller geographic areas for a more detailed understanding of HPV vaccination coverage nationwide.

"Our findings demonstrate the need to adopt geospatial, standardized and collaborative approaches in future studies that allow for the effective mapping, detection and reporting of geographic areas with low HPV vaccination coverage," Fuemmeler said.

Patients with acute myeloid leukemia (AML), the most common form of acute leukemia in adults, that has gone into remission following initial chemotherapy remain in remission longer and have improved overall survival when they are given a pill form of the cancer drug azacitidine as a maintenance treatment, according to a randomized, international phase 3 clinical trial for which Weill Cornell Medicine and NewYork-Presbyterian are trial sites. This is the first time a maintenance treatment for AML has shown such a strong benefit for patients, and it is already being adopted as part of standard care.

The results, which were published Dec. 24 in the New England Journal of Medicine, led to the U.S. Food and Drug Administration's approval in September 2020 of oral azacitidine, known by the trade name Onureg, as a maintenance therapy for AML.

"At last, we have an effective treatment that can be given in the post-remission setting to help keep AML patients in remission and improve their survival," said senior author Dr. Gail Roboz, professor of medicine in the Division of Hematology and Medical Oncology and director of the Clinical and Translational Leukemia Program at Weill Cornell Medicine, a hematologist/oncologist at NewYork-Presbyterian/Weill Cornell Medical Center and principal investigator of the clinical trial at Weill Cornell Medicine and NewYork-Presbyterian. "We are especially gratified that the drug is very well-tolerated, so that quality of life is not compromised."

AML is a devastating, life-threatening hematological cancer. According to the National Cancer Institute, AML strikes about 20,000 people per year in the United States, and kills more than 11,000. It mainly affects middle-aged and older adults. The five-year survival rate is about 30 percent overall, but only about 10 percent for patients older than 65. Patients with AML frequently relapse, even after achieving complete remission with initial chemotherapy.

The randomized phase 3 clinical trial of 472 patients from 148 medical centers around the world, known as the QUAZAR AML-001 Trial, tested whether relapse could be delayed using oral azacitidine as a maintenance therapy. The investigators found that patients taking 300 mg of the drug for two weeks every month had statistically and clinically significant improvements in relapse-free survival (RFS) and overall survival (OS). Median RFS and OS were, respectively, 10.2 months and 24.7 months with oral azacitidine, versus only 4.8 and 14.8 months for patients taking placebo. Two years from the start of the maintenance treatment, 50.6 percent of the azacitidine patients had survived, compared with 37.1 percent of the placebo patients. Side effects were moderate and manageable.

Azacitidine is thought to work principally as a "hypomethylating" drug that removes chemical marks called methyl groups from DNA in cells. Methyl groups regulate gene activity, usually by silencing nearby genes, and removal of methyl groups is thought to restore activity of tumor suppressor genes that counter cancerous cell proliferation.

Side effects with oral azacitidine that were somewhat more common in the treatment group included vomiting, low white blood cell counts, and infections, but these were generally considered manageable and did not result in treatment discontinuation. QUAZAR was the first large international AML maintenance trial to systematically assess quality of life throughout the trial, and patients in the treatment and placebo groups scored similarly on quality of life-related measures, demonstrating the tolerability of oral azacitidine.

Dr. Roboz, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a paid consultant for Celgene and Bristol Myers-Squibb, sponsors of the research, notes that some patients taking the new maintenance therapy have survived for many years.

"One of my patients on the trial was so critically ill when she was initially diagnosed that she was told to get her affairs in order, but her AML was put into remission, and she has been receiving oral azacitidine maintenance therapy as part of the QUAZAR trial since 2013," Dr. Roboz said.

Many college students fully recover from infectious mononucleosis (which is almost always caused by Epstein-Barr virus) within 1-6 weeks, but some go on to develop chronic fatigue syndrome, also called myalgic encephalomyelitis (ME/CFS). A longitudinal study from DePaul University and Northwestern University followed 4,501 college students to examine risk factors that may trigger longer illness. The research appears in the journal Clinical Infectious Diseases and was funded by the National Institute of Allergy and Infectious Diseases.

Previous retrospective studies found that risk factors for developing ME/CFS after catching mono included preexisting physical symptoms and the number of days spent in bed, according to co-principal investigators Leonard A. Jason, professor of psychology at DePaul University; and Dr. Ben Z. Katz, a professor of pediatrics at Northwestern University Feinberg School of Medicine and a pediatric infectious disease specialist at Ann & Robert H. Lurie Children's Hospital of Chicago.

"We are the only study to collect comprehensive biological and behavioral data prior to illness onset, which for the first time allowed us to identify some of the predisposing circumstances or conditions that make certain individuals more likely to get ill due to mono and stay ill," says Jason, director of the Center for Community Research at DePaul.

Of the 4,501 college students in the study, 238 or 5.3% developed mononucleosis; and 55 of those (23%) met criteria for ME/CFS six months later, 20 of whom (8%) met criteria for severe ME/CFS. Researchers found that those who developed ME/CFS had more physical symptoms and immune irregularities at baseline, but they did not start out with statistically significantly more psychological symptoms such as stress, depression, anxiety or abnormal coping.

"Some people who are attacked by a virus stay sick. What we've found is that their emotional functioning and psychological states are not statistically different from those who get attacked by the same virus and recover. This becomes important validating information for those people who have this illness," says Jason.

Participants in the study each completed seven different surveys to assess potential symptoms of ME/CFS. They also received a comprehensive psychiatric exam, and provided samples of serum, plasma and white blood cells. In future publications, researchers aim to analyze cytokine networks in participants' blood and other risk factors. Deficiencies in certain cytokines "might suggest predisposing irregularities in immune response," write the researchers. Vicky Whittemore, the Program Director at the National Institute of Neurological Disorders and Stroke (NINDS), stated that NINDS is supporting follow-up research to continue to study this cohort, and to examine possible predictors of COVID-19 as well.

"Since we have baseline data on nearly all of the 4500 students, we can use our same database to tease out risk factors for COVID infection as well as prolonged recovery from that illness," says Katz.

UPTON, NY - New results from an atmospheric study over the Eastern North Atlantic reveal that tiny aerosol particles that seed the formation of clouds can form out of next to nothingness over the open ocean. This "new particle formation" occurs when sunlight reacts with molecules of trace gases in the marine boundary layer, the atmosphere within about the first kilometer above Earth's surface. The findings, published in the journal Nature Communications, will improve how aerosols and clouds are represented in models that describe Earth's climate so scientists can understand how the particles--and the processes that control them--might have affected the planet's past and present, and make better predictions about the future.

"When we say 'new particle formation,' we're talking about individual gas molecules, sometimes just a few atoms in size, reacting with sunlight," said study co-author Chongai Kuang, a member of the Environmental and Climate Sciences Department at the U.S. Department of Energy's Brookhaven National Laboratory. "It's interesting to think about how something of that scale can have such an impact on our climate--on how much energy gets reflected or trapped in our atmosphere," he said.

But modeling the details of how aerosol particles form and grow, and how water molecules condense on them to become cloud droplets and clouds, while taking into consideration how different aerosol properties (e.g., their size, number, and spatial distribution) affect those processes is extremely complex--especially if you don't know where all the aerosols are coming from. So a team of scientists from Brookhaven and collaborators in atmospheric research around the world set out to collect data in a relatively pristine ocean environment. In that setting, they expected the concentration of trace gases to be low and the formation of clouds to be particularly sensitive to aerosol properties--an ideal "laboratory" for disentangling the complex interactions.

"This was an experiment that really leveraged broad and collaborative expertise at Brookhaven in aerosol observations and cloud observations," Kuang said. Three of the lead researchers--lead authors Guangjie Zheng and Yang Wang, and Jian Wang, principal investigator of the Aerosol and Cloud Experiments in the Eastern North Atlantic (ACE-ENA) campaign--began their involvement with the project while working at Brookhaven and have remained close collaborators with the Lab since moving to Washington University in St. Louis in 2018.

Land and sea

The study made use of a long-term ground-based sampling station on Graciosa Island in the Azores (an archipelago 850 miles west of continental Portugal) and a Gulfstream-1 aircraft outfitted with 55 atmospheric instrument systems to take measurements at different altitudes over the island and out at sea. Both the ground station and aircraft belong to the DOE Office of Science's Atmospheric Radiation Measurement (ARM) user facility, managed and operated by a consortium of nine DOE national laboratories.

The team flew the aircraft on "porpoise flights," ascending and descending through the boundary layer to get vertical profiles of the particles and precursor gas molecules present at different altitudes. And they coordinated these flights with measurements taken from the ground station.

The scientists hadn't expected new particle formation to be happening in the boundary layer in this environment because they expected the concentration of the critical precursor trace gases would be too low.

"But there were particles that we measured at the surface that were larger than newly formed particles, and we just didn't know where they came from," Kuang said.

The aircraft measurements gave them their answer.

"This aircraft had very specific flight patterns during the measurement campaign," Kuang said. "They saw evidence that new particle formation was happening aloft--not at the surface but in the upper boundary layer." The evidence included a combination of elevated concentrations of small particles, low concentrations of pre-existing aerosol surface area, and clear signs that reactive trace gases such as dimethyl sulfide were being transported vertically--along with atmospheric conditions favorable for those gases to react with sunlight.

"Then, once these aerosol particles form, they attract additional gas molecules, which condense and cause the particles to grow to around 80-90 nanometers in diameter. These larger particles then get transported downward--and that's what we're measuring at the surface," Kuang said.

"The surface measurements plus the aircraft measurements give us a really good spatial sense of the aerosol processes that are happening," he noted.

At a certain size, the particles grow large enough to attract water vapor, which condenses to form cloud droplets, and eventually clouds.

Both the individual aerosol particles suspended in the atmosphere and the clouds they ultimately form can reflect and/or absorb sunlight and affect Earth's temperature, Kuang explained.

Study implications

So now that the scientists know new aerosol particles are forming over the open ocean, what can they do with that information?

"We'll take this knowledge of what is happening and make sure this process is captured in simulations of Earth's climate system," Kuang said.

Another important question: "If this is such a clean environment, then where are all these precursor gases coming from?" Kuang asked. "There are some important precursor gases generated by biological activity in the ocean (e.g., dimethyl sulfide) that may also lead to new particle formation. That can be a nice follow-on study to this one--exploring those sources."

Understanding the fate of biogenic gases such as dimethyl sulfide, which is a very important source of sulfur in the atmosphere, is key to improving scientists' ability to predict how changes in ocean productivity will affect aerosol formation and, by extension, climate.